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Brahmaiah, Battula*, SaiLakshmi Valeti, Durga Sri Sravya S., Vijaya Lakshmi Putta, Sunandha Karpurapu, and Navya Sri S. "Design a Low Power and High Speed Parity Checker using Exclusive or Gates." International Journal of Innovative Technology and Exploring Engineering (IJITEE) 10, no. 4 (2021): 121–25. https://doi.org/10.35940/ijitee.D8522.0210421.
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In the presented paper we designed the parity checker by using EX-OR modules. The two EX-OR modules are presented to design the parity checker and correlated their outcomes based on the constraints like power, area, delay and power delay product (PDP). The previous design is with eight transistors EX-OR, but in the present six transistors EX-OR is used to design the parity checker. While correlating the parity checker design with 8T EX-OR and 6T EX-OR, the 6T EX-OR parity checker design gives optimized power, delay, area and PDP over the 8T EX-OR parity checker design. Simulations are done by using the 130nm mentor graphics tool. Finally the constraints like power, area, delay and PDP gets optimized successfully with the presented technology. Also, alternatively we can replace EX-OR modules with NAND modules to design parity checker.
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Battula, Brahmaiah, Valeti SaiLakshmi, Karpurapu Sunandha, S. Durga Sri Sravya, Putta Vijaya Lakshmi, and S. Navya Sri. "Design a Low Power and High Speed Parity Checker using Exclusive–or Gates." International Journal of Innovative Technology and Exploring Engineering 10, no. 4 (2021): 121–25. http://dx.doi.org/10.35940/ijitee.d8522.0210421.
Full textAbstract:
In the presented paper we designed the parity checker by using EX-OR modules. The two EX-OR modules are presented to design the parity checker and correlated their outcomes based on the constraints like power, area, delay and power delay product (PDP). The previous design is with eight transistors EX-OR, but in the present six transistors EX-OR is used to design the parity checker. While correlating the parity checker design with 8T EX-OR and 6T EX-OR, the 6T EX-OR parity checker design gives optimized power, delay, area and PDP over the 8T EX-OR parity checker design. Simulations are done by using the 130nm mentor graphics tool. Finally the constraints like power, area, delay and PDP gets optimized successfully with the presented technology. Also, alternatively we can replace EXOR modules with NAND modules to design parity checker.
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Jones, Steven P., and Saida Ben Bihi. "Static frictional resistance with the Slide low-friction elastomeric ligature system." Australasian Orthodontic Journal 25, no. 2 (2009): 136–41. http://dx.doi.org/10.2478/aoj-2009-0020.
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Abstract Aim This ex-vivo study compared the static frictional resistance of a low-friction ligation system against a conventional elastomeric module, and studied the effect of storage in a simulated oral environment on the static frictional resistance of both ligation systems. Methods Eighty stainless steel brackets were tested by sliding along straight lengths of 0.018 inch round and 0.019 x 0.025 inch rectangular stainless steel wires ligated with either conventional elastomerics or the Slide system (Leone, Florence, Italy). During the tests the brackets and wires were lubricated with artificial saliva. A specially constructed jig assembly was used to hold the bracket and archwire securely. The jig was clamped in an Instron universal load testing machine. Crosshead speed was controlled via a microcomputer connected to the Instron machine. The static frictional forces at 0 degree bracket/wire angulation were measured for both systems, fresh from the pack and after storage in artificial saliva at 37 °C for 24 hours. Results The results of this investigation demonstrated that the Slide ligatures produced significantly lower static frictional resistance than conventional elastomeric modules in the fresh condition and after 24 hours of storage in a simulated oral environment (p < 0.001). Storage for 24 hours in artificial saliva had no effect on the static frictional resistance of conventional elastomeric modules and the Slide system (p = 0.525). Conclusions The claim by the manufacturer that the Slide system produces lower frictional resistance than conventional elastomeric modules is upheld.
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da Silva Antunes, Ricardo Filipe, Mariana Babor, Mikhail Pomaznoy, et al. "Differences in T cell responses to Bordetella Pertussis in adults as a function of whole cell versus acellular childhood vaccination." Journal of Immunology 202, no. 1_Supplement (2019): 196.12. http://dx.doi.org/10.4049/jimmunol.202.supp.196.12.
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Abstract In the mid-1990s vaccine-related side effects prompted the replacement of the whole Pertussis (wP) by a new acellular Pertussis vaccine (aP). Unexpectedly, whooping cough cases have recently increased, and the switch to the aP vaccine suspected to underlie this rise in morbidity, despite the use of routine boosters. Here we compared the immune responses to aP boosters in children who received their initial doses with either wP or aP vaccines. The use of ex vivo AIM assays highlighted a Th2 vs Th1/Th17 differential polarization of PT-specific memory CD4+ T cells as a function of childhood vaccination. The nature of the differences was further investigated for memory subset composition, activation, exhaustion marker expression, and transcriptomic profiles. Remarkably, donors originally primed with aP were defective in their ex vivo capacity to expand memory cells following a booster aP immunization and less capable to proliferate in vitro in response to PT epitopes. By contrast antibody responses are boosted in both aP and wP cohorts following IgG subclass distribution. Most recently, we have assessed early immune responses followed aP boosting for the aP and wP cohorts using longitudinal transcriptomics data from PBMC. We have identified several modules of genes that are co-expressed; using cell frequency data from CyTOF we infer modules correlated with specific cell types. Furthermore, we identified certain modules that show differential expression profiles between the two cohorts and are mostly enriched in immune related functions. In conclusion, our data suggest that the original priming after birth with aP and wP vaccines induce different T cell phenotypes associated with long-term T cell polarization.
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Shimizu, Ryo, Yasuyuki Ota, Akira Nagaoka, Kenji Araki, and Kensuke Nishioka. "Non-Contact Monitoring of Operating Conditions for Solar Cells in a Photovoltaic Module Using a Surface Potential Meter for Detecting the Risk of Fire." Applied Sciences 13, no. 18 (2023): 10391. http://dx.doi.org/10.3390/app131810391.
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Fires in photovoltaic modules are caused by hot spots, which are typically monitored by thermal images. This method helps visualize the hot spot, but it is affected by the environment (solar irradiance, wind, ambient temperature) and is not reproducible. Assessing the heat dissipation of the hot cell can be used for alternative assessment of the fire risk. This method was validated by comparing the value measured by the surface potential meter and the module potential measured directly by adding a bypass measurement circuit. The substantial reverse-bias voltage caused by mismatching or partial shading (depending on the operating conditions) leads to local heat consumption of the partially shaded solar cells and potentially causes fire. The fire risk can be assessed in the worst-case conditions (ex. 1380 W/m2 solar irradiance) by non-contact measurement of the reverse-bias voltage and calculating the heat dissipation and temperature rise. This work suggested that −13 V is the criterion and was close to the known value of reverse voltage for Si cells. The current technology inspects solar cells before assembly to the module, and there is no way of inspecting in the product test or detecting after degradation that can be covered by the proposed method in this work.
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R, Rakesh C., Chetan S, and J. S. Baligar. "Design of 16 Bit RISC Processor and Implementation using MIPS Technique." Scholars Journal of Engineering and Technology 11, no. 11 (2023): 287–92. http://dx.doi.org/10.36347/sjet.2023.v11i11.002.
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This research paper presents design & simulation of a high performance five stage pipelined 8 bit or 16-bit Microprocessor without Interlocked Pipeline Stages (MIPS), which is a Reduced Instruction Set Computing (RISC) architecture based processor. The purpose of RISC microprocessor is to execute a minuscule batch of instructions, with the intention of proliferating the celerity of the processor. This processor was designed with 5 phases of pipeline in particular Instruction Fetch (IF), Instruction Decode & Register Fetch (ID), Execution & Address Calculation (EX), Memory Access (MEM) and Write Back (WB) modules. The designing process was done using a myriad of modules which are the ALU, Control Unit, Program Counter, MUX, Instruction Memory, Data Memory, CPU, Register File, and Sign Extension. The Proposed design is developed by Verilog HDL and Simulated by Modelsim 6.4 c and Synthesized by Xilinx tool and proposed system implemented in FPGA Spartan 3 XC3S 200 TQ-144.
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Doblado, Laura Rodríguez, Cristina Martínez-Ramos, and Manuel Monleón Pradas. "Multimodular Bio-Inspired Organized Structures Guiding Long-Distance Axonal Regeneration." Biomedicines 10, no. 9 (2022): 2228. http://dx.doi.org/10.3390/biomedicines10092228.
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Axonal bundles or axonal tracts have an aligned and unidirectional architecture present in many neural structures with different lengths. When peripheral nerve injury (PNI), spinal cord injury (SCI), traumatic brain injury (TBI), or neurodegenerative disease occur, the intricate architecture undergoes alterations leading to growth inhibition and loss of guidance through large distance. In order to overcome the limitations of long-distance axonal regeneration, here we combine a poly-L-lactide acid (PLA) fiber bundle in the common lumen of a sequence of hyaluronic acid (HA) conduits or modules and pre-cultured Schwann cells (SC) as cells supportive of axon extension. This multimodular preseeded conduit is then used to induce axon growth from a dorsal root ganglion (DRG) explant placed at one of its ends and left for 21 days to follow axon outgrowth. The multimodular conduit proved effective in promoting directed axon growth, and the results may thus be of interest for the regeneration of long tissue defects in the nervous system. Furthermore, the hybrid structure grown within the HA modules consisting in the PLA fibers and the SC can be extracted from the conduit and cultured independently. This “neural cord” proved to be viable outside its scaffold and opens the door to the generation of ex vivo living nerve in vitro for transplantation.
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He, Zhen, Teding Chang, Yu Chen, Hongjie Wang, Lei Dai, and Hesong Zeng. "PARM1 Drives Smooth Muscle Cell Proliferation in Pulmonary Arterial Hypertension via AKT/FOXO3A Axis." International Journal of Molecular Sciences 24, no. 7 (2023): 6385. http://dx.doi.org/10.3390/ijms24076385.
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Pulmonary arterial hypertension (PAH) is a group of severe, progressive, and debilitating diseases with limited therapeutic options. This study aimed to explore novel therapeutic targets in PAH through bioinformatics and experiments. Weighted gene co-expression network analysis (WGCNA) was applied to detect gene modules related to PAH, based on the GSE15197, GSE113439, and GSE117261. GSE53408 was applied as validation set. Subsequently, the validated most differentially regulated hub gene was selected for further ex vivo and in vitro assays. PARM1, TSHZ2, and CCDC80 were analyzed as potential intervention targets for PAH. Consistently with the bioinformatic results, our ex vivo and in vitro data indicated that PARM1 expression increased significantly in the lung tissue and/or pulmonary artery of the MCT-induced PAH rats and hypoxia-induced PAH mice in comparison with the respective controls. Besides, a similar expression pattern of PARM1 was found in the hypoxia- and PDGF--treated isolated rat primary pulmonary arterial smooth muscle cells (PASMCs). In addition, hypoxia/PDGF--induced PARM1 protein expression could promote the elevation of phosphorylation of AKT, phosphorylation of FOXO3A and PCNA, and finally the proliferation of PASMCs in vitro, whereas PARM1 siRNA treatment inhibited it. Mechanistically, PARM1 promoted PAH via AKT/FOXO3A/PCNA signaling pathway-induced PASMC proliferation.
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Rony Irawanto, Reka Permata Sari, Bagyo Yanuwiadi, Amin Setyo Leksono, and Soemarno. "Introduction of Aquatic Plant Diversity as An Educational Model for Phytoremediation in the Purwodadi Botanic Garden." Proceeding International Seminar of Science and Technology 4 (April 17, 2025): 249–56. https://doi.org/10.33830/isst.v4i1.5258.
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Purwodadi Botanic Garden is an ex-situ plant conservation area which has five main functions, namely: conservation, research, education, ecotourism and environmental services. This article aims to measure understanding of the phytoremediation model for aquatic plants in the Purwodadi Botanic Garden. This research uses mixed methods with qualitative and quantitative approaches. Data was obtained from direct observation of aquatic plants in the garden and questionnaires from technical assistance, environmental education lectures and socialization activities. This research presents the process of introducing aquatic plants diversity over the last eight years, from manual models such as booklets, leaflets and modules, to electronic models using QR codes, websites, videos with information labels, banners and brochures. Apart from that, it also presents public perceptions regarding environmental phytoremediation technology using aquatic plants. Because 48% to 67% of respondents lack sufficient knowledge. They still do not know the potential of plants or about phytoremediation. Thus, the educational model for solving environmental problems (water pollution) using aquatic plants becomes very important.
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Amadi, Christopher C., P. C. Aguodoh, and Noble Amaugo. "Design and Implementation of a Web Based Prisons Management and Police Investigation System." International Journal of Trend in Scientific Research and Development 2, no. 1 (2017): 483–93. https://doi.org/10.31142/ijtsrd7020.
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Information Technology IT has cut across all the areas of our society. In the light of this, I studied the Management Information System for Nigerian Prisons Service, Afara, Umuahia, Abia State with the aim of developing a software that can maintain an up to date record ofinmates as well as rendering quick and efficient services to the prisoners and also aid the Nigerian Police Force NPF with a database of records for their investigations as concerns ex convicts. Bearing in mind that the management of most prisons in Nigeria is currently done manually. This manual process of managing the prison's records and procedures makes every available document prone to damage or theft. This project took time to go into relevant details within the scope and time frame to try and proffer quick and very affordable solution to this issue. Thisproject was done using basic Hyper Text Markup Language HTML for visible web contents, javascript, Asp.Net for server scripting and MySQL database was used tostore and manage the prisoner's records. The project was implemented successfullyand the result obtained provides a single management systemwhich integrates all the relevant information about a prisoner, staff and other implementable modules in a singleproject. It can easily be accessed by the NPF to get relevant details in cases that concerns ex convicts or even prison officials. Amadi Christopher C | Aguodoh P. C | Amaugo Noble "Design and Implementation of a Web-Based Prisons Management and Police Investigation System" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-2 | Issue-1 , December 2017, URL: https://www.ijtsrd.com/papers/ijtsrd7020.pdf
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Bogenberger, James M., James Rudd, Donald Chow, et al. "Pharmacological Validation Of Potentiating Targets From SAHA RNA-Interference Modifier Screens In Acute Myeloid Leukemia." Blood 122, no. 21 (2013): 3832. http://dx.doi.org/10.1182/blood.v122.21.3832.3832.
