Journal articles: 'PI4KA'

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Borawski, Jason, Philip Troke, Xiaoling Puyang, Veronica Gibaja, ShanChaun Zhao, Craig Mickanin, Juliet Leighton-Davies, et al. "Class III Phosphatidylinositol 4-Kinase Alpha and Beta Are Novel Host Factor Regulators of Hepatitis C Virus Replication." Journal of Virology 83, no. 19 (July 15, 2009): 10058–74. http://dx.doi.org/10.1128/jvi.02418-08.

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ABSTRACT Host factor pathways are known to be essential for hepatitis C virus (HCV) infection and replication in human liver cells. To search for novel host factor proteins required for HCV replication, we screened a subgenomic genotype 1b replicon cell line (Luc-1b) with a kinome and druggable collection of 20,779 siRNAs. We identified and validated several enzymes required for HCV replication, including class III phosphatidylinositol 4-kinases (PI4KA and PI4KB), carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and mevalonate (diphospho) decarboxylase. Knockdown of PI4KA could inhibit the replication and/or HCV RNA levels of the two subgenomic genotype 1b clones (SG-1b and Luc-1b), two subgenomic genotype 1a clones (SG-1a and Luc-1a), JFH-1 genotype 2a infectious virus (JFH1-2a), and the genomic genotype 1a (FL-1a) replicon. In contrast, PI4KB knockdown inhibited replication and/or HCV RNA levels of Luc-1b, SG-1b, and Luc-1a replicons. The small molecule inhibitor, PIK93, was found to block subgenomic genotype 1b (Luc-1b), subgenomic genotype 1a (Luc-1a), and genomic genotype 2a (JFH1-2a) infectious virus replication in the nanomolar range. PIK93 was characterized by using quantitative chemical proteomics and in vitro biochemical assays to demonstrate PIK93 is a bone fide PI4KA and PI4KB inhibitor. Our data demonstrate that genetic or pharmacological modulation of PI4KA and PI4KB inhibits multiple genotypes of HCV and represents a novel druggable class of therapeutic targets for HCV infection.

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Dorobantu, Cristina M., Christian Harak, Rahel Klein, Lonneke van der Linden, Jeroen R. P. M. Strating, Hilde M. van der Schaar, Volker Lohmann, and Frank J. M. van Kuppeveld. "Tyrphostin AG1478 Inhibits Encephalomyocarditis Virus and Hepatitis C Virus by Targeting Phosphatidylinositol 4-Kinase IIIα." Antimicrobial Agents and Chemotherapy 60, no. 10 (August 1, 2016): 6402–6. http://dx.doi.org/10.1128/aac.01331-16.

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ABSTRACTEncephalomyocarditis virus (EMCV), like hepatitis C virus (HCV), requires phosphatidylinositol 4-kinase IIIα (PI4KA) for genome replication. Here, we demonstrate that tyrphostin AG1478, a known epidermal growth factor receptor (EGFR) inhibitor, also inhibits PI4KA activity, bothin vitroand in cells. AG1478 impaired replication of EMCV and HCV but not that of an EMCV mutant previously shown to escape PI4KA inhibition. This work uncovers novel cellular and antiviral properties of AG1478, a compound previously regarded only as a cancer chemotherapy agent.

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Sun, Suqing, Peng Wang, Lijie Ren, Hongli Wang, Yanli Zhan, and Shimin Shan. "Sevoflurane Suppresses Colon Cancer Cell Malignancy by Regulating circ-PI4KA." OncoTargets and Therapy Volume 14 (May 2021): 3319–33. http://dx.doi.org/10.2147/ott.s295552.

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Pagnamenta, Alistair T., Malcolm F. Howard, Eva Wisniewski, Niko Popitsch, Samantha J. L. Knight, David A. Keays, Gerardine Quaghebeur, et al. "Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis." Human Molecular Genetics 24, no. 13 (April 8, 2015): 3732–41. http://dx.doi.org/10.1093/hmg/ddv117.

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Klima, Martin, Adriana Baumlova, Dominika Chalupska, Hubert Hřebabecký, Milan Dejmek, Radim Nencka, and Evzen Boura. "The high-resolution crystal structure of phosphatidylinositol 4-kinase IIβ and the crystal structure of phosphatidylinositol 4-kinase IIα containing a nucleoside analogue provide a structural basis for isoform-specific inhibitor design." Acta Crystallographica Section D Biological Crystallography 71, no. 7 (June 30, 2015): 1555–63. http://dx.doi.org/10.1107/s1399004715009505.

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Phosphatidylinositol 4-phosphate (PI4P) is the most abundant monophosphoinositide in eukaryotic cells. Humans have four phosphatidylinositol 4-kinases (PI4Ks) that synthesize PI4P, among which are PI4K IIβ and PI4K IIα. In this study, two crystal structures are presented: the structure of human PI4K IIβ and the structure of PI4K IIα containing a nucleoside analogue. The former, a complex with ATP, is the first high-resolution (1.9 Å) structure of a PI4K. These structures reveal new details such as high conformational heterogeneity of the lateral hydrophobic pocket of the C-lobe and together provide a structural basis for isoform-specific inhibitor design.

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Tai, Andrew W., and Shadi Salloum. "The Role of the Phosphatidylinositol 4-Kinase PI4KA in Hepatitis C Virus-Induced Host Membrane Rearrangement." PLoS ONE 6, no. 10 (October 12, 2011): e26300. http://dx.doi.org/10.1371/journal.pone.0026300.

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Balla, Andras, Yeun Ju Kim, Peter Varnai, Zsofia Szentpetery, Zachary Knight, Kevan M. Shokat, and Tamas Balla. "Maintenance of Hormone-sensitive Phosphoinositide Pools in the Plasma Membrane Requires Phosphatidylinositol 4-Kinase IIIα." Molecular Biology of the Cell 19, no. 2 (February 2008): 711–21. http://dx.doi.org/10.1091/mbc.e07-07-0713.

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Type III phosphatidylinositol (PtdIns) 4-kinases (PI4Ks) have been previously shown to support plasma membrane phosphoinositide synthesis during phospholipase C activation and Ca2+ signaling. Here, we use biochemical and imaging tools to monitor phosphoinositide changes in the plasma membrane in combination with pharmacological and genetic approaches to determine which of the type III PI4Ks (α or β) is responsible for supplying phosphoinositides during agonist-induced Ca2+ signaling. Using inhibitors that discriminate between the α- and β-isoforms of type III PI4Ks, PI4KIIIα was found indispensable for the production of phosphatidylinositol 4-phosphate (PtdIns4P), phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], and Ca2+ signaling in angiotensin II (AngII)-stimulated cells. Down-regulation of either the type II or type III PI4K enzymes by small interfering RNA (siRNA) had small but significant effects on basal PtdIns4P and PtdIns(4,5)P2 levels in 32P-labeled cells, but only PI4KIIIα down-regulation caused a slight impairment of PtdIns4P and PtdIns(4,5)P2 resynthesis in AngII-stimulated cells. None of the PI4K siRNA treatments had a measurable effect on AngII-induced Ca2+ signaling. These results indicate that a small fraction of the cellular PI4K activity is sufficient to maintain plasma membrane phosphoinositide pools, and they demonstrate the value of the pharmacological approach in revealing the pivotal role of PI4KIIIα enzyme in maintaining plasma membrane phosphoinositides.

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Ziyad, Safiyyah, Jesse D. Riordan, Ann M. Cavanaugh, Trent Su, Gloria E. Hernandez, Georg Hilfenhaus, Marco Morselli, et al. "A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis." Cell Reports 22, no. 5 (January 2018): 1211–24. http://dx.doi.org/10.1016/j.celrep.2018.01.017.

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Sohn, Mira, Pavlina Ivanova, H. Alex Brown, Daniel J. Toth, Peter Varnai, Yeun Ju Kim, and Tamas Balla. "Lenz-Majewski mutations in PTDSS1 affect phosphatidylinositol 4-phosphate metabolism at ER-PM and ER-Golgi junctions." Proceedings of the National Academy of Sciences 113, no. 16 (April 4, 2016): 4314–19. http://dx.doi.org/10.1073/pnas.1525719113.

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Lenz-Majewski syndrome (LMS) is a rare disease characterized by complex craniofacial, dental, cutaneous, and limb abnormalities combined with intellectual disability. Mutations in the PTDSS1 gene coding one of the phosphatidylserine (PS) synthase enzymes, PSS1, were described as causative in LMS patients. Such mutations render PSS1 insensitive to feedback inhibition by PS levels. Here we show that expression of mutant PSS1 enzymes decreased phosphatidylinositol 4-phosphate (PI4P) levels both in the Golgi and the plasma membrane (PM) by activating the Sac1 phosphatase and altered PI4P cycling at the PM. Conversely, inhibitors of PI4KA, the enzyme that makes PI4P in the PM, blocked PS synthesis and reduced PS levels by 50% in normal cells. However, mutant PSS1 enzymes alleviated the PI4P dependence of PS synthesis. Oxysterol-binding protein–related protein 8, which was recently identified as a PI4P-PS exchanger between the ER and PM, showed PI4P-dependent membrane association that was significantly decreased by expression of PSS1 mutant enzymes. Our studies reveal that PS synthesis is tightly coupled to PI4P-dependent PS transport from the ER. Consequently, PSS1 mutations not only affect cellular PS levels and distribution but also lead to a more complex imbalance in lipid homeostasis by disturbing PI4P metabolism.

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Bojjireddy, Naveen, Janos Botyanszki, Gerald Hammond, Donald Creech, Richard Peterson, Daniel C. Kemp, Mark Snead, et al. "Pharmacological and Genetic Targeting of the PI4KA Enzyme Reveals Its Important Role in Maintaining Plasma Membrane Phosphatidylinositol 4-Phosphate and Phosphatidylinositol 4,5-Bisphosphate Levels." Journal of Biological Chemistry 289, no. 9 (January 10, 2014): 6120–32. http://dx.doi.org/10.1074/jbc.m113.531426.

