Journal articles on the topic 'Herec a prostor'

ABSTRACT Sporulation of Saccharomyces cerevisiae is a developmental process in which four haploid spores are generated inside a diploid cell. Gip1, a sporulation-specific targeting subunit of protein phosphatase type 1, together with its catalytic subunit, Glc7, colocalizes with septins along the extending prospore membrane and is required for septin organization and spore wall formation. However, the mechanism by which Gip1-Glc7 phosphatase promotes these events is unclear. We show here that Ysw1, a sporulation-specific coiled-coil protein, has a functional relationship to Gip1-Glc7 phosphatase. Overexpression of YSW1 partially suppresses the sporulation defect of a temperature-sensitive allele of gip1. Ysw1 interacts with Gip1 in a two-hybrid assay, and this interaction is required for suppression. Ysw1 tagged with green fluorescent protein colocalizes with septins and Gip1 along the extending prospore membrane during spore formation. Sporulation is partially defective in ysw1Δ mutant, and cytological analysis revealed that septin structures are perturbed and prospore membrane extension is aberrant in ysw1Δ cells. These results suggest that Ysw1 functions with the Gip1-Glc7 phosphatase to promote proper septin organization and prospore membrane formation.

Summary Maciej Urbanowski has published here hitherto unknown letters to Kazimierz Wyka by Stanisław Piasecki and Włodzimierz Pietrzak, written in 1935-1938. Their correspondence adds a new insight into what we know of the life of Kazimierz Wyka, one of the most outstanding 20thcentury Polish critics and literary scholars. The letters take us right behind the scenes of the failed attempts to recruit Wyka’s pen for “Prosto z mostu”, the leading periodical of the literary right in interwar Poland. The generational literary and political sensitivities which Wyka and the writers gathered round Piasecki’s weekly had in common were not enough, as Urbanowski argues, to overcome his more fundamental reservations. Wyka thought highly of some of the contributors of “Prosto z mostu”, but was put off by the paper’s nationalist ideological line. Nonetheless, Piasecki’s and Pietrzak’s letters give us a sense of the complex pattern of inner differences and divisions that characterized the new literary generation of the 1930s.

ABSTRACT Spore formation in Saccharomyces cerevisiae occurs via the de novo synthesis of the prospore membrane during the second meiotic division. Prospore membrane formation is triggered by assembly of a membrane-organizing center, the meiotic outer plaque (MOP), on the cytoplasmic face of the spindle pole body (SPB) during meiosis. We report here the identification of two new components of the MOP, Ady4p and Spo74p. Ady4p and Spo74p interact with known proteins of the MOP and are localized to the outer plaque of the SPB during meiosis II. MOP assembly and prospore membrane formation are abolished in spo74Δ/spo74Δ cells and occur aberrantly in ady4Δ/ady4Δ cells. Spo74p and the MOP component Mpc70p are mutually dependent for recruitment to SPBs during meiosis. In contrast, both Ady4p and Spo74p are present at SPBs, albeit at reduced levels, in cells that lack the MOP component Mpc54p. Our findings suggest a model for the assembled MOP in which Mpc54p, Mpc70p, and Spo74p make up a core structural unit of the scaffold that initiates synthesis of the prospore membrane, and Ady4p is an auxiliary component that stabilizes the plaque.

Abstract Spore formation in Saccharomyces cerevisiae requires the de novo synthesis of prospore membranes and spore walls. Ady3p has been identified as an interaction partner for Mpc70p/Spo21p, a meiosis-specific component of the outer plaque of the spindle pole body (SPB) that is required for prospore membrane formation, and for Don1p, which forms a ring-like structure at the leading edge of the prospore membrane during meiosis II. ADY3 expression has been shown to be induced in midsporulation. We report here that Ady3p interacts with additional components of the outer and central plaques of the SPB in the two-hybrid assay. Cells that lack ADY3 display a decrease in sporulation efficiency, and most ady3Δ/ady3Δ asci that do form contain fewer than four spores. The sporulation defect in ady3Δ/ady3Δ cells is due to a failure to synthesize spore wall polymers. Ady3p forms ring-like structures around meiosis II spindles that colocalize with those formed by Don1p, and Don1p rings are absent during meiosis II in ady3Δ/ady3Δ cells. In mpc70Δ/mpc70Δ cells, Ady3p remains associated with SPBs during meiosis II. Our results suggest that Ady3p mediates assembly of the Don1p-containing structure at the leading edge of the prospore membrane via interaction with components of the SPB and that this structure is involved in spore wall formation.

94 Background: The PROSPER trial demonstrated prolonged MFS and OS for men with nmCRPC and rapidly rising PSA treated with ENZA vs placebo, both in combination with androgen deprivation therapy (ADT). The final survival analysis of PROSPER (Sternberg et al. NEJM 2020) recently reported a median OS of 67.0 months (95% CI, 64.0 to not reached) with ENZA and 56.3 months (95% CI, 54.4 to 63.0) with placebo (hazard ratio [HR] for death, 0.73; 95% CI, 0.61 to 0.89; P = .001). Post hoc analyses of PROSPER evaluating PSA dynamics have demonstrated longer MFS with greater PSA decline (Hussain et al. ESMO Sept 19-21, 2020. Poster 685P) and increased risk of metastases in patients with even modest PSA progression vs those without (Saad et al. Eur Urol 2020). Here we further explored the relationship between PSA dynamics and outcomes in PROSPER using uniquely defined PSA subgroups of decline. Methods: Eligible men in PROSPER had nmCRPC, a PSA level ≥ 2 ng/mL at baseline, and a PSA doubling time ≤ 10 months. Men continued ADT, were randomized 2:1 to ENZA 160 mg once daily vs placebo, and had PSA evaluation at week 17 and every 16 weeks thereafter. This post hoc analysis evaluated OS and MFS for 4 mutually exclusive subgroups defined by PSA nadir using men with PSA reduction < 50% as the reference group. The HR is based on an unstratified Cox proportional hazards analysis model. Results: 1401 men were enrolled in PROSPER; 933 were treated with ENZA and PSA data were available for 905. Measured at nadir, 38% of these men achieved PSA reduction ≥ 90% (actual nadir < 0.2 ng/mL), and another 27% achieved PSA reduction ≥ 90% (actual nadir ≥ 0.2 ng/mL). Among men in the placebo arm of PROSPER only 3/457 reported PSA reduction ≥ 90%. Median OS and MFS increased with increasing depth of PSA decline (Table). Conclusions: In men with nmCRPC and rapidly rising PSA treated with ADT plus ENZA, there was a close relationship between the degree of PSA decline and survival outcomes. Defining PSA by both percent decline and actual decline below 0.2 ng/mL revealed a previously under-appreciated relationship between these PSA metrics and highlights the importance of PSA nadir as an intermediate biomarker in nmCRPC. Clinical trial information: NCT02003924. [Table: see text]

ABSTRACT SPS1 encodes a sporulation-specific protein with homology to the Ste20/p21-activated kinase family. Deletion of SPS1 impinges on the formation of the spore wall, which surrounds each of the haploid nuclei generated by the meiotic divisions. Here, we demonstrate that the new internal membranes that surround the meiotic nuclei appear normal in the absence of Sps1p. Analyses of spore wall layers by immunohistochemistry suggest that the inner layers are not efficiently deposited. The defect in spore wall morphogenesis is most likely a consequence of mislocalization of enzymes required for the synthesis of the spore wall layers as both Chs3p, the major chitin synthase in yeast, and Gsc2/Fks2p, a glucan synthase transcriptionally upregulated during sporulation, fail to reach the prospore membrane in the sps1 mutant. Furthermore, localization of Chs3p to the prospore membrane is not dependent on Shc1p, a sporulation-specific homolog of Chs4p, which is required for recruitment of Chs3p to the bud neck in vegetative cells. Sps1p colocalized with Chs3p to peripheral and internal punctate structures and prospore membranes. We propose that Sps1p promotes sporulation, in part, by regulating the intracellular movement of proteins required for spore wall formation.

Membrane contact sites are regulated through the controlled recruitment of constituent proteins. Yeast vacuolar protein sorting 13 (Vps13) dynamically localizes to membrane contact sites at endosomes, vacuoles, mitochondria, and the endoplasmic reticulum under different cellular conditions and is recruited to the prospore membrane during meiosis. Prior to our recent work, the mechanism for localization at contact sites was largely unknown. We identified Ypt35 as a novel Vps13 adaptor for endosomes and the nucleus-vacuole junction. Furthermore, we discovered a conserved recruitment motif in Ypt35 and found related motifs in the prospore membrane and mitochondrial adaptors, Spo71 and Mcp1, respectively. All three adaptors compete for binding to a six-repeat region of Vps13, suggesting adaptor competition regulates Vps13 localization. Here, we summarize and discuss the implications of our work, highlighting key outstanding questions.

Autophagy is a process of cellular self-degradation in which portions of the cytoplasm are sequestered within cytosolic double-membrane vesicles and delivered to the lysosome/vacuole. This process occurs in all eukaryotic cells and is partly a stress response; autophagy is induced during starvation and hypoxia. However, autophagy also plays a role during development and is associated with a range of diseases. Accumulating data also suggest the involvement of autophagy in aging. For example, the role of various hormones and nutrient sensing pathways in life span extension may involve autophagy. Similarly, autophagy is the primary mechanism for removing damaged organelles, such as mitochondria, which may have a direct impact on aging. Here, we review the role of autophagy, with an emphasis on the signaling pathways that are involved in regulation, and the consequences of autophagy induction with regard to aging.

Sporulation of Saccharomyces cerevisiae is a developmental process in which a single cell is converted into four haploid spores. GIP1, encoding a developmentally regulated protein phosphatase 1 interacting protein, is required for spore formation. Here we show that GIP1 and the protein phosphatase 1 encoded by GLC7 play essential roles in spore development. The gip1Δ mutant undergoes meiosis and prospore membrane formation normally, but is specifically defective in spore wall synthesis. We demonstrate that in wild-type cells, distinct layers of the spore wall are deposited in a specific temporal order, and that gip1Δ cells display a discrete arrest at the onset of spore wall deposition. Localization studies revealed that Gip1p and Glc7p colocalize with the septins in structures underlying the growing prospore membranes. Interestingly, in the gip1Δ mutant, not only is Glc7p localization altered, but septins are also delocalized. Similar phenotypes were observed in a glc7–136 mutant, which expresses a Glc7p defective in interacting with Gip1p. These results indicate that a Gip1p–Glc7p phosphatase complex is required for proper septin organization and initiation of spore wall formation during sporulation.