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Abstract The lysine deacetylase inhibitor suberoylanilide acid (SAHA) exhibits promising but limited activity in the treatment of acute myeloid leukemia (AML). To identify potential targets for rational combination therapies that increase the efficacy of SAHA in AML, we performed a functional RNA-interference (RNAi) drug modifier screen to identify genes that, when inhibited, potentiate or antagonize the in vitro anti-leukemic activity of SAHA. A total of 901 kinase, phosphatase and closely associated signaling genes were silenced in TF-1, HEL and THP-1 cells, with four different siRNA sequences per gene, both alone and in combination with SAHA treatment. Screen hit lists for each cell line were over-laid on an integrated functional relationship network. A community detection algorithm was then applied to this sub-network and siRNA sensitive modules were identified. Each module represents a highly connected set of genes in the integrated network. To identify pathways represented by each module, enrichment was evaluated using the National Cancer Institute (NCI) Protein Interaction Database (PID) pathways. Both cell line-specific and universal sensitizing targets, grouped into a small number of pathways, emerged from these screens. Seven pharmacologic inhibitors interfering with these pathways have been assessed in a panel of four or five AML cell lines, including SET-2, TF-1, HEL, THP-1, and OCI-AML3. Of the seven tested inhibitors targeting SAHA sensitizing networks, one combination exhibiting universal SAHA sensitization in all AML cell lines tested was further assessed in drug dose response assays using ex vivo cultures of bone marrow mononuclear cell populations derived from patients with various myeloid malignancies. The combination demonstrated “one-sided” SAHA EC50 fold-enhancement, as well as strong synergy by “two-sided” CalcuSyn combination index determination in all ex vivo specimens examined to date (N=6), including polycythemia vera (PV), chronic myelomonocytic leukemia (CMML), myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndrome, MDS transformed to AML, and de novo AML samples. Thus, this first reported large-scale SAHA RNAi modifier screen in AML has identified a specific pathway/target whose inhibition broadly synergizes with HDAC inhibition in myeloid malignancies. A novel compound putatively targeting this respective pathway/target is currently in early clinical development and has shown limited single-agent activity. With the full dataset presented, we will propose a novel rational combination to enhance the activity of HDAC inhibition in AML and other myeloid malignancies that could be translated into design of a clinical trial. Disclosures: No relevant conflicts of interest to declare.
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Koristka, Stefanie, Marc Cartellieri, Anja Feldmann, et al. "Flexible Antigen-Specific Redirection of Human Regulatory T Cells Via a Novel Universal Chimeric Antigen Receptor System." Blood 124, no. 21 (2014): 3494. http://dx.doi.org/10.1182/blood.v124.21.3494.3494.
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Abstract Based on compelling evidence from a vast number of in vitro and in vivostudies, Tregs have become an attractive cell population to treat or even prevent auto- and alloimmunity including Graft-versus-Host disease (GvHD). However, several safety concerns still exist as for example the risk of global immunosuppression using polyclonal Tregs. In fact, experiments in mice showed that adoptive transfer or induction of antigen-specific Tregs is more potent regarding suppression of pathogenic immune responses when compared to polyclonal Treg populations. Unfortunately, the isolation and expansion of naturally occurring antigen-specific Tregs is technically difficult, labour-intensive, and time-consuming. An attractive way to overcome these limitations and to endow polyclonal Treg populations with a desired antigen-specificity is their engraftment with chimeric antigen receptors (CARs). In this context, CAR-modification represents a promising approach to redirect polyclonal Tregs in an antigen-specific manner to suppress ongoing self-destructive immune responses at the site of inflammation. Nevertheless, until now redirection of CAR-engineered T cells is limited to a single target antigen, restricting this approach to an unflexible monospecific therapy. Therefore, we developed a more flexible universal CAR (UCAR) platform that allows redirection of T cells to an in principal unrestricted number of surface antigens. T cells are engrafted with UCARs that bind to a small peptide epitope derived from a human nuclear protein. Cross-linkage to target cells is mediated by independent target modules that provide antigen-specificity and comprise the peptide epitope recognized by the UCAR. In order to target different tissue antigens, the target modules can easily be exchanged. Thereby, once established, the treatment strategy can easily be applied to various auto- and alloimmune diseases. At present, the CD45RA+ population is the Treg subset of choice for a clinical application as these cells have the highest capacity to maintain phenotypic and functional Treg properties upon prolonged ex vivo expansion. Here we show that highly pure, sorted CD4+CD25+CD127lowCD45RA+ Tregs can be genetically manipulated using lentiviral gene transfer, resulting in approximately 70 % of UCAR-expressing Treg cells. The transduction procedure itself did not affect the phenotype of UCAR-engineered Tregs as it was similar to non-transduced wildtype cells. Both Treg populations presevered FOXP3 expression even after prolonged in vitro cultivation (> 95 % FOXP3+). Upon incubation with antigen-positive target cells and a respective target module UCAR-engineered Tregs upregulate the activation markers CD69 and LAP demonstrating that the cells can be restimulated antigen-specifically. Most importantly, UCAR-engrafted Tregs were functionally activated upon antigen encounter, demonstrated by suppression of proliferation and expansion of cocultured autologous T effector cells. Taken together, our results pave the way towards an application of UCAR technology for a site-specific recruitment of CAR-modified Tregs into inflamed tissues aiming at re-establishing immune homeostasis. Due to its high flexibility UCAR-engrafted Tregs can easily and universally be used for treatment of various autoimmune diseases or GvHD just by exchanging the tissue-specific target modules. Disclosures Cartellieri: Cellex Patient Treatment GmbH: Employment. Ehninger:GEMoaB GmbH: Employment, Patents & Royalties. Ehninger:GEMoaB GmbH: Consultancy, Patents & Royalties. Bachmann:GEMoaB GmbH: Consultancy, Patents & Royalties.
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Cornel, P., and S. Krause. "Membrane bioreactors in industrial wastewater treatment – European experiences, examples and trends." Water Science and Technology 53, no. 3 (2006): 37–44. http://dx.doi.org/10.2166/wst.2006.074.
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In wastewater treatment, micro- and ultra-filtration membranes are used for the separation of the activated sludge (biomass) from the treated water. This offers the advantages of a complete removal of solids and bacteria, as well as most of the viruses, namely those attached to the suspended solids. Compared to the conventional activated sludge process (CAS) this technology allows a much higher biomass concentration (MLSS) whereby the reactor volume and the footprint decreases. With increasing MLSS, the viscosity of the sludge increases, which leads to reduced oxygen transfer rates. Depending on the type of membrane and membrane module, the pre-treatment has to be more sophisticated to prevent clogging and sludging of the modules. Due to fouling and scaling, the flux through the membranes will decrease with time. The decrease depends on the water quality as well as on the measurements taken to minimize fouling. Mainly, three strategies are available: lowering the flux, increasing the “crossflow” and cleaning of the membranes. Different strategies including backwash and chemical cleaning “in situ”, “on air” and “ex situ” can be applied. It has been proven more effective to apply preventive regular cleaning. Besides the energy demand for oxygen supply – which is typically in the range of 0.3 kWh/m3 for municipal wastewater – the energy for fouling prevention is substantial. Immersed membranes need approximately 0.4 to 1 kWh/m3 for the coarse bubble aeration, whereas tubular modules require 1 to 4 kWh/m3 pump energy. For proper design of industrial wastewater treatment, the verification of applicability and the development of adequate cleaning strategies, it is a precondition to run pilot tests for a sufficient period of time with the wastewater to be treated. More than 100 industrial wastewater treatment membrane bioreactors (MBR) are in operation in Europe. Data of three case studies for a sewage sludge dewatering plant in UK (12,000 m3/d), a plant for the treatment of pharmaceutical wastewater in Germany (3,600 m3/d), as well for revamping of an chemical WWTP &gt;2,000 m3/d in Italy, are given. MBRs will be used in future wherever high quality effluent is required, because of a sensitive receiving water body or due to the fact of water reuse as process water. MBRs are a perfect pre-treatment in industrial applications when further treatment with nanofiltration or reverse osmosis is considered. The technique is advanced and can be applied both in municipal and industrial wastewater treatment. Higher operational costs must be balanced by superior effluent quality.
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Aboah, Joshua, Andrea Apolloni, Raphaël Duboz, et al. "Ex-ante impact of pest des petits ruminant control on micro and macro socioeconomic indicators in Senegal: A system dynamics modelling approach." PLOS ONE 18, no. 7 (2023): e0287386. http://dx.doi.org/10.1371/journal.pone.0287386.
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Vaccination is considered as the main tool for the Global Control and Eradication Strategy for peste des petits ruminants (PPR), and the efficacity of the PPR-vaccine in conferring long-life immunity has been established. Despite this, previous studies asserted that vaccination can be expensive and consequently, the effectiveness of disease control may not necessarily translate to overall profit for farmers. Also, the consequences of PPR control on socioeconomic indicators like food and nutrition security at a macro-national level have not been explored thoroughly. Therefore, this study seeks to assess ex-ante the impact of PPR control strategies on farm-level profitability and the socioeconomic consequences concerning food and nutrition security at a national level in Senegal. A bi-level system dynamics model, compartmentalised into five modules consisting of integrated production-epidemiological, economics, disease control, marketing, and policy modules, was developed with the STELLA Architect software, validated, and simulated for 30 years at a weekly timestep. The model was parameterised with data from household surveys from pastoral areas in Northern Senegal and relevant existing data. Nine vaccination scenarios were examined considering different vaccination parameters (vaccination coverage, vaccine wastage, and the provision of government subsidies). The findings indicate that compared to a no-vaccination scenario, all the vaccination scenarios for both 26.5% (actual vaccination coverage) and 70% (expected vaccination coverage) resulted in statistically significant differences in the gross margin earnings and the potential per capita consumption for the supply of mutton and goat meat. At the prevailing vaccination coverage (with or without the provision of government subsidies), farm households will earn an average gross margin of $69.43 (annually) more than without vaccination, and the average per capita consumption for mutton and goat meat will increase by 1.13kg/person/year. When the vaccination coverage is increased to the prescribed threshold for PPR eradication (i.e., 70%), with or without the provision of government subsidies, the average gross margin earnings would be $72.23 annually and the per capita consumption will increase by 1.23kg/person/year compared to the baseline (without vaccination). This study’s findings offer an empirical justification for a sustainable approach to PPR eradication. The information on the socioeconomic benefits of vaccination can be promoted via sensitization campaigns to stimulate farmers’ uptake of the practice. This study can inform investment in PPR control.
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Khanmohammadi Otaghsara, A. "Comparisonal investigation of Rap personality disorder in youngsters." European Psychiatry 26, S2 (2011): 1028. http://dx.doi.org/10.1016/s0924-9338(11)72733-x.
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Introduction & objectivesPersonality disorder, formerly referred to as a Character Disorder, is a class of mental disorders characterized by rigid and on-going patterns of feeling, thinking, and behavior. The underlying belief systems informing these patterns are referred to as fixed fantasies or “dysfunctional schemata” (Cognitive modules). The inflexibility and pervasiveness of these behavioral patterns often cause serious personal and social difficulties, as well as a general functional impairment. So the study examined a new view in personality and mental disorders named “Rap” disorder. In the domain we compare the youngster with and without disorder. The Rap disorder people are known with unusual hair model, nihilistic and anarchistic thinking, unusual and bizarre behavior, reading of meaningfulness poet and sings, doing immoral behavior against society norms and so on.MethodsMethod research is Causative - Comparative (Ex post facto). 200 youngster, 100 with the disorder and 100 without the disorder, were randomly selected and Eysenc's Personality Questionnaire (EPQ) was administered on them.ResultsFindings showed the Rap youngster are high in extroversion and emotional instability than normal youngster.ConclusionsIt is recommended that the appropriate behavior education specially moral and religious education can avoid tendency to this behavior disorder and reduce the bad effects of the behavior in society.
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Carmienke, Solveig, Jens Baumert, Lars Gabrys, et al. "Participation in structured diabetes mellitus self-management education program and association with lifestyle behavior: results from a population-based study." BMJ Open Diabetes Research & Care 8, no. 1 (2020): e001066. http://dx.doi.org/10.1136/bmjdrc-2019-001066.