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Balla, Andras, Galina Tuymetova, Arnold Tsiomenko, Péter Várnai, and Tamas Balla. "A Plasma Membrane Pool of Phosphatidylinositol 4-Phosphate Is Generated by Phosphatidylinositol 4-Kinase Type-III Alpha: Studies with the PH Domains of the Oxysterol Binding Protein and FAPP1." Molecular Biology of the Cell 16, no. 3 (March 2005): 1282–95. http://dx.doi.org/10.1091/mbc.e04-07-0578.

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The PH domains of OSBP and FAPP1 fused to GFP were used to monitor PI(4)P distribution in COS-7 cells during manipulations of PI 4-kinase (PI4K) activities. Both domains were associated with the Golgi and small cytoplasmic vesicles, and a small fraction of OSBP-PH was found at the plasma membrane (PM). Inhibition of type-III PI4Ks with 10 μM wortmannin (Wm) significantly reduced but did not abolish Golgi localization of either PH domains. Downregulation of PI4KIIα or PI4KIIIβ by siRNA reduced the localization of the PH domains to the Golgi and in the former case any remaining Golgi localization was eliminated by Wm treatment. PLC activation by Ca2+ ionophores dissociated the domains from all membranes, but after Ca2+ chelation, they rapidly reassociated with the Golgi, the intracellular vesicles and with the PM. PM association of the domains was significantly higher after the Ca2+ transient and was abolished by Wm pretreatment. PM relocalization was not affected by down-regulation of PI4KIIIβ or -IIα, but was inhibited by down-regulation of PI4KIIIα, or by 10 μM PAO, which also inhibits PI4KIIIα. Our data suggest that these PH domains detect PI(4)P formation in extra-Golgi compartments under dynamic conditions and that various PI4Ks regulate PI(4)P synthesis in distinct cellular compartments.

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Karakas, Esra, Cyntia Taveneau, Stéphane Bressanelli, Massimo Marchi, Bruno Robert, and Stéphane Abel. "Derivation of original RESP atomic partial charges for MD simulations of the LDAO surfactant with AMBER: applications to a model of micelle and a fragment of the lipid kinase PI4KA." Journal of Biomolecular Structure and Dynamics 35, no. 1 (March 21, 2016): 159–81. http://dx.doi.org/10.1080/07391102.2015.1135822.

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Tartaglione, Sara, Patrizia Mancini, Valentina Viggiani, Piero Chirletti, Antonio Angeloni, and Emanuela Anastasi. "PIVKA-II: A biomarker for diagnosing and monitoring patients with pancreatic adenocarcinoma." PLOS ONE 16, no. 5 (May 20, 2021): e0251656. http://dx.doi.org/10.1371/journal.pone.0251656.

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Background Pancreatic adenocarcinoma (PDAC) is an incurable cancer without adequate tumor markers. Our previous study has showed a better diagnostic performance of Protein Induced by Vitamin K Absence II (PIVKA-II) compared to currently used PDAC biomarkers. To corroborate our previous data with a larger sample size and to assess a possible role of PIVKA-II in predicting surgical success. Additionally, to further evaluate the hypothesis of a direct PIVKA-II production by PDAC cells, we examined PIVKA-II tissue expression in a case of PDAC using immunofluorescence. Methods We enrolled 76 newly diagnosed PDAC patients and selected 11 patients to determine PIVKA-II levels also after surgical resection. An immunofluorescence (IF) study of PIVKA-II tissue expression was carried out in one of them. PIVKA-II serum values were measured by chemiluminescent enzyme immunoassay method (CLEIA) on LUMIPULSE G1200 (Fujirebio-Europe, Belgium). Results PIVKA-II serum levels were above the cut-off at baseline in 71 patients (94%) with a median value of 464 mAU/Ml (range 27–40783 mAU/mL); the sensitivity and specificity were 78.67% and 90.67% respectively. Patients with pre-operative PIVKA-II positivity showed a significant decrease (P < 0.015) of median PIVKA-II serum concentrations after surgery: 820 (91–40783) mAU/mL at diagnosis vs 123 (31–4666) mAU/mL post-operatively. IF assay on PDAC sections demonstrated PIVKA-II expression in cancer cells. Conclusion These data are the first showing a decreased PIVKA-II serum levels after surgery in PDAC patients and reporting PIVKA-II expression in PDAC tissue. Further studies are needed to confirm these findings and to determine PIVKA-II usefulness in diagnosing and monitoring PDAC patients.

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Xu, Fei, Lulu Zhang, Wenting He, Di Song, Xiaomeng Ji, and Jianyong Shao. "The Diagnostic Value of Serum PIVKA-II Alone or in Combination with AFP in Chinese Hepatocellular Carcinoma Patients." Disease Markers 2021 (February 8, 2021): 1–9. http://dx.doi.org/10.1155/2021/8868370.

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Background. At present, the diagnostic accuracy of alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) surveillance is insufficient. It remains controversial whether prothrombin induced by vitamin K absence II (PIVKA-II) has a better diagnostic value than AFP for HCC patients. Objective. To investigate the diagnostic role of PIVKA-II alone or in combination with AFP in Chinese HCC patients. Methods. Serum AFP and PIVKA-II levels were detected and analyzed in 308 HCC afflicted patients and 120 unafflicted controls. The receiver operator curve (ROC) and area under the curve (AUC) were conducted to evaluate the clinical value of AFP and PIVKA-II for diagnosing HCC and early HCC. Results. In the whole HCC cohort, the diagnostic values of PIVKA-II were better than that of AFP. The AUC of PIVKA-II and AFP was 0.90 (95% CI 0.87-0.94) and 0.79 (95% CI 0.74-0.84), respectively. “AFP + PIVKA-II” yielded a high sensitivity of 95.1% and a specificity of 83.3%, with the AUC 0.89 (95% CI 0.85-0.93). In the early stage HCC group, the diagnostic accuracy of PIVKA-II was also better than that of AFP. The AUC of PIVKA-II and AFP was 0.83 (95% CI 0.77-0.89) and 0.75 (95% CI 0.68-0.81), respectively. “AFP + PIVKA-II” achieved the sensitivity of 83.3% and specificity of 89.1%, with an AUC of 0.86 (95% CI 0.81-0.91). Moreover, for AFP-negative HCC patients, serum PIVKA-II showed good diagnostic performance, with an AUC of 0.804 (95% CI 0.720-0.887). Besides, elevated PIVKA-II level was a strong independent risk factor for HCC patients with portal vein tumor thrombus (PVTT) ( OR = 4.890 , P = 0.020 ). Conclusion. PIVKA-II is superior to AFP in HCC screening, and AFP in combination with PIVKA-II significantly improves the diagnostic value for Chinese HCC patients. PIVKA-II could effectively indicate HCC accompanied by PVTT and help to optimize the therapeutic strategy.

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de Graaf, Petra, Wilbert T. Zwart, Remco A. J. van Dijken, Magdalena Deneka, Thomas K. F. Schulz, Niels Geijsen, Paul J. Coffer, et al. "Phosphatidylinositol 4-Kinaseβ Is Critical for Functional Association of rab11 with the Golgi Complex." Molecular Biology of the Cell 15, no. 4 (April 2004): 2038–47. http://dx.doi.org/10.1091/mbc.e03-12-0862.

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Phosphatidylinositol 4-kinaseβ (PI4Kβ) plays an essential role in maintaining the structural integrity of the Golgi complex. In a search for PI4Kβ-interacting proteins, we found that PI4Kβ specifically interacts with the GTP-bound form of the small GTPase rab11. The PI4Kβ-rab11 interaction is of functional significance because inhibition of rab11 binding to PI4Kβ abolished the localization of rab11 to the Golgi complex and significantly inhibited transport of vesicular stomatitis virus G protein from the Golgi complex to the plasma membrane. We propose that a novel function of PI4Kβ is to act as a docking protein for rab11 in the Golgi complex, which is important for biosynthetic membrane transport from the Golgi complex to the plasma membrane.

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Widdershoven, J., P. van Munster, R. De Abreu, H. Bosman, T. van Lith, M. van der Putten-van Meyel, K. Motohara, and I. Matsuda. "Four methods compared for measuring des-carboxy-prothrombin (PIVKA-II)." Clinical Chemistry 33, no. 11 (November 1, 1987): 2074–78. http://dx.doi.org/10.1093/clinchem/33.11.2074.

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Abstract PIVKA-II (Protein Induced by Vitamin K Absence) is abnormal des-carboxylated prothrombin, which is present in vitamin K deficiency or in patients using warfarin. With a sensitive method for PIVKA-II, biochemical vitamin K deficiency can be established before clinical symptoms occur. We give an overview of methods used to detect PIVKA-II, and four selected methods are inter-compared: (a) measuring total factor II including PIVKA-II by using Echis carinatus snake venom as an activator of prothrombin; (b) measuring PIVKA-II by using snake venom as an activator of factor II after adsorption of functional factor II onto barium sulfate; (c) electrophoresis-immunofixation method; and (d) enzyme immunoassay. We found d to be the most sensitive and reliable method for PIVKA-II.

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von Kries, R., M. J. Shearer, J. Widdershoven, K. Motohara, G. Umbach, and U. Göbel. "Des-Gamma-Carboxyprothrombin (PIVKA II) and Plasma Vitamin K1 in Newborns and Their Mothers." Thrombosis and Haemostasis 68, no. 04 (1992): 383–87. http://dx.doi.org/10.1055/s-0038-1646281.