Objective: For Gleason Score (GS) 3+3:6 prostate cancer (PC) cases, recent guidelines recommend clinical follow-up instead of radical treatment due to complications. One of the most important disadvantages of clinical follow-up is that low-grade PC may include local aggressive behavior. Hence, our aim here was to investigate the incidence of extraprostatic extension (EPE), a local aggressive behavior, in GS6 PC cases. Material and Methods: We examined 119 materials diagnosed with prostatic adenocarcinoma (GS 3+3:6) with no tertiary pattern and that were sent to our department as radical prostatectomy materials between January 2010 – May 2019. We investigated how many of the materials had EPE. Results: We observed EPE in 16 (13.45%) of our cases. 5 of the cases had vesicula seminalis invasion (pT3b) and 11 had EPE and/or bladder neck invasion (pT3a) without vesicula seminalis invasion. Conclusion: Among our patients diagnosed with GS-6 PC, we observed EPE (pT3) in 13.45% and vesicula seminalis invasion (pT3b) in 4.2%, which suggests that the possibility of EPE is not uncommon in GS-6 PC. Based on these findings, we argue that patients with GS-6 PC under clinical follow-up should be followed more carefully for EPE. Keywords: prostate cancer; gleason score; extraprostatic extension

Abstract STUDY QUESTION Can the Poor Responder Outcome Prediction (PROsPeR) score identify live birth outcomes in subpopulations of patients with poor ovarian response (POR) defined according to the ESHRE Bologna criteria (female age, anti-Müllerian hormone (AMH), number of oocytes retrieved during the previous cycle (PNO) after treatment with originator recombinant human follitropin alfa? SUMMARY ANSWER The PROsPeR score discriminated the probability of live birth in patients with POR using observational data with fair discrimination (AUC ≅ 70%) and calibration, and the AUC losing less than 5% precision compared with a model developed using the observational data. WHAT IS KNOWN ALREADY Although scoring systems for the likelihood of live birth after ART have been developed, their accuracy may be insufficient, as they have generally been developed in the general population with infertility and were not validated for patients with POR. The PROsPeR score was developed using data from the follitropin alfa (GONAL-f; Merck KGaA, Darmstadt, Germany) arm of the Efficacy and Safety of Pergoveris in Assisted Reproductive Technology (ESPART) randomized controlled trial (RCT) and classifies women with POR as mild, moderate or severe, based upon three variables: female age, serum AMH level and number of oocytes retrieved during the previous cycle (PNO). STUDY DESIGN, SIZE, DURATION The external validation of the PROsPeR score was completed using data derived from eight different centres in France. In addition, the follitropin alfa data from the ESPART RCT, originally used to develop the PROsPeR score, were used as reference cohort. The external validation of the PROsPeR score l was assessed using AUC. A predetermined non-inferiority limit of 0.10 compared with a reference sample and calibration (Hosmer–Lemeshow test) were the two conditions required for evaluation. PARTICIPANTS/MATERIALS, SETTING, METHODS The observational cohort included data from 8085 ART treatment cycles performed with follitropin alfa in patients with POR defined according to the ESHRE Bologna criteria (17.6% of the initial data set). The ESPART cohort included 477 ART treatment cycles with ovarian stimulation performed with follitropin alfa in patients with POR. MAIN RESULTS AND THE ROLE OF CHANCE The external validation of the PROsPeR score to identify subpopulations of women with POR with different live birth outcomes was shown in the observational cohort (AUC = 0.688; 95% CI: 0.662, 0.714) compared with the ESPART cohort (AUC = 0.695; 95% CI: 0.623, 0.767). The AUC difference was −0.0074 (95% CI: −0.083, 0.0689). This provided evidence, with 97.5% one-sided confidence, that there was a maximum estimated loss of 8.4% in discrimination between the observational cohort and the ESPART cohort, which was below the predetermined margin of 10%. The Hosmer–Lemeshow test did not reject the calibration when comparing observed and predicted data (Hosmer–Lemeshow test = 1.266688; P = 0.260). LIMITATIONS, REASONS FOR CAUTION The study was based on secondary use of data that had not been collected specifically for the analysis reported here and the number of characteristics used to classify women with POR was limited to the available data. The data were from a limited number of ART centres in a single country, which may present a bias risk; however, baseline patient data were similar to other POR studies. WIDER IMPLICATIONS OF THE FINDINGS This evaluation of the PROsPeR score using observational data supports the notion that the likelihood of live birth may be calculated with reasonable precision using three readily available pieces of data (female age, serum AMH and PNO). The PROsPeR score has potential to be used to discriminate expected probability of live birth according to the degree of POR (mild, moderate, severe) after treatment with follitropin alfa, enabling comparison of performance at one centre over time and the comparison between centres. STUDY FUNDING/COMPETING INTEREST(S) This analysis was funded by Merck KGaA, Darmstadt, Germany. P.L. received grants from Merck KGaA, outside of the submitted work. N.M. reports grants, personal fees and non-financial support from Merck KGaA outside the submitted work. T.D.H. is Vice President and Head of Global Medical Affairs Fertility, Research and Development at Merck KGaA, Darmstadt, Germany. P.A. has received personal fees from Merck KGaA, Darmstadt, Germany, outside the submitted work. C.R. has received grants and personal fees from Gedeon Richter and Merck Serono S.A.S., France, an affiliate of Merck KGaA, Darmstadt, Germany, outside the submitted work. P.S. reports congress support from Merck Serono S.A.S., France (an affiliate of Merck KGaA, Darmstadt, Germany), Gedeon Richter, TEVA and MDS outside the submitted work. C.A., J.P., G.P. and R.W. declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A

COVID-19 pandemic has disrupted the Indian agricultural system extensively. Nevertheless, the recent quarterly GDP estimates post-COVID scenario showcase robustness and resilience in Indian agriculture, the only sector to register a positive growth of 3.4% during the financial year (FY here after) 2020–21 (Quarter 1: April 2020 to June 2020). At the same time, the immediate past quarter growth was estimated at 5.9% witnessing a decline by 2.5% point. In this context, we aim to synthesize the early evidence of the COVID-19 impact on the Indian agricultural system viz., production, marketing and consumption followed by a set of potential strategies to recover and prosper post-pandemic. Survey findings indicate that the pandemic has affected production and marketing through labour and logistical constraints, while the negative income shock restricted access to markets and increased prices of food commodities affecting the consumption pattern. The pandemic wreaked a substantial physical, social, economic and emotional havoc on all the stakeholders of Indian agricultural system. Seizing the crisis as an opportunity, the state announced a raft of measures and long-pending reforms. We propose a 10-point strategy ranging from social safety nets, family farming, monetizing buffer stock, staggered procurement to secondary agriculture to revive and prosper post-pandemic.

84 Background: Previous reports on the PROSPER trial have shown that enzalutamide (ENZA) plus androgen deprivation therapy (ADT) significantly improves metastasis-free survival and overall survival (OS) over placebo (PBO) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) and rapidly rising prostate-specific antigen (PSA) levels. (Hussain et al. N Engl J Med. 2018;378:2465-2474/Sternberg et al. N Engl J Med. 2020;382:2197-2206). To inform decision-making for specific patients, we report here a post hoc analysis of OS and safety in subgroups of PROSPER by age and region. Methods: PROSPER included men with nmCRPC and a PSA doubling time ≤ 10 months. Enrolled men continued ADT and were randomized 2:1 to ENZA 160 mg once daily vs PBO. We performed a multivariable analysis for OS, including age (≤ 70 yrs and > 70 yrs), geographic region, and other variables and further examined exposure-adjusted adverse events (AEs) by age and region. Results: Based on this post hoc analysis, OS benefit with ENZA treatment was similar across geographic regions (table) and for patients aged ≥ 70 yrs (hazard ratio [HR] 0.73; 95% CI 0.58-0.9) and those aged < 70 yrs (HR 0.72, 95% CI 0.5-1.04). In our multivariate analysis, 3 factors emerged as significantly impacting estimated OS: Eastern Cooperative Oncology Group (ECOG) performance status (1 vs 0; HR 1.7; 95% CI 1.4-2.1), log of PSA (HR 1.2; 95% CI 1.1-1.3), and use of subsequent therapy (yes vs no; HR 2.5; 95% CI 2.1-3.1). Overall safety was consistent between age groups and across geographic regions. The proportion of patients reporting any grade treatment-emergent AEs (TEAEs) related to ENZA use was similar between age groups but decreased with increasing age. Conclusions: In men with nmCRPC and rapidly rising PSA, ENZA plus ADT treatment reduced the risk of death, regardless of age or geographic location. Patients reported any grade TEAEs at a similar proportion in both arms. Variables impacting OS included ECOG status, log PSA, and subsequent therapy. Clinical trial information: NCT02003924. [Table: see text]

Kin selection theory defines the conditions for which altruism or ‘helping’ can be favoured by natural selection. Tests of this theory in cooperatively breeding animals have focused on the short-term benefits to the recipients of help, such as improved growth or survival to adulthood. However, research on early-life effects suggests that there may be more durable, lifelong fitness impacts to the recipients of help, which in theory should strengthen selection for helping. Here, we show in cooperatively breeding banded mongooses ( Mungos mungo ) that care received in the first 3 months of life has lifelong fitness benefits for both male and female recipients. In this species, adult helpers called ‘escorts’ form exclusive one-to-one caring relationships with specific pups (not their own offspring), allowing us to isolate the effects of being escorted on later reproduction and survival. Pups that were more closely escorted were heavier at sexual maturity, which was associated with higher lifetime reproductive success for both sexes. Moreover, for female offspring, lifetime reproductive success increased with the level of escorting received per se , over and above any effect on body mass. Our results suggest that early-life social care has durable benefits to offspring of both sexes in this species. Given the well-established developmental effects of early-life care in laboratory animals and humans, we suggest that similar effects are likely to be widespread in social animals more generally. We discuss some of the implications of durable fitness benefits for the evolution of intergenerational helping in cooperative animal societies, including humans. This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine’.

ABSTRACT The de novo formation of multilayered spore walls inside a diploid mother cell is a major landmark of sporulation in the yeast Saccharomyces cerevisiae. Synthesis of the dityrosine-rich outer spore wall takes place toward the end of this process. Bisformyl dityrosine, the major building block of the spore surface, is synthesized in a multistep process in the cytoplasm of the prospores, transported to the maturing wall, and polymerized into a highly cross-linked macromolecule on the spore surface. Here we present evidence that the sporulation-specific protein Dtr1p (encoded by YBR180w) plays an important role in spore wall synthesis by facilitating the translocation of bisformyl dityrosine through the prospore membrane. DTR1 was identified in a genome-wide screen for spore wall mutants. The null mutant accumulates unusually large amounts of bisformyl dityrosine in the cytoplasm and fails to efficiently incorporate this precursor into the spore surface. As a result, many mutant spores have aberrant surface structures. Dtr1p, a member of the poorly characterized DHA12 (drug:H+ antiporter with 12 predicted membrane spans) family, is localized in the prospore membrane throughout spore maturation. Transport by Dtr1p may not be restricted to its natural substrate, bisformyl dityrosine. When expressed in vegetative cells, Dtr1p renders these cells slightly more resistant against unrelated toxic compounds, such as antimalarial drugs and food-grade organic acid preservatives. Dtr1p is the first multidrug resistance protein of the major facilitator superfamily with an assigned physiological role in the yeast cell.

Archaea often thrive in environmental extremes, enduring levels of heat, pressure, salinity, pH, and radiation that prove intolerable to most life. Many environmental extremes raise the propensity for DNA damaging events and thus, impact DNA stability, placing greater reliance on molecular mechanisms that recognize DNA damage and initiate accurate repair. Archaea can presumably prosper in harsh and DNA-damaging environments in part due to robust DNA repair pathways but surprisingly, no DNA repair pathways unique to Archaea have been described. Here, we review the most recent advances in our understanding of archaeal DNA repair. We summarize DNA damage types and their consequences, their recognition by host enzymes, and how the collective activities of many DNA repair pathways maintain archaeal genomic integrity.