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ObjectiveWhether participation in structured diabetes self-management education programs (DSME) for participants with diabetes mellitus is associated with a healthy lifestyle in routine care apart from randomized-controlled studies remains unclear and is this studies’ research question.Research design and methodsWe identified 1300 persons with diabetes mellitus drawn from the cross-sectional population-based analysis German Health Update 2014/2015 (GEDA 2014/2015), which integrated the modules of the European Health Interview Survey (EHIS) wave 2. Of those, 816 were ever-DSME participants and 484 never-participants. We conducted multivariable weighted logistic regression analyses for lifestyle differences comparing ever-DSME and never-DSME participants. Lifestyle was defined by physical activity (PA), current smoking, fruit/vegetable consumption and body mass index (BMI). Age, sex, socioeconomic status, living together, limitation due to health problems for at least for 6 months, self-efficacy and attention to one’s health were included as confounders in the regression models.ResultsEver-DSME participants engaged significantly more often in cycling at least 1 day per week (OR 1.62, 95% CI: 1.15–2.30) and performed significantly more often aerobic endurance training of 150 min per week (including walking: OR 1.42, 95% CI: 1.03–1.94, without walking: OR 1.48, 95% CI: 1.08–2.03) compared with never-DSME participants. Ever-DSME participants were significantly more often ex-smoker compared with never-DSME participants (OR 1.39, 95% CI: 1.03–1.88). DSME attendance was not significantly associated with current smoking, BMI and fruit or vegetable consumption.ConclusionDSME participation is associated with a moderately healthier lifestyle particularly for PA even in routine healthcare. Study results emphasize the importance of a broadly dissemination of DSME access for nationwide diabetes healthcare. Future studies should adjust for DSME participation when investigating lifestyle in persons with diabetes.
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Valero, V., L. Ottaviani, A. Lyoussi, et al. "3-D thermal and radiation-matter interaction simulations of a SiC solid-state detector for neutron flux measurements in JSI TRIGA Mark II research reactor." EPJ Web of Conferences 253 (2021): 04009. http://dx.doi.org/10.1051/epjconf/202125304009.
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Neutron detection is a relevant topic in the field of nuclear instrumentation. It is at the heart of the concerns for fusion applications (neutron diagnostics, measurements inside the Test Blanket Modules TBM) as well as for fission applications (in-core and ex-core monitoring, neutron mapping or safety applications in research reactors). Moreover, due to the even more harsh conditions of the future experimental reactors such as the Jules Horowitz Reactor (JHR) or International Thermonuclear Experimental Reactor (ITER), neutron detectors need to be adapted to high neutron and γ fluxes, high nuclear heating rates and high temperatures. Consequently, radiation and temperature hardened sensors with fast response, high energy resolution and stability in a mixed neutron and γ environment are required. All these requirements make wide-bandgap semiconductors and, more precisely, Silicon Carbide (SiC) serious candidates due to their intrinsic characteristics in such extreme environments. Thus, since the last decades, SiC-based detectors are developed and studied for neutron detection in various nuclear facilities. In this paper, a SiC-based neutron detector is 3-D designed and studied through thermal and radiation-matter interaction numerical simulations for a future irradiation campaign at the Jožef Stefan Institute TRIGA Mark II research reactor in Slovenia. Firstly, this paper presents the scientific background and issues of our SiC-based detectors. In a second part the 3-D geometry is shown. Thereafter, the 3-D numerical thermal simulation results are reported. Finally, the 3-D numerical radiation/matter interaction simulations results are presented.
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Williams, J. F., M. Fuller, and M. B. Smith. "Smoking habits of UK military personnel on deployment: Exercise SAIF SAREEA 3." BMJ Military Health 166, no. 6 (2020): 396–400. http://dx.doi.org/10.1136/bmjmilitary-2019-001364.
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IntroductionChanges of environment brought about by deployments are often attributed to an increase in smoking of service personnel. Electronic cigarettes are recognised as being a viable aid to quitting smoking but are currently banned from sale in Oman and were therefore banned during exercise SAIF SAREEA 3 (SS3). This paper sought to establish whether smoking increased on this exercise and for what reasons. Also, if deployed smoking cessation services are likely to be used, if available.MethodsQuestionnaires were distributed to deployed troops at various locations in theatre for data collection.ResultsSmoking prevalence increased by 5.2% (29) in the deployed population by the end of the exercise. The largest increase was seen in those smoking 20 cigarettes a day or more, rising by 269.8% (73) with a mean increase of 9 cigarettes per day. During the exercise the number of personnel using electronic cigarettes decreased and individuals’ rate of electronic cigarette use also decreased. Those who smoked less during the exercise did mainly through choice (56.8%). 50% (280) of all individuals who increased smoking habits during the exercise did so out of boredom.ConclusionsDuring exercise SS3 the number of individuals who smoked and the quantity they smoked increased. The ban on electronic cigarettes in Oman and while on exercise potentially had an effect on the increased smoking habits. There is an argument to include smoking cessation material in medical modules to prevent ex-smokers from restarting, continue to aid those quitting and potentially lessen severity of increasing smoking habits while deployed.
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Jones, Leigh A., David A. Skibinski, Lin Wu Xie, et al. "Type-1 T cell responses and gene signatures driven by a novel virus-like particle (VLP) influenza A (H1N1) vaccine." Journal of Immunology 196, no. 1_Supplement (2016): 215.7. http://dx.doi.org/10.4049/jimmunol.196.supp.215.7.
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Abstract Effective influenza vaccination is currently assessed by the induction of antibodies directed against the influenza virus envelope glycoprotein hemagglutinin (HA; HAI test) otherwise known as seroconversion. However, protective antibody responses are sub-optimal in some vaccinated populations, particularly in the elderly. Furthermore, many clinical studies highlight the importance of T cells in driving protection. Therefore, a need exists for vaccine strategies which can engage both the humoral and cell mediated arms of the immune response. Herein, we describe the induction of anti-influenza T cell responses following vaccination with a novel VLP vaccine. Peripheral blood mononuclear cells (PBMCs) stimulated ex vivo with either influenza or vaccine specific antigens led to increased CD4+ and CD8+ T cell proliferation and increased production of cytokines such as IL-17A, IL-17F, IL-5, IL-13, IL-9, IL-10, IL-21 and, most significantly, IFN-γ. A subset of individuals demonstrated a shift from a pre-vaccination IL-5- and IL-13- driven type-2 response to a more protective IFN-γ driven type-1 response following vaccination with VLP. Microarray of whole blood samples collected pre- and post-vaccination with VLP revealed significantly different transcriptional profiles. The top most significantly downregulated gene following VLP vaccination, DEAD Box Helicase 17 (DDX17), was also found to have reduced protein expression in PBMCs by flow cytometry. Finally, weighted gene correlation network analysis (WGCNA) revealed that the post vaccination reduction in protein expression of DDX17, increase in HAI titres and increase in T cell proliferation correlates with particular gene modules.
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Cao, Siyan, Khai Nguyen, Kaiming Ma, Marco Colonna, and Parakkal Deepak. "MULTI-OMICS CHARACTERIZATION OF PERIANAL FISTULIZING CROHN’S DISEASE IDENTIFY PATHOGENESIS AND NOVEL THERAPEUTIC TARGETS." Inflammatory Bowel Diseases 31, Supplement_1 (2025): S58. https://doi.org/10.1093/ibd/izae282.137.
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Abstract INTRODUCTION The management of perianal fistulizing CD (PCD) is a major clinical challenge, where its underlying etiology remains elusive. MATERIALS & METHODS We recruited patients with 1) PCD (n = 24); 2) CD without perianal disease (NPCD; n = 10); 3) idiopathic or cryptoglandular perianal fistulas (IPF; n = 29). Biopsies were taken from the fistula tracts, openings of the fistulas, and rectal mucosa during examination under anesthesia or colonoscopy. CyTOF, single cell RNA-sequencing (scRNA-seq), spatial transcriptomics, immunohistochemistry (IHC), ex vivo cell stimulation, and integrated analysis of published scRNA-seq datasets were performed. RESULTS CyTOF revealed a skewed mucosal immune landscape in PCD compared to NPCD and IPF. PCD expanded Th17 cells in the fistula tracts and IL17-producing CD8 T cells (Tc17) in the rectum. Altered exhaustion markers CD39 and CD127 were present in CD4 and CD8 T cells from PCD fistula tracts, fistula openings, and rectum. Regulatory B cells, with immunomodulatory function in the gut, were dramatically diminished in PCD compared to IPF. In addition, PCD fistula tracts, fistula openings, and rectum all exhibited substantially higher CD172+TREM1+ macrophages, which are associated with anti-TNF resistance in luminal CD. ScRNA-seq unraveled immune and non-immune cell compartments in PCD and IPF fistula tracts. PCD fistulas showed hyperactivated pathogenic pathways including interferon (IFN)G response, TNF signaling, and IL6-JAK-STAT3 in myeloid cells. Similarly, stromal cells from PCD fistulas exhibited higher activities in IFNG and TNF response, TNF signaling, and epithelial-mesenchymal transition (EMT). In addition to fistula tracts, luminal (rectal and ileal) cells from PCD patients also expressed greater levels of IFNG-responsive and EMT genes compared to those without perianal disease (Figure 1). Moreover, we showed that both fistula tracts and ileal mucosa from PCD patients harbored expanded IFNG+ Th17 cells with elevated expression of inflammatory mediators (Figure 2). Further analysis revealed cellular modules associated with anti-TNF therapy in PCD patients. The findings were independently validated using spatial transcriptomics, IHC, and ex vivo stimulation of PCD cells. CONCLUSION Using multi-omics analysis of perianal fistula tracts and luminal tissues from extensive patient cohorts, we revealed previously unknown immune, stromal, and epithelial cell landscapes of PCD. In addition to IL17 signaling, T cell exhaustion, pathogenic macrophages, and pro-inflammatory/remodeling fibroblasts, our data highlight the pathogenic role of hyperactivated IFNG signaling in both fistula tracts and luminal mucosa of patients with PCD. This study identified IFNG as a potential therapeutic target for PCD. Figure 1. IFN-γ signaling is a distinguishing feature of PCD. (A) Pathway rank plot of top pathways in PCD compared to IPF fistula. (B) Pathway rank plot of top upregulated pathways in rectum (active PCD vs inactive PCD), colon and terminal ileum (PCD vs NPCD). (C) Representative IHC image and quantification of IFN-γ and p-STAT1 staining of IPF and PCD fistula tracts. (D) UMAP plot comparing rectal epithelial cell clusters between healthy, active PCD, and inactive PCD (PCD-healed). (E) UMAP plot of single-cell module scores for IFNG response (left), TNF response (center), and EMT (right) pathways in PCD rectal epithelial cells. (F) Dot plot indicating transcription factory activity of STAT1, NFKB1, and NFKB2 in rectal epithelial cells clusters 1, 9, and 12 (as in D). (G) Bar plot of top transcription factors driving EMT gene expression in rectal epithelial cells. Figure 2. Pathogenic mononuclear phagocytes (MNP)-Th17 interaction underlies IFN-γ response in PCD. (A) Volcano plot highlighting select upregulated ligand-receptor signaling pairs. (B) Bar plots indicating IFNG senders significantly enriched in PCD. (C) Volcano plot of differentially expressed myeloid genes between PCD and IPF. (D) UMAP plot of NLRP3, AREG, SIRPA (CD172a), TREM1, TNF, and IL1B expression in myeloid cells. (E) UMAP plot of single-cell module scores for LPS signaling in IPF and PCD myeloid cells. (F) Volcano plot showing top enriched LR signaling pairs between MNPs and CD4 T cells in PCD.
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Olaniyi, Francis O., and Dumisani R. Nzima. "In-Service Teachers’ Perception of Continuing Education Programmes in Two African Universities." American International Journal of Social Science Research 4, no. 2 (2019): 127–35. http://dx.doi.org/10.46281/aijssr.v4i2.375.
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The study compared the in-service teachers’ perception of continuing education programmes from two universities in Africa; University of Zululand, South Africa (UZ), and Adekunle Ajasin University, Akungba-Akoko, Nigeria, (AAU). The study covers the impact, effectiveness and efficiency of UZ and AAU on in-service teachers’ of continuing education programmes. The target population and sample for the study were the current teachers of continuing education programmes of these universities. The instrument tagged ‘Questionnaire for Perceptions of Continuing Education Programmes by in-service Teachers’ (QPCEPIT) was designed and used for data collection. The descriptive survey research design of ex-post facto was adopted for the study. 150 questionnaires were randomly used for pilot study, carried out at Ekiti State University, Ado Ekiti, Nigeria, whilst 500 questionnaires each were administered at both UZ and AAU of which 365 and 321 responses were valid and analysed respectively. Four research questions were carefully formulated to ascertain the perceptions of continuing education programmes by in-service teachers in the selected universities. Inferential statistics was used to draw conclusions and test the research questions for the study. The results of the comparative study revealed that the conclusiveness of the learning environment, the nature and quality of student support services provided, the quality and learners’ perception of course modules or materials, accommodation problems and venue of the programme were the major predictors for motivation of in-service teachers of the programme. Based on the findings of the study recommendations were made on how the programme will have impact on the in-service teachers and how the universities that are running the programme will be effectively and efficiently manage the programme for the acceleration and advancement of socio-economic growth in South Africa, Nigeria, and the world at large.
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Shah, Viral, George Giotopoulos, Hikari Osaki, et al. "Acute Resistance to BET Inhibitors Remodels Compensatory Transcriptional Programs Via p300 Co-Activation." Blood 144, Supplement 1 (2024): 722. https://doi.org/10.1182/blood-2024-202515.