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SummaryAssessments of the vitamin K status in newborns and their mothers by means of des-γ-carboxy-prothrombin (PIVKA II) measurement have given equivocal results. Part of the variability could be attributed to differences in sensitivity (i.e. the ability to detect small concentrations) and validity (i.e. ability to detect vitamin K deficiency) of the methods applied. None of these methods have yet been validated with respect to plasma vitamin K1. In 22 healthy mother/infant pairs PIVKA II was determined using three different assays including ratio Xa/ecarin (Xa/ec), crossed immunoelectrophoresis (CIE), and an ELISA with a monoclonal antibody (MAB). The results were compared with conventional clotting tests and plasma vitamin K1. The following results were obtained:Cord blood: Clotting tests within age-related normal ranges; PIVKA II detection rates: 0/22 (Xa/ec), 1/22 (CIE), 4/22 (MAB); plasma vitamin K1: undetectable in 20/22.Mothers: Clotting tests all within normal range; PIVKA II detection rates: 1/22 (Xa/ec), 0/22 (CIE), 5/22 (MAB); plasma vitamin K1 (pg/ml) for all mothers (median; range): 186; 55–833; for PIVKA II positive mothers: 213; 59–699.PIVKA II detectability in newborns and mothers was not correlated. The results show an increase in sensitivity for PIVKA II detection in the order of MAB ≫CIE >Xa/ec. Due to the very low plasma vitamin K1 at birth, no correlation was possible between cord PIVKA II detectability and plasma vitamin K1. However, in mothers at term PIVKA II MAB appears to be unrelated to the vitamin K status.

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Bovill, EG, RF Soll, M. Lynch, F. Bhushan, M. Landesman, M. Freije, W. Church, T. McAuliffe, K. Davidson, and J. Sadowski. "Vitamin K1 metabolism and the production of des-carboxy prothrombin and protein C in the term and premature neonate." Blood 81, no. 1 (January 1, 1993): 77–83. http://dx.doi.org/10.1182/blood.v81.1.77.77.

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Abstract This study investigated the incidences of undercarboxylated (protein induced by vitamin K absence: PIVKA) prothrombin and protein C in 496 neonates across a wide range of gestational ages. These findings are related to vitamin K1 levels (an indicator of cofactor availability) and vitamin K1 epoxide levels (a measure of the efficiency of the hepatic vitamin K cycle). PIVKA protein C was present in at least trace amounts in 27% of infants; whereas, PIVKA prothrombin was present in 7% of infants. PIVKA prothrombin and protein C were present at high plasma concentrations in 2% to 3% of term and preterm neonates and both PIVKA protein C and prothrombin increased with gestational age. Despite elevated plasma concentrations of PIVKA protein C and diminished levels of normally carboxylated protein C, clinical thrombosis was not observed. The mean (+/- SD) vitamin K1 level in the study population was 0.009 +/- 0.02 nmol/L (adult reference interval: 0.3 to 2.6 nmol/L) with no clear relationship between vitamin K1 levels and production of PIVKA protein C or prothrombin. By comparison with adults, the epoxide form of the vitamin comprised an abnormally high proportion of total vitamin K1; this suggests possible inefficiencies in hepatic reductase cycling.

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Bovill, EG, RF Soll, M. Lynch, F. Bhushan, M. Landesman, M. Freije, W. Church, T. McAuliffe, K. Davidson, and J. Sadowski. "Vitamin K1 metabolism and the production of des-carboxy prothrombin and protein C in the term and premature neonate." Blood 81, no. 1 (January 1, 1993): 77–83. http://dx.doi.org/10.1182/blood.v81.1.77.bloodjournal81177.

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This study investigated the incidences of undercarboxylated (protein induced by vitamin K absence: PIVKA) prothrombin and protein C in 496 neonates across a wide range of gestational ages. These findings are related to vitamin K1 levels (an indicator of cofactor availability) and vitamin K1 epoxide levels (a measure of the efficiency of the hepatic vitamin K cycle). PIVKA protein C was present in at least trace amounts in 27% of infants; whereas, PIVKA prothrombin was present in 7% of infants. PIVKA prothrombin and protein C were present at high plasma concentrations in 2% to 3% of term and preterm neonates and both PIVKA protein C and prothrombin increased with gestational age. Despite elevated plasma concentrations of PIVKA protein C and diminished levels of normally carboxylated protein C, clinical thrombosis was not observed. The mean (+/- SD) vitamin K1 level in the study population was 0.009 +/- 0.02 nmol/L (adult reference interval: 0.3 to 2.6 nmol/L) with no clear relationship between vitamin K1 levels and production of PIVKA protein C or prothrombin. By comparison with adults, the epoxide form of the vitamin comprised an abnormally high proportion of total vitamin K1; this suggests possible inefficiencies in hepatic reductase cycling.

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Gandham, Goutham, Hridya Jayamohanan, Bharadwaj Ponnada, Anil Kumar, Sudhindran S, and Pavithran Keechilat. "Correlation of serum PIVKA-II and AFP level with portal vein tumor thrombus and BCLC stage in newly diagnosed hepatocellular carcinoma patients." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16608-e16608. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16608.

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e16608 Background: Protein Induced by Vitamin K Absence-II (PIVKA-II) is a tumor marker specific for hepatocellular carcinoma (HCC). PIVKA-II levels correspond with HCC oncogenesis and disease progression. Portal vein tumor thrombus (PVTT) in patients with HCC is a significant factor that affect treatment and prognosis. In this study we assessed the predictive value of PIVKA-II and AFP for vascular invasion and BCLC stage in newly diagnosed HCC patients. Methods: We retrospectively reviewed records of newly diagnosed HCC patients at a tertiary hospital in India between January 2019 to December 2019. Clinical details, BCLC stage, radiological imaging records, serum levels of PIVKA-II and AFP at the time of diagnosis were obtained from medical records. Diagnostic accuracy and cut-off value of PIVKA-II in patients with portal invasion were calculated using receiver operator curve (ROC) analysis. Multiple pairwise comparisions between BCLC stage with PIVKA-II and AFP levels were analysed using Kruskal-Wallis test. Results: Out of 162 newly diagnosed HCC patients 42(25.9%) were detected with PVTT on imaging such as contrast-enhanced computed tomography or magnetic resonance imaging at the time of diagnosis.120(74.1%) patients without PVTT were taken as controls for the analysis. Serum level of PIVKA-II in HCC patients with PVTT was significantly higher than in HCC patients without PVTT (1152.57 mAU/ml vs 146.39 mAU/ml; p = 0.001). AUROC of PIVKA-II was 0.796 (95%CI 0.70-0.892, p = 0.000).The optimal cut-off value of PIVKA-II was 271.81 mAU/ml with a sensitivity of 78.6% and specificity of 52.4%, and the diagnostic accuracy was 59.98%. AUROC of AFP was 0.619 (95%CI 0.59-0.72, p = 0.001). Median PIVKA-II value increased from BCLC stage A to D. Kruskal-Wallis test showed a significant difference of PIVKA-II levels between all stages except stage A and B (p values for stage A-B (0.297), A-C (0.000), A-D(0.000),whereas for AFP results were significant only between stages A and C (p values for stage A-B (0.348), A-C (0.003), A-D(0.206). Conclusions: Serum PIVKA-II level appears as a good predictive marker for PVTT and BCLC stage when compared to AFP which may guide therapeutic strategy and assessment of prognosis in newly diagnosed HCC patients.

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Wood, Christopher S., Chia-Sui Hung, Yu-San Huoh, Carl J. Mousley, Christopher J. Stefan, Vytas Bankaitis, Kathryn M. Ferguson, and Christopher G. Burd. "Local control of phosphatidylinositol 4-phosphate signaling in the Golgi apparatus by Vps74 and Sac1 phosphoinositide phosphatase." Molecular Biology of the Cell 23, no. 13 (July 2012): 2527–36. http://dx.doi.org/10.1091/mbc.e12-01-0077.

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In the Golgi apparatus, lipid homeostasis pathways are coordinated with the biogenesis of cargo transport vesicles by phosphatidylinositol 4-kinases (PI4Ks) that produce phosphatidylinositol 4-phosphate (PtdIns4P), a signaling molecule that is recognized by downstream effector proteins. Quantitative analysis of the intra-Golgi distribution of a PtdIns4P reporter protein confirms that PtdIns4P is enriched on the trans-Golgi cisterna, but surprisingly, Vps74 (the orthologue of human GOLPH3), a PI4K effector required to maintain residence of a subset of Golgi proteins, is distributed with the opposite polarity, being most abundant on cis and medial cisternae. Vps74 binds directly to the catalytic domain of Sac1 (KD = 3.8 μM), the major PtdIns4P phosphatase in the cell, and PtdIns4P is elevated on medial Golgi cisternae in cells lacking Vps74 or Sac1, suggesting that Vps74 is a sensor of PtdIns4P level on medial Golgi cisternae that directs Sac1-mediated dephosphosphorylation of this pool of PtdIns4P. Consistent with the established role of Sac1 in the regulation of sphingolipid biosynthesis, complex sphingolipid homeostasis is perturbed in vps74Δ cells. Mutant cells lacking complex sphingolipid biosynthetic enzymes fail to properly maintain residence of a medial Golgi enzyme, and cells lacking Vps74 depend critically on complex sphingolipid biosynthesis for growth. The results establish additive roles of Vps74-mediated and sphingolipid-dependent sorting of Golgi residents.

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Melia, C. E., H. M. van der Schaar, A. W. M. de Jong, H. R. Lyoo, E. J. Snijder, A. J. Koster, F. J. M. van Kuppeveld, and M. Bárcena. "The Origin, Dynamic Morphology, and PI4P-Independent Formation of Encephalomyocarditis Virus Replication Organelles." mBio 9, no. 2 (April 17, 2018): e00420-18. http://dx.doi.org/10.1128/mbio.00420-18.

