Miracle-dz/UniFAR-FTUs huggingface dataset:
Zinc fingers and homeoboxes 2 is required for diethylnitrosamine‐induced liver tumor formation in C57BL/6 mice

Liver cancer, comprised mainly of hepatocellular carcinoma (HCC), is the third leading cause of cancer deaths worldwide and increasing in Western countries. We previously identified the transcription factor Zinc Fingers and Homeoboxes 2 (Zhx2) as a regulator of hepatic gene expression, and many Zhx2 target genes are dysregulated in HCC. Here, we investigate HCC in Zhx2-deficient mice using the Diethylnitrosamine (DEN)-induced liver tumor model. Our study using whole-body Zhx2 knock-out (Zhx2KO) mice revealed the complete absence of liver tumors 9 and 10 months after DEN exposure.Analysis soon after DEN treatment showed no differences in expression of the DEN bioactivating enzyme CYP2E1 and DNA polymerase delta 2, or in the numbers of γH2AX foci between Zhx2KO and wild-type (Zhx2wt) mice. The absence of Zhx2, therefore, did not alter DEN bioactivation or DNA damage. Zhx2KO livers showed fewer positive foci for Ki67 staining and reduced IL-6 and AKT2 expression compared to Zhx2wt livers, suggesting that Zhx2 loss reduces liver cell proliferation and may account for reduced tumor formation. Tumors were reduced but not absent in DEN-treated liver-specific Zhx2 knock-out mice, suggesting that Zhx2 acts in both hepatocytes and non-parenchymal cells to inhibit tumor formation. Analysis of data from The Cancer Genome Atlas and Clinical Proteomic Tumor Consortium indicated that ZHX2 mRNA and protein levels were significantly higher in HCC patients and associated with clinical pathological parameters. Conclusions In contrast to previous studies in human hepatoma cell lines and other HCC mouse models showing that Zhx2 acts as a tumor suppressor, our data indicate that Zhx2 acts as an oncogene in the DEN-induced HCC model and is consistent with the higher ZHX2 expression in HCC patients.
NPAS4 supports drug-cue associations and relapse-like behavior through regulation of the cell type-specific activation balance in the nucleus accumbens

Use of addictive substances creates powerful drug-cue associations that often trigger relapse. Drug seeking is gated in the nucleus accumbens (NAc) by competing activation of D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs) that promote, and D2 dopamine receptor-expressing neurons (D2-MSNs) that oppose, drug seeking. We show here that the ensemble of neurons in the NAc that induce the neuronal activity-regulated transcription factor, Neuronal PAS Domain Protein 4 (NPAS4), is required for cocaine-context associations. In addition, NPAS4 functions within NAc D2-MSNs to govern the activation balance of NAc D1-MSNs and D2-MSNs necessary for drug-context memories and cue-induced cocaine, but not sucrose, seeking. NPAS4 regulates drug-cue associations and preponderant D1-MSN activation by influencing a program of gene expression that blocks cocaine-induced potentiation of prefrontal cortical excitatory drive onto D2-MSNs. Together our findings reveal that NPAS4 is a key player governing NAc MSN cell-type activation balance and promoting drug-cue associations and relapse vulnerability.
Systèmes dynamiques holomorphes : explosion de points périodiques paraboliques

L'essentiel de cette these est consacree a l'etude d'une famille d'applications holomorphes au voisinage d'un de ses elements qui admet un point periodique indifferent. Apres avoir rappele quelques outils theoriques essentiellement introduits par A. Douady dans cette optique (cylindres associes a un point periodique indifferent), nous appliquons ces techniques aux deformations parmi les polynomes du second degre de z→z2 + 1/4 : nous analysons successivement les formes limites que peuvent prendre les ensembles de Julia pour la distance de Hausdorff entre compacts, les formes limites de leurs rayons externes, puis les formes limites de details convenablement agrandis de l'ensemble de Mandelbrot. Puis nous passons au degre 3, ou nous appliquons ces techniques pour monter que l'ensemble des polynomes a Julia connexe n'est pas localement connexe, et etudions les deformations de z→z + z3, plus compliquees car dependant de facon essentielle de deux parametres. Enfin nous donnons quelques resultats varies concernant la dynamique des polynomes : resultats combinatoires, ou nous justifions un algorithme permettant de decrire la combinatoire de l'ensemble de Mandelbrot, puis montrons que les arbres de Hubbard periodiques de degre 2 peuvent etre incarnes par des polynomes; resultat topologique prouvant la cellularite de l’ensemble des polynomes a Julia connexe en tout degre.
Triple simultaneous Fourier series equations involving associated Legendre function