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In acute myeloid leukemia (AML), bromodomain and extraterminal protein inhibitors (BETi) have shown modest response rates, primarily due to non-genetic resistance. Resistance development requires cell survival and adaptation under therapeutic pressure. However, the precise mechanisms driving these processes, as well as the relationship between the initial adaptation and subsequent resistance evolution, remain elusive. In this study, we aimed to discover and therapeutically explore chromatin adaptation patterns to BETi at an early treatment stage and follow the evolutionary routes of this adaptation until the development of established resistance. We assessed early transcriptional responses via SLAMSeq or nuclear RNASeq and chromatin binding dynamics of key transcription factors/co-regulators involved in BRD4 recruitment 24 hr post-BETi. ChIPSeq was performed for RUNX1 (wild type and fused to RUNX1T1), FLI1, PU.1, LMO2, ERG, p300, CDK9 and the histone mark H3K27ac as well as ATACSeq in AML models driven by RUNX1-RUNX1T1 rearrangement, a subtype sensitive to BETi. These revealed that within 24 hr of treatment, BETi-induced release of BRD4 from chromatin initiated an acute compensatory feedback that mitigated downregulation or even increasedthe expression of specific transcriptional modules critical for AML maintenance. Notably, p300, a direct recruiter of BRD4 to chromatin, was redistributed to the same regions where BRD4 was lost, suggesting an acute compensatory role for p300. Moreover, a similar p300-mediated “rescue” of BETi was observed in another AML model - with mutated NPM1. We functionally tested this “rescue” using matched SLAMSeq and ChIP in a model of sequential BET inhibition for 24 hr followed by PROTAC-based degradation of p300 during the final 4 hr of BETi. Here, the initially rescued critical transcriptional modules were abrogated through p300 degradation, validating our mechanism. Using RNASeq following pharmacological inhibition across cell lines representative of different AML subtypes, we found that BRD4 and p300 control similar transcriptional programs. Sequential BETi followed by inhibition of p300 lysine acetyltransferase activity resulted in robust downregulation of key transcriptional modules across various AML subtypes, including those rescued by p300 after single BETi. This sequential treatment exhibited optimal synergistic efficacy, leading to enhanced cell death in vitro in cell lines, murine AML models and patient samples ex vivo and also in vivo in a primary murine t(8;21) AML model, without affecting normal hematopoiesis. We further tracked transcriptional changes and the dynamics of p300 binding at chromatin across resistance evolution to BETi in models representative for RUNX1-RUNX1T1-rearranged (SKNO1) and NPM1-mutated AML (OCI-AML3). p300 activity was critical throughout all resistance adaptation stages, although the specific transcriptional programs it regulated varied between the two AML subtypes. In OCI-AML3 cells, p300 was most essential during early stages of resistance, regulating transitional transcriptional patterns for AML homeostasis such as an inflammatory signature centered around S100A8/9 and an Interferon-responsive program (ISG). p300 inhibition led to a downregulation of S100A8/9 and a strong induction of ISG. Confirmatory assays, such as inducible RNAi knockdown or pharmacologic inhibition of mediators of these programs, demonstrated a pro-resistance role for S100A8/9 and an apoptosis-inducing role for ISG induction. In contrast, in SKNO1 cells, p300 drove a linear resistance evolution, and was necessary at all stages, albeit that only a few central targets mediated established BETi resistance. The most significant inducer of resistance here was NCAM1, which we and others have previously associated with resistance in AML. Notably, p300 inhibition significantly reduced NCAM1 expression, and inducible knockdown of NCAM1 re-sensitized BETi-resistant SKNO1 cells to BETi.Altogether, our study is one of the first to elucidate mechanisms underpinning acute resistance, in this case to BETi through p300 activity with in vivo corroboration. Moreover, we demonstrate how these mechanisms transition to chronic resistance. Importantly, our data suggest that sequential treatment with BET and p300 inhibition may effectively prevent resistance development, thereby improving therapeutic outcomes.
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de Jong, Sytske, Fabiellen C. Pereira, Alejandro R. Castillo, Wilbert F. Pellikaan, and Pablo Gregorini. "The Effects of a Small Dose of Tannin Supplementation on In Vitro Fermentation Characteristics of Different Forages." Animals 15, no. 9 (2025): 1269. https://doi.org/10.3390/ani15091269.
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Pastoral systems in New Zealand are under societal pressure due to their increasing negative environmental impact in terms of greenhouse gas emissions. This study was conducted to investigate the effects of supplementing a mixture containing hydrolysable and condensed tannins on the in vitro fermentation characteristics and gas production of three different forages, Lolium perenne, Medicago sativa, and Plantago lanceolata. Three fermentation runs of 48 h were conducted using the ANKOM gas production technique, with each pertaining to a particular forage with or without (control) tannin. Tannins were added to the fermentable substrate (i.e., forage) at a level of 0.3%. For each run, rumen fluid was collected from two fistulated Holstein Friesian × Jersey cows. The ANKOM RF gas production modules were used to monitor gas pressure and temperature every 5 min. At the end of each run, the pH of the fluid was measured, gas vials were taken for methane (CH4) measurements and liquor samples were taken to measure volatile fatty acids (VFA) and NH3 concentrations. The addition of tannins reduced the fractional rate of gas production for alfalfa (p ≤ 0.04) but increased it for ryegrass and plantain. There was a tendency for reduced gas production for ryegrass when tannins were added (p = 0.10). There was also a tendency for CH4 production to reduce (p < 0.10) and N2O to increase (p = 0.10) when tannins were added. Iso-butyrate tended to be lower for ryegrass control than to ryegrass with tannins (p = 0.08). Valerate concentration was lower for plantain control than to plantain with tannins. No effects were detected for gas composition (p > 0.05) or VFA concentrations (p > 0.05) when fermenting alfalfa. Under the condition of this study, these results may suggest that low-level tannin addition to the diet may affect rumen-fermentation pattern with a potential reduction of CH4 production in Lolium perenne-based diets. Further research is required on the effect of low levels of tannin supplementation under ex vitro and in vivo conditions as tannin supplementation effects might be substrate-dependent.
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Mukherjee, Chiradeep, Saradindu Panda, Asish Kumar Mukhopadhyay, and Bansibadan Maji. "Synthesis of standard functions and generic Ex-OR module using layered T gate." International Journal of High Performance Systems Architecture 7, no. 2 (2017): 70. http://dx.doi.org/10.1504/ijhpsa.2017.087164.
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Maji, Bansibadan, Asish Kumar Mukhopadhyay, Chiradeep Mukherjee, and Saradindu Panda. "Synthesis of standard functions and generic Ex-OR module using layered T gate." International Journal of High Performance Systems Architecture 7, no. 2 (2017): 70. http://dx.doi.org/10.1504/ijhpsa.2017.10008112.
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Naldini, Matteo Maria, Gabriele Casirati, Erika Zonari, et al. "Dissecting Ex Vivo Expansion of Mobilized Peripheral Blood Hematopoietic Stem and Progenitor Cells By Single Cell RNA Sequencing." Blood 132, Supplement 1 (2018): 3343. http://dx.doi.org/10.1182/blood-2018-99-111879.
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Abstract Hematopoietic stem and progenitor cell (HSPC) expansion remains an important unmet goal for ex vivo gene therapy based on gene addition and editing to compensate for the negative impact of the gene transfer procedure enabling faster engraftment and less complications. Additionally, ex vivo expansion of corrected cells may improve efficacy at more sustainable manufacturing costs by downscaling transduction. To date, our knowledge of precise mechanisms of action of expansion compounds is limited, and it remains unclear whether cord blood expansion protocols also maintain stemness of mobilized peripheral blood CD34+ cells (mPB), the preferred HSPC source for gene therapy. We performed serial (day 0,4,8) droplet-based single cell RNA sequencing (scRNAseq) on lentivirally transduced mPB expanded with UM171 to dissect cellular heterogeneity, monitor population dynamics over time and identify a transcriptional profile of primitive cells in culture. By associating published HSPC gene expression profiles to our scRNAseq dataset from uncultured mPB, we found that 45% of cells harbored a myelo-lymphoid signature. Smaller cell clusters expressed a shared erythroid (ERY) and megakaryocytic (MK) signature (20%), or a more primitive multipotent HSC-like signature (15%) characterized by enhanced JAK/STAT signaling and expression of HSC associated genes (AVP, HOPX, ID3). Unsupervised ordering of cells within pseudotime separated emerging MK/ERYpoiesis (FCER1A, HBD) from lympho-myelopoiesis (CD52, JUN), with intermediate states of more primitive progenitors located in between. After 4 days in culture, we noted a general increase in nuclear and mitochondrial gene transcription with activation of oxidative metabolism, paralleled by cell cycle activation, as expected from cytokine stimulation. By d8 of culture these changes leveled off but remained higher than uncultured cells. Of note, cells at d8 revealed an activation of cellular stress response pathways (e.g. TNFa, IFNg) hinting towards a compromised culture that may eventually exhaust HSC. Unsupervised clustering of cultured mPB highlighted a dramatic expansion (70-80%) of MK/ERY progenitor cells with high cycling activity with only 20-30% cells showing myelo-lymphoid transcriptional features. In line, pseudotime analysis highlighted a main ERY and MK trajectory separated from that of cells characterized by the expression of HSPC genes (HOPX, SPINK2) and of an emerging myeloid trajectory (MPO). To profile HSC in culture, we sorted and sequenced CD34+90+201+ cells from d4 expansion culture (3% of total cells), which we show to contain >70% of SCID repopulating potential. ScRNAseq revealed transcriptional similarity with the myelo-lymphoid progenitor cluster identified in the unsorted d4 culture. Unsupervised clustering of the CD34+90+201+ population revealed cell cycle dependent heterogeneity, identifying a highly quiescent cluster with expression of HSC-like signatures. This cluster was also characterized by relatively low gene expression, possibly reflecting a non-activated cell state consistent with primitive HSPC. Pseudotime analysis produced a four-branched minimum spanning tree, which retained a clear cell cycle and metabolic effect. Top variable genes included cell cycle, glycolytic, mitochondrial and ribosomal genes, identifying different metabolic modules along the branched trajectory. These results highlight that cell heterogeneity within a purified, HSC-enriched population is driven mainly by metabolic activation and cell cycle status. As a complementary approach, we purified LT-HSC from uncultured mPB (CD34+38-90+45RA-49f+), marked them with CFSE and expanded them in UM171 culture. LT-HSCs expanded on average 3.5 fold in 7 days, with the following distribution: 0 divisions: 3%; 1: 26%; 2: 47%; 3: 21%; 4: 3%. We performed scRNAseq on LT-HSC pre culture and after 7d separating a highly proliferative (≥2 divisions) and quiescent (0 - 1 division) fraction, allowing us to obtain unprecedented insight into the response of engrafting cells to ex vivo culture and set a framework to dissect self-renewal (HSC expansion), HSC maintenance and loss through differentiation as potential culture outcomes. Our combined functional/transcriptomic approach will define new HSC markers in culture and greatly facilitate side-by-side comparison of different expansion protocols towards rapid clinical translation. Disclosures No relevant conflicts of interest to declare.
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Prediletto, E., C. Cubuk, E. Pontarini, et al. "POS0138 RHEUMATOID SYNOVIAL FIBROBLASTS DISPLAY IMPRINTED MEMORY OF THEIR SYNOVIAL ENDOTYPE WHICH CAN BE PLASTICALLY MODULATED BY B-CELLS CROSSTALK." Annals of the Rheumatic Diseases 81, Suppl 1 (2022): 296.1–296. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2758.
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BackgroundDespite advances in the treatment of Rheumatoid Arthritis (RA), synthetics and biologicals drugs are ineffective in ~40% of patients. The origin of this refractoriness is unclear, but several clues point at the synovial microenvironment (SE) and the relative cellular heterogeneity between patients. We previously described the existence of different RA endotypes such as the lympho-myeloid, LM, which is B-cell rich and the fibroid-paucimmune, FPI, which is devoid of B-cells. While there is clear evidence that the crosstalk between stromal and immune cells in rheumatoid joints is critical for the perpetuation of chronic inflammation and autoimmunity, it is currently unknown whether transcriptional signatures identified in synovial fibroblasts (SFs) derived from different RA endotypes are driven by “imprinted” properties of the SFs or are shaped by the interaction with infiltrating immune cells in the RA joints.ObjectivesI) to identify “imprinted” vs “inducible” RASFs signatures trough the comparison of freshly isolated SFs and primary established SFs cultures obtained from LM vs FPI RA synovial biopsies and ii) to investigate the identified RASF signature as predictive biomarkers of disease evolution and of response to conventional and biological DMARDs.MethodsWe performed flowcytometry and single cell RNA sequencing (sc-RNAseq) on SFs obtained from LM and FPI biopsies, in isolation or in co-culture with RA B cells. Next, supernatant has been screened trough Multiplex and ELISA. Furthermore, we compared our results to publicly available sc-RNAseq datasets on freshly isolated SFs and to our bulk-RNAseq data from clinical trials patients.ResultsHierarchical clustering from sc-RNAseq transcriptional profiling of LM vs FPI RASF - after several cell passages - identified profoundly different gene signatures: whereby LM-RASF were characterised by genes involved in inflammation, proteoglycan formation and integrin binding, FPI-RASF were defined by genes related to collagen biosynthesis. Comparing the above signatures with those of freshly isolated RASF we identified both imprinted (i.e. maintained through several in vitro passages) and inducible (i.e. loss after long term culture) gene signatures. Notably, RA B-cells co-cultured with FPI-RASF profoundly altered the FPI-RASF transcriptional profile including the ex-novo expression of gene signatures typical of LM-RASF. Consensus gene modules constructed on LM vs FPI RASF imprinted gene signatures could be tracked in longitudinal whole tissue bulk RNA-seq data obtained from both early arthritis and established RA and were associated with synovial pathotype-specific histological and clinical features. Finally, modulation of FPI-RASF related genes following B-cell depletion identified poor responders to Rituximab in the R4RA randomised clinical trial.ConclusionOur work demonstrates that RASFs from different endotypes display imprinted memory of their original synovial tissue when maintained in culture over several months. We also demonstrated that imprinted memory typical of RASF isolated from B-cell rich LM synovial tissues can be dynamically modulated in FPI RASF following crosstalk with RA B cells. Finally, consensus gene modules based on FPI vs LM RASF-gene signatures were able inform on response/resistance to targeted biologic therapies.References[1]Lewis, M. J. et al. Molecular Portraits of Early Rheumatoid Arthritis Identify Clinical and Treatment Response Phenotypes. Cell Rep (2019)[2]Humby, F. et al. Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients. Ann Rheum Dis (2019)[3]Zhang, F. et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol (2019)[4]Humby, F. et al. Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA). Lancet (2021)Disclosure of InterestsNone declared
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Latif, Nurlaela, and Ady Rukma. "Pengaruh Pengetahuan Multimedia Pembelajaran, Berpifikir Kritis terhadap Efektifitas Modul E-Learning Mahasiswa Fakultas Teknik UNM." JURNAL SOSIAL EKONOMI DAN HUMANIORA 10, no. 4 (2024): 566–75. https://doi.org/10.29303/jseh.v10i4.709.