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ABSTRACTPicornaviruses induce dramatic rearrangements of endomembranes in the cells that they infect to produce dedicated platforms for viral replication. These structures, termed replication organelles (ROs), have been well characterized for theEnterovirusgenus of thePicornaviridae. However, it is unknown whether the diverse RO morphologies associated with enterovirus infection are conserved among other picornaviruses. Here, we use serial electron tomography at different stages of infection to assess the three-dimensional architecture of ROs induced by encephalomyocarditis virus (EMCV), a member of theCardiovirusgenus of the family of picornaviruses that is distantly related. Ultrastructural analyses revealed connections between early single-membrane EMCV ROs and the endoplasmic reticulum (ER), establishing the ER as a likely donor organelle for their formation. These early single-membrane ROs appear to transform into double-membrane vesicles (DMVs) as infection progresses. Both single- and double-membrane structures were found to support viral RNA synthesis, and progeny viruses accumulated in close proximity, suggesting a spatial association between RNA synthesis and virus assembly. Further, we explored the role of phosphatidylinositol 4-phosphate (PI4P), a critical host factor for both enterovirus and cardiovirus replication that has been recently found to expedite enterovirus RO formation rather than being strictly required. By exploiting an EMCV escape mutant, we found that low-PI4P conditions could also be overcome for the formation of cardiovirus ROs. Collectively, our data show that despite differences in the membrane source, there are striking similarities in the biogenesis, morphology, and transformation of cardiovirus and enterovirus ROs, which may well extend to other picornaviruses.IMPORTANCELike all positive-sense RNA viruses, picornaviruses induce the rearrangement of host cell membranes to form unique structures, or replication organelles (ROs), that support viral RNA synthesis. Here, we investigate the architecture and biogenesis of cardiovirus ROs and compare them with those induced by enteroviruses, members of the well-characterized picornavirus genusEnterovirus. The origins and dynamic morphologies of cardiovirus ROs are revealed using electron tomography, which points to the endoplasmic reticulum as the donor organelle usurped to produce single-membrane tubules and vesicles that transform into double-membrane vesicles. We show that PI4P, a critical lipid for cardiovirus and enterovirus replication, is not strictly required for the formation of cardiovirus ROs, as functional ROs with typical morphologies are formed under phosphatidylinositol 4-kinase type III alpha (PI4KA) inhibition in cells infected with an escape mutant. Our data show that the transformation from single-membrane structures to double-membrane vesicles is a conserved feature of cardiovirus and enterovirus infections that likely extends to other picornavirus genera.

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Roberts, Michael Symmons. "Pika." Grand Street, no. 70 (2002): 179. http://dx.doi.org/10.2307/25008611.

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Sun, Hui-Chuan, Xiao-Dong Zhu, Cheng Huang, Ying-Hao Shen, Ning-Ling Ge, Jin-Jin Zhu, Bin Xu, et al. "Early tumor marker decrease to predict the efficacy of combination therapy with lenvatinib plus anti-PD-1 antibodies in unresectable hepatocellular carcinoma (uHCC)." Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021): 304. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.304.

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304 Background: Combination therapy with anti-angiogenic agents plus anti-PD-1 antibodies has shown high anti-tumor activity in uHCC. However, predicting the efficacy of this combination therapy remains a challenge. Methods: This study included consecutive patients with uHCC who received lenvatinib (8 mg/d regardless of body weight) and an anti-PD-1 antibody as first-line systemic therapy between Sep 2018 and July 2020, and had at least one imaging evaluation. Tumor response was assessed every 2 months (± 2 week) by the investigators using modified RECIST criteria. Patients were evaluated as having a radiological response (complete or partial response) or non-radiological response (stable disease or progressive disease) at the best overall response evaluation. Serum tumor markers for HCC, including alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), were evaluated at baseline and 2-3 weeks after therapy was initiated and their association with radiological response were assessed. Patients with baseline AFP or PIVKA-II between the upper limit of normal and the maximum measuring range of the kit were evaluable for AFP decrease or PIVKA-II decrease. Results: A total of 76 patients were eligible for this study. Baseline AFP ≥400 ng/mL or PIVKA-II ≥400 mAU/mL was not associated with radiological response (P = 0.167 and P = 0.916, respectively). At 2-3 weeks after the initiation of therapy, 51 patients were evaluable for AFP decrease; 78.4% experienced a > 20% AFP decrease and 51.0% experienced a > 50% AFP decrease. Patients with a > 50% AFP decrease had a higher rate of radiological response than those with AFP increase or a ≤50% AFP decrease (73.1% vs 32.0%, P = 0.003). In 57 patients evaluable for PIVKA-II decrease, 50.9% and 35.1% experienced a > 20% and > 50% PIVKA-II decrease, respectively. Patients with a > 50% PIVKA-II decrease had a higher rate of radiological response than those with PIVKA-II increase or a ≤50% PIVKA-II decrease (85.0% vs 29.7%, P < 0.001). Both AFP decrease > 50% and PIVKA-II decrease > 50% predicted radiological response, with an area under receiver operating characteristic curve of 0.706 (95% CI, 0.560-0.852, P = 0.012) and 0.752 (95% CI, 0.621-0.883, P = 0.001), respectively. Furthermore, patients with a > 20% AFP or PIVKA-II increase from baseline had a lower rate of radiological response (0% vs 57.4%, P = 0.043; and 21.7% vs 69.7%, P < 0.001, respectively). Conclusions: A tumor marker decrease was seen in most patients as early as 2-3 weeks after the initiation of the combination therapy. Early on-treatment AFP or PIVKA-II decrease may serve as a predictor for objective response for patients with uHCC receiving combination anti-angiogenic and immune therapy.

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Yi, Shuhua, Jianjun Chen, Yu Qin, and Gaowei Xu. "The burying and grazing effects of plateau pika on alpine grassland are small: a pilot study in a semiarid basin on the Qinghai-Tibet Plateau." Biogeosciences 13, no. 22 (November 23, 2016): 6273–84. http://dx.doi.org/10.5194/bg-13-6273-2016.

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Abstract. There is considerable controversy about the effects of plateau pika (Ochotona curzoniae, hereafter pika) on alpine grassland on the Qinghai-Tibet Plateau (QTP). On the one hand, pika is considered a keystone species. On the other hand, it is being poisoned. Although significant efforts have been made to study the effects of pika at a quadrat scale ( ∼ m2), our knowledge about its distribution and effects at a larger scale is very limited. In this study, we investigated the direct effects, i.e., burying and grazing, of pika by upscaling field sampling at a quadrat scale to a plot scale ( ∼ 1000 m2) by aerial photographing. Altogether 168 plots were set on four different types of alpine grassland in a semiarid basin on the QTP. Results showed that (1) the effects of pika pile burying on the reduction of vegetation cover, biomass, soil carbon, and nitrogen were less than 10 %, which was much smaller than the effects of bald patches; and (2) pika consumed 8–21 % of annual net primary production of grassland. We concluded that the direct burying and grazing effects of pika on alpine grassland were minor in this region. The quadcopter is an efficient and economic tool for long-term repeated monitoring over large regions for further understanding the role of pika.

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Zhang, Dongjing, Zhihong Liu, Xueru Yin, Xiaolong Qi, Bingyun Lu, Yuanyuan Liu, and Jinlin Hou. "Prognostic value of PIVKA-II in hepatocellular carcinoma patients receiving curative ablation: A systematic review and meta-analysis." International Journal of Biological Markers 33, no. 3 (April 16, 2018): 266–74. http://dx.doi.org/10.1177/1724600818760234.

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Background: Several studies have been conducted to evaluate the prognostic value of prothrombin induced by vitamin K absence-II (PIVKA-II) overexpression in hepatocellular carcinoma patients treated with curative ablation. However, the results remain controversial. The purpose of this meta-analysis was to explore the correlation between PIVKA-II expression and survival outcomes in these patients. Methods: We performed a systematic literature search in PubMed, EMBASE, Medline, Cochrane Library, and Web of Science to identify the relevant articles investigating the prognostic value of PIVKA-II in patients with hepatocellular carcinoma. Combined hazard ratios (HR) and their 95% confidence intervals (CI) for overall survival and recurrence-free survival were calculated as the analysis endpoints. Results: A total of 15 cohorts encompassing 5647 patients were included. The results indicated that elevated PIVKA-II was significantly associated with poorer overall survival (HR 1.59; 95% CI 1.40, 1.82; P < 0.001) and recurrence-free survival (HR 1.76; 95% CI 1.42, 2.17; P < 0.001). Similar results were observed in the subgroup analysis based on sample size, analytical method, treatment modality, and cut-off value. Conclusions: This meta-analysis suggests that elevated PIVKA-II is a predictor of unfavorable overall survival and recurrence-free survival in hepatocellular carcinoma patients receiving curative ablation. More rigorous studies are warranted to confirm the clinical utility of PIVKA-II in determining hepatocellular carcinoma prognosis.

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Maniscalco, Lorella, Katia Varello, Simona Zoppi, Giuseppina Abbamonte, Marta Ferrero, Elena Torres, Federica Ostorero, Francesca Rossi, and Elena Bozzetta. "Abnormal Prothrombin (PIVKA-II) Expression in Canine Tissues as an Indicator of Anticoagulant Poisoning." Animals 11, no. 9 (September 6, 2021): 2612. http://dx.doi.org/10.3390/ani11092612.

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PIVKA-II is an aberrant form of vitamin K that has been demonstrated to be increased in human coagulation disorders and in some neoplastic diseases. In veterinary medicine, PIVKA-II levels have been demonstrated to be useful for distinguishing anticoagulant poisoning from other coagulopathies. In forensic pathology, there is the need to distinguish malicious poisoning from other causes of death and, in some cases, identifying poisoned dogs from dogs that died as a result of other coagulative disorders can be challenging. In this study, dogs that suddenly died underwent necropsy, histological examination, and toxicological analysis to establish cause of death. PIVKA-II immunohistochemical expression was evaluated on hepatic and renal tissues, and on neoplastic lesions when present. A total of 61 dogs were analyzed and anticoagulant substances were identified in 16 of the 61. Immunolabelling for PIVKA-II was observed in 27 of 61 cases in the liver and in 24 of 61 cases in the kidneys. Among the poisoned dogs, the PIVKA-II expression was present in the liver in 15 of 16 cases and in the kidneys in 16 of 16. Neoplastic lesions represented mainly by haemangiosarcomas were negative. This study highlights how the immunohistochemical expression of PIVKA-II in hepatic and renal tissues can be useful to identify patients with coagulative disorders due to clinical condition or the ingestion of anticoagulants substances.