In this paper, we have considered the two sets of triple series equations of the first kind and second kind, which are the generalization of dual series equations involving Associated Legendre functions & solved the two sets of series equations. such simultaneous Fourier equations occur in many problems in hydrodynamics, elasticity and electromagnetism, involving a spherical or spheroidal boundary when different conditions are prescribed on different parts of the boundary.
Nano-scale solution of the Poisson-Nernst-Planck (PNP) equations in a fraction of two neighboring cells reveals the magnitude of intercellular electrochemical waves

The basic building blocks of the electrophysiology of cardiomyocytes are ion channels integrated in the cell membranes. Close to the ion channels there are very strong electrical and chemical gradients. However, these gradients extend for only a few nano-meters and are therefore commonly ignored in mathematical models. The full complexity of the dynamics is modelled by the Poisson-Nernst-Planck (PNP) equations but these equations must be solved using temporal and spatial scales of nano-seconds and nano-meters. Here we report solutions of the PNP equations in a fraction of two abuttal cells separated by a tiny extracellular space. We show that when only the potassium channels of the two cells are open, a stationary solution is reached with the well-known Debye layer close to the membranes. When the sodium channels of the left cell are opened, a very strong and brief electrochemical wave emanates from the channels. If the extracellular space is sufficiently small and the number of sodium channels is sufficiently high, the wave extends all the way over to the neighboring cell and may therefore explain cardiac conduction even at very low levels of gap junctional coupling.
Coherence of Terrestrial Vertebrate Species Richness with External Drivers Across Scales and Taxonomic Groups

Aim Understanding connections between environment and biodiversity is crucial for conservation, identifying causes of ecosystem stress, and predicting population responses to changing environments. Explaining biodiversity requires an understanding of how species richness and environment co-vary across scales. Here, we identify scales and locations at which biodiversity is generated and correlates with environment. Location Full latitudinal range per continent. Time period Present-day. Major taxa studied Terrestrial vertebrates: all mammals, carnivorans, bats, songbirds, humming-birds, amphibians. Methods We describe the use of wavelet power spectra, cross-power and coherence for identifying scale-dependent trends across Earth’s surface. Spectra reveal scale- and location-dependent coherence between species richness and topography (E), mean annual precipitation (Pn), temperature (Tm) and annual temperature range (∆T). Results > 97% of species richness of taxa studied is generated at large scales, i.e. wavelengths 103 km, with 30–69% generated at scales 104 km. At these scales, richness tends to be highly coherent and anti-correlated with E and ∆T, and positively correlated with Pn and Tm. Coherence between carnivoran richness and ∆T is low across scales, implying insensitivity to seasonal temperature variations. Conversely, amphibian richness is strongly anti-correlated with ∆T at large scales. At scales 103 km, examined taxa, except carnivorans, show highest richness within the tropics. Terrestrial plateaux exhibit high coherence between carnivorans and E at scales ∼ 103 km, consistent with contribution of large-scale tectonic processes to biodiversity. Results are similar across different continents and for global latitudinal averages. Spectral admittance permits derivation of rules-of-thumb relating long-wavelength environmental and species richness trends. Main conclusions Sensitivities of mammal, bird and amphibian populations to environment are highly scale-dependent. At large scales, carnivoran richness is largely independent of temperature and precipitation, whereas amphibian richness correlates strongly with precipitation and temperature, and anti-correlates with temperature range. These results pave the way for spectral-based calibration of models that predict biodiversity response to climate change scenarios.
The relationship between spectral and plant diversity: disentangling the influence of metrics and habitat types

Biodiversity monitoring is crucial for ecosystem conservation, yet field data collection is limited by costs, time, and extent. Remote sensing represents a convenient approach providing frequent, near-real-time information over wide areas. According to the Spectral Variation Hypothesis (SVH), spectral diversity (SD) is an effective proxy of environmental heterogeneity, which ultimately relates to plant diversity. So far, studies testing the relationship between SD and biodiversity have reported contradictory findings, calling for a thorough investigation of the key factors (e.g., metrics applied, ecosystem type) and the conditions under which such a relationship holds true. This study investigates the applicability of the SVH for plant diversity monitoring at the landscape scale by comparing the performance of three different types of SD metrics. Species richness and functional diversity were calculated for more than 2000 cells forming a grid covering the Czech Republic. Within each cell, we quantified SD using a Landsat-8 “greenest pixel” composite by applying: i) the standard deviation of NDVI, ii) Rao’s Q entropy index, and iii) richness of “spectral communities”. Habitat type (i.e., land cover) was included in the models describing the relationship between SD and ground biodiversity. Both species richness and functional diversity show positive and significant relationships with each SD metric tested. However, SD alone accounts for a small fraction of the deviance explained by the models. Furthermore, the strength of the relationship depends significantly on habitat type and is highest in natural transitional areas. Our results underline that, despite the stability in the significance of the link between SD and plant diversity at this scale, the applicability of SD for biodiversity monitoring is context-dependent and the factors mediating such a relationship must be carefully considered to avoid drawing misleading conclusions. Highlights Plant species richness and functional diversity show significant and positive relationships with spectral diversity Spectral diversity alone explains a small fraction of the total variability in ground biodiversity Slight differences among the performances of the spectral diversity metrics tested The relationship between spectral and plant diversity is context-dependent
Vitamin B12 produced by gut bacteria modulates excitatory neurotransmission