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This study is an Ex Post Facto study because the independent variables are not manipulated or subjected to specific treatments; instead, they are analyzed based on symptoms that appeared in respondents before the study's initiation. Adopting a cause-and-effect approach of "if x then y," this study does not involve direct control over the independent variables. Three variables are examined: two independent variables, Multimedia and Critical Thinking, and one dependent variable, the Effectiveness of the e-module. The relationship between the variables is analyzed using the correlation method, while the module's effectiveness is assessed through a quasi-experiment involving four control classes and four experimental classes. The study's results indicate that: (1) Multimedia and Critical Thinking collectively influence the Effectiveness of the E-learning Module, (2) Multimedia has a significant individual effect, whereas Critical Thinking has only a minimal impact, and (3) the Paired Samples t-test reveals an increase in learning outcomes, with an average difference of -13.92 between the Pre-Test and Post-Test. The regression analysis yielded a value of 71.314, categorizing it as effective. This e-learning module has demonstrated considerable effectiveness in enhancing understanding related to Multimedia.
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Мацкевич, О. В. "MICROCLONAL REPRODUCTION OF HAZELNUTS." Bulletin of Uman National University of Horticulture 1 (August 2022): 106–15. http://dx.doi.org/10.31395/2310-0478-2022-1-106-115.
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For the rapid introduction of large quantities of high-quality hazelnut planting material, it is important to use various modifications of microclonal propagation: classic on gel media, bioreactors with periodic flooding (TiS) and photoautotrophic methods. At the first stage of classical methods there are three main problems: phenol formation; endogenous contamination; selection of trophic and hormonal determinants of in vitro ontogenesis. In cases of infection of mother plants with viruses, viroids, it is mandatory to use meristem explants with a size of not more than 0.3 mm, followed by diagnosis of the effectiveness of recovery. To prevent self-intoxication with phenol-like oxidation products, a set of measures is used to prepare explant donors and modify nutrient media. The most common artificial nutrient media are Driver and Buzzard (DKW) and Nas and Read (NRM). Hazelnuts are sensitive to excess nitrogen and calcium and copper deficiency in artificial nutrient media. On media with a high N content, regenerants have shortened and thickened shoots, often with signs of hypehydration. Inhibition of calcium uptake by nitrogen leads to necrotization of shoot tips and root tips. The incorporation of iron ions into the metabolism of a plant depends on their valence and the form of chelating agents. During the multiplication and induction of rhizogenesis in aseptic conditions, mainly synthetic cytokinin benzylaminopurine and auxin indolylbutyric acid are used. The effectiveness of hormones increases with the use of combinations within groups, in particular cytokinins are benzylaminopurine and kinetin. At the stage of multiplication there is a predominance of cytokinins over auxins, and at the stage of rhizogenesis the number of auxins in the environment is greater than the number of cytokinins. Of the organic components, vitamins B1, B6, C, PP, amino acids and inositol are added to the environment. Ex vitro acclimatization of plants is carried out on peat-pearlite substrates in closed soil or modules of photoautrophic microclonal propagation with increased light intensity and high carbon dioxide content. The photoautotrophic method combines animation, rhizogenesis and acclimatization at the same time. The effectiveness of adaptation to factor-nestatic conditions increases with mycorrhizae by fungi of the genera Glomus, Trichoderma, Tuber in the transfer of plants from aseptic conditions.
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Hadjiyanni, Irene, Laurie L. Baggio, Philippe Poussier, and Daniel J. Drucker. "Exendin-4 Modulates Diabetes Onset in Nonobese Diabetic Mice." Endocrinology 149, no. 3 (2007): 1338–49. http://dx.doi.org/10.1210/en.2007-1137.
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Activation of the glucagon-like peptide-1 receptor (GLP-1R) is associated with expansion of β-cell mass due to stimulation of cell proliferation and induction of antiapoptotic pathways coupled to β-cell survival. Although the GLP-1R agonist Exenatide (exendin-4) is currently being evaluated in subjects with type 1 diabetes, there is little information available about the efficacy of GLP-1R activation for prevention of experimental type 1 diabetes. We examined the consequences of exendin-4 (Ex-4) administration (100 ng once daily and 2 μg twice daily) on diabetes onset in nonobese diabetic mice beginning at either 4 or 9 wk of age prior to the onset of diabetes. Ex-4 treatment for 26 wk (2 μg twice daily) initiated at 4 wk of age delayed the onset of diabetes (P = 0.007). Ex-4-treated mice also exhibited a significant reduction in insulitis scores, enhanced β-cell mass, and improved glucose tolerance. Although GLP-1R mRNA transcripts were detected in spleen, thymus, and lymph nodes from nonobese diabetic mice, Ex-4 treatment was not associated with significant changes in the numbers of CD4+ or CD8+ T cells or B cells in the spleen. However, Ex-4 treatment resulted in an increase in the number of CD4+ and CD8+ T cells in the lymph nodes and a reduction in the numbers of CD4+CD25+Foxp3+ regulatory T cells in the thymus but not in lymph nodes. These findings demonstrate that sustained GLP-1R activation in the absence of concomitant immune intervention may be associated with modest but significant delay in diabetes onset in a murine model of type 1 diabetes.
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Fairhurst, Katherine, Harriet Cook, Joseph Vane-Daniel, Alison Hunter-Smith, and Richard Sutton. "Abstract P4-07-03: LONG TERM PATIENT REPORTED OUTCOMES FOLLOWING THERAPEUTIC MAMMAPLASTY." Clinical Cancer Research 31, no. 12_Supplement (2025): P4–07–03—P4–07–03. https://doi.org/10.1158/1557-3265.sabcs24-p4-07-03.
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Abstract Background: Therapeutic Mammaplasty (TM) is a safe oncoplastic surgical technique aiming to extend the boundaries of traditional breast conserving therapy (BCT) by removing larger breast volumes to reduce and/or lift the breast, without compromising cosmetic or oncological outcomes. Several systematic reviews have emphasised the paucity of Patient Reported Outcome Measures (PROMs) following TM. This study aimed to assess the long-term PROMs following TM performed in our centre over a 17-year period. Methods: Eligible women who underwent TM between 2005 and 2021 were invited to participate by returning the BREAST-Q questionnaire (combination of BCT and Reduction/Mastopexy modules). Surveys were returned by post or online from August to December 2023 (minimum 20-months post TM). Raw responses were transformed using Rasch conversion tables (0=worst;100=best) and descriptive summary statistics generated. Clinical outcome data was collected from digital hospital records/databases and analysed using descriptive summary statistics. Results: Of 246 patients who underwent TM, n=21 (8.5%) subsequently required completion mastectomy, n=15 (6.1%) developed recurrence/metastatic disease and n=22 (8.9%) died. Questionnaires were returned by n=103/188 (53.4%) participants. Only n=4/103 (3.9%) participants were current smokers at the time of surgery; n=10/103 (9.7%) were ex-smokers. Neoadjuvant treatment was given to n=31/103 (30.1%) patients. Most tumours were T1 (n=53/103, 51.5%) or T2 (n=36/103, 34.9%). Only n=19/103 (18.4%) patients had immediate contralateral symmetrizing surgery at the time of TM, but a further n=34/103 (33.0%) had delayed symmetrization surgery. Few women suffered complications (n=15/103, 14.6%), all were minor and there were no peri-operative deaths. Most women received adjuvant radiotherapy (n=95/103, 92.2%); around two thirds received adjuvant endocrine treatment (n=63/103, 61.2%). Overall, patients reported median scores of 69 (IQR 53-83.5) and 70 (IQR 54-86) for satisfaction with breasts for BCT/breast reduction modules respectively. Median wellbeing scores were physical (chest wall) 82 (IQR 66-100), physical (reduction) 72 (IQR 59-82) and psychosocial 77 (IQR 62-93) with lowest scores for sexual wellbeing 59 (IQR 36-79). Comparison was made with published long-term PROMs 12 years following immediate breast reconstruction (IBR) (Johnson et al doi:10.1093/bjs/znad276) using a minimal clinically important difference in mean scores of 4-points for satisfaction with breasts/psychosocial/sexual wellbeing and 3-points for physical wellbeing. TMs performed from 2005 to 2015 (n=40, 8-18 years previously) had significantly better mean long-term satisfaction with breasts scores (TM 72.3(BCT)/74.5(reduction) than all forms of IBR (Implant/expander 54.7; Latissimus Dorsi flap (LD) 59; Abdominal flaps 67.6). Sexual wellbeing scores were also significantly higher for TM (57.4) than for all forms of IBR (Implant/expander 44.7;LD 47.4;Abdominal 51.2). Psychosocial wellbeing scores for TM (78) were higher than both implant/expander 72.2 and LD 73.3 IBR, but comparable to abdominal flap IBR (77.6). TM physical (chest wall) wellbeing scores (80.6) were comparable to implant/expander (82.1) and LD (79.5) IBR, but significantly lower than abdominal flap IBR (87.8). Conclusions: TM has a long-lasting positive impact on quality-of-life following breast cancer treatment. Patient satisfaction with breasts, sexual and psychosocial wellbeing may be significantly higher in the long term than all types of IBR. Physical wellbeing outcomes are comparable to both implant/expander and LD flap IBR but worse than abdominal flaps in our series. With the now growing body of evidence suggesting BCT may also confer a survival advantage over mastectomy, this data suggesting that overall, quality of life is better in the long term, further supports offering oncoplastic BCT preferentially whenever it is oncologically feasible. Citation Format: Katherine Fairhurst, Harriet Cook, Joseph Vane-Daniel, Alison Hunter-Smith, Richard Sutton. LONG TERM PATIENT REPORTED OUTCOMES FOLLOWING THERAPEUTIC MAMMAPLASTY [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-07-03.
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Val, Christian, Pascal Couderc, and Nadia Boulay. "Stacking of Known Good Rebuilt Wafers without TSV - Industrial Applications." Additional Conferences (Device Packaging, HiTEC, HiTEN, and CICMT) 2011, DPC (2011): 001126–74. http://dx.doi.org/10.4071/2011dpc-tp36.
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The 3-D interconnection started at 3D PLUS in 1996 and led to the stacking of nearly all types of analogical and logical components, sensors, MEMS, etc for the Hi-Rel field (Space, Defence, Medical, Industrial). This technology is extremely robust (−130 °C +175 °C, 40000g), and is fully qualified by all worldwide most important Space Agencies, for Defence applications and Harsh environment. A technological break started in 2002 ; it consisted in another 20 to 30 reduction factor of the weight and volume of these 3-D modules. The Z pitch is 100 μm and the X Y size is given by the size of the larger die plus 100 μm of polymer around it. This is a stacked of Known Good Rebuilt Wafer of full wafer level technique. The dice are received in wafers and following operations are carried out :- Pick, flip and place of the good dice on a “sticking skin”- Moulding of the whole of this « pseudo wafer » in order to obtain what we call a « Known Good Rebuilt Wafer (KGRW) ». These two first steps are already developed by Freescale (RCP technique up to 300mm), then Infineon and Nanium (ex Infineon/Quimoda) and now about ten companies are developing this 2-D approach:- Stacking and gluing of KGRW 1, 2, 3..., n, by means of an adhesive film- Dicing of these stacked rebuilt wafers by techniques identical to the dicing of standard wafers- Metallization of the dicing streets with nickel + gold by electroless chemical plating identical to the UBM plating technique- Direct laser patterning by laser with our edge connection technique up to 100 μm pitch. Below this pitch, the Thru Polymer Via (TPV) are made through the stacked wafers. The equivalent pitch will be 20 μm. it can be noticed that the shielding can be made on the dicing street.- Electrical test at the stacked wafer level- Singulation This approach allows to use standard dice without any modification. It is multi sources and the stacking of the good rebuilt wafers allows to obtain an excellent yield. A development agreement has been signed with a semiconductors manufacturer. Smart card application- A development is in progress with the most worldwide important manufacturer of smart cards in order to integrate 5 levels of dice within a cavity of 550 μm inside the 800 μm SIM card. Medical applications will be presented:- Micro modulator with 5 ASICs within a 3 mm diameter tube,- Prototypes for the major US pacemaker manufacturer (Medtronic) and one European pacemaker manufacturer (Sorin/Ela Medical). A full pacemaker module of 0,5 cm3 (16 times smaller than the standard pacemaker: 8 cm3) will be shown- Micro camera for Hard X-Ray for Philips Medical (DE). Industrial applications- Abandoned sensors for Airbus and industrial areas. This « full wafer level » approach will allow to build System in Package (SiP) or “Abandoned Sensors” at very low costs, since the process uses mainly the steps of wafers building; the “panelization” allows to be in parallel processing from A to Z steps. Moreover, the use of Known Good Rebuilt Wafer like the RCP allows to stack Good wafer at the reverse what is impossible with the wafer to wafer approach.
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Alves, Marcos Antônio, Cristiano Lopes Carvalhaes, and Paulo Roberto de Sousa. "Pós-graduação Lato Sensu: apontamentos para a gestão estratégica a partir das expectativas dos candidatos." ForScience 8, no. 2 (2020): e00858. http://dx.doi.org/10.29069/forscience.2020v8n2.e858.