Both protease- and reactive oxygen species (ROS)-mediated proteolysis are thought to be key effectors of tissue remodeling. We have previously shown that comparison of amino acid composition can predict the differential susceptibilities of proteins to photo-oxidation. However, predicting protein susceptibility to endogenous proteases remains challenging. Here, we aim to develop bioinformatics tools to (i) predict cleavage site locations (and hence putative protein susceptibilities) and (ii) compare the predicted vulnerabilities of skin proteins to protease- and ROS-mediated proteolysis. The first goal of this study was to experimentally evaluate the ability of existing protease cleavage site prediction models (PROSPER and DeepCleave) to identify experimentally determined MMP9 cleavage sites in two purified proteins and in a complex human dermal fibroblast-derived extracellular matrix (ECM) proteome. We subsequently developed deep bidirectional recurrent neural network (BRNN) models to predict cleavage sites for 14 tissue proteases. The predictions of the new models were tested against experimental datasets and combined with amino acid composition analysis (to predict ultraviolet radiation (UVR)/ROS susceptibility) in a new web app: the Manchester proteome susceptibility calculator (MPSC). The BRNN models performed better in predicting cleavage sites in native dermal ECM proteins than existing models (DeepCleave and PROSPER), and application of MPSC to the skin proteome suggests that: compared with the elastic fiber network, fibrillar collagens may be susceptible primarily to protease-mediated proteolysis. We also identify additional putative targets of oxidative damage (dermatopontin, fibulins and defensins) and protease action (laminins and nidogen). MPSC has the potential to identify potential targets of proteolysis in disparate tissues and disease states.

Pentecostalism in Africa has evolved as different streams characterized by particular modes of articulating the Christian message. The older independent churches were known for their emphasis on healing and prophecy and the classical Pentecostals talked much about speaking in tongues and holiness. Although these themes are present in contemporary Pentecostal discourse the new churches are best known for their messages of empowerment and prosperity that are meant to address the aspirations of Africa’s upwardly mobile youth. Using the writings of two of the movements most influential leaders from Ghana, this article discusses the ways in which the story of the Patriarchs, especially Jacob, has been reinterpreted to fit into the message of upward mobility and the principles that are meant to lead up to it. It is argued here that although the authors did not intend to misapply Scripture, by reinterpreting the schemes of Jacob in terms of the principles of success, they fail to take account of the element of ‘grace’ which is able to turn the worst of sinners into saints. Jacob did not succeed because he applied the principles of success but because God touched him with his grace during the time of wrestling with the angel.

Vps13 family proteins are proposed to function in bulk lipid transfer between membranes, but little is known about their regulation. During sporulation of Saccharomyces cerevisiae, Vps13 localizes to the prospore membrane (PSM) via the Spo71–Spo73 adaptor complex. We previously reported that loss of any of these proteins causes PSM extension and subsequent sporulation defects, yet their precise function remains unclear. Here, we performed a genetic screen and identified genes coding for a fragment of phosphatidylinositol (PI) 4-kinase catalytic subunit and PI 4-kinase noncatalytic subunit as multicopy suppressors of spo73Δ. Further genetic and cytological analyses revealed that lowering PI4P levels in the PSM rescues the spo73Δ defects. Furthermore, overexpression of VPS13 and lowering PI4P levels synergistically rescued the defect of a spo71Δ spo73Δ double mutant, suggesting that PI4P might regulate Vps13 function. In addition, we show that an N-terminal fragment of Vps13 has affinity for the endoplasmic reticulum (ER), and ER-plasma membrane (PM) tethers localize along the PSM in a manner dependent on Vps13 and the adaptor complex. These observations suggest that Vps13 and the adaptor complex recruit ER-PM tethers to ER-PSM contact sites. Our analysis revealed that involvement of a phosphoinositide, PI4P, in regulation of Vps13, and also suggest that distinct contact site proteins function cooperatively to promote de novo membrane formation.

Animal cooperation has puzzled biologists for a long time as its existence seems to contravene the basic notion of evolutionary biology that natural selection favours ‘selfish’ genes that promote only their own well-being. Evolutionary game theory has shown that cooperators can prosper in populations of selfish individuals if they occur in clusters, interacting more frequently with each other than with the selfish. Here we show that social networks of primates possess the necessary social structure to promote the emergence of cooperation. By simulating evolutionary dynamics of cooperative behaviour on interaction networks of 70 primate groups, we found that for most groups network reciprocity augmented the fixation probability for cooperation. The variation in the strength of this effect can be partly explained by the groups’ community modularity—a network measure for the groups’ heterogeneity. Thus, given selective update and partner choice mechanisms, network reciprocity has the potential to explain socially learned forms of cooperation in primate societies.

Smk1 is a meiosis-specific MAPK that controls spore wall morphogenesis in Saccharomyces cerevisiae. Although Smk1 is activated by phosphorylation of the threonine (T) and tyrosine (Y) in its activation loop, it is not phosphorylated by a dual-specificity MAPK kinase. Instead, the T is phosphorylated by the cyclin-dependent kinase (CDK)–activating kinase, Cak1. The Y is autophosphorylated in an intramolecular reaction that requires a meiosis-specific protein named Ssp2. The meiosis-specific CDK-like kinase, Ime2, was previously shown to positively regulate Smk1. Here we show that Ime2 activity is required to induce the translation of SSP2 mRNA at anaphase II. Ssp2 protein is then localized to the prospore membrane, the structure where spore wall assembly takes place. Next the carboxy-terminal portion of Ssp2 forms a complex with Smk1 and stimulates the autophosphorylation of its activation-loop Y residue. These findings link Ime2 to Smk1 activation through Ssp2 and define a developmentally regulated mechanism for activating MAPK at specific locations in the cell.

During meiosis II in the yeast Saccharomyces cerevisiae, the cytoplasmic face of the spindle pole body changes from a site of microtubule initiation to a site of de novo membrane formation. These membranes are required to package the haploid meiotic products into spores. This functional change in the spindle pole body involves the expansion and modification of its cytoplasmic face, termed the outer plaque. We report here that SPO21is required for this modification. The Spo21 protein localizes to the spindle pole in meiotic cells. In the absence of SPO21the structure of the outer plaque is abnormal, and prospore membranes do not form. Further, decreased dosage of SPO21 leaves only two of the four spindle pole bodies competent to generate membranes. Mutation of CNM67, encoding a known component of the mitotic outer plaque, also results in a meiotic outer plaque defect but does not block membrane formation, suggesting that Spo21p may play a direct role in initiating membrane formation.

Every person is surrounded by different things with various time of consumption. The most of people sees a product life cycle from a marketing point of view. The product has got to prosper on the market place and to earn money for the organisation and to be cheap for the customer. However, the market has changed dramatically. Organisations have not adapted on these conditions yet. The article tries to assess different views on the product life cycle according to publications. The need of an adjustment of the product life cycle is described here with regard to the process approach in management systems of organisations. Another resource of knowledge for products is based on years of observation of the nature. There are also discussed general requirements for the product from a common domestic customer. The goal of this article is to contribute to a new approach to the product life cycle, which includes all these aspects. Products have to get closer to the concept of the sustainable living as a way overcoming of the crisis. They can not be conceived only grossly economically.

ABSTRACTGram-positive bacteria naturally produce extracellular vesicles. However, little is known regarding the functions of Gram-positive bacterial extracellular vesicles, especially in the bacterial community. Here, we investigated the role ofStaphylococcus aureusextracellular vesicles in interbacterial communication to cope with antibiotic stress. We found thatS. aureusliberated BlaZ, a β-lactamase protein, via extracellular vesicles. These extracellular vesicles enabled other ampicillin-susceptible Gram-negative and Gram-positive bacteria to survive in the presence of ampicillin. However,S. aureusextracellular vesicles did not mediate the survival of tetracycline-, chloramphenicol-, or kanamycin-susceptible bacteria. Moreover,S. aureusextracellular vesicles did not contain theblaZgene. In addition, the heat-treatedS. aureusextracellular vesicles did not mediate the survival of ampicillin-susceptible bacteria. The β-lactamase activities ofS. aureussoluble and extracellular vesicle-associated BlaZ were similar, but only the extracellular vesicle-associated BlaZ was resistant to protease digestion, which suggests that the enzymatic activity of BlaZ in extracellular vesicles is largely protected by the vesicle structure. Our observations provide evidence of the important role ofS. aureusextracellular vesicles in antibiotic resistance, which allows the polymicrobial community to continue to evolve and prosper against antibiotics.

Septin complexes display remarkable plasticity in subunit composition, yet how a new subunit assembled into higher-order structures confers different functions is not fully understood. Here, this question is addressed in budding yeast, where during meiosis Spr3 and Spr28 replace the mitotic septin subunits Cdc12 and Cdc11 (and Shs1), respectively. In vitro, the sole stable complex that contains both meiosis-specific septins is a linear Spr28–Spr3–Cdc3–Cdc10–Cdc10–Cdc3–Spr3–Spr28 hetero-octamer. Only coexpressed Spr3 and Spr28 colocalize with Cdc3 and Cdc10 in mitotic cells, indicating that incorporation requires a Spr28-Spr3 protomer. Unlike their mitotic counterparts, Spr28-Spr3–capped rods are unable to form higher-order structures in solution but assemble to form long paired filaments on lipid monolayers containing phosphatidylinositol-4,5-bisphosphate, mimicking presence of this phosphoinositide in the prospore membrane. Spr28 and Spr3 fail to rescue the lethality of a cdc11Δ cdc12Δ mutant, and Cdc11 and Cdc12 fail to restore sporulation proficiency to spr3Δ/spr3Δ spr28Δ/spr28Δ diploids. Thus, specific meiotic and mitotic subunits endow septin complexes with functionally distinct properties.

Smk1 is a meiosis-specific MAP kinase (MAPK) in budding yeast that is required for spore formation. It is localized to prospore membranes (PSMs), the structures that engulf haploid cells during meiosis II (MII). Similar to canonically activated MAPKs, Smk1 is controlled by phosphorylation of its activation-loop threonine (T) and tyrosine (Y). However, activation loop phosphorylation occurs via a noncanonical two-step mechanism in which 1) the cyclin-dependent kinase activating kinase Cak1 phosphorylaytes T207 during MI, and 2) Smk1 autophosphorylates Y209 as MII draws to a close. Autophosphorylation of Y209 and catalytic activity for substrates require Ssp2, a meiosis-specific protein that is translationally repressed until anaphase of MII. Ama1 is a meiosis-specific targeting subunit of the anaphase-promoting complex/cyclosome that regulates multiple steps in meiotic development, including exit from MII. Here, we show that Ama1 activates autophosphorylation of Smk1 on Y209 by promoting formation of the Ssp2/Smk1 complex at PSMs. These findings link meiotic exit to Smk1 activation and spore wall assembly.