A growing body of evidence indicates that gut microbiota influence brain function and behavior. However, the molecular basis of how gut bacteria modulate host nervous system function is largely unknown. Here we show that vitamin B12-producing bacteria that colonize the intestine can modulate excitatory synaptic transmission and behavior in the host Caenorhabditis elegans. We find that vitamin B12 reduces cholinergic signaling in the nervous system through rewiring of the methionine (Met)/S-Adenosylmethionine (SAM) cycle in the intestine. We identify a conserved metabolic crosstalk between the Met/SAM cycle and the choline oxidation pathway. We show that metabolic rewiring of these pathways by vitamin B12 reduces cholinergic transmission by limiting the availability of free choline required by neurons to synthesize acetylcholine. Our study reveals a gut-brain communication pathway by which enteric bacteria modulate host behavior and may affect mental health.
Calcium binding and permeation in TRPV channels: Insights from molecular dynamics simulations

Some calcium channels selectively permeate Ca2+, despite the high concentration of monovalent ions in the surrounding environment, which is essential for many physiological processes. Without atomistic and dynamical ion permeation details, the underlying mechanism of Ca2+ selectivity has long been an intensively studied, yet controversial, topic. This study takes advantage of the homologous Ca2+-selective TRPV6 and non-selective TRPV1 and utilizes the recently solved open-state structures and a newly developed multi-site calcium model to investigate the ion binding and permeation features in TRPV channels by molecular dynamics simulations. Our results revealed that the open-state TRPV6 and TRPV1 show distinct ion-binding patterns in the selectivity filter, which lead to different ion permeation features. Two Ca2+ ions simultaneously bind to the selectivity filter of TRPV6 compared with only one Ca2+ in case of TRPV1. Multiple Ca2+ binding at the selectivity filter of TRPV6 permeated in a concerted manner, which could efficiently block the permeation of Na+. Cations of various valences differentiate between the binding sites at the entrance of the selectivity filter in TRPV6. Ca2+ preferentially binds to the central site with a higher probability of permeation, repelling Na+ to a peripheral site. Therefore, we believe that ion binding competition at the selectivity filter of calcium channels, including the binding strength and number of binding sites, determines Ca2+ selectivity under physiological conditions. Additionally, our results showed that pore helix flexibility and the cytosolic domain of TRPV channels regulate ion permeability.
IL-10 inhibits STAT1-dependent macrophage accumulation during microbiota-induced colitis

Loss of IL-10R function leads to severe early onset colitis and in murine models is associated with the accumulation of immature inflammatory colonic macrophages. We have shown that IL-10R-deficient colonic macrophages exhibit increased STAT1-dependent gene expression, suggesting that IL-10R-mediated inhibition of STAT1 signaling in newly recruited colonic macrophages might interfere with the development of an inflammatory phenotype. Indeed Stat1-/- mice exhibit defects in colonic macrophage accumulation following Helicobacter hepaticus infection and IL-10R blockade, and this was phenocopied in mice lacking IFNGR, an inducer of STAT1 activation. Radiation chimeras demonstrated that reduced accumulation of STAT1-deficient macrophages was based on a cell-intrinsic defect. Unexpectedly, mixed radiation chimeras generated with both WT and IL-10R-deficient bone marrow indicated that rather than directly interfering with STAT1 function, IL-10R prevents the generation of a cell extrinsic signal that promotes the accumulation of immature macrophages. These results define essential mechanisms controlling inflammatory macrophage accumulation in inflammatory bowel diseases. Summary Intrinsic STAT1-function drives the accumulation of macrophages within the colon following the loss of IL-10R signaling. IL-10R prevents this STAT1-dependent process through a non-cell autonomous mechanism.
The cytidine deaminase APOBEC3G drives cancer mutagenesis and clonal evolution in bladder cancer