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O objetivo deste artigo foi analisar o perfil de candidatos a cursos de Pós-Graduação Lato Sensu e identificar pontos estratégicos para uma melhor condução do curso e aprendizagem do aluno. Um questionário foi aplicado e continha questões demográficas e outras relacionadas com as expectativas da formação, motivos para cursá-la e critérios de decisão. Um total de 136 candidatos foram entrevistados e eles externaram a importância de cada item em uma escala Likert de 1 a 9 pontos. Os resultados indicaram que dentre os candidatos entrevistados, a maioria compreendeu: homens (61.03%), entre 20 e 29 anos (49.26%), solteiros (61.03%), que concluíram graduação (94.11%) em instituições privadas (75%) entre 2016-2015 (26.47%) ou 2014-2011 (37.5%). A formação é buscada por iniciativa própria e eles demonstraram alta expectativa quanto à formação teórica e profissional. Módulos comuns para diferentes cursos, ações de marketing aproveitando as oportunidades de mercado, descontos para ex-alunos de graduação e especialização e currículo voltado ao mercado foram as principais proposições percebidas e discutidas. Este trabalho retoma um tema de grande importância para a educação superior, fornece uma revisão normativa histórica e pode servir de apoio para gestores educacionais, empresas privadas e pesquisadores envolvidos nesta formação. Palavras-chave: Pós-Graduação Lato Sensu. Especialização. Educação superior. Perfil do candidato. Lato Sensu postgraduate courses: strategic management based on candidates’ expectations Abstract The aim of this paper was to analyze the profile of candidates for Lato Sensu Postgraduate courses and to identify strategic points for a better conduction of the course and students learning. A survey was conducted with demographic and course expectations questions, considering the reasons for taking it and decision-making. A total of 136 candidates were interviewed and they expressed the importance of each item on a 1-9 point Likert scale. The results indicated that among the candidates interviewed, the majority were: men (61.03%); 20-29 years old (49.26%); single (61.03%); who completed their undergraduate degree (94.11%); in private institutions (75%); between 2016-2015 (26.47%) or 2014-2011 (37.5%). The graduation is sought on their own initiative and they showed high expectations regarding theoretical and professional training. Common modules for different courses, marketing actions taking advantage of market opportunities, discounts for undergraduate and specialization students and curriculum aimed at the market were the main proposals perceived and discussed. This research takes up a topic of great importance for higher education, provides a historical normative review and may be used as support for educational managers, business and researchers involved in this field. Keywords: Lato Sensu Postgraduate Courses. Specialization. Strategic Management. Candidates’ Profile.
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Silva, Miguel R., João A. Dias-de-Oliveira, António M. Pereira, Nuno M. Alves, Álvaro M. Sampaio, and António J. Pontes. "Design of Kinematic Connectors for Microstructured Materials Produced by Additive Manufacturing." Polymers 13, no. 9 (2021): 1500. http://dx.doi.org/10.3390/polym13091500.
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The main characteristic of materials with a functional gradient is the progressive composition or the structure variation across its geometry. This results in the properties variation in one or more specific directions, according to the functional application requirements. Cellular structure flexibility in tailoring properties is employed frequently to design functionally-graded materials. Topology optimisation methods are powerful tools to functionally graded materials design with cellular structure geometry, although continuity between adjacent unit-cells in gradient directions remains a restriction. It is mandatory to attain a manufacturable part to guarantee the connectedness between adjoining microstructures, namely by ensuring that the solid regions on the microstructure’s borders i.e., kinematic connectors) match the neighboring cells that share the same boundary. This study assesses the kinematic connectors generated by imposing local density restrictions in the initial design domain (i.e., nucleation) between topologically optimised representative unit-cells. Several kinematic connector examples are presented for two representatives unit-cells topology optimised for maximum bulk and shear moduli with different volume fractions restrictions and graduated Young’s modulus. Experimental mechanical tests (compression) were performed, and comparison studies were carried out between experimental and numerical Young’s modulus. The results for the single maximum bulk for the mean values for experimental compressive Young’s modulus (Ex¯) with 60%Vf show a deviation of 9.15%. The single maximum shear for the experimental compressive Young’s modulus mean values (Ex¯) with 60%Vf, exhibit a deviation of 11.73%. For graded structures, the experimental mean values of compressive Young’s moduli (Ex¯), compared with predicted total Young’s moduli (ESe), show a deviation of 6.96 for the bulk graded structure. The main results show that the single type representative unit-cell experimental Young’s modulus with higher volume fraction presents a minor deviation compared with homogenized data. Both (i.e., bulk and shear moduli) graded microstructures show continuity between adjacent cells. The proposed method proved to be suitable for generating kinematic connections for the design of shear and bulk graduated microstructured materials.
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Chlup, Hynek, Jan Skočilas, Jaromír Štancl, Milan Houška, and Rudolf Žitný. "Effects of Extrusion and Irradiation on the Mechanical Properties of a Water–Collagen Solution." Polymers 14, no. 3 (2022): 578. http://dx.doi.org/10.3390/polym14030578.
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This article describes 1D extension tests on bovine collagen samples (8% collagen in water). At such a high collagen concentration, the mechanical properties of semi-solid samples can be approximated by hyperelastic models (two-parametric HGO and Misof models were used), or simply by Hooke’s law and the modulus of elasticity E. The experiments confirm a significant increase in the E-modulus of the samples irradiated with high-energy electrons. The modulus E ~ 9 kPa of non-irradiated samples increases monotonically up to E ~ 250 kPa for samples absorbing an e-beam dose of ~3300 Gy. This amplification is attributed to the formation of cross-links by irradiation. However, E-modulus can be increased not only by irradiation but also by exposure to a high strain rate. For example, soft isotropic collagen extruded through a 200 mm long capillary increases the modulus of elasticity from 9 kPa to 30 kPa, and the increase is almost isotropic. This stiffening occurs when the corrugated collagen fibers are straightened and are aligned in the flow direction. It seems that the permanent structural changes caused by extrusion mitigate the effects of the ex post applied irradiation. Irradiation of extruded samples by 3300 Gy increases the modulus of E-elasticity only three times (from 30 kPa to approximately 90 kPa). Extruded and ex post irradiated samples show slight anisotropy (the stiffness in the longitudinal direction is on an average greater than the transverse stiffness).
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Lee, Joo Yeong, Sang Won Kwak, Jung-Hong Ha, and Hyeon-Cheol Kim. "Ex-Vivo Comparison of Torsional Stress on Nickel–Titanium Instruments Activated by Continuous Rotation or Adaptive Motion." Materials 13, no. 8 (2020): 1900. http://dx.doi.org/10.3390/ma13081900.
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This study aimed to evaluate the effect of adaptive motion applied to conventional nickel-titanium (NiTi) rotary instruments on torsional stress generation during shaping procedure. One hundred and twenty mesio-buccal canals of molars were randomly assigned to two groups according to the kinetics; adaptive motion (AD) and continuous rotation (CR). Each group was divided into four subgroups (n = 15) according to the NiTi instrument systems: HyFlex EDM, One Curve, Twisted File Adaptive, and ProTaper Next. A glide path was established with PathFile #1, for each file group being used with either of the kinetic movements. During the instrumentation with the designated motion and file system, the generated torque was measured via the control unit and acquisition module. Based on the acquired data, the maximum and total torque were calculated. The data were statistically analyzed using Kruskal–Wallis and Mann–Whitney tests at a significance level of 95%. The maximum and total torque generated by all instruments were significantly reduced by the adaptive motion (p < 0.05). In the CR group, HyFlex EDM generated the highest maximum and total stress. In the AD group, HyFlex EDM showed the highest maximum torsional stress, and One Curve showed the highest total torsional stress (p < 0.05). The TF Adaptive instrument with adaptive movement produced the lowest maximum and total torsional stress (p < 0.05). Under the conditions of this study, the use of adaptive motion would be useful to reduce the torsional stress of instrument and root dentin. The reduction of torsional stress through adaptive motion may enhance the durability of instruments and reduce the potential risk of dentinal cracks.
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Gandolfi, Sara, Michal Sheffer, Emily Lowry, et al. "Identification of Molecular Markers of Tumor Cell Sensitivity and Resistance to Natural Killer Cells through Genome-Wide CRISPR Activation and CRISPR Editing Screens in Multiple Myeloma Cell Lines: Implications for Anti-Myeloma Immunotherapy." Blood 132, Supplement 1 (2018): 1115. http://dx.doi.org/10.1182/blood-2018-99-118736.
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Abstract Natural killer (NK) cells represent a promising immunotherapeutic approach as they can potently kill tumor cells without triggering graft-versus-host reactions. Indeed, infusion of high numbers of NK cells, either autologous or allogeneic, after their ex vivo expansion and activation, has been feasible and safe in clinical studies. However, prior studies and early clinical trials indicate that tumor cells can exhibit decreased response to NK due to the protective effect of nonmalignant mesenchymal stromal cells; and depending on the genetic background of the tumor cells. To our knowledge, since earlier subgenome-scale RNAi-based studies, there have been no genome-wide CRISPR-based screens to identify candidate markers conferring tumor cell resistance or sensitivity to NK cells in multiple myeloma (MM). To address this void, and building on a recent loss-of-function (LOF) study by our group on solid tumors, we sought to identify genes regulating the response of MM cells to the cytotoxic activity of NK cells by conducting a genome-wide CRISPR/Cas9-based gene editing (Brunello library of sgRNA) and gene activation (Calabrese library of sgRNA) screens in MM.1S cells co-cultured with primary NK (pNK) cells (effector-to-target [E:T] ratio of 3.75:1) derived from healthy donor peripheral blood mononuclear cells (PBMCs) cultured in vitro in GMP SCGM medium with IL-2. Briefly, MM.1S cells engineered to stably express the nuclease SpCas9 (Brunello) or a catalytically inactive programmable RNA-dependent DNA-binding protein (dCas9)-VP64 (Calabrese) were also transduced with lentiviral particles for a pool of ~70,000 (Brunello library) or ~120,000 (Calabrese) sgRNAs, targeting exons of ~20,000 genes (plus non-targeting control sgRNAs), under conditions of transduction which allow for an average of no more than 1 sgRNA to be incorporated in a given cell. This allowed us to convert the initial population of MM.1S cells into heterogeneous pools in which each gene is subject to individual LOF or gain-of-function (GOF), due to Cas9-mediated editing, by only 1 sgRNA. Flow cytometry was performed to verify pNK viability, purity (CD56 and CD3), and expression of p46 receptor, surrogate marker of NK cell activity. These screens identified genes whose knock-out (Brunello sgRNA library) or activation (Calabrese sgRNA library) led to NK cells resistance or potential sensitivity. The hits observed in the current MM-oriented study exhibited, compared to our similar studies in solid tumor model, substantial gene level differences, but notable overlap at the pathway level (including death receptor pathways, NK activating pathways), which suggests that mechanisms determining tumor cell response vs. resistance to NK cells operate through modules consistent across tumors, but manifested through potentially different members of the respective pathways in different neoplasms. For instance, in this MM-oriented study, we identified that NK cell sensitivity of tumor cells is modulating by activation of several metabolic and homeostatic genes, receptor kinases, and interestingly membrane-bound proteins of the mucin family, e.g. MUC1, and MUC4, which have been reported to play a role in NK-mediated tumor killing in other types of cancer. MUC1 in particular has a clinical relevance as a small molecule inhibitor with prior preclinical studies in MM is available. Interestingly, our GOF screen identified as potential NK cell sensitizers TNFRSF10B, a death receptor related to TNFRSF10A (a hit identified in our studies in solid tumors), the putative death receptor adaptor TRADD, and the NK ligands PVR and ULBP1. Interestingly, genes such as PTEN and TP53, commonly associated with high-risk MM, didn't affect the response to NK cell, suggesting that NK cell-based therapies may potentially have a role in treatment of MM patients with high-risk clinical or biological features. In conclusion, this is the first study applying both LOF and GOF genome-wide screens to NK cell response in MM. The combination of such screens performed in parallel provide complementary and orthogonal information that allows us to identify genes that might not have been appreciated if only either LOF or GOF alone screens had been performed. We envision that the methodology and results presented herein will provide a framework towards validation of molecular markers which can help to optimize and individualize the use of NK cell-based therapy in MM. Disclosures Mitsiades: Abbvie: Research Funding; TEVA: Research Funding; EMD Serono: Research Funding; Janssen/ Johnson & Johnson: Research Funding; Takeda: Other: employment of a relative.
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Wauquier, Fabien, Audrey Daneault, Henri Granel, et al. "Human Enriched Serum Following Hydrolysed Collagen Absorption Modulates Bone Cell Activity: from Bedside to Bench and Vice Versa." Nutrients 11, no. 6 (2019): 1249. http://dx.doi.org/10.3390/nu11061249.
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Collagen proteins are crucial components of the bone matrix. Since collagen-derived products are widely used in the food and supplement industry, one may raise the question whether collagen-enriched diets can provide benefits for the skeleton. In this study, we designed an innovative approach to investigate this question taking into account the metabolites that are formed by the digestive tract and appear in the circulation after ingestion of hydrolysed collagen. Blood samples collected in clinical and pre-clinical trials following ingestion and absorption of hydrolysed collagen were processed and applied on bone-related primary cell cultures. This original ex vivo methodology revealed that hydrolysed collagen-enriched serum had a direct impact on the behaviour of cells from both human and mouse origin that was not observed with controls (bovine serum albumin or hydrolysed casein-enriched serum). These ex vivo findings were fully in line with in vivo results obtained from a mouse model of post-menopausal osteoporosis. A significant reduction of bone loss was observed in mice supplemented with hydrolysed collagen compared to a control protein. Both the modulation of osteoblast and osteoclast activity observed upon incubation with human or mouse serum ex vivo and the attenuation of bone loss in vivo, clearly indicates that the benefits of hydrolysed collagen for osteoporosis prevention go beyond the effect of a simple protein supplementation.