Abstract The European climate and energy framework for 2030 is highlighting the reduction of man-made CO2 by increasing the use of renewable energy to mitigate climate change. In this spirit, Germany has decided to erase the coal use as an energy source by 2038 completely. Inevitably, this strategy promises a feasible, responsible, and sustainable post-mining management, because 200 years of coal mining have created numerous challenges necessary to tend to once the mining ends. Thus, the Research Institute for Post-Mining (FZN) at the TH Georg Agricola University in Bochum, Germany, has developed a holistic approach to meet these post-mining challenges including further expertise present at our university. Here, the four strategic research pillars are (1) technical geoecology and hydrogeology to avoid and mitigate risks underground, (2) geomonitoring to evaluate and protect the surface, (3) industrial heritage preservation and engineering to secure and reuse brownfields such as mine sites, and (4) economic transformation planning of mining regions to enable a prosper future for generations to come. In all efforts, we aim to achieve the fundamental goals of the UN to deal with the resources of our planet responsibly and sustainably. Furthermore, we are synergizing increasingly with national and international networks in the interest of social, economic, and environmental stakeholders.

5515 Background: PROSPER previously demonstrated a statistically significant and clinically meaningful improvement in metastasis-free survival (MFS) (hazard ratio [HR] 0.29; 95% CI 0.24-0.35; P < .001) in men with nmCRPC and rapidly rising prostate-specific antigen (PSA) who received ENZA. When first reported, OS was immature with only 165 of 596 (28%) prespecified deaths. Here we report results from the final OS analysis. Methods: Men with nmCRPC, PSA doubling time ≤ 10 mo, and PSA ≥ 2 ng/mL at screening continued androgen deprivation therapy (ADT) and were randomized 2:1 to ENZA 160 mg or PBO. OS treatment effect was assessed using a group sequential testing procedure with O’Brien-Fleming-type alpha spending function ( P ≤ .021 required for statistical significance). Medians were estimated using the Kaplan-Meier method; 95% CIs using a stratified Cox regression model. Results: As of Oct 15, 2019 (median follow-up ≈ 48 mo), there were 466 deaths (288 [30.9%] and 178 [38.0%] in the ENZA and PBO arms, respectively). ENZA significantly prolonged OS compared with PBO (HR 0.73; 95% CI 0.61-0.89; P = .0011). Median OS was 67.0 mo (95% CI 64.0-not reached) in the ENZA arm and 56.3 mo (95% CI 54.4-63.0) in the PBO arm. Subsequent antineoplastic therapies were initiated after treatment discontinuation by 310 (33%) men in the ENZA arm vs 303 (65%) in the PBO arm. Median duration of treatment was 33.9 mo vs 14.2 mo with ENZA vs PBO, respectively. Grade ≥ 3 adverse events (AEs) were reported by 48% of men in the ENZA arm vs 27% in the PBO arm (16% vs 6% were drug related, respectively). AEs with event rates per 100 patient-yr that were ≥ 2 points higher with ENZA vs PBO were falls (9 vs 4), fatigue (14 vs 12), and hypertension (7 vs 5). Conclusions: ENZA treatment resulted in a statistically significant 27% reduced risk of death compared with PBO, demonstrating that initiation of ENZA + ADT before the onset of detectable metastasis improves OS in men with CRPC and rapidly rising PSA. This OS benefit ensues despite crossover from the PBO arm to ENZA and higher rates of subsequent antineoplastic therapies in men from the PBO arm. Safety was consistent with previous clinical trials. This final OS analysis from PROSPER provides prospective validation of MFS as a potential surrogate endpoint for OS in nmCRPC and supports the continued use of ENZA + ADT as a standard of care in men with nmCRPC and rapidly rising PSA. Clinical trial information: NCT02003924 .

These medication errors have occurred in health care facilities at least once. They will happen again—perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them at your inservice training programs. Your assistance is required to continue this feature. The reports described here were received through the Institute for Safe Medication Practices (ISMP) Medication Errors Reporting Program. Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below. Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMP Web site ( www.ismp.org ), by calling 800-FAIL-SAFE, or via e-mail at ismpinfo@ismp.org . ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications.

The village innovation program is here to increase community productivity and economic independence and is ready to build competitive resources. This articile aims, i.e: 1) to identify the process of developing the village innovation program in the three villages of Serang district, 2) to analyze the effectiveness of the existing village innovation program in Serang district, and 3) to determine the process of developing the Village Innovation Program Desa Innovation in three villages in Serang district. The collection of data and information sources is carried out using primary and secondary methods. Qualitative collection is carried out through Focus Group Discussion (FGD) techniques, and in-depth interviews, especially to parties or actors who are directly involved in the Village Innovation Program (Program Inovasi Desa/PID), FGD and in-depth interviews were conducted with several members who had long been members of the farmer groups. Likewise, the role of village local assistants is important in assisting the community in carrying out this program in order to prosper the community's economy. The results of this study state that the implementation of the Village Innovation Program for the community explains that the priority of farmer groups in this village innovation program will increase the market scale with a weight of 0.27 and market scale results with a weight of 0.26, and the Consistency Index (CI) of 0.04 with Consistency Ratio (CR) 0.90, this states that farmer groups prioritize market scale results.

185 Background: Men with nonmetastatic castration-resistant prostate cancer (nmCRPC) are at high risk of developing metastatic CRPC. In the primary analysis of PROSPER, enzalutamide (ENZA) provided a statistically significant and clinically meaningful improvement in metastasis-free survival (MFS) in men with nmCRPC. Here we report the impact of prior therapy on MFS. Methods: Eligible men with nmCRPC, prostate-specific antigen (PSA) doubling time ≤ 10 months, and PSA ≥ 2 ng/mL at screening continued androgen deprivation therapy and were randomized 2:1 to ENZA 160 mg or placebo (PBO). The primary endpoint was MFS. Results: 1401 men were enrolled, with a median age of 74 y (range, 50-95 y). In all men, ENZA reduced the risk of metastasis or death by 71% (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.24-0.35; P < .0001). The treatment effect consistently favored ENZA regardless of whether men had prior bilateral orchiectomy, prior radiation, ≤1 or > 1 prior hormonal therapy, or prior bone-targeting therapy (Table). Men who received > 1 prior hormonal therapy had a shorter median MFS than those who received ≤1 line of hormonal therapy (5 months and 3 months in the ENZA and PBO groups, respectively). Conclusions: In men with nmCRPC and rapidly rising PSA, ENZA treatment resulted in a clinically meaningful reduction in the risk of developing metastases or death irrespective of prior surgery, radiation, or bone-targeting therapy. MFS was longer in men who had received ≤1 prior hormonal therapy. Clinical trial information: NCT02003924. [Table: see text]

It is now common to study the Enlightenment ‘in national context’, and in few cases has the approach been more fertile than in the study of the Scottish Enlightenment. The danger of this approach, however, is that it deflects attention from the international connections of the Enlightenment, fragmenting the movement as a whole. It is argued here that the Enlightenment is better understood as an intellectual movement which was both cosmopolitan and patriotic, and that this is particularly evident in its commitment to political economy, as the key to improving the human condition in this world. The argument is developed through a comparison of Scottish and Neapolitan political economy from the mid- to the later eighteenth century. Though set apart by very different economic circumstances, the Scots and the Neapolitans had a common point of reference in French economic writings, and through these Hume's ideas in particular were transmitted to Naples. It was from within this common intellectual framework that the Scots and the Neapolitans elaborated their distinctive positions on the scope for free trade between nations. If Hume and Smith believed that poor countries such as Scotland would prosper through greater free trade, while Genovesi and Galiani argued that only by measures of protection could the abundant natural resources of the kingdom of Naples be harnessed to its benefit, their differences derived from shared premises, and a comparable fear of the inclination of the leading mercantile powers, Britain and France, to control trade to their sole advantage.

Law No. 6 of 2014 on Villages, provides an important position for the village to play its role in development. The important role of the village is the local authority possessed by the village in managing its household. Village economy is one of the important factors in assessing the success of village development. The village economic problems need to be solved by handling thoroughly, starting from the construction of infrastructure facilities, to developing the potential of the village to be optimized into opportunities for business opportunities that prosper the village community. Village Owned Enterprises, here in after referred to as BUMDes, become one of the important mandates contained in the Village Law. BUMDes urgency is affirmed in Permendesa number 4 of 2015. The context of BUMDes establishment is expected to be the driving force of the village economy, meaning that the establishment of BUMDes is not merely an orientation to the profit of the institution, but the more essence is the establishment of BUMDes should be able to provide both economic and social benefits to villagers.The type of this research is descriptive qualitative, with the aim to identify and analyze the feasibility aspects of BUMDes business in terms of social and economic aspects. The results showed that BUMDesIjen Lestari Tamansarivillage District of Banyuwangi gave positive impacts economically and socially for the villagers like directly or indirectly. BUMDes's main business sector engaged in tourism management has an impact for residents around Ijen region, in the form of additional income from multiplayer tourism effects. The direct impact of BUMDes employees' involvement in the management of activities and community involvement in BUMDes businesses such as local food producers packed with BUMDes and community-based homestay managers.Keywords: BUMDes, Social Aspect, Economic Aspect, Banyuwangi

Tujuan penulisan artikel ini adalah untuk menganalisis pendidikan seni teater Ethiopia sebagai bentuk seni kreatif. Di Ethiopia, seni teater baru terbentuk tahun 1978, yang hingga sekarang belum menunjukkan kemajuannya. Kurikulum pendidikan seni teater di Ethiopia belum terlihat baik, dalam arti masih terdapat kekurangan di sana sini, sehingga sampai sekarang masih perlu penyempurnaan. Pendidikan seni teater ditopang oleh jurusan seni yang lain di Universitas Addis Ababa. Hal ini menyebabkan aspek musik, tari, seni rupa, dan seni kriya ikut membentuk terbentuknya pendidikan seni teater. Sekarang, pendidikan seni teater disuntik dengan seni teater tradisional yang menyebabkan bentuknya menjadi seni kreatif namun tidak menunjukkan teater yang mapan. Setiap teater di Ethiopia memilih bahan baku untuk memakmurkan pendidikan seni teater yang sekarang sedang digarap dalam kurikulum pendidikan seni teater Ethiopia. Kata Kunci: teater, pendidikan seni, kurikulum, senikreatif, Ethiopia CURRICULUM ANALYSIS OF THETHEATRE ARTS EDUCATION DEPARTMENT IN ETHIOPIA Abstract The purpose of this article is to analyze the theatrearts education in Ethiopia as a form of creative arts. In Ethiopia, the new theatrearts were formed in 1978, which until now has not shown significant progress. There are still shortages here and there in the curriculum for theatre arts education in Ethiopia, so that it still needs improvement. Theatre education is supported by other art majors at Addis Ababa University. This has caused aspects of music, dance, visual arts, and art to form the formation of theatrearts education. Now, the theatrearts education isinjected with traditional theatre arts, causing their form to become creative arts but not showing established theatre. Likewise, theatre arts in Ethiopia choose raw materials to prosper the theatrearts education which is now being worked on in the Ethiopian theatre arts education curriculum. Keywords: theatre, arts education, curriculum, creative arts, Ethiopia

An account of desire as a species of belief may owe its appeal to the details of its proposal as to precisely what sort of beliefs desires are to be identified with, and its downfall may be due to those details it does provide. For example, it may be proposed that the desire that α is in fact the belief that it ought to be that α, or is morally good or desirable that it should be the case that α. Here the appeal might be that of forging a link between the holding of a moral belief and the acknowledgment that one has a reason for acting a certain way; and the shortcoming of the suggestion is its evident implausibility: even if the ‘necessity’ direction could be established, having a desire hardly seems sufficient for the holding of any such belief. Again: it might be proposed, perhaps simply to bring some order into the realm of propositional attitudes by reducing some to others, that the belief with which we should identify a’s desire that α is a’s belief that he will or would be happy if α. This proposed identification can be seen to be incorrect by consideration of examples such as the following, due to J. Gosling. An aging and ailing parent might forego numerous pleasures in order that his children should reap the benefits of his saving and have a good start in life – perhaps by receiving an expensive education – after his impending death. Oearly he may want that they should so benefit even if he does not believe in an after-death existence in which he might come to know of, and so take pleasure in, his children’s subsequent well-being. So his wanting that they should prosper cannot consist in his believing that he will be happy if/when they do, since he has no expectation of even being in existence in that eventuality. As Gosling puts it, there is a clear difference (illustrable with far less dramatic examples than this one) between thinking that something’s coming about will bring one pleasure, on the one hand, and viewing the prospect of its coming about with pleasure, on the other.