Mutagenic processes leave distinct signatures in cancer genomes. The mutational signatures attributed to APOBEC3 cytidine deaminases are pervasive in human cancers. However, data linking individual APOBEC3 proteins to cancer mutagenesis in vivo are limited. Here, we show that transgenic expression of human APOBEC3G promotes mutagenesis, genomic instability, and kataegis, leading to shorter survival in a murine bladder cancer model. Acting as mutagenic fuel, APOBEC3G increases the clonal diversity of bladder cancers, driving divergent cancer evolution. We characterize the single base substitution signature induced by APOBEC3G in vivo, showing the induction of a mutational signature different from that caused by APOBEC3A and APOBEC3B. Analysis of thousands of human cancers reveals the contribution of APOBEC3G to the mutational profiles of multiple cancer types, including bladder cancer. Our findings define the role of APOBEC3G in cancer mutagenesis and clonal heterogeneity. These results potentially inform future therapeutic efforts that restrict tumor evolution.
Design principles for selective polarization of PAR proteins by cortical flows

Clustering of membrane-associated molecules has long been proposed to promote size-dependent interactions with the actomyosin cortical network, thereby allowing them to be transported by actin flow. Consistent with such a model, clustering of the conserved polarity protein PAR-3 in the C. elegans zygote is essential for its polarization by cortical actomyosin flows, and clusters of PAR-3 visibly move with flows. However, here we show that advection by cortical flow is independent of clustering. Clustered and non-clustered PAR-3 variants are advected equally well over short timescales by cortical actin flow as are other PAR proteins. Moreover, we see no strong links between advection and either cluster size or diffusivity that would be consistent with size-dependent interactions with the actin cortex. Instead, using a combination of experiment and theory, we find that efficient long range transport of PAR proteins by cortical flow is primarily tuned by the stability of membrane association, which is enhanced by clustering and determines the persistence of both transport by flow and the resulting asymmetries once flows cease. Consistent with this model, stabilizing membrane association was sufficient to induce segregation of a non-segregating PAR protein, effectively inverting its polarity. We conclude that the impact of advection on membrane-associated proteins is much broader than previously anticipated and thus cells must appropriately tune membrane association dynamics to achieve selectivity in the long range transport of membrane-associated molecules by cortical flows. Highlights - Advection of PAR-3 is independent of cluster size and diffusivity - Selective advection cannot explain specificity of long range transport by cortical flows - Membrane binding kinetics are a primary determinant of differential segregation - Ectopic stabilization of membrane association is sufficient to anteriorize posterior protein PAR-2
DNA damage-induced YTHDC1 O-GlcNAcylation promotes homologous recombination by enhancing N6-methyladenosine binding

N6-methyladenosine (m6A) is the most prevalent RNA modification, and its regulators include writers, readers and erasers. m6A is under stringent control and takes part in many biological events, but it is not known whether there is an interplay between m6A and glycosylation. Here we investigated an m6A reader, YTHDC1, which has been shown to be recruited to the DNA-RNA hybrid at DNA damage sites and regulate homologous recombination (HR) during DNA damage repair. We found that YTHDC1 is subject to O-linked β-N-acetylglucosamine (O-GlcNAc) modification at Ser396 upon DNA damage, which is pivotal for YTHDC1 chromatin binding and ionization radiation induced foci (IRIF) formation. RNA immunoprecipitation (RIP) and molecular dynamics (MD) simulations indicate that O-GlcNAcylation is vital for YTHDC1 to bind with m6A RNA. Fluorescence recovery after photo bleaching (FRAP) analysis revealed that YTHDC1 O-GlcNAcylation is essential for DNA damage-induced YTHDC1-m6A condensate formation. We further demonstrate that YTHDC1 O-GlcNAcylation promotes HR-mediated DNA damage repair and cell survival, probably through recruitment of Rad51 to the damage sites. We propose that YTHDC1 O-GlcNAcylation is instrumental for HR and genome stability.
Combined blockade of VEGF, Angiopoietin-2, and PD1 reprograms glioblastoma endothelial cells into quasi-antigen-presenting cells

Glioblastoma (GBM) remains a highly aggressive and uniformly fatal primary tumor, which resists cytotoxic, targeted, antiangiogenic, and immune therapies, even when used in combination. Here we report that tumor endothelial cell dysfunction confers resistance to immunotherapy in preclinical GBM models. Anti-VEGF-therapy-induced vascular normalization is insufficient to fully restore the endothelial cell function. Strikingly, concomitant blockade of Ang2, VEGF, and PD1 reprograms dysfunctional endothelial cells to quasi-antigen presenting cells and upregulates receptors required for cytotoxic T lymphocyte entry into the tumor. Blocking VEGF, Ang2, and PD1 induces durable anti-tumor T cell responses. Upregulation of the transcription factor T