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Darmadi, Darmadi, and Riska Habriel Ruslie. "Association between Prothrombin Induced by Vitamin K Absence-II (PIVKA-II) and Barcelona Clinic Liver Cancer (BCLC) Stage, Tumor Size, Portal Venous Thrombosis in Hepatocellular Carcinoma Patients." Sains Malaysiana 50, no. 2 (February 28, 2021): 475–80. http://dx.doi.org/10.17576/jsm-2021-5002-18.

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Hepatocellular carcinoma is one of the major cancer problems in the world because of the low early screening awareness in patients. Serum alpha-fetoprotein is not adequate as a single screening tool, especially for small HCCs, thus, prothrombin induced by vitamin K absence-II (PIVKA-II) can help in detecting small HCCs. Barcelona Clinic Liver Cancer (BCLC) stage remains to be the preferred HCC classification because it can predict the outcome and help in choosing available treatment options according to stages. This study aims to investigate the association between PIVKA-II levels with BCLC stage, tumor size, portal venous thrombosis in HCC patients. We enrolled patients with newly diagnosed HCC at the Adam Malik General Hospital, Medan, Indonesia from January to December 2018. Patients with HCC were classified according to BCLC stages, findings of portal venous thrombosis and tumor size from triphasic CT scan were noted, and serum PIVKA-II levels were measured. Sixty patients were included in this study. There were significant differences in serum PIVKA-II levels with different stages of BCLC (p < 0.001). Significantly higher serum PIVKA-II levels were detected in patients with portal venous thrombosis (p < 0.001) and larger size tumors (p < 0.003). Our study shows that serum PIVKA-II levels can help to diagnose, differentiate between stages of BCLC, and determine the prognosis in patients with HCC.

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Shrestha, Mohan Bikram, and Ritu Gurung. "Distribution of Royle’s Pika Ochotona roylei in Parvati Kunda Groundwater Complex." Nepal Journal of Environmental Science 7 (December 31, 2019): 11–15. http://dx.doi.org/10.3126/njes.v7i0.34318.

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Royle’s Pika Ochotona roylei is high altitude animal belonging to the family Ochotonidae in order Lagomorpha. Royle’s Pika was reported in different locations between an elevation of 2180 to 5950 meters above sea level (m asl). This study carried in February and October 2017 recorded a small population of Royle’s Pika in the Parvati Kunda Groundwater Complex of Gatlang village in Rasuwa District, Nepal. A total of 12 Royle’s pika individuals were head counted from three sites while Pika foraged plants were observed in other sites. Pika was observed in talus groove amidst Rhododendron-fir forest, Fir-hemlock forest, and Rhododendron shrub close to the alpine meadow. Pika in the study was distributed from the Parvati Kunda wetland proximity at an elevation of 2605 m with a direct count of 2 individuals to an elevation of 3000 m asl beneath Tshumer hill with a headcount of 7 individuals. However, the population of Royle’s Pika in the area was estimated more. The population density of 6 individuals/hectare was calculated in the area, which is relatively lower than the population density accounted for in other areas.

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Caviglia, Gian Paolo, Michela Ciruolo, Maria Lorena Abate, Patrizia Carucci, Emanuela Rolle, Chiara Rosso, Antonella Olivero, et al. "Alpha-Fetoprotein, Protein Induced by Vitamin K Absence or Antagonist II and Glypican-3 for the Detection and Prediction of Hepatocellular Carcinoma in Patients with Cirrhosis of Viral Etiology." Cancers 12, no. 11 (October 31, 2020): 3218. http://dx.doi.org/10.3390/cancers12113218.

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International guidelines recommend the use of ultrasound as a surveillance tool for hepatocellular carcinoma (HCC) in patients with cirrhosis, while the role of serum biomarkers is still debated. We investigated serum alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist II (PIVKA-II) and glypican-3 (GPC-3) diagnostic accuracy for HCC detection and prediction in patients with liver cirrhosis of viral etiology under surveillance. A total of 349 patients (200 cirrhosis and 149 HCC) were enrolled. The 200 patients with cirrhosis consisted of 114 patients still HCC-free after 36 months of follow-up and 86 patients that developed HCC after 13.8 (11.0–19.8) months. AFP, PIVKA-II and GPC-3 were measured in serum samples collected at tumor diagnosis in the 149 patients with HCC, and at the beginning of follow-up in the 200 patients with cirrhosis. The higher performance for HCC detection was observed for PIVKA-II (area under the curve (AUC) = 0.790), followed by AFP (AUC = 0.737) and GPC-3 (AUC = 0.637); the combination of AFP + PIVKA-II improved the diagnostic accuracy to AUC = 0.822. Serum PIVKA-II values, but not AFP and GPC-3, were significantly higher in the 86 cirrhotics that developed HCC compared with the 114 cirrhotics still HCC-free after 36 months of follow-up (p = 0.020). PIVKA-II ≥ 55 mAU/mL allowed to identify patients with cirrhosis at higher risk of HCC development (Log-rank test, p < 0.001; adjusted Hazard Ratio = 1.99, p = 0.001). In conclusion, the measurement of PIVKA-II in patients with cirrhosis may be useful to tailor personalized surveillance strategies.

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Tartaglione, Sara, Teresa Granato, Emanuela Anastasi, Antonio Angeloni, Cinzia Marchese, Lucia Manganaro, Valentina Viggiani, Serena Rita Zarrillo, and Irene Pecorella. "Protein Induced by Vitamin K Absence II (PIVKA-II) as a potential serological biomarker in pancreatic cancer: a pilot study." Biochemia medica 29, no. 2 (April 14, 2019): 352–58. http://dx.doi.org/10.11613/bm.2019.020707.

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Introduction: Protein induced by vitamin K absence II (PIVKA-II) is an abnormal prothrombin increased in gastrointestinal malignancy. We aimed to evaluate PIVKA-II in comparison to established pancreatic cancer (PC) biomarkers (CA 19-9, carcinoembryonic antigen (CEA) and CA 242) measured in PC patients and in patients with benign pancreatic diseases. Materials and methods: We studied 26 PC patients (Group 1) and 20 patients with benign pancreatic diseases (Group 2). PIVKA-II and CEA were measured by chemiluminescent enzyme immunoassay method (CLEIA) on LUMIPULSE G1200 (Fujirebio-Europe, Gent, Belgium), CA 19-9 and CA 242 were measured by ELSA (CisBio Bioassays, Codolet, France) and EIA (Fujirebio Diagnostics AB, Göteborg, Sweden), respectively. Receiver operating characteristic (ROC) analysis was performed to assess biomarkers’ diagnostic characteristics in both groups. Results: Median and interquartile range (IQR) in Group 1 and Group 2 were: 1749.0 (320.2 – 3921.0) vs. 31.0 (23.0 – 43.0) mAU/mL (P < 0.001) for PIVKA-II, 260.0 (158.7 – 272.0) vs. 45.2 (9.0 – 58.0) U/mL (P = 0.034) for CA 19-9, 104.0 (30.2 – 150.0) vs. 7.2 (4.8 – 26.0) U/mL (P < 0.050) for CA 242, 9.4 (5.3 – 37.5) vs. 4.5 (1.8 – 7.0) ng/mL (P = 0.021) for CEA. Areas under the ROC curve of PIVKA-II, CA 19-9, CA 242, CEA were 0.86 (95% CI: 0.71 – 1.00), 0.58 (95% CI: 0.38 – 0.78), 0.73 (95% CI: 0.54 – 0.92), 0.64 (95% CI: 0.44 – 0.85), respectively. Conclusions: PIVKA-II is significantly higher in PC than in benign pancreatic diseases. PIVKA-II shows a rather good diagnostic performance compared to CA 19-9, CEA and CA242, thus its determination could help PC management.

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Qin, Yu, Shuhua Yi, Yongjian Ding, Wei Zhang, Yan Qin, Jianjun Chen, and Zhiwei Wang. "Effect of plateau pika disturbance and patchiness on ecosystem carbon emissions in alpine meadow in the northeastern part of Qinghai–Tibetan Plateau." Biogeosciences 16, no. 6 (March 19, 2019): 1097–109. http://dx.doi.org/10.5194/bg-16-1097-2019.

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Abstract. Plateau pika (Ochotona curzoniae) disturbance and patchiness intensify the spatial heterogeneous distribution of vegetation productivity and soil physicochemical properties, which may alter the ecosystem carbon emission process. Nevertheless, previous research has mostly focused on the homogeneous vegetation patches rather than heterogeneous land surface. Thus, this study aims to improve our understanding of the difference in ecosystem respiration (Re) over heterogeneous land surface in an alpine meadow grassland. Six different land surface types, namely large bald patches, medium bald patches, small bald patches, intact grassland, above pika tunnel and pika pile, were selected to analyze the response of Re to pika disturbance and patchiness and the key controlling factors. The results showed that (1) Re in intact grassland was 0.22–1.07 times higher than pika pile and bald patches, (2) soil moisture (SM) of intact grassland was 2 %–11 % higher than that of pika pile and bald patches, despite the fact that pika disturbance increased the water infiltration rate while soil temperature (ST) in intact grassland was 1–3∘ less than pika pile and bald patches, (3) soil organic carbon (SOC) and total nitrogen (TN) in intact grassland were approximately 50 % and 60 % less than above pika tunnel, whereas they were 10 %–30 % and 22 %–110 % higher than pika pile and bald patches, and (4) Re was significantly correlated with SM, TN and vegetation biomass (P<0.05). Our results suggested that pika disturbance and patchiness altered the ecosystem carbon emission pattern, which was mainly attributed to the reduction in soil water and supply of substrates. Given the wide distribution of pikas and the large area of bald patches, the varied Re in heterogeneous land surfaces should not be neglected in the estimation of ecosystem carbon emissions at the plot or regional scale.