Abstract. The branched vs. isoprenoid index of tetraethers (BIT index) in Lake Challa sediments has been applied as a monsoon precipitation proxy on the assumption that the primary source of branched tetraether lipids (brGDGTs) was soil washed in from the lake's catchment. However, water column production has since been identified as the primary source of brGDGTs in Lake Challa, meaning that there is no longer a clear mechanism linking BIT index variation and precipitation. Here we investigate BIT index variation and GDGT concentrations at a decadal resolution over the past 2200 years, in combination with GDGT data from profundal surface sediments and 45 months of sediment-trap deployment. The 2200 year record reveals high-frequency variability in GDGT concentrations, and therefore the BIT index. Also surface sediments collected in January 2010 show a distinct shift in GDGT composition relative to those collected in August 2007. Increased bulk flux of settling particles with high Ti / Al ratios during March–April 2008 reflect an event of high detrital input to Lake Challa, concurrent with intense precipitation at the onset of the principal rain season that year. Although brGDGT distributions in the settling material are initially unaffected, this soil erosion event is succeeded by a large diatom bloom in July–August 2008 and a concurrent increase in GDGT-0 fluxes. Near-zero crenarchaeol fluxes indicate that no thaumarchaeotal bloom developed during the subsequent austral summer season; instead a peak in brGDGT fluxes is observed in December 2008. We suggest that increased nutrient availability, derived from eroded soil washed into the lake, stimulated both diatom productivity and the GDGT-0 producing archaea which help decompose dead diatoms passing through the suboxic zone of the water column. This disadvantaged the Thaumarchaeota that normally prosper during the following austral summer. Instead, a bloom of supposedly heterotrophic brGDGT-producing bacteria occurred. Episodic recurrence of such high soil-erosion events, integrated over multi-decadal and longer timescales and possibly enhanced by other mechanisms generating low BIT index values in dry years, can explain the positive relationship between the sedimentary BIT index and monsoon precipitation at Lake Challa. However, application elsewhere requires ascertaining the local situation of lacustrine brGDGT production and of variables affecting the productivity of Thaumarchaeota.

In general, cities have developed and expanded in places where natural and environmental conditions were the most favourable, and they can only continue to prosper by conserving the natural resources that are the drivers of their wealth and quality of life. Four out of five European citizens live in urban areas and the quality of life is greatly influenced by the urban environment. Here, gardens, parks and green open spaces improve air quality and reduce the impact of stormwater events by reducing the value of the runoff coefficient; they offer lower temperatures in hot urban islands and represent habitats for biodiversity. Gardens in many cities, such as our case study of Coimbra, were initially built for decorative, architectural, and leisure purposes, or with specific academic goals in mind, but their size or urban relevance often made them important factors in city planning and resources' sustainability, as well as for the wellbeing of their citizens. Sustainable water management in urban areas involves promoting rational water use, and also the identification of strategic reserves to deal with droughts when they occur. By improving the management of the urban water cycle as a whole a more efficient use of resources can be achieved, providing not only economic benefits but also improving social and environmental outcomes. Because water is a limited and scarce resource it must be used in gardens in an efficient and sustainable way. For this reason grasses, trees, shrubs and flower beds must be provided only with enough water to satisfy their needs. Using the Landscape Coefficient Formula, the amount of water needed for irrigation can be expressed as a percentage of reference evapotranspiration (ET0). The value of evapotranspiration should be adjusted to best meet the water demands of a given assortment of plant species. In this paper we present a study performed at the Botanical Garden of the University of Coimbra (BGUC). Monthly and annual levels of precipitation were evaluated along with the air temperature and evapotranspiration to determine the climatological water balance through water shortages and surpluses. The results were compared with the levels of water consumption (from the water supply and spring water collector) and the efficiency of irrigation was assessed, adjusted for plant type, enabling the identification of procedures and opportunities to maximize the efficient use and sustainable management of water.

51 Background: The landscape of M0 CRPC has changed with the recent demonstration of metastasis-free survival (MFS) and overall survival (OS) improvements with the use of ARPIs in clinical trial settings. However, the extrapolation of this data to clinical practice is limited by strict exclusion criteria in these trials, including prior or concurrent malignancy, cardiovascular disease, or hypertension. The purpose of this study was to assess real-world outcomes in patients with M0 CRPC treated with ARPIs compared to historical controls. Methods: We designed a retrospective cohort study with the inclusion of patients in Alberta, Canada diagnosed with M0 CRPC between 2001-2020. Via chart review, we identified baseline characteristics, potential confounders, treatment details, and clinical outcomes. The primary outcome of interest was MFS. Secondary outcomes included: second progression-free survival (PFS2) and OS. Median survival times were measured using the Kaplan-Meier method and the log-rank test was used for comparison of outcomes based on ARPI exposure. Cox proportional hazard regression models were used to calculate hazard ratios (HR) accounting for impact of PSA doubling time (PSADT), use of osteoclast inhibiting agents, and presence of pelvic lymphadenopathy. Results: We identified 211 patients across multiple centres in Alberta with M0 CRPC, with 54 having received apalutamide (40/54), enzalutamide (7/54), or darolutamide (7/54). Median age at M0 CRPC diagnosis was 74 years; median PSADT was 4.4 months; and 19% of patients (40/211) had pelvic lymphadenopathy at diagnosis. Median MFS in patients treated with ARPIs was 47.5 months compared to 20.6 months in those not treated with ARPIs (HR, 0.23; 95% confidence interval [CI], 0.11-0.49; p < 0.001). Median PFS2 in ARPI treated patients was 66.3 months compared with 35.6 months (HR, 0.40; 95% CI, 0.18-0.87; p = 0.022). Median OS for patients treated with ARPI was not reached. Conclusions: Given the older age of men with advanced prostate cancer, real-world outcomes that include patients with comorbidities are important adjuncts to the interpretation of clinical trials exploring the benefit of novel therapeutics. Here, we demonstrate that in a real-world, unselected population of men with M0 CRPC, apalutamide, enzalutamide, and darolutamide seem to confer similar MFS and PFS2 benefits to those demonstrated in the SPARTAN, PROSPER, and ARAMIS studies. Real-world OS data remain immature and will be an important addition to these findings.