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Kovacs, A., C. Galbraith, R. Sheldon, U. Gallo-Orsi, and L. Lopes. "An Adaptive Management Framework Concept for the Sustainable Use of the Saker Falcon." Raptors Conservation, no. 2 (2023): 465–68. http://dx.doi.org/10.19074/1814-8654-2023-2-465-468.
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The Saker Falcon (Falco cherrug) is listed on the International Union for Conservation of Nature (IUCN) Red List as Globally Endangered. It breeds across continental middle latitudes, with its range spanning over 7,000 km from Central Europe to Western China, and 3,000 north to south. Most populations are migratory and a number of different routes have been confirmed by field observations and satellite tracking. One of the principal threats affecting its global population is unsustainable trapping/harvest on the breeding grounds and along the migration routes. The Saker Falcon is listed in Appendix II of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES), which enables trade subject to the development of a Non-Detriment Finding (NDF). Under the Convention on the Conservation of Migratory Species of Wild Animals (CMS), the species is listed under Appendix I (with the exception of the Mongolian population which is listed in Appendix II), meaning that take is generally prohibited, except for the Mongolian population. The Saker Falcon Global Action Plan (SakerGAP) was adopted by CMS Parties in 2014 and a Saker Falcon Task Force (STF) was established to oversee implementation. One of the key aims of the STF is to develop an Adaptive Management Framework (AMF) that moves the current illegal, and presumably unsustainable trapping activity, into a system that is legal, controlled, and sustainable. Such a system will need to be carefully developed, implemented, and monitored, and conforms with requirements under CMS and CITES. To develop such a framework the STF established an Adaptive Management Framework Discussion Group (AMF DG) to conceptualize a modular AMF as a tool to assist the decision-making of stakeholders, especially international partners, and national authorities, on the sustainable use of the Saker Falcon. The objective is to design an international AMF which integrates nine modules: 1) global governance and data management, including effective sustainable use models and a sustainable, international quota scheme, 2) internationally harmonized policy and law-making that ensures sustainability, 3) reinforced law enforcement, 4) effective awareness raising, 5) effective monitoring and research schemes, 6) complementary ex situ conservation measures, 7) compensatory in situ conservation measures, 8) effective stakeholder engagement, cooperation, and networking to respond to the socio-economic and cultural drivers of Saker Falcon use, and 9) the involvement of rural communities in the conservation management of the Saker Falcon. Currently, a significant degree of uncertainty and speculation accompanies the population estimates for certain key Range States, especially in Asia. Therefore, while designing the AMF, the STF is seeking to find a careful balance between the benefits of an internationally coordinated sustainable use framework and the inherent risks of taking Saker Falcons from the wild in large numbers. According to the draft AMF, the legal harvest may conditionally be allowed in larger, stable, or increasing Saker Falcon populations in parts of its global range, only if legal, ecological, and socio-economic safeguards for sustainability are met and the origin of falcons is identifiable. Depleted or decreasing breeding populations may not currently be considered suitable for any harvest and are illegal as currently listed in CMS Appendix 1. However, the AMF must mitigate the illegal taking of wild falcons along the flyways and in wintering areas. This would require an international harmonization of alternative policies, and legal and wildlife management tools. As well as a concerted international data sharing to ensure that harvest that is assessed non-detrimental at the Range State level does not affect negatively the Saker Falcon populations of other Range States.
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Su, Junjing, Charmilie C. Logan, Alun D. Hughes, et al. "Impact of chronic hypoxia on proximal pulmonary artery wave propagation and mechanical properties in rats." American Journal of Physiology-Heart and Circulatory Physiology 314, no. 6 (2018): H1264—H1278. http://dx.doi.org/10.1152/ajpheart.00695.2017.
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Arterial stiffness and wave reflection are important components of the ventricular afterload. Therefore, we aimed to assess the arterial wave characteristics and mechanical properties of the proximal pulmonary arteries (PAs) in the hypoxic pulmonary hypertensive rat model. After 21 days in normoxic or hypoxic chambers (24 animals/group), animals underwent transthoracic echocardiography and PA catheterization with a dual-tipped pressure and Doppler flow sensor wire. Wave intensity analysis was performed. Artery rings obtained from the pulmonary trunk, right and left PAs, and aorta were subjected to a tensile test to rupture. Collagen and elastin content were determined. In hypoxic rats, proximal PA wall thickness, collagen content, tensile strength per unit collagen, maximal elastic modulus, and wall viscosity increased, whereas the elastin-to-collagen ratio and arterial distensibility decreased. Arterial pulse wave velocity was also increased, and the increase was more prominent in vivo than ex vivo. Wave intensity was similar in hypoxic and normoxic animals with negligible wave reflection. In contrast, the aortic maximal elastic modulus remained unchanged, whereas wall viscosity decreased. In conclusion, there was no evidence of altered arterial wave propagation in proximal PAs of hypoxic rats while the extracellular matrix protein composition was altered and collagen tensile strength increased. This was accompanied by altered mechanical properties in vivo and ex vivo. NEW & NOTEWORTHY In rats exposed to chronic hypoxia, we have shown that pulse wave velocity in the proximal pulmonary arteries increased and pressure dependence of the pulse wave velocity was steeper in vivo than ex vivo leading to a more prominent increase in vivo.
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Blažo, Ondrej. "A New Regime on Protection of Public Procurement Against Foreign Subsidies Distorting the Internal Market: Mighty Paladin or Giant on the Feet of Clay?" International and Comparative Law Review 21, no. 2 (2021): 138–61. http://dx.doi.org/10.2478/iclr-2021-0016.
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Summary As a response to possible distortive effects of foreign subsidies, which are not covered by the current rules of the World Trade Organization and primary and secondary law of the EU, on 6th May 2021 the European Commission introduced a new regime against foreign subsidies by introducing the proposal of the Regulation on foreign subsidies distorting the internal market. This new proposal includes three so-called modules: a set of measures of general application that governs the ex officio review of subsidies (Module 1), specific rules on concentrations (Module 2) and specific rules in public procurement in the EU (Module 3). The paper will focus on some of the features of Module 3 and assess the context, feasibility, and possible consequences for the course of public procurement in the EU covered by the public procurement directives
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Toran, Paul, Matthew A. Held, and Don M. Wojchowski. ""RHEX" / C1ORF186 Governs JAK2 Activation, Differentially Modulates STAT-5 and -3, Balances Human Erythroblast Development, and Becomes Essential during Red Cell Formation." Blood 136, Supplement 1 (2020): 1–2. http://dx.doi.org/10.1182/blood-2020-142739.
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Introduction: Via phospho-PTM-targeted LC/MS proteomics, we identified RHEX as an EPO- and pY-regulated integral plasma membrane adaptor protein that associates with the h-EPOR and supports early stage human* (pro)erythroblast expansion (dexamethasone system) (JEM 211:1715-22). [*RHEX has no orthologues, is conserved in H sapiens and primates, but is not represented among mouse, rat or lower vertebrates]. Presently, by employing a 3-phase HSC-to-RBC ex vivo system, shRNA lentivirus mediated knockdowns (KD's), cytohistomorphology imaging, and molecular phenotyping (including RNA seq), we have now discovered and defined three major novel effects that RHEX exerts on erythroblast formation. As an introduction to findings: 1] RHEX supports erythroblast proliferation, balances differentiation, and is essential for the formation of maturing late-stage erythroblasts. 2] RHEX governs EPO activation of not only p-AKT, p-ERK1/2, p-STAT5 and p-STAT3 but also p-JAK2, while also inversely modulating total STAT5 and STAT3 levels. 3] RNA-seq analyses reveal that the knockdown of RHEX sharply alters factors networked within "signal transduction", "plasma membrane" and "protein binding" as top GO terms. KEGG analysis defines adhesion proteins, and oxidative factors that are strongly modulated upon RHEX KD. RHEX therefore coordinates EPO/EPOR/JAK2 signals that dynamically regulate erythroblast maturation. Results: In primary HSC- derived erythroid progenitor cells (EPCs), RHEX knockdown (KD) attenuated (pro)erythroblast proliferation up to 50% of control cultures (shNT EPCs), especially during culture phases II (SCF, EPO) and III (EPO only). During development, erythroblast phenotypes were altered in three impacting ways. During early phase-II, RHEX KD heightened the frequency of polychromatic erythroblasts (200 % over controls) (Fig panel A). During late phase-II, this increase in sh-RHEX polychromatic erythroblast frequencies persisted, while parallel control shNT erythroblasts advanced to orthochromatic erythroblasts at frequencies significantly above sh-RHEX EPCs. The orthochromatic stage therefore marks a developmental point that is first compromised due to RHEX KD. During phase-III, the late-stage development of sh-RHEX EPCs became corrupted due to RHEX KD to the extent that terminally differentiating erythroblasts became markedly mis-shapen, and failed to efficiently convert to reticulocytes and erythrocytes (Fig panel B). By d6 of phase-III, in fact, intact cells were challenging to identify in sh-RHEX EPC cultures. When EPO/EPOR/JAK2 signaling modules were analyzed, RHEX's KD in UT7epo cells dysregulated EPO- activation of not only p-ERK1/2, p-AKT, p-STAT5, p-STAT3 but also pY-JAK2 (each multi-fold). In UT7epo RHEX KD cells, total STAT5 levels were elevated, while total STAT3 levels decreased (up to10-fold). Compartmentalized signaling within membrane and cytoplasmic cell fractions was also analyzed. In control shNT cells, activated pY-JAK2 was predominantly membrane-associated. RHEX KD, however, resulted in aberrantly heightened levels of pY-JAK2 in cytoplasm. This displacement effect was also observed for activated pY-STAT5. Findings suggest that RHEX may promote the membrane association of activated pY-JAK2. In addition, RHEX KD proved to markedly limit UT7epo cell-cell aggregation. To gain insight into cellular pathways that RHEX supports, RNAseq was performed using P-I d6 erythroblasts (unaffected by RHEX KD in morphologies). For factors differentially expressed due to RHEX KD plasma membrane adhesion proteins were highly represented, with high confidence. Transcripts altered 2 to &gt;10-fold, include ITGB2, ITGaX, ITGaM, ICAM3, SEL-L, CD38, CD84, PLEXIND, PANNEXIN2, ADGRG3 - and each exhibited patterned erythroid expression. Select oxidizing enzymes were also elevated in RHEX KD erythroblasts as MPO, EPX, and the NADPH oxidase subunits NCF1, NCF4 and NCF2 (50+ fold). Future investigations will assess the extent to which such factors underlie RHEX's pro-erythropoietic roles. Summary: As an EPO/EPOR/JAK2 target, RHEX governs EPO- activation of JAK2, pY-JAK2's membrane vs cytoplasmic localization, and levels of total STAT5 and STAT3. During late erythropoiesis, RHEX's actions become essential for the integrity of maturing erythroblasts. Associated mechanisms may involve RHEX's effects on cell adhesion and/or oxidation. Figure Disclosures No relevant conflicts of interest to declare.
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Spycher, Martin, Jan Doran, and Peter Lerch. "Reconstituted High Density Lipoprotein (rHDL) Modulates Platelet Activity In Vitro and Ex Vivo." Thrombosis and Haemostasis 80, no. 08 (1998): 316–20. http://dx.doi.org/10.1055/s-0037-1615194.
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SummaryA reconstituted high density lipoprotein (rHDL) prepared for clinical use was tested for its influence on platelet activity modulated by various stimuli. In a first series of in vitro experiments, rHDL was added to blood in a concentration series, and platelet rich plasma (PRP) was isolated. Platelets were stimulated with arachidonic acid, collagen, epinephrine or ADP, and platelet aggregation was assessed. rHDL mediated a dose dependent inhibition of the platelet activity. With purified platelets rHDL inhibited the release reaction induced by collagen, but not by thrombin, as measured by CD62P (P-Selectin) expression on the plasma membrane. Ex vivo experiments were performed with PRP from volunteers, previously infused with 25 mg rHDL/kg body weight and 40 mg rHDL/kg body weight, respectively. Platelet activity in PRP was assessed before, and up to 30 h after the end of the rHDL infusion. A transient inhibition of the platelet aggregation induced by arachidonic acid and collagen was observed which was more pronounced in the group receiving 40 mg rHDL/kg body weight. In both groups of experiments, in vitro and ex vivo, the inhibition of the platelet activity was also dependent on the stimulus used.
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Kumar, Ch Sravan, K. V. Prakash, Sanjeeva Reddy, et al. "Development of Cotton stalk harvesting machine for ex-situ application." Ecology, Environment and Conservation 28, no. 08 (2022): S61—S66. http://dx.doi.org/10.53550/eec.2022.v28i08s.011.
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Cotton (Gossypium hirsutum) is an important commercial crop in India. Annually 30.79 million tons of cotton stalk residue is being generated in India. In India, after harvesting cotton lint, cotton stalks are removed by either manual uprooting or cutting them using sickle above the ground level, which is a laborious operation and contributes to increase in crop production. After removing cotton stalks from field, farmers are burning cotton stalks in their fields. Burning of stalks increases CO2, CO, N2O and NOx in the atmosphere which leads to increase in air pollution. Instead of burning the stalks in fields, cotton stalks have the potential to be used for ex-situ application such as, raw material for briquettes due to its high lignocellulosic nature. Ex-situ utilization cotton stalk aids in generating additional income to farmers. In order to utilize the cotton stalk for ex-situ application a cotton stalk harvester was developed and evaluated in the field conditions which gave the following results; mean chopped length 122.7 mm, bulk density 197.86 kgm-3, fineness modulus 1.828, machine output of 1259.85 kgh-1, chopping height 118.6 mm field capacity 0.17 ha h-1, and fuel consumption of 7.54lh-1.