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Wu, Yi-Nan, Yu-Jun Ma, Wen-Ling Liu, and Wu-Zhao Zhang. "Modeling the Spatial Distribution of Plateau Pika (Ochotona curzoniae) in the Qinghai Lake Basin, China." Animals 9, no. 10 (October 21, 2019): 843. http://dx.doi.org/10.3390/ani9100843.

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The plateau pika (Ochotona curzoniae) is a keystone species in the alpine rangeland ecosystem of the Qinghai–Tibetan Plateau. Most previous studies of habitat selection by plateau pika have been conducted at a local microhabitat scale; however, little is known about the relationship between the distribution of plateau pika and macrohabitat factors at broad spatial scales. Using a presence-only ecological niche model (maximum entropy, Maxent), we predicted the distribution of plateau pika in the Qinghai Lake basin based on a set of environmental and anthropogenic variables at 1-km spatial resolution, and identified key macrohabitat factors that contribute to the predictive performance. Our results showed suitable area for plateau pika in the Qinghai Lake basin being approximately 3982 km2, which is 15.8% of the land area in the whole watershed. The distance to road emerged as the most important predictor of the distribution patterns of plateau pika, while the soil type was of ancillary importance. Mean air temperature of wettest quarter, distance to resident site and altitude also produced high gains in defining plateau pika’s distribution. A higher predictive accuracy was achieved by the model that combined environmental and anthropogenic variables. With the constraint of human factors, the presence probability of plateau pika in about 1661 km2 will increase. These findings demonstrate the impact of human activities on the distribution of plateau pika, and the importance of vegetation reservation for plateau pika control.

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LIU, HANWU, LI ZHOU, WEI LIU, and HUAKUN ZHOU. "USING A CELLULAR-AUTOMATA MODEL TO INVESTIGATE THE EFFECTS OF GRAZING ON PLATEAU PIKA POPULATION DYNAMICS." International Journal of Biomathematics 04, no. 03 (September 2011): 275–87. http://dx.doi.org/10.1142/s179352451100126x.

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The plateau pika is a keystone species of Qinghai–Tibet plateau, but its overabundance aggravates the degradation of alpine meadow. Grazing is the most convenient manner to utilize alpine meadow. Grazing would change vegetation condition, that is, change the habitat of plateau pika and so lead to variation of plateau pika population. Based on ecological characteristics of plateau pika and alpine meadow, a cellular-automata model is established to investigate the influence of grazing on dynamics of plateau pika population. Vegetation shortens with the increase of grazing intensity. When grazing intensity is light, the height of vegetation under summer grazing, continuous grazing, rotational grazing and winter grazing decrease in turn. The ACC (average carrying capacity of plateau pika) is higher on degraded meadow and is lower on undegraded meadow. On undegraded meadow grazing affects the value of ACC, whereas, on degraded meadow grazing has slight effect on it. On undegraded meadow, plateau pika occupies all cells speedly, the amount of damaged cells and the average amount of live holes in occupied cells decrease or hold the line on temporal dimension. On degraded meadow, the dispersal of plateau pika is restrained, the amount of damaged cells and the average amount of live holes in occupied cells increase on temporal dimension.

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Dornan, Gillian L., Jacob A. McPhail, and John E. Burke. "Type III phosphatidylinositol 4 kinases: structure, function, regulation, signalling and involvement in disease." Biochemical Society Transactions 44, no. 1 (February 9, 2016): 260–66. http://dx.doi.org/10.1042/bst20150219.

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Many important cellular functions are regulated by the selective recruitment of proteins to intracellular membranes mediated by specific interactions with lipid phosphoinositides. The enzymes that generate lipid phosphoinositides therefore must be properly positioned and regulated at their correct cellular locations. Phosphatidylinositol 4 kinases (PI4Ks) are key lipid signalling enzymes, and they generate the lipid species phosphatidylinositol 4-phosphate (PI4P), which plays important roles in regulating physiological processes including membrane trafficking, cytokinesis and organelle identity. PI4P also acts as the substrate for the generation of the signalling phosphoinositides phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). PI4Ks also play critical roles in a number of pathological processes including mediating replication of a number of pathogenic RNA viruses, and in the development of the parasite responsible for malaria. Key to the regulation of PI4Ks is their regulation by a variety of both host and viral protein-binding partners. We review herein our current understanding of the structure, regulatory interactions and role in disease of the type III PI4Ks.

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Wei, W. R., J. D. He, and Q. Y. Zheng. "Plateau pikas (Ochotona curzoniae) at low densities have no destructive effect on winter pasture in alpine meadows." Rangeland Journal 42, no. 1 (2020): 55. http://dx.doi.org/10.1071/rj19042.

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The plateau pika (Ochotona curzoniae) is a common small mammal species present in the alpine meadow ecosystem on the Qinghai-Tibetan Plateau (QTP), and is regarded as a pest in alpine meadows when population density exceeds a certain threshold. However, whether pikas with a low population density have a detrimental effect on alpine meadows in winter pasture is unknown. Vegetation and soil were sampled in eight individual pika patchy home ranges and eight control areas, and we found vegetation and soil properties showed different trends in the pika home ranges. Plateau pika activity significantly increased the below-ground biomass, soil pH and total potassium, but had no significant effect on the plant species richness or diversity, soil moisture, NH4-N, NO3-N, total phosphorus, available phosphorus and soil organic content. However, plateau pika activity reduced some vegetation and soil properties (e.g. vegetation cover, vegetation height, aboveground biomass, graminoids, soil bulk density and available potassium). These results imply that pika activity may improve some soil nutrients but have no destructive effect on winter pasture at a low population density.

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Mikhaylova, Marina, Pasham Parameshwar Reddy, and Michael R. Kreutz. "Role of neuronal Ca2+-sensor proteins in Golgi–cell-surface membrane traffic." Biochemical Society Transactions 38, no. 1 (January 19, 2010): 177–80. http://dx.doi.org/10.1042/bst0380177.

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The regulated local synthesis of PtdIns4P and PtdIns(4,5)P2 is crucial for TGN (trans-Golgi network)–plasma membrane trafficking. The activity of PI4Kβ (phosphoinositide 4-kinase IIIβ) at the Golgi membrane is a first mandatory step in this process. In addition to PI4Kβ activity, elevated Ca2+ levels are also needed for the exit of vesicles from the TGN. The reason for this Ca2+ requirement is at present unclear. In the present review, we discuss the role of neuronal Ca2+-sensor proteins in the regulation of PI4Kβ and suggest that this regulation might impose a need for elevated Ca2+ levels for a late step of vesicle assembly.

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Mozrzymas, Renata, Dariusz Walkowiak, Sławomira Drzymała-Czyż, Patrycja Krzyżanowska-Jankowska, Monika Duś-Żuchowska, Łukasz Kałużny, and Jarosław Walkowiak. "Vitamin K Status in Adherent and Non-Adherent Patients with Phenylketonuria: A Cross-Sectional Study." Nutrients 12, no. 6 (June 14, 2020): 1772. http://dx.doi.org/10.3390/nu12061772.

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This is the first study to evaluate vitamin K status in relation to dietary intake and phenylalanine dietary compliance in patients with phenylketonuria (PKU). The dietary and PKU formula intake of vitamin K was calculated in 34 PKU patients, with vitamin K status determined by the measurement of prothrombin induced by vitamin K absence (PIVKA-II). Blood phenylalanine concentrations in the preceding 12 months were considered. There were significantly more phenylalanine results exceeding 6 mg/dL in patients with normal PIVKA-II concentrations than in those with abnormal PIVKA-II levels (p = 0.035). Similarly, a higher total intake of vitamin K and dietary vitamin intake expressed as μg/day (p = 0.033 for both) and %RDA (p = 0.0002 and p = 0.003, respectively) was observed in patients with normal PIVKA-II levels. Abnormal PIVKA-II concentrations were associated with a lower OR (0.1607; 95%CI: 0.0273–0.9445, p = 0.043) of having a median phenylalanine concentration higher than 6 mg/dL. In conclusion, vitamin K deficiency is not uncommon in phenylketonuria and may also occur in patients with adequate vitamin K intake. PKU patients with better dietary compliance have a higher risk of vitamin K deficiency. The present findings highlight the need for further studies to re-evaluate dietary recommendations regarding vitamin K intake, both concerning formula-based and dietary consumption of natural products.

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Harrington, D. J., H. Western, C. Seton-Jones, S. Rangarajan, T. Beynon, and M. J. Shearer. "A study of the prevalence of vitamin K deficiency in patients with cancer referred to a hospital palliative care team and its association with abnormal haemostasis." Journal of Clinical Pathology 61, no. 4 (October 8, 2007): 537–40. http://dx.doi.org/10.1136/jcp.2007.052498.

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Background:Many patients with advanced cancer are malnourished. Anorexia is common, as is the use of chemotherapy, which may cause nausea and poor appetite. Ten per cent of these patients experience haemorrhagic events.Aim:Since vitamin K deficiency (VKD) causes bleeding, to establish the prevalence of VKD in patients with advanced cancer receiving palliative care.Methods:Serum concentrations of vitamin K1 and undercarboxylated factor II (PIVKA-II) were determined in 46 (17 male/29 female) inpatients aged 26–85 (mean 58) years. INR and liver function tests (bilirubin, ALT, GGT and ALP) were also performed.Results:Vitamin K1 was below the lower limit of the reference range (0.33 nmol/l) in 22% of patients. 78% of patients had some degree of functional VKD indicated by raised (>0.2 AU/ml) PIVKA-II. Six patients (13%) had a prolonged INR, all of whom had raised PIVKA-II and GGT; 4 also had vitamin K1 <0.33 nmol/l. Three patients (6.5%) had clinically significant VKD characterised by INR >1.5, PIVKA-II >10 AU/ml, and undetectable vitamin K1.Conclusions:Patients with advanced cancer are prone to VKD which, while usually subclinical, may develop to a clinically relevant prolongation of the INR. Serum measurements of vitamin K1 and PIVKA-II can be used to detect VKD and monitor vitamin K status before an increased risk of bleeding develops.

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Kapp-Barnea, Yaara, Lihi Ninio-Many, Koret Hirschberg, Mitsunori Fukuda, Andreas Jeromin, and Ronit Sagi-Eisenberg. "Neuronal Calcium Sensor-1 and Phosphatidylinositol 4-Kinase β Stimulate Extracellular Signal-regulated Kinase 1/2 Signaling by Accelerating Recycling through the Endocytic Recycling Compartment." Molecular Biology of the Cell 17, no. 9 (September 2006): 4130–41. http://dx.doi.org/10.1091/mbc.e05-11-1014.

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We demonstrate that recycling through the endocytic recycling compartment (ERC) is an essential step in FcεRI-induced activation of extracellular signal-regulated kinase (ERK)1/2. We show that ERK1/2 acquires perinuclear localization and colocalizes with Rab 11 and internalized transferrin in FcεRI-activated cells. Moreover, a close correlation exists between the amount of ERC-localized ERK1/2 and the amount of phospho-ERK1/2 that resides in the nucleus. We further show that by activating phosphatidylinositol 4-kinase β (PI4Kβ) and increasing the cellular level of phosphatidylinositol(4) phosphate, neuronal calcium sensor-1 (NCS-1), a calmodulin-related protein, stimulates recycling and thereby enhances FcεRI-triggered activation and nuclear translocation of ERK1/2. Conversely, NCS-1 short hairpin RNA, a kinase dead (KD) mutant of PI4Kβ (KD-PI4Kβ), the pleckstrin homology (PH) domain of FAPP1 as well as RNA interference of synaptotagmin IX or monensin, which inhibit export from the ERC, abrogate FcεRI-induced activation of ERK1/2. Consistently, NCS-1 also enhances, whereas both KD-PI4Kβ and FAPP1-PH domain inhibit, FcεRI-induced release of arachidonic acid/metabolites, a downstream target of ERK1/2 in mast cells. Together, our results demonstrate a novel role for NCS-1 and PI4Kβ in regulating ERK1/2 signaling and inflammatory reactions in mast cells. Our results further identify the ERC as a crucial determinant in controlling ERK1/2 signaling.

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Tonkyn, David, Kaitlyn Hanley, and Katie Quakenbush. "Factors influencing American Pika (Ochotona princeps) distributions in the Beartooth Mountains and implications of a warming climate." UW National Parks Service Research Station Annual Reports 39 (December 15, 2016): 43–50. http://dx.doi.org/10.13001/uwnpsrc.2016.5283.

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Over the next century, temperatures are expected to rise by 1-4°C in the Greater Yellowstone Region. This will force alpine species such as the American pika (Ochotona princeps) to compensate, shift in distribution, or disappear. If pika are limited by temperatures, they may disappear from warmer, lower elevation southwest-facing sites and find refuge in cooler, higher elevation northeast-facing sites. However, populations have been found across a range of elevations, suggesting they are instead limited by food or a need for large talus slopes. We explored these possibilities in the Beartooth Mountains, near Yellowstone, by surveying 31 pika populations and asking whether pika density varied with elevation, food availability, or aspect, all related to temperatures, or with talus area, which is not. Pika density was estimated by latrine density, which ranged from 14.6 to 167.4 per ha and declined slightly with elevation but was unrelated to vegetation. From a preliminary analysis of 61 sites, we estimated an occupancy probability of 0.89, with occupancy most strongly related to talus area. We will test and refine these results by predicting the locations of additional colonies, and by incorporating microclimate data into an ecophysiological model of temperature dependence in pika, with the long-term goal of predicting the fate of pika under a warming climate. Featured photo by Diana R on Unsplash. https://unsplash.com/photos/g6CD00mDN5A

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Yang, Tian, Hao Xing, Guoqiang Wang, Nianyue Wang, Miaoxia Liu, Cunling Yan, Huijun Li, et al. "A Novel Online Calculator Based on Serum Biomarkers to Detect Hepatocellular Carcinoma among Patients with Hepatitis B." Clinical Chemistry 65, no. 12 (December 1, 2019): 1543–53. http://dx.doi.org/10.1373/clinchem.2019.308965.

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Abstract BACKGROUND Early detection of hepatocellular carcinoma (HCC) among hepatitis B virus (HBV)-infected patients remains a challenge, especially in China. We sought to create an online calculator of serum biomarkers to detect HCC among patients with chronic hepatitis B (CHB). METHODS Participants with HBV-HCC, CHB, HBV-related liver cirrhosis (HBV-LC), benign hepatic tumors, and healthy controls (HCs) were recruited at 11 Chinese hospitals. Potential serum HCC biomarkers, protein induced by vitamin K absence or antagonist-II (PIVKA-II), α-fetoprotein (AFP), lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3) and α-L-fucosidase (AFU) were evaluated in the pilot cohort. The calculator was built in the training cohort via logistic regression model and validated in the validation cohort. RESULTS In the pilot study, PIVKA-II and AFP showed better diagnostic sensitivity and specificity compared with AFP-L3 and AFU and were chosen for further study. A combination of PIVKA-II and AFP demonstrated better diagnostic accuracy in differentiating patients with HBV-HCC from patients with CHB or HBV-LC than AFP or PIVKA-II alone [area under the curve (AUC), 0.922 (95% CI, 0.908–0.935), sensitivity 88.3% and specificity 85.1% for the training cohort; 0.902 (95% CI, 0.875–0.929), 87.8%, and 81.0%, respectively, for the validation cohort]. The nomogram including AFP, PIVKA-II, age, and sex performed well in predicting HBV-HCC with good calibration and discrimination [AUC, 0.941 (95% CI, 0.929–0.952)] and was validated in the validation cohort [AUC, 0.931 (95% CI, 0.909–0.953)]. CONCLUSIONS Our results demonstrated that a web-based calculator including age, sex, AFP, and PIVKA-II accurately predicted the presence of HCC in patients with CHB. ClinicalTrials.gov Identifier NCT03047603

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Kondo, Akira, Hirokazu Kondo, Yoshihisa Nakagawa, Hiroyuki Ito, Daiki Shimomura, Noriko Hatanaka, Yoshikazu Yamamoto, Misato Nakatani, Eri Iwai-Kanai, and Shuji Matsuo. "Influence of Warfarin Therapy on Prothrombin Production and Its Posttranslational Modifications." Journal of Applied Laboratory Medicine 5, no. 6 (June 28, 2020): 1216–27. http://dx.doi.org/10.1093/jalm/jfaa069.

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Abstract Background Protein induced by vitamin K absence-II (PIVKA-II) is produced by the liver during hepatoma and upon warfarin administration. Those patients have disturbed protein synthesis and glycosylation in the liver. This decreases the number of γ-carboxyglutamyl (Gla) residues on prothrombin, converting prothrombin into PIVKA-II. The mechanism of this conversion, however, is not clearly understood. Methods Prothrombin was isolated from healthy and warfarin-treated individuals whose liver function of protein production was quantitatively normal. Glycan structures in the purified prothrombin containing PIVKA-II were qualitatively analyzed by high performance liquid chromatography after labeling the glycan with fluorophore 2-aminobenzamide. Results The concentration of PIVKA-II was significantly higher in the warfarin-treated individuals than in the healthy individuals (P< 0.001). Although protein production in the liver was normal in both groups, the concentration of prothrombin was lower in the warfarin-treated individuals than in the healthy individuals (P < 0.001). The main glycan was A2 in the healthy and warfarin-treated individuals (86.6 ± 4.4% and 85.6 ± 3.4%, respectively). Eight types of glycan were characterized in both groups, although generation of PIVKA-II in the warfarin-treated individuals did not lead to variation in glycosylation of prothrombin. Conclusions Warfarin therapy leads to lower amounts of prothrombin and Gla residues within prothrombin without exerting qualitative and quantitative change in glycan profile and protein synthetic function in the liver.

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Zhou, Jiyong, Wenbo Sun, Junhua Wang, Junqing Guo, Wei Yin, Nanping Wu, Lanjuan Li, et al. "Characterization of the H5N1 Highly Pathogenic Avian Influenza Virus Derived from Wild Pikas in China." Journal of Virology 83, no. 17 (June 24, 2009): 8957–64. http://dx.doi.org/10.1128/jvi.00793-09.

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ABSTRACT The highly pathogenic H5N1 avian influenza virus emerged from China in 1996 and has spread across Eurasia and Africa, with a continuous stream of new cases of human infection appearing since the first large-scale outbreak among migratory birds at Qinghai Lake. The role of wild birds, which are the natural reservoirs for the virus, in the epidemiology of the H5N1 virus has raised great public health concern, but their role in the spread of the virus within the natural ecosystem of free-ranging terrestrial wild mammals remains unclear. In this study, we investigated H5N1 virus infection in wild pikas in an attempt to trace the circulation of the virus. Seroepidemiological surveys confirmed a natural H5N1 virus infection of wild pikas in their native environment. The hemagglutination gene of the H5N1 virus isolated from pikas reveals two distinct evolutionary clades, a mixed/Vietnam H5N1 virus sublineage (MV-like pika virus) and a wild bird Qinghai (QH)-like H5N1 virus sublineage (QH-like pika virus). The amino acid residue (glutamic acid) at position 627 encoded by the PB2 gene of the MV-like pika virus was different from that of the QH-like pika virus; the residue of the MV-like pika virus was the same as that of the goose H5N1 virus (A/GS/Guangdong [GD]/1/96). Further, we discovered that in contrast to the MV-like pika virus, which is nonpathogenic to mice, the QH-like pika virus is highly pathogenic. To mimic the virus infection of pikas, we intranasally inoculated rabbits, a species closely related to pikas, with the H5N1 virus of pika origin. Our findings first demonstrate that wild pikas are mammalian hosts exposed to H5N1 subtype avian influenza viruses in the natural ecosystem and also imply a potential transmission of highly pathogenic avian influenza virus from wild mammals into domestic mammalian hosts and humans.

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Li, Wei-Dong, and Andrew T. Smith. "Dramatic decline of the threatened Ili pika Ochotona iliensis (Lagomorpha: Ochotonidae) in Xinjiang, China." Oryx 39, no. 1 (January 2005): 30–34. http://dx.doi.org/10.1017/s0030605305000062.

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The Vulnerable Ili pika Ochotona iliensis (Lagomorpha: Ochotonidae) is a poorly known mammal species that inhabits a restricted geographic range in the Tian Shan Mountains, Xinjiang Uygur Autonomous Region, China. It was discovered in 1983, described in 1986, and subsequently investigated over the following decade. As no studies were conducted on this pika during the next 10 years, a comprehensive census was undertaken in the summers of 2002 and 2003, including all sites where it had previously been observed. Evidence of the Ili pika was found at only 6 of 14 sites censused, and was extinct in two of six regions, including the type and paratype localities (Jilimalale Mountain). Ili pika populations appear to have declined in three of six regions, and in only one region did the population appear to be comparable to a decade earlier. Like all rock-dwelling pikas, the Ili pika has a low population density and rate of reproduction. Additionally, populations on its preferred habitat of cliff faces are highly fragmented. Increased temperatures, possibly due to global warming, and increased grazing pressure may have interacted with the normal population dynamics of the Ili pika to contribute to its recent dramatic decline. We recommend that the Ili pika's Red List status be changed from Vulnerable to Endangered.

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Wu, Liujie, Ayan Sadhukhan, Yuriko Kobayashi, Naohisa Ogo, Mutsutomo Tokizawa, Raj Kishan Agrahari, Hiroki Ito, et al. "Involvement of phosphatidylinositol metabolism in aluminum-induced malate secretion in Arabidopsis." Journal of Experimental Botany 70, no. 12 (April 12, 2019): 3329–42. http://dx.doi.org/10.1093/jxb/erz179.

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Abstract To identify the upstream signaling of aluminum-induced malate secretion through aluminum-activated malate transporter 1 (AtALMT1), a pharmacological assay using inhibitors of human signal transduction pathways was performed. Early aluminum-induced transcription of AtALMT1 and other aluminum-responsive genes was significantly suppressed by phosphatidylinositol 4-kinase (PI4K) and phospholipase C (PLC) inhibitors, indicating that the PI4K–PLC metabolic pathway activates early aluminum signaling. Inhibitors of phosphatidylinositol 3-kinase (PI3K) and PI4K reduced aluminum-activated malate transport by AtALMT1, suggesting that both the PI3K and PI4K metabolic pathways regulate this process. These results were validated using T-DNA insertion mutants of PI4K and PI3K-RNAi lines. A human protein kinase inhibitor, putatively inhibiting homologous calcineurin B-like protein-interacting protein kinase and/or Ca-dependent protein kinase in Arabidopsis, suppressed late-phase aluminum-induced expression of AtALMT1, which was concomitant with the induction of an AtALMT1 repressor, WRKY46, and suppression of an AtALMT1 activator, Calmodulin-binding transcription activator 2 (CAMTA2). In addition, a human deubiquitinase inhibitor suppressed aluminum-activated malate transport, suggesting that deubiquitinases can regulate this process. We also found a reduction of aluminum-induced citrate secretion in tobacco by applying inhibitors of PI3K and PI4K. Taken together, our results indicated that phosphatidylinositol metabolism regulates organic acid secretion in plants under aluminum stress.

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Li, Yaoming, Lili Jiang, Wangwang Lv, Shujuan Cui, Lirong Zhang, Qi Wang, Fandong Meng, et al. "Fungal pathogens pose a potential threat to animal and plant health in desertified and pika-burrowed alpine meadows on the Tibetan Plateau." Canadian Journal of Microbiology 65, no. 5 (May 2019): 365–76. http://dx.doi.org/10.1139/cjm-2018-0338.

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Intact Tibetan meadows provide significant defense against soil-borne pathogen dispersal. However, dramatic meadow degradation has been observed due to climate change and pika damage, but their impacts on soil-borne pathogens are still unclear. With approximately 40% of the world’s population living in Tibetan Plateau and its downstream watersheds, this lack of knowledge should be of great concern. Here, we used Illumina amplicon sequencing to characterize the changes in potential human, domestic animal, plant, and zoonotic bacterial and fungal pathogens in nondegraded, desertified, and pika-burrowed meadows. The relative abundance of bacterial domestic animal pathogens and zoonotic pathogens were significantly increased by desertification. Pika burrowing significantly increased the relative abundance of bacterial human pathogens and zoonotic pathogens. The species richness and relative abundance of fungal pathogens was significantly increased by desertification and pika burrowing. Accordingly, fungal plant and animal pathogens categorized by FUNGuid significantly increased in desertified and pika-burrowed meadows. Soil chemical and plant properties explained 38% and 64% of the bacterial and fungal pathogen community variance, respectively. Therefore, our study indicates for the first time that both alpine meadow desertification and pika burrowing could potentially increase infectious disease risks in the alpine ecosystem, especially for fungal diseases.

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Shank, Christopher C. "Are American Pikas (Ochotona princeps) in the Canadian Rockies vulnerable to climate change?" Canadian Field-Naturalist 129, no. 3 (October 22, 2015): 254. http://dx.doi.org/10.22621/cfn.v129i3.1724.

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The American Pika (Ochotona princeps) is vulnerable to climate change as a result of its dependence on cool, moist conditions. Most research on climatic determinants of American Pika distribution has been done in the United States where conditions are different from those in the higher-latitude pika ranges of the Canadian Rockies. I examined recent (1980–2009) and future (2050s and 2080s) average and maximum mean summer temperatures for 114 current American Pika locations in Alberta to assess whether future conditions are likely to place these animals at risk. At all current sites, mean summer temperatures (MSTs) in the 2050s are expected to be below that chosen by the United States Fish and Wildlife Service as a threshold for at-risk status of O. princeps. By the 2050s, most current American Pika locations have sufficient elevation within 5 km to allow individuals to migrate vertically to reach habitat with MST similar to that of their current location. Even in the 2080s, almost all current sites have sufficient elevation within 5 km to maintain extreme single-year and average MSTs lower than the highest values recorded at those sites in the recent past (13.9°C and 12.5°C respectively). However, by the 2080s under an extreme greenhouse gas emissions scenario, only 34% of current pika sites will allow for such migration. Although considerable uncertainty remains, particularly with respect to availability of habitat, these results suggest that American Pika populations in Alberta will likely be capable of persisting throughout this century, although their survival will depend increasingly on successful vertical migration.

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Pang, Xiao Pan, and Zheng Gang Guo. "Plateau pika disturbances alter plant productivity and soil nutrients in alpine meadows of the Qinghai-Tibetan Plateau, China." Rangeland Journal 39, no. 2 (2017): 133. http://dx.doi.org/10.1071/rj16093.

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Plateau pika (Ochotona curzoniae) is an endemic mammal in the Qinghai-Tibetan Plateau, and its activities create extensive disturbances on vegetation and soil of alpine meadow. Field surveys at two sites were conducted to determine the effects of plateau pika disturbances on important soil factors and plant biomass of vegetated land, and their relationships of the same alpine meadow type. Our study showed that plateau pika disturbances significantly increased soil organic carbon, soil total nitrogen, graminoid biomass and the number of plant species, and significantly decreased soil moisture and forb biomass, although they had no significant impacts on soil total phosphorus, soil total potassium and total biomass on vegetated land. Our study further showed that soil organic carbon, soil total nitrogen, graminoid biomass and the number of plant species were much higher at intermediate disturbance intensities than those at low and high disturbance intensities in the disturbed areas, and soil moisture showed a decreasing trend with the increase of disturbance intensity. Plateau pika disturbances altered the contribution of some important soil nutrients and moisture to plant biomass, and had different impact on the best models between plant biomass (total biomass, graminoid biomass and forb biomass) and predominant soil factors. Our results demonstrated that the optimal disturbance intensities of plateau pika were beneficial to alpine meadow. These results highlighted the influence of the presence of plateau pika and its disturbance intensity on key soil nutrients and plant productivity on vegetated land of the same alpine meadow type, which will help us better understand the role of plateau pika in the alpine meadow ecosystem.

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Pataer, Apar. "Target Misfolded Protein Clearance Pathway for Cancer Therapy." Proceedings 40, no. 1 (January 24, 2020): 45. http://dx.doi.org/10.3390/proceedings2019040045.

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The role of RNA-dependent protein kinase R (PKR) and its association with misfolded protein expression in cancer cells are unclear. Herein we report that PKR regulates misfolded protein clearance by preventing it release through exosomes and promoting lysosomal degradation of misfolded prion proteins in cancer cells. We demonstrated that PKR contributes to the lysosome function and regulates misfolded prion protein clearance. We hypothesized that PKR-associated lysosome function is critical for cancer but not normal cell survival, representing an effective approach for highly targeted cancer therapy. In screening a compound library, we identified two PKR-associated compound 1 did not affect normal cells but selectively induced cell death in cancer cells depending on their PKR expression status. Pac 1 significantly inhibited the growth of human lung and breast xenograft tumors in mice with no toxicity. Pac 1 binds to PI4K2A and disrupts the PKR/PI4K2A associated lysosome complex, contributing to destabilization of cancer cell lysosomes and triggering cell death. We observed that PKR and PI4K2A play significant prognostic roles in breast cancer patients. These results demonstrate that targeting of a PI4K2A/PKR lysosome complex may be an effective approach for cancer therapy.

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Journal articles on the topic 'PI4KA'

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