A checklist of world species of Microgastrinae parasitoid wasps (Hymenoptera: Braconidae) is provided. A total of 81 genera and 2,999 extant species are recognized as valid, including 36 nominal species that are currently considered as species inquirendae. Two genera are synonymized under Apanteles. Nine lectotypes are designated. A total of 318 new combinations, three new replacement names, three species name amendments, and seven species status revised are proposed. Additionally, three species names are treated as nomina dubia, and 52 species names are considered as unavailable names (including 14 as nomina nuda). A total of three extinct genera and 12 extinct species are also listed. Unlike in many previous treatments of the subfamily, tribal concepts are judged to be inadequate, so genera are listed alphabetically. Brief diagnoses of all Microgastrinae genera, as understood in this paper, are presented. Illustrations of all extant genera (at least one species per genus, usually more) are included to showcase morphological diversity. Primary types of Microgastrinae are deposited in 108 institutions worldwide, although 76% are concentrated in 17 collections. Localities of primary types, in 138 countries, are reported. Recorded species distributions are listed by biogeographical region and by country. Microgastrine wasps are recorded from all continents except Antarctica; specimens can be found in all major terrestrial ecosystems, from 82°N to 55°S, and from sea level up to at least 4,500 m a.s.l. The Oriental (46) and Neotropical (43) regions have the largest number of genera recorded, whereas the Palaearctic region (28) is the least diverse. Currently, the highest species richness is in the Palearctic region (827), due to more historical study there, followed by the Neotropical (768) and Oriental (752) regions, which are expected to be the most species rich. Based on ratios of Lepidoptera and Microgastrinae species from several areas, the actual world diversity of Microgastrinae is expected to be between 30,000–50,000 species; although these ratios were mostly based on data from temperate areas and thus must be treated with caution, the single tropical area included had a similar ratio to the temperate ones. Almost 45,000 specimens of Microgastrinae from 67 different genera (83% of microgastrine genera) have complete or partial DNA barcode sequences deposited in the Barcode of Life Data System; the DNA barcodes represent 3,545 putative species or Barcode Index Numbers (BINs), as estimated from the molecular data. Information on the number of sequences and BINs per genus are detailed in the checklist. Microgastrinae hosts are here considered to be restricted to Eulepidoptera, i.e., most of the Lepidoptera except for the four most basal superfamilies (Micropterigoidea, Eriocranioidea, Hepialoidea and Nepticuloidea), with all previous literature records of other insect orders and those primitive Lepidoptera lineages being considered incorrect. The following nomenclatural acts are proposed: 1) Two genera are synonymyzed under Apanteles: Cecidobracon Kieffer & Jörgensen, 1910, new synonym and Holcapanteles Cameron, 1905, new synonym; 2) Nine lectotype designations are made for Alphomelon disputabile (Ashmead, 1900), Alphomelon nigriceps (Ashmead, 1900), Cotesia salebrosa (Marshall, 1885), Diolcogaster xanthaspis (Ashmead, 1900), Dolichogenidea ononidis (Marshall, 1889), Glyptapanteles acraeae (Wilkinson, 1932), Glyptapanteles guyanensis (Cameron, 1911), Glyptapanteles militaris (Walsh, 1861), and Pseudapanteles annulicornis Ashmead, 1900; 3) Three new replacement names are a) Diolcogaster aurangabadensis Fernandez-Triana, replacing Diolcogaster indicus (Rao & Chalikwar, 1970) [nec Diolcogaster indicus (Wilkinson, 1927)], b) Dolichogenidea incystatae Fernandez-Triana, replacing Dolichogenidea lobesia Liu & Chen, 2019 [nec Dolichogenidea lobesia Fagan-Jeffries & Austin, 2019], and c) Microplitis vitobiasi Fernandez-Triana, replacing Microplitis variicolor Tobias, 1964 [nec Microplitis varicolor Viereck, 1917]; 4) Three names amended are Apanteles irenecarrilloae Fernandez-Triana, 2014, Cotesia ayerzai (Brèthes, 1920), and Cotesia riverai (Porter, 1916); 5) Seven species have their status revised: Cotesia arctica (Thomson, 1895), Cotesia okamotoi (Watanabe, 1921), Cotesia ukrainica (Tobias, 1986), Dolichogenidea appellator (Telenga, 1949), Dolichogenidea murinanae (Capek & Zwölfer, 1957), Hypomicrogaster acarnas Nixon, 1965, and Nyereria nigricoxis (Wilkinson, 1932); 6) New combinations are given for 318 species: Alloplitis congensis, Alloplitis detractus, Apanteles asphondyliae, Apanteles braziliensis, Apanteles sulciscutis, Choeras aper, Choeras apollion, Choeras daphne, Choeras fomes, Choeras gerontius, Choeras helle, Choeras irates, Choeras libanius, Choeras longiterebrus, Choeras loretta, Choeras recusans, Choeras sordidus, Choeras stenoterga, Choeras superbus, Choeras sylleptae, Choeras vacillatrix, Choeras vacillatropsis, Choeras venilia, Cotesia asavari, Cotesia bactriana, Cotesia bambeytripla, Cotesia berberidis, Cotesia bhairavi, Cotesia biezankoi, Cotesia bifida, Cotesia caligophagus, Cotesia cheesmanae, Cotesia compressithorax, Cotesia delphinensis, Cotesia effrena, Cotesia euphobetri, Cotesia elaeodes, Cotesia endii, Cotesia euthaliae, Cotesia exelastisae, Cotesia hiberniae, Cotesia hyperion, Cotesia hypopygialis, Cotesia hypsipylae, Cotesia jujubae, Cotesia lesbiae, Cotesia levigaster, Cotesia lizeri, Cotesia malevola, Cotesia malshri, Cotesia menezesi, Cotesia muzaffarensis, Cotesia neptisis, Cotesia nycteus, Cotesia oeceticola, Cotesia oppidicola, Cotesia opsiphanis, Cotesia pachkuriae, Cotesia paludicolae, Cotesia parbhanii, Cotesia parvicornis, Cotesia pratapae, Cotesia prozorovi, Cotesia pterophoriphagus, Cotesia radiarytensis, Cotesia rangii, Cotesia riverai, Cotesia ruficoxis, Cotesia senegalensis, Cotesia seyali, Cotesia sphenarchi, Cotesia sphingivora, Cotesia transuta, Cotesia turkestanica, Diolcogaster abengouroui, Diolcogaster agama, Diolcogaster ambositrensis, Diolcogaster anandra, Diolcogaster annulata, Diolcogaster bambeyi, Diolcogaster bicolorina, Diolcogaster cariniger, Diolcogaster cincticornis, Diolcogaster cingulata, Diolcogaster coronata, Diolcogaster coxalis, Diolcogaster dipika, Diolcogaster earina, Diolcogaster epectina, Diolcogaster epectinopsis, Diolcogaster grangeri, Diolcogaster heterocera, Diolcogaster homocera, Diolcogaster indica, Diolcogaster insularis, Diolcogaster kivuana, Diolcogaster mediosulcata, Diolcogaster megaulax, Diolcogaster neglecta, Diolcogaster nigromacula, Diolcogaster palpicolor, Diolcogaster persimilis, Diolcogaster plecopterae, Diolcogaster plutocongoensis, Diolcogaster psilocnema, Diolcogaster rufithorax, Diolcogaster semirufa, Diolcogaster seyrigi, Diolcogaster subtorquata, Diolcogaster sulcata, Diolcogaster torquatiger, Diolcogaster tristiculus, Diolcogaster turneri, Diolcogaster vulcana, Diolcogaster wittei, Distatrix anthedon, Distatrix cerales, Distatrix cuspidalis, Distatrix euproctidis, Distatrix flava, Distatrix geometrivora, Distatrix maia, Distatrix tookei, Distatrix termina, Distatrix simulissima, Dolichogenidea agamedes, Dolichogenidea aluella, Dolichogenidea argiope, Dolichogenidea atreus, Dolichogenidea bakeri, Dolichogenidea basiflava, Dolichogenidea bersa, Dolichogenidea biplagae, Dolichogenidea bisulcata, Dolichogenidea catonix, Dolichogenidea chrysis, Dolichogenidea coffea, Dolichogenidea coretas, Dolichogenidea cyane, Dolichogenidea diaphantus, Dolichogenidea diparopsidis, Dolichogenidea dryas, Dolichogenidea earterus, Dolichogenidea ensiger, Dolichogenidea eros, Dolichogenidea evadne, Dolichogenidea falcator, Dolichogenidea gelechiidivoris, Dolichogenidea gobica, Dolichogenidea hyalinis, Dolichogenidea iriarte, Dolichogenidea lakhaensis, Dolichogenidea lampe, Dolichogenidea laspeyresiella, Dolichogenidea latistigma, Dolichogenidea lebene, Dolichogenidea lucidinervis, Dolichogenidea malacosomae, Dolichogenidea maro, Dolichogenidea mendosae, Dolichogenidea monticola, Dolichogenidea nigra, Dolichogenidea olivierellae, Dolichogenidea parallelis, Dolichogenidea pelopea, Dolichogenidea pelops, Dolichogenidea phaenna, Dolichogenidea pisenor, Dolichogenidea roepkei, Dolichogenidea scabra, Dolichogenidea statius, Dolichogenidea stenotelas, Dolichogenidea striata, Dolichogenidea wittei, Exoryza asotae, Exoryza belippicola, Exoryza hylas, Exoryza megagaster, Exoryza oryzae, Glyptapanteles aggestus, Glyptapanteles agynus, Glyptapanteles aithos, Glyptapanteles amenophis, Glyptapanteles antarctiae, Glyptapanteles anubis, Glyptapanteles arginae, Glyptapanteles argus, Glyptapanteles atylana, Glyptapanteles badgleyi, Glyptapanteles bataviensis, Glyptapanteles bistonis, Glyptapanteles borocerae, Glyptapanteles cacao, Glyptapanteles cadei, Glyptapanteles cinyras, Glyptapanteles eryphanidis, Glyptapanteles euproctisiphagus, Glyptapanteles eutelus, Glyptapanteles fabiae, Glyptapanteles fulvigaster, Glyptapanteles fuscinervis, Glyptapanteles gahinga, Glyptapanteles globatus, Glyptapanteles glyphodes, Glyptapanteles guierae, Glyptapanteles horus, Glyptapanteles intricatus, Glyptapanteles lamprosemae, Glyptapanteles lefevrei, Glyptapanteles leucotretae, Glyptapanteles lissopleurus, Glyptapanteles madecassus, Glyptapanteles marquesi, Glyptapanteles melanotus, Glyptapanteles melissus, Glyptapanteles merope, Glyptapanteles naromae, Glyptapanteles nepitae, Glyptapanteles nigrescens, Glyptapanteles ninus, Glyptapanteles nkuli, Glyptapanteles parasundanus, Glyptapanteles penelope, Glyptapanteles penthocratus, Glyptapanteles philippinensis, Glyptapanteles philocampus, Glyptapanteles phoebe, Glyptapanteles phytometraduplus, Glyptapanteles propylae, Glyptapanteles puera, Glyptapanteles seydeli, Glyptapanteles siderion, Glyptapanteles simus, Glyptapanteles speciosissimus, Glyptapanteles spilosomae, Glyptapanteles subpunctatus, Glyptapanteles thespis, Glyptapanteles thoseae, Glyptapanteles venustus, Glyptapanteles wilkinsoni, Hypomicrogaster samarshalli, Iconella cajani, Iconella detrectans, Iconella jason, Iconella lynceus, Iconella pyrene, Iconella tedanius, Illidops azamgarhensis, Illidops lamprosemae, Illidops trabea, Keylimepie striatus, Microplitis adisurae, Microplitis mexicanus, Neoclarkinella ariadne, Neoclarkinella curvinervus, Neoclarkinella sundana, Nyereria ituriensis, Nyereria nioro, Nyereria proagynus, Nyereria taoi, Nyereria vallatae, Parapanteles aethiopicus, Parapanteles alternatus, Parapanteles aso, Parapanteles atellae, Parapanteles bagicha, Parapanteles cleo, Parapanteles cyclorhaphus, Parapanteles demades, Parapanteles endymion, Parapanteles epiplemicidus, Parapanteles expulsus, Parapanteles fallax, Parapanteles folia, Parapanteles furax, Parapanteles hemitheae, Parapanteles hyposidrae, Parapanteles indicus, Parapanteles javensis, Parapanteles jhaverii, Parapanteles maculipalpis, Parapanteles maynei, Parapanteles neocajani, Parapanteles neohyblaeae, Parapanteles nydia, Parapanteles prosper, Parapanteles prosymna, Parapanteles punctatissimus, Parapanteles regalis, Parapanteles sarpedon, Parapanteles sartamus, Parapanteles scultena, Parapanteles transvaalensis, Parapanteles turri, Parapanteles xanthopholis, Pholetesor acutus, Pholetesor brevivalvatus, Pholetesor extentus, Pholetesor ingenuoides, Pholetesor kuwayamai, Promicrogaster apidanus, Promicrogaster briareus, Promicrogaster conopiae, Promicrogaster emesa, Promicrogaster grandicula, Promicrogaster orsedice, Promicrogaster repleta, Promicrogaster typhon, Sathon bekilyensis, Sathon flavofacialis, Sathon laurae, Sathon mikeno, Sathon ruandanus, Sathon rufotestaceus, Venanides astydamia, Venanides demeter, Venanides parmula, and Venanides symmysta.

ABSTRACT Prospore membrane formation consists of de novo double-membrane formation, which occurs during the developmental process of sporulation in Saccharomyces cerevisiae. Membranes are formed into their proper size and shape, and thus, prospore membrane formation has been studied as a general model of membrane formation. We identified SPO73, previously shown to be required for spore wall formation, as an additional gene involved in prospore membrane extension. Genetic and cell biological analyses suggested that Spo73 functions on the prospore membrane with other factors in prospore membrane extension, counteracting the bending force of the prospore membrane. Spo73 is the first dysferlin domain-only protein ever analyzed. The dysferlin domain is conserved from yeast to mammals and is found in dysferlin proteins, which are involved in dysferlinopathy, although the precise function of the domain is unknown. Continued analysis of Spo73 will contribute to our understanding of the function of dysferlin domains and dysferlinopathy. Sporulation of Saccharomyces cerevisiae is a developmental process in which an ascus containing four haploid spores forms from a diploid cell. During this process, newly formed membrane structures called prospore membranes extend along the nuclear envelope and engulf and package daughter nuclei along with cytosol and organelles to form precursors of spores. Proteins involved in prospore membrane extension, Vps13 and Spo71, have recently been reported; however, the overall mechanism of membrane extension remains unclear. Here, we identified Spo73 as an additional factor involved in prospore membrane extension. Analysis of a spo73∆ mutant revealed that it shows defects similar to those of a spo71∆ mutant during prospore membrane formation. Spo73 localizes to the prospore membrane, and this localization is independent of Spo71 and Vps13. In contrast, a Spo73 protein carrying mutations in a surface basic patch mislocalizes to the cytoplasm and overexpression of Spo71 can partially rescue localization to the prospore membrane. Similar to spo71∆ mutants, spo73∆ mutants display genetic interactions with the mutations in the SMA2 and SPO1 genes involved in prospore membrane bending. Further, our bioinformatic analysis revealed that Spo73 is a dysferlin domain-only protein. Thus, these results suggest that a dysferlin domain-only protein, Spo73, functions with a dual pleckstrin homology domain protein, Spo71, in prospore membrane extension. Analysis of Spo73 will provide insights into the conserved function of dysferlin domains, which is related to dysferlinopathy. IMPORTANCE Prospore membrane formation consists of de novo double-membrane formation, which occurs during the developmental process of sporulation in Saccharomyces cerevisiae. Membranes are formed into their proper size and shape, and thus, prospore membrane formation has been studied as a general model of membrane formation. We identified SPO73, previously shown to be required for spore wall formation, as an additional gene involved in prospore membrane extension. Genetic and cell biological analyses suggested that Spo73 functions on the prospore membrane with other factors in prospore membrane extension, counteracting the bending force of the prospore membrane. Spo73 is the first dysferlin domain-only protein ever analyzed. The dysferlin domain is conserved from yeast to mammals and is found in dysferlin proteins, which are involved in dysferlinopathy, although the precise function of the domain is unknown. Continued analysis of Spo73 will contribute to our understanding of the function of dysferlin domains and dysferlinopathy.

Prostate cancer (PCa) is the most commonly diagnosed solid organ cancer in men worldwide. Current diagnosis of PCa includes use of initial prostate specific antigen assay which has a high false positive rate, low specificity, and low sensitivity. The side effects of unnecessary prostate biopsies that healthy men are subjected to, often result in unintended health complications. New PCa biomarkers are being discovered to address this unmet need. Here, we report on the creation of a composite score (Prostac) based on three recently discovered PCa biomarkers, Plasmacytoma Variant Translocation 1 (PVT1) exons 4A, 4B, and 9. Statistical analysis of copy numbers derived from a real-time quantitative polymerase chain (qPCR) reaction - based assay, showed these PCa biomarkers to be linearly separable and significantly over expressed in PCa epithelial cells. We train a supervised learning algorithm using support vector machines to generate a classification hyperplane from which a user-friendly composite score is developed. Cross validation of Prostac using data from prostate epithelial cells (RWPE1) and PCa cells (MDA PCa 2b) accurately classified 100% of PCa cells. Creation of the Prostac score lays the groundwork for clinical trial of its use in PCa diagnosis.

This article sets forth the argument that Christian ministry in Africa must become socially and culturally informed and constructed or else it will not touch the African soul and thus remain superficial. Black African people aspire above everything else to experience fullness of life and wellbeing here and now, as demonstrated by their greetings that are actually an enquiry into each other’s health and an expression of the wish for the other’s good health and wellbeing. The mainline churches that operate in Africa should embrace the scripturally sound Christian healing ministry in obedience to Christ’s commission to preach the gospel and heal the sick, if they are to prosper. Hence, this article discusses the following eight points, namely, (1) good health and healing as Africans’ important aspiration, (2) healing as the work of God and thus of the church, (3) the imperative of serious consideration of and respect for the African worldview, (4) membership decline and mainline churches’ loss of influence, (5) rethinking church in African Christianity, (6) the need for the black African church to adopt a therapeutic or healing community ecclesial model in order to position itself strategically to cater for the holistic needs of African (South African) church members and surrounding communities, (7) the rationale of the healing ministry in today’s Reformed Church in Africa and (8) the recommended healing ministry. The article closes with a few concluding statements and advice

The microtubule contribution to myocyte mechanics has been a controversial topic over the years. Utilizing high-speed, super-resolution imaging, we were recently able to directly observe microtubule behavior in working myocytes (Robison et al., Science 2016). Strikingly, we found that microtubules buckle like springs between sarcomeric attachment points, providing a mechanical resistance that limits sarcomere shortening and stretch. Further, we identified that post-translational “detyrosination” of microtubules regulates their attachment to the sarcomere, and thus the microtubule contribution to both passive and active mechanics. Here we present new data identifying microtubule detyrosination as a compelling therapeutic target for the treatment of human heart failure. Using quantitative mass spectrometry, we have probed the cytoskeletal changes that occur during the progression of human heart failure in over 40 patient samples at different stages and etiologies of disease. We find that progressive upregulation and stabilization of the structural cytoskeleton, particularly microtubules and intermediate filaments, is a robust hallmark of human heart failure. Next, we have performed detailed biophysical studies on isolated myocytes from explanted failing and non-failing human hearts. Using advanced imaging, single myocyte tensile tests and atomic force microscopy (e.g. Prosser et al., Science 2011; Robison et al. Science 2016), we have interrogated the contribution of detyrosinated microtubules to the active and passive mechanics of human myocytes. We find that by reducing microtubule detyrosination, we can robustly improve contractile function. Suppressing detyrosination significantly lowers passive stiffness at physiologic rates, while robustly improving contraction velocity, fractional shortening, and relaxation speed. Of note, the improvement in mechanics correlates with the severity of disease, as myocytes from end-stage patients show greater benefits than those from non-failing or compensated hypertrophic hearts. In conclusion, our work demonstrates pre-clinical efficacy for suppressing detyrosinated microtubules to improve myocyte mechanics in human heart failure.

IntroductionThe American artist Ryan Trecartin makes digital videos that centre on the self-presentations common to video-sharing sites such as YouTube. Named by New Yorker critic Peter Schjeldahl as “the most consequential artist to have emerged since the 1980s” (84), Trecartin’s works are like high-octane domestic dramas told in the first-person, blending carnivalesque and horror sensibilities through multi-layered imagery, fast-paced editing, sprawling mise-en-scène installations and heavy-handed digital effects. Featuring narcissistic young-adult characters (many of whom are played by the artist and his friends), Trecartin’s scripted videos portray the self as fundamentally performed and kaleidoscopically mediated. His approach is therefore exemplary of some of the key concepts of automediality, which, although originating in literary studies, address concerns relevant to contemporary art, such as the blurring of life-story, self-performance, identity, persona and technological mediation. I argue that Trecartin’s work is a form of automedial art that combines camp personas with what Sianne Ngai calls the “zany” aesthetics of neoliberalism—the 24/7 production of affects, subjectivity and sociability which complicate distinctions between public and private life.Performing the Script: The Artist as Automedial ProsumerBoth “automedia” and “automediality” hold that the self (the “auto”) and its forms of expression (its “media”) are intimately linked, imbricated within processes of cultural and technological mediation. However, whereas “automedia” refers to general modes of self-presentation, “automediality” was developed by Jörg Dünne and Christian Moser to explicitly relate to the autobiographical. Noting a tendency in literary studies to under-examine how life stories are shaped by their mediums, Dünne and Moser argued that the digital era has made it more apparent how literary forms are involved in complex processes of mediation. Sidonie Smith and Julia Watson, in response, called for an expansion of autobiography into “life writing,” claiming that automediality is useful as a theoretical frame for contemplating the growth of self-presentation platforms online, shifting from the life-narrative genre of autobiography towards more discursive and irresolute forms of first-person expression (4). One’s life story, in this context, can be communicated obliquely and performatively, with the choice of media inextricably contributing to the subjectivity that is being produced, not just as a tool for rendering a pre-existent self. Lauren Berlant conceives of life writing as a laboratory for “theorizing ‘the event’” of life rather than its narration or transcription (Prosser 181). Smith and Watson agree, describing automediality as the study of “life acts” that operate as “prosthetic extension[s] of the self in networks” (78). Following this, both “automedia” and “automediality” can be understood as expanding upon the “underlying intermedial premises” (Winthrop-Young 188) of media theory, addressing how technologies and mediums do not just constitute sensory extensions of the body (Mcluhan) but also sensory extensions of identity—armed with the potential to challenge traditional ideas of how a “life” is conveyed. For Julie Rak, “automedia” describes both the theoretical framing of self-presentation acts and the very processes of mediation the self-presenter puts themselves through (161). She prefers “automedia” over “automediality” due to the latter’s tendency to be directed towards the textual products of self-presentation, rather than their processes (161). Given Trecartin’s emphasis on narrative, poetic text, performativity, technology and commodification, both “automedia” and “automediality” will be relevant to my account here, highlighting not just the crossovers between the two terms but also the dual roles his work performs. Firstly, Trecartin’s videos express his own identity through the use of camp personas and exaggerated digital tropes. Secondly, they reflexively frame the phenomenon of online self-presentation, aestheticizing the “slice of life” and “personal history” posturings found on YouTube in order to better understand them. The line between self-presenter and critic is further muddied by the fact that Trecartin makes many of his videos free to download online. As video artist and YouTuber, he is interested in the same questions that Smith and Watson claim are central to automedial theory. When watching Youtube performers, they remind themselves to ask: “How is the aura of authenticity attached to an online performance constructed by a crew, which could include a camera person, sound person, director, and script-writer? Do you find this self-presentation to be sincere or to be calculated authenticity, a pose or ‘manufactured’ pseudo-individuality?” (124). Rather than setting out to identify “right” from “wrong” subjectivities, the role of both the automedia and automediality critic is to illuminate how and why subjectivity is constructed across distinct visual and verbal forms, working against the notion that subjectivity can be “an entity or essence” (Smith and Watson 125).Figure 1: Ryan Trecartin, Item Falls (2013), digital video stillGiven its literary origins, automediality is particularly relevant to Trecartin’s work because writing is so central to his methods, grounding his hyperactive self-presentations in the literary as well as the performative. According to Brian Droitcour, all of Trecartin’s formal devices, from the camerawork to the constructed sets his videos are staged in, are prefigured by the way he uses words. What appears unstructured and improvised is actually closely scripted, with Trecartin building on the legacies of conceptual poetry and flarf poetry (an early 2000s literary genre in which poetry is composed of collages of serendipitously found words and phrases online) to bring a loose sense of narrativization to his portrayals of characters and context. Consider the following excerpt from the screenplay for K-Corea INC. K (Section A) (2009)— a work which centres on a CEO named Global Korea (a pun on “career”) who presides over symbolic national characters whose surnames are also “Korea”:North America Korea: I specialize in Identity Tourism, ?Agency...I just stick HERE, and I Hop Around–HEY GLOBAL KOREA!?Identifiers: That’s Global, That’s Global, That’s GlobalFrench adaptation Korea: WHAT!?Global Korea: Guys I just Wanted to show You Your New Office!Health Care, I don’t Care, It’s All WE Care, That’s WhyWE don’t Care.THIS IS GLOBAL!Identified: AHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHGlobal Korea: Global, Global !!Identified: AHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHFigure 2: Ryan Trecartin, K-Corea INC. K (Section A) (2009), digital video stillTrecartin’s performers are guided by their lines, even down to the apparently random use of commas, question marks and repeated capital letters. As a consequence, what can be alienating on the page is made lively when performed, his words instilled with the over-the-top personalities of each performer. For Droitcour, Trecartin’s genius lies in his ability to use words to subliminally structure his performances. Each character makes the artist’s poetic texts—deranged and derivative-sounding Internet-speak—their own “at the moment of the utterance” (Droitcour). Wayne Koestenbaum similarly argues that voice, which Trecartin often digitally manipulates, is the “anxiety point” in his works, fixing his “retardataire” energies on the very place “where orality and literacy stage their war of the worlds” (276).This conflict that Koestenbaum describes, between orality and literacy, is constitutive of Trecartin’s automedial positioning of the self, which presents as a confluence of life narrative, screenplay, social-media posing, flarf poetry and artwork. His videos constantly criss-cross between pre-production, production and postproduction, creating content at every point along the way. This circuitousness is reflected by the many performers who are portrayed filming each other as they act, suggesting that their projected identities are entangled with the technologies that facilitate them.Trecartin’s A Family Finds Entertainment (2004)—a frenetic straight-to-camera chronicle of the coming-out of a gay teenager named Skippy (played by the artist)—was included in the 2006 Whitney Biennial, after which time his work became known around the world as an example of “postproduction” art. This refers to French curator and theorist Nicholas Bourriaud’s 2001 account of the blurring of production and consumption, following on from his 1997 theory of relational aesthetics, which became paradigmatic of critical art practice at the dawn of Web 2.0. Drawing from Marcel Duchamp and the Situationists, in Postproduction: Culture as Screenplay: How Art Reprograms the World, Bourriaud addressed new forms of citation, recycling and détournement, which he saw as influenced by digital computing, the service economies and other forms of immaterial social relations that, throughout the 1990s, transformed art from a subcultural activity to a key signifier and instrument of global capitalism.Because “word processing” was “indexed to the formal protocol of the service industry, and the image-system of the home computer […] informed and colonized from the start by the world of work” (78), Bourriaud claimed that artists at the start of the twenty-first century were responding to the semiotic networks that blur daily and professional life. Postproduction art looked like it was “issued from a script that the artist projects onto culture, considered the framework of a narrative that in turn projects new possible scripts, endlessly” (19). However, whereas the artists in Bourriaud’s publication, such as Plamen Dejanov and Philippe Parreno, made art in order to create “more suitable [social] arrangements” (76), Trecartin is distinctive not only because of his bombastic style but also his apparent resistance to socio-political amelioration.Bourriaud’s call for the elegant intertextual “scriptor” as prosumer (88)—who creatively produces and consumes, arranges and responds—was essentially answered by Trecartin with a parade of hyper-affective and needy Internet characters whose aims are not to negotiate new social terrain so much as to perform themselves crazy, competing with masses of online information, opinions and jostling identities. Against Bourriaud’s strategic prosumerism, Trecartin, in his own words, chases “a kind of natural prosumerism synonymous with existence” (471). Although his work can be read as a response to neoliberal values, unlike Bourriaud, he refuses to treat postproduction methods as tools to conciliate this situation. Instead, his scripted videos present postproduction as the lingua franca of daily life. In aiming for a “natural prosumerism,” his work rhetorically asks, in paraphrase of Berlant: “What does it mean to have a life, is it always to add up to something?” (Prosser 181). Figure 3: Ryan Trecartin, A Family Finds Entertainment (2004), digital video stillPluralist CampTrecartin’s scripts direct his performers but they are also transformed by them, his words acquiring their individualistic tics, traits and nuances. As such, his self-presentations are a long way from Frederic Jameson’s account of pastiche as a neutral practice of imitation—“a blank parody” (125) that manifests as an addiction rather than a critical judgement. Instead of being uncritically blank, we could say that Trecartin’s characters have too much content and too many affects, particularly those of the Internet variety. In Ready (Re’Search Wait’S) (2009-2010), Trecartin (playing a character named J.J. Check, who wants to re-write the U.S constitution) states at one point: “Someone just flashed an image of me; I am so sure of it. I am such as free download.” Here, pastiche turns into a performed glitch, hinting at how authentic speech can be composed of an amalgam of inauthentic sources—a scrambling of literary forms, movie one-liners, intrusive online advertising and social media jargon. His characters constantly waver between vernacular clichés and accretions of data: “My mother accused me of being accumulation posing as independent free will,” says a character from Item Falls (2013)What makes Trecartin’s video work so fascinating is that he frames what once would have been called “pastiche” and fills it with meaning, as if sincerely attuned to the paradoxes of “anti-normative” posturing contained in the term “mass individualism.” Even when addressing issues of representational politics, his dialogue registers as both authentic and insipid, as when, in CENTER JENNY (2013), a conversation about sexism being “the coolest style” ends with a woman in a bikini asking: “tolerance is inevitable, right?” Although there are laugh-out-loud elements in all of his work—often from an exaggeration of superficiality—there is a more persistent sense of the artist searching for something deeper, perhaps sympathetically so. His characters are eager to self-project yet what they actually project comes off as too much—their performances are too knowing, too individualistic and too caught up in the Internet, or other surrounding technologies.When Susan Sontag wrote in 1964 of the aesthetic of “camp” she was largely motivated by the success of Pop art, particularly that of her friend Andy Warhol. Warhol’s work looked kitsch yet Sontag saw in it a genuine love that kitsch lacks—a sentiment akin to doting on something ugly or malformed. Summoning the dandy, she claimed that whereas “the dandy would be continually offended or bored, the connoisseur of Camp is continually amused, delighted. The dandy held a perfumed handkerchief to his nostrils and was liable to swoon; the connoisseur of Camp sniffs the stink and prides himself on his strong nerves” (292).As an artistic device, camp essentially wallows in all the bad fetishisms that Frankfurt School theorists lamented of capitalism. The camp appropriator, does, however, convey himself as existing both inside and outside this low culture, communicating the “stink” of low culture in affecting ways. Sontag viewed camp, in other words, as at once deconstructive and reconstructive. In playing appearances off against essences, camp denies the self as essence only to celebrate it as performance.In line with accounts of identity in automediality and automedia theory, camp can be understood as performing within a dialectical tension between self and its representation. The camp aesthetic shows the self as discursively mediated and embedded in subjective formations that are “heterogeneous, conflictual, and intersectional” (Smith and Watson 71). Affiliated with the covert expression of homosexual and queer identity, the camp artist typically foregrounds art as taste, and taste as mere fashion, while at the same time he/she suggests how this approach is shaped by socio-political marginalization. For Eve Kosofsky Sedgwick, the criticality of camp is “additive and accretive” rather than oppositional; it is a surplus form that manifests as “the ‘over’-attachment to fragmentary, marginal, waste or leftover products” (149).Trecartin, who identifies as gay, parodies the excesses of digital identity while at the same time, from camp and queer perspectives, he asks us to take these identifications seriously—straight, gay, transsexual, bisexual, inter-sexual, racial, post-racial, mainstream, alternative, capitalist or anarchist. This pluralist agenda manifests in characters who speak as though everything is in quotation marks, suggesting that everything is possible. Dialogue such as “I’m finally just an ‘as if’”, “I want an idea landfill”, and “It reminds me of the future” project feelings of too much and not enough, transforming Warhol’s cool, image-oriented version of camp (transfixed by TV and supermarket capitalism) into a hyper-affective Internet camp—a camp that feeds on new life narratives, identity postures and personalities, as stimuli.In emphasising technology as intrinsic to camp self-presentation, Trecartin treats intersectionality and intermediality as if corresponding concepts. His characters, caught between youthhood and adulthood, are inbetweeners. Yet, despite being nebulous, they float free of normative ideals only in the sense that they believe everybody not only has the right to live how they want to, but to also be condemned for it—the right to intolerance going hand-in-hand with their belief in plurality. This suggests the paradoxical condition of pluralist, intersectional selfhood in the digital age, where one can position one’s identity as if between social categories while at the same time weaponizing it, in the form of identity politics. In K-Corea INC. K (Section A) (2009), Global Korea asks: “Who the fuck is that baby shit-talker? That’s not one of my condiments,” which is delivered with characteristic confidence, defensiveness and with gleeful disregard for normative speech. Figure 4: Ryan Trecartin, CENTER JENNY (2013), digital video stillThe Zaniness of the Neoliberal SelfIf, as Koestenbaum claims, Trecartin’s host of characters are actually “evolving mutations of a single worldview” (275), then the worldview they represent is what Sianne Ngai calls the “hypercommodified, information saturated, performance driven conditions of late capitalism” (1). Self-presentation in this context is not to be understood so much as experienced through prisms of technological inflection, marketing spiel and pluralist interpretative schemas. Ngai has described the rise of “zaniness” as an aesthetic category that perfectly encapsulates this capitalist condition. Zany hyperactivity is at once “lighthearted” and “vehement,” and as such it is highly suited to the contemporary volatility of affective labour; its tireless overlapping of work and play, and the networking rhetoric of global interconnectedness (Ngai, 7). This is what Luc Boltanski and Eve Chiapello have termed the “connexionist” spirit of capitalism, where a successful career is measured by one’s capacity to be “always pursuing some sort of activity, never to be without a project, without ideas, to be always looking forward to, and preparing for, something along with other persons, whose encounter is the result of being always driven by the drive for activity” (Chiapello and Fairclough 192).For Ngai, the zany—epitomized by Jim Carrey’s character in Cable Guy (1996) or Wile E. Coyote from the Looney Tunes cartoons—performs first and asks questions later. As such, their playfulness is always performed in a way that could spin out of control, as when Trecartin’s humour can, in the next moment, appear psychotic. Ngai continues:What is essential to zaniness is its way of evoking a situation with the potential to cause harm or injury […]. For all their playfulness and commitment to fun, the zany’s characters give the impression of needing to labor excessively hard to produce our laughter, straining themselves to the point of endangering not just themselves but also those around them. (10)Using sinister music scores, anxiety-inducing editing and lighting that references iconic DIY horror films such as the Blair Witch Project (1999), Trecartin comically frames the anxieties and over-produced individualism of the global neoliberalist project, but in ways that one is unsure what to do with it. “Don’t look at me—look at your mother, and globalize at her,” commands Global Korea. Set in temporary (read precarious) locations that often resemble both domestic and business environments, his world is one in which young adults are incessantly producing themselves as content, as if unstable market testers run riot, on whose tastes our future global economic growth depends.Michel Foucault defined this neoliberal condition as “the application of the economic grid to social phenomena” (239). As early as 1979 he claimed that workers in a neoliberal context begin to regard the self as an “abilities-machine” (229) where they are less partners in the processes of economic exchange than independent producers of human capital. As Jodi Dean puts it, with the totalization of economic production, neoliberal processes “simultaneously promote the individual as the primary unit of capitalism and unravel the institutions of solidaristic support on which this unit depends” (32). As entrepreneurs of the self, people under neoliberalism become producers for whom socialization is no longer a byproduct of capitalist production but can be the very means through which capital is produced. With this in mind, Trecartin’s portrayal of the straight-to-camera format is less a video diary than a means for staging social auditions. His performers (or contestants), although foregrounding their individualism, always have their eyes on group power, suggesting a competitive individualism rather than the countering of normativity. Forever at work and at play, these comic-tragics are ur-figures of neoliberalism—over-connected and over-emotional self-presenters who are unable to stop, in fear they will be nothing if not performing.ConclusionPortraying a seemingly endless parade of neoliberal selves, Trecartin’s work yields a zany vision that always threatens to spin out of control. As a form of Internet-era camp, he reproduces automedial conceptions of the self as constituted and expanded by media technologies—as performative conduits between the formal and the socio-political which go both ways. This process has been described by Berlant in terms of life writing, but it applies equally to Trecartin, who, through a “performance of fantasmatic intersubjectivity,” facilitates “a performance of being” for the viewer “made possible by the proximity of the object” (Berlant 25). Inflating for both comic and tragic effect a profoundly nebulous yet weaponized conception of identity, Trecartin’s characters show the relation between offline and online life to be impossible to essentialize, laden with a mix of conflicting feelings and personas. 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