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Irie, Masao, Masahiro Okada, Yukinori Maruo, Goro Nishigawa, and Takuya Matsumoto. "Shear Bond Strength of Resin Luting Materials to Lithium Disilicate Ceramic: Correlation between Flexural Strength and Modulus of Elasticity." Polymers 15, no. 5 (2023): 1128. http://dx.doi.org/10.3390/polym15051128.
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This study investigates the effect of the curing mode (dual-cure vs. self-cure) of resin cements (four self-adhesive and seven conventional cements) on their flexural strength and flexural modulus of elasticity, alongside their shear bond strength to lithium disilicate ceramics (LDS). The study aims to determine the relationship between the bond strength and LDS, and the flexural strength and flexural modulus of elasticity of resin cements. Twelve conventional or adhesive and self-adhesive resin cements were tested. The manufacturer’s recommended pretreating agents were used where indicated. The shear bond strengths to LDS and the flexural strength and flexural modulus of elasticity of the cement were measured immediately after setting, after one day of storage in distilled water at 37 °C, and after 20,000 thermocycles (TC 20k). The relationship between the bond strength to LDS, flexural strength, and flexural modulus of elasticity of resin cements was investigated using a multiple linear regression analysis. For all resin cements, the shear bond strength, flexural strength, and flexural modulus of elasticity were lowest immediately after setting. A clear and significant difference between dual-curing and self-curing modes was observed in all resin cements immediately after setting, except for ResiCem EX. Regardless of the difference of the core-mode condition of all resin cements, flexural strengths were correlated with the LDS surface upon shear bond strengths (R2 = 0.24, n = 69, p < 0.001) and the flexural modulus of elasticity was correlated with them (R2 = 0.14, n = 69, p < 0.001). Multiple linear regression analyses revealed that the shear bond strength was 17.877 + 0.166, the flexural strength was 0.643, and the flexural modulus was (R2 = 0.51, n = 69, p < 0.001). The flexural strength or flexural modulus of elasticity may be used to predict the bond strength of resin cements to LDS.
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Clayton, Zachary S., Vienna E. Brunt, David A. Hutton, et al. "Tumor Necrosis Factor Alpha-Mediated Inflammation and Remodeling of the Extracellular Matrix Underlies Aortic Stiffening Induced by the Common Chemotherapeutic Agent Doxorubicin." Hypertension 77, no. 5 (2021): 1581–90. http://dx.doi.org/10.1161/hypertensionaha.120.16759.
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Aortic stiffening is a major independent risk factor for cardiovascular diseases, kidney dysfunction, and cognitive impairment. Doxorubicin chemotherapy-treated cancer survivors have greater aortic stiffness relative to healthy controls, but the mechanisms by which doxorubicin induces arterial stiffening are unknown. We tested the hypothesis that doxorubicin increases aortic stiffness by increasing intrinsic mechanical wall stiffness due to proinflammatory signaling-induced adverse structural changes, including collagen deposition (fibrosis), elastin fragmentation, and formation of AGEs (advanced glycation end products). In vivo aortic stiffness (assessed via aortic pulse wave velocity), aortic intrinsic wall stiffness (ex vivo assessment of elastic modulus), and potential underlying mechanisms were assessed 4 weeks after administration of doxorubicin (10 mg/kg) or vehicle (saline) in young adult male C57BL6/J mice. Aortic pulse wave velocity increased by ~30% following doxorubicin (pre: 341±18 versus post: 431±28 cm/s, mean±SEM, P =0.001) and aortic elastic modulus was ~100% higher following doxorubicin (5438±445 kPa) versus vehicle (2659±433 kPa; P =0.003). These effects of doxorubicin were associated with an ~3-fold greater formation of AGEs ( P =0.01) and an ~50% reduction in elastin ( P =0.01), whereas collagen deposition was unaffected. Doxorubicin increased aortic proinflammatory cytokines ( P =0.03) without a compensatory increase in the anti-inflammatory cytokine interleukin-10. Direct ex vivo exposure of aorta rings to doxorubicin mimicked the increase in aortic elastic modulus observed in vivo with doxorubicin, whereas TNF-α (tumor necrosis factor-α) inhibition prevented this response. Doxorubicin induces aortic stiffening in vivo due, in part, to an increase in intrinsic wall stiffness associated with elastin degradation and AGEs formation and mediated by TNF-α-dependent vascular inflammation.
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Danielsson, Jennifer, Aisha S. Kuforiji, Gene T. Yocum, et al. "Agonism of the TMEM16A calcium-activated chloride channel modulates airway smooth muscle tone." American Journal of Physiology-Lung Cellular and Molecular Physiology 318, no. 2 (2020): L287—L295. http://dx.doi.org/10.1152/ajplung.00552.2018.
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TMEM16A (anoctamin 1) is an important calcium-activated chloride channel in airway smooth muscle (ASM). We have previously shown that TMEM16A antagonists such as benzbromarone relax ASM and have proposed TMEM16A antagonists as novel therapies for asthma treatment. However, TMEM16A is also expressed on airway epithelium, and TMEM16A agonists are being investigated as novel therapies for cystic fibrosis. There are theoretical concerns that agonism of TMEM16A on ASM could lead to bronchospasm, making them detrimental as airway therapeutics. The TMEM16A agonist Eact induced a significant contraction of human ASM and guinea pig tracheal rings in an ex vivo organ bath model. Pretreatment with two different TMEM16A antagonists, benzbromarone or T16Ainh-A01, completely attenuated these Eact-induced contractions. Pretreatment with Eact alone augmented the maximum acetylcholine contraction. Pretreatment of A/J mice in vivo with nebulized Eact caused an augmentation of methacholine-induced increases in airway resistance measured by the forced oscillatory technique (flexiVent). Pretreatment with the TMEM16A antagonist benzbromarone significantly attenuated methacholine-induced increases in airway resistance. In in vitro cellular studies, TMEM16A was found to be expressed more abundantly in ASM compared with epithelial cells in culture (8-fold higher in ASM). Eact caused an increase in intracellular calcium in human ASM cells that was completely attenuated by pretreatment with benzbromarone. Eact acutely depolarized the plasma membrane potential of ASM cells, which was attenuated by benzbromarone or nifedipine. The TMEM16A agonist Eact modulates ASM contraction in both ex vivo and in vivo models, suggesting that agonism of TMEM16A may lead to clinically relevant bronchospasm.
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Barbian, Hannah J., Melanie S. Seaton, Srinivas D. Narasipura та ін. "β-catenin regulates HIV latency and modulates HIV reactivation". PLOS Pathogens 18, № 3 (2022): e1010354. http://dx.doi.org/10.1371/journal.ppat.1010354.
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Latency is the main obstacle towards an HIV cure, with cure strategies aiming to either elicit or prevent viral reactivation. While these strategies have shown promise, they have only succeeded in modulating latency in a fraction of the latent HIV reservoir, suggesting that the mechanisms controlling HIV latency are not completely understood, and that comprehensive latency modulation will require targeting of multiple latency maintenance pathways. We show here that the transcriptional co-activator and the central mediator of canonical Wnt signaling, β-catenin, inhibits HIV transcription in CD4+ T cells via TCF-4 LTR binding sites. Further, we show that inhibiting the β-catenin pathway reactivates HIV in a primary TCM cell model of HIV latency, primary cells from cART-controlled HIV donors, and in CD4+ latent cell lines. β-catenin inhibition or activation also enhanced or inhibited the activity of several classes of HIV latency reversing agents, respectively, in these models, with significant synergy of β-catenin and each LRA class tested. In sum, we identify β-catenin as a novel regulator of HIV latency in vitro and ex vivo, adding new therapeutic targets that may be combined for comprehensive HIV latency modulation in HIV cure efforts.
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Tornabene, Susan P., Angelo Iatridis, David Wesbrook, Robert Dyga, and Mark Miller. "Clinical Evaluation of a New Pump Interface Module (PIM) Safety Device." Journal of ExtraCorporeal Technology 20 (1988): 41–43. http://dx.doi.org/10.1051/ject/198820s041.
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The Pump Interface Module (PIM) is a new safety device intended to be used in conjunction with a Cobe Air Emboli Protection System (AEPS) and a roller or centrifugal pump. The PIM is a relay device that upon receiving an alarm signal from the AEPS, interrupts line voltage, thus stopping the arterial pump. The purpose of this clinical trial was to verify the utility and user advantages of the PIM when employed with a variety of pumps. The study first involved ex vivo tests using the bovine model. These tests looked at different AEPS positioning, different blood flows, and simulation of a variety of clinical conditions. The clinical study evaluated the PIM using five different types of pumps during 160 open heart procedures. The pumps used were a Cinco (n = 28), Sarns 5000 (n = 47), Sarns 7000 (n = 33), Biomedicus 520 (n = 27), and Biomedicus 540 (n = 25). In all instances the PIM immediately stopped the arterial pump when an alarm signal was received from the AEPS system. The PIM is an effective and practical safety device for use with the tested pumps.
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Broxmeyer, Hal E., Ferdinand Kappas, Nirit Mor-Vaknin, et al. "DEK Regulates Hematopoietic Stem Engraftment and Progenitor Cell Proliferation." Blood 118, no. 21 (2011): 1275. http://dx.doi.org/10.1182/blood.v118.21.1275.1275.
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Abstract Abstract 1275 Hematopoiesis is regulated by cell-cell and cytokine-cell interactions on hematopoietic stem (HSCs) and progenitor (HPCs) cells. In our continuing efforts to elucidate players involved in regulation of HSC and HPC growth, we focused on DEK, an abundant and unusual protein found in multicellular organisms. DEK has two DNA binding modules and has some affinity for specific DNA sequences, but primarily recognizes and binds to superhelical and cruciform DNA and induces positive supercoiling. DEK manifests multiple cellular activities, which include transcriptional repression and activation, mRNA processing, and chromatin architectural functions. We recently demonstrated that DEK modulates global heterochromatin integrity in vivo. Interestingly, DEK, can leave the cell and act as a chemoattractant for CD8+T cells and natural killer cells. Being intrigued that a nuclear protein was able to be secreted by hematopoietic cells, and act on other hematopoietic cells, we hypothesized that DEK might play a role in HSC/HPC function and hematopoiesis. In order to determine if DEK had an effect on steady state hematopoiesis, BM and spleen cells from DEK −/− mice were compared to that of wildtype (WT) control mice for absolute numbers and cycling status of HPC. Absolute numbers of CFU-GM, BFU-E, and CFU-GEMM per femur and per spleen were increased in DEK −/− mice. These effects were consistent with significantly increased percentages of HPCs in S-Phase of the cell cycle in DEK −/− BM and spleen, suggesting that DEK acts as a negative regulator of HPC proliferation in vivo. To confirm this, recombinant human DEK was tested for effects on HPC proliferation using unseparated mouse BM and low density human CB cells. DEK, dose-dependently suppressed colony formation by mouse BM CFU-GM stimulated by either IL-3 or GM-CSF, each alone; it did not influence colony formation stimulated by M-CSF alone. However, it dose-dependently inhibited CFU-GM colony formation by either IL-3, GM-CSF, or M-CSF when these cytokines were combined with the potent co-stimulating cytokine SCF. In fact, inhibition by DEK was greater on CFU-GM stimulated by the combination of IL-3, GM-CSF or M-CSF, each in the presence of SCF, compared to CFU-GM stimulated by IL-3, GM-CSF or M-CSF each alone in terms of percent inhibition, as well as the amount of DEK required to inhibit colony formation. Similar results were noted for HPCs present in human CB. This suggests that immature subsets of HPCs are more sensitive in vitro to the suppressive effects of DEK, than are the more mature HPCs. To determine if the DEK effects were directly or indirectly manifesting on the HPCs, DEK was assessed for effects on single isolated CD34+ cord blood cells, each in a single well stimulated by EPO, GM-CSF, IL-3, and SCF. DEK significantly decreased the number of wells containing a CFU-GM-, BFU-E-, or CFU-GEM- colony, demonstrating that DEK initiates it's suppressive effect directly on HPC. Using a mouse competitive repopulating HSC assay in vivo, allows assessment of the short- and longer-term repopulating HSC, and transplantation of BM cells from primary to secondary lethally-irradiated recipients in a non-competitive assay describes the longer-term repopulating HSC, and can offer information on the self-renewal capacity of this population of HSCs. While there was no difference in the HSC repopulating capacity of DEK −/− and WT shorter-term repopulating cells (months 1 and 2 for blood chimerism), there was a significant decrease in DEK −/− compared to WT BM cell repopulation at month 4 in the blood, and month 6 in the BM. This decreased repopulation of DEK −/− compared to WT HSC was even more apparent in secondary mouse recipients suggesting that DEK played a positive role in engraftment of longer-term repopulating HSCs, and perhaps in the self-renewal capacity of mouse BM HSCs. These studies demonstrate a here-to-fore unknown role for DEK in the regulation of HPCs, HSCs and hematopoiesis. DEK could have separate effects on HPC and HSC, as suggested by the direct acting effects of DEK on single HPC. Alternatively, DEK may alone, or in addition allow HSC to favor a self-renewal, vs. a differentiation pathway to HPC. Thus, DEK has potent effects on HSCs, HPCs, and hematopoiesis, and may be of potential clinical value for enhancing HSC activity/proliferation in vivo, or in an ex-vivo situation. Disclosures: No relevant conflicts of interest to declare.