Nicotinamide riboside or IL-17A signaling blockers to prevent liver disorders

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Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing.

Enteroviruses are suspected to contribute to insulin-producing β cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show that coxsackievirus B type 4 (CVB4) infection in human islet-engrafted mice and in rat insulinoma cells displays loss of unconventional prefoldin RPB5 interactor (URI) and PDX1, affecting β cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in β cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in β cells are more glucose tolerant. Mechanistically, URI loss triggers estrogen receptor nuclear translocation leading to DNA methyltransferase 1 (DNMT1) expression, which induces Pdx1 promoter hypermethylation and silencing. Consequently, demethylating agent procainamide-mediated DNMT1 inhibition reinstates PDX1 expression and protects against diabetes in pancreatic URI-depleted mice . Finally, the β cells of human diabetes patients show correlations between viral protein 1 and URI, PDX1, and DNMT1 levels. URI and DNMT1 expression and PDX1 silencing provide a causal link between enterovirus infection and diabetes.Human diabetic pancreatic samples and data were obtained from the CNIO Biobank thanks to the help of Maria-Jesus Artiga and from Biobanc-Mur, MarBiobank, Vasque Biobank, and Andalusian Public Health System Biobank, integrated in the Spanish Biobank Network and funded by Instituto de Salud Carlos III. We are also thankful to the Biobank of IDIBAPS, Barcelona, for providing samples to A.N. Samples were processed following standard operating procedures with the appropriate approval of the Ethics and Scientific Committees. We also thank the CNIO Mouse Genome Editing Core Unit as well as the CNIO Genomics Unit for their support. We are also thankful to Dr. K. Qvortrup (University of Copenhagen, Denmark) for the electron microscopy. This work was funded by grant to J.P.W. supported by the National Institutes of Health NIAID/NIDDK R01 AI116920, and by grants to N.D. supported by the EFSD/JRDF/Lilly Programme through the European Foundation for the Study of Diabetes (EFSD) and and by the State Research Agency (AEI, 10.13039/501100011033) from the Spanish Ministry of Science and Innovation (projects SAF2016-76598-R, SAF2017-92733-EXP, and RTI2018-094834-B-I00) through the European Regional Development Fund (ERDF). This work was developed at the CNIO, which is funded by the Health Institute Carlos III (ISCIII) and the Spanish Ministry of Science and Innovation.S

Endogenous retroviruses shape pluripotency specification in mouse embryos.

The smooth and precise transition from totipotency to pluripotency is a key process in embryonic development, generating pluripotent stem cells capable of forming all cell types. While endogenous retroviruses (ERVs) are essential for early development, their precise roles in this transition remains mysterious. Using cutting-edge genetic and biochemical techniques in mice, we identify MERVL-gag, a retroviral protein, as a crucial modulator of pluripotent factors OCT4 and SOX2 during lineage specification. MERVL-gag tightly operates with URI, a prefoldin protein that concurs with pluripotency bias in mouse blastomeres, and which is indeed required for totipotency-to-pluripotency transition. Accordingly, URI loss promotes a stable totipotent-like state and embryo arrest at 2C stage. Mechanistically, URI binds and shields OCT4 and SOX2 from proteasome degradation, while MERVL-gag displaces URI from pluripotent factor interaction, causing their degradation. Our findings reveal the symbiotic coevolution of ERVs with their host cells to ensure the smooth and timely progression of early embryo development.acknowledgments: We thank all mouse providers as described in Materials and Methods. We also thank the cniO Animal Facility for mouse maintenance. We acknowledge M. Ko (Keio University, Systems Medicine, Japan) for providing the pZscan4- emerald reporter plasmid. Funding: S.d.l.R. was supported by a fellowship from the comunidad de Madrid and by funds from the Severo Ochoa- cniO. this work was funded by grants to n.d. supported by the State Research Agency (Aei; 10.13039/501100011033) from the Spanish Ministry of Science and innovation (Rti2018- 094834- B- i00 and Pid2021- 122695OB- i00), also including the idiFFeR network of excellence (Red2022- 134792- t), cofunded by european Regional development Fund (eRdF), by the comunidad Autónoma de Madrid (S2017/BMd- 3817), and by the Asociación española contra el cáncer (Aecc) (PRYGn211184dJOU). this work was developed at the cniO funded by the health institute carlos iii (iSciii) and the Spanish Ministry of Science and innovation. Author contributions: S.d.l.R. designed and performed the experiments and analyzed all the data. S.d.l.R. analyzed all the bioinformatics data. M.d.M.R. performed some experiments. P.v. and S.O. performed microinjection in vivo and chimera embryo assay. S.d.l.R and n.d. developed the project and wrote the manuscript. n.d. conceived the project and secured funding. Competing interests:the authors declare that they have no competing interests. Data and materials availability: All data are available in the main text or Materials and Methods. Materials are available upon request to n.d. and the sharing of materials described in this work will be subject to standard material transfer agreementsS

Coxsackievirus B Type 4 Infection in beta Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing

Enteroviruses are suspected to contribute to insulin-producing beta cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show that coxsackievirus B type 4 (CVB4) infection in human islet-engrafted mice and in rat insulinoma cells displays loss of unconventional prefoldin RPB5 interactor (URI) and PDX1, affecting beta cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in beta cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in beta cells are more glucose tolerant. Mechanistically, URI loss triggers estrogen receptor nuclear translocation leading to DNA methyltransferase 1 (DNMT1) expression, which induces Pdx1 promoter hypermethylation and silencing. Consequently, demethylating agent procainamide-mediated DNMT1 inhibition reinstates PDX1 expression and protects against diabetes in pancreatic URI-depleted mice . Finally, the beta cells of human diabetes patients show correlations between viral protein 1 and URI, PDX1, and DNMT1 levels. URI and DNMT1 expression and PDX1 silencing provide a causal link between enterovirus infection and diabetes

Diagenesis- and thermal maturity-evolution of the Silurian unconventional hydrocarbon deposits (Tassili n’Ajjer plateau, Algeria): Clay mineralogy, graptolite reflectance, and K–Ar dating

peer reviewedThe need for determining the thermal maturity of Lower Paleozoic rocks has increased with the intensified unconventional shale oil/gas resources exploration within North Africa, Arabian Peninsula, and the adjoining regions. Indeed, Lower Paleozoic strata represent an increasingly important resource that is related to the globally widespread occurrence of graptolite-bearing marine sediments in an expansive shelf area of the Gondwana. However, some crucial information for basin analysis remains poorly understood even across the largest hydrocarbon-producing province in Algeria. The present study provides a solid understanding of the diagenesis- and thermal maturity-evolution from the Tassili n’Ajjer plateau while involving multiple and independent approaches, such as clay mineralogy, petrography, graptolite reflectance, source rock maturity, as well as illite K−Ar geochronology. The combined use of X-ray analysis and field emission scanning electron microscope evidenced kaolinite, illite, and iron-rich chlorite as the main authigenic mineral phases. K−Ar data indicate that episodic in situ illite crystallization occurred at different times, the oldest illite at about 335 Ma and the youngest illite between 238 to 179 Ma, under diagenetic-to-hydrothermal conditions. Paleotemperature estimates (~165–232°C) derived from illite crystallinity (0.37–1.58 Δ°2θ), and graptolite reflectance (VReqv, 1.09–1.84%) values indicate deep diagenetic-low anchizone boundary conditions. This is broadly suggestive of late oil-to-dry gas zones of hydrocarbon generation and destruction, notably in the western sector of the study area. At least two heating events and diagenetic fluid flow processes are identified mainly in response to various tectonic events. They are largely due to fault reactivations, and migration of hot, potassium-rich, fluids throughout the Phanerozoic. Additionally, these events and processes had a later influence on the hydrocarbon maturation, migration, and/or entrapment, especially along the inherited N-S lineaments and Hoggar Massif mega-shear zones in the westernmost part of the Tassili n’Ajjer plateau. Lastly, it is important to highlight that the promising areas offering the highest potential for future unconventional hydrocarbon resource exploration could be most likely those bordering major lineaments, coupled with subsequent igneous activity, where unrestricted hydrothermal fluids are frequently reported, as well as the maturation, being much more advanced.Silurian succession from North Africa - Sedimentology, ichnology and thermal history for a new era of hydrocarbon exploratio

AMP-Activated Kinase AMPK Is Expressed in Boar Spermatozoa and Regulates Motility

The main functions of spermatozoa required for fertilization are dependent on the energy status and metabolism. AMP-activated kinase, AMPK, acts a sensor and regulator of cell metabolism. As AMPK studies have been focused on somatic cells, our aim was to investigate the expression of AMPK protein in spermatozoa and its possible role in regulating motility. Spermatozoa from boar ejaculates were isolated and incubated under different conditions (38,5°C or 17°C, basal medium TBM or medium with Ca2+ and bicarbonate TCM, time from 1–24 hours) in presence or absence of AMPK inhibitor, compound C (CC, 30 µM). Western blotting reveals that AMPK is expressed in boar spermatozoa at relatively higher levels than in somatic cells. AMPK phosphorylation (activation) in spermatozoa is temperature-dependent, as it is undetectable at semen preservation temperature (17°C) and increases at 38,5°C in a time-dependent manner. AMPK phosphorylation is independent of the presence of Ca2+ and/or bicarbonate in the medium. We confirm that CC effectively blocks AMPK phosphorylation in boar spermatozoa. Analysis of spermatozoa motility by CASA shows that CC treatment either in TBM or in TCM causes a significant reduction of any spermatozoa motility parameter in a time-dependent manner. Thus, AMPK inhibition significantly decreases the percentages of motile and rapid spermatozoa, significantly reduces spermatozoa velocities VAP, VCL and affects other motility parameters and coefficients. CC treatment does not cause additional side effects in spermatozoa that might lead to a lower viability even at 24 h incubation. Our results show that AMPK is expressed in spermatozoa at high levels and is phosphorylated under physiological conditions. Moreover, our study suggests that AMPK regulates a relevant function of spermatozoa, motility, which is essential for their ultimate role of fertilization

Transcriptional regulation of gene expression during osmotic stress responses by the mammalian target of rapamycin

Although stress can suppress growth and proliferation, cells can induce adaptive responses that allow them to maintain these functions under stress. While numerous studies have focused on the inhibitory effects of stress on cell growth, less is known on how growth-promoting pathways influence stress responses. We have approached this question by analyzing the effect of mammalian target of rapamycin (mTOR), a central growth controller, on the osmotic stress response. Our results showed that mammalian cells exposed to moderate hypertonicity maintained active mTOR, which was required to sustain their cell size and proliferative capacity. Moreover, mTOR regulated the induction of diverse osmostress response genes, including targets of the tonicity-responsive transcription factor NFAT5 as well as NFAT5-independent genes. Genes sensitive to mTOR-included regulators of stress responses, growth and proliferation. Among them, we identified REDD1 and REDD2, which had been previously characterized as mTOR inhibitors in other stress contexts. We observed that mTOR facilitated transcription-permissive conditions for several osmoresponsive genes by enhancing histone H4 acetylation and the recruitment of RNA polymerase II. Altogether, these results reveal a previously unappreciated role of mTOR in regulating transcriptional mechanisms that control gene expression during cellular stress responses

Amplicon-Dependent CCNE1 Expression Is Critical for Clonogenic Survival after Cisplatin Treatment and Is Correlated with 20q11 Gain in Ovarian Cancer

Genomic amplification of 19q12 occurs in several cancer types including ovarian cancer where it is associated with primary treatment failure. We systematically attenuated expression of genes within the minimally defined 19q12 region in ovarian cell lines using short-interfering RNAs (siRNA) to identify driver oncogene(s) within the amplicon. Knockdown of CCNE1 resulted in G1/S phase arrest, reduced cell viability and apoptosis only in amplification-carrying cells. Although CCNE1 knockdown increased cisplatin resistance in short-term assays, clonogenic survival was inhibited after treatment. Gain of 20q11 was highly correlated with 19q12 amplification and spanned a 2.5 Mb region including TPX2, a centromeric protein required for mitotic spindle function. Expression of TPX2 was highly correlated with gene amplification and with CCNE1 expression in primary tumors. siRNA inhibition of TPX2 reduced cell viability but this effect was not amplicon-dependent. These findings demonstrate that CCNE1 is a key driver in the 19q12 amplicon required for survival and clonogenicity in cells with locus amplification. Co-amplification at 19q12 and 20q11 implies the presence of a cooperative mutational network. These observations have implications for the application of targeted therapies in CCNE1 dependent ovarian cancers

Bacterial Toxins and the Nervous System: Neurotoxins and Multipotential Toxins Interacting with Neuronal Cells

Toxins are potent molecules used by various bacteria to interact with a host organism. Some of them specifically act on neuronal cells (clostridial neurotoxins) leading to characteristics neurological affections. But many other toxins are multifunctional and recognize a wider range of cell types including neuronal cells. Various enterotoxins interact with the enteric nervous system, for example by stimulating afferent neurons or inducing neurotransmitter release from enterochromaffin cells which result either in vomiting, in amplification of the diarrhea, or in intestinal inflammation process. Other toxins can pass the blood brain barrier and directly act on specific neurons

Glucose-induced posttranslational activation of protein phosphatases PP2A and PP1 in yeast

The protein phosphatases PP2A and PP1 are major regulators of a variety of cellular processes in yeast and other eukaryotes. Here, we reveal that both enzymes are direct targets of glucose sensing. Addition of glucose to glucose-deprived yeast cells triggered rapid posttranslational activation of both PP2A and PP1. Glucose activation of PP2A is controlled by regulatory subunits Rts1, Cdc55, Rrd1 and Rrd2. It is associated with rapid carboxymethylation of the catalytic subunits, which is necessary but not sufficient for activation. Glucose activation of PP1 was fully dependent on regulatory subunits Reg1 and Shp1. Absence of Gac1, Glc8, Reg2 or Red1 partially reduced activation while Pig1 and Pig2 inhibited activation. Full activation of PP2A and PP1 was also dependent on subunits classically considered to belong to the other phosphatase. PP2A activation was dependent on PP1 subunits Reg1 and Shp1 while PP1 activation was dependent on PP2A subunit Rts1. Rts1 interacted with both Pph21 and Glc7 under different conditions and these interactions were Reg1 dependent. Reg1-Glc7 interaction is responsible for PP1 involvement in the main glucose repression pathway and we show that deletion of Shp1 also causes strong derepression of the invertase gene SUC2. Deletion of the PP2A subunits Pph21 and Pph22, Rrd1 and Rrd2, specifically enhanced the derepression level of SUC2, indicating that PP2A counteracts SUC2 derepression. Interestingly, the effect of the regulatory subunit Rts1 was consistent with its role as a subunit of both PP2A and PP1, affecting derepression and repression of SUC2, respectively. We also show that abolished phosphatase activation, except by reg1Δ, does not completely block Snf1 dephosphorylation after addition of glucose. Finally, we show that glucose activation of the cAMP-PKA (protein kinase A) pathway is required for glucose activation of both PP2A and PP1. Our results provide novel insight into the complex regulatory role of these two major protein phosphatases in glucose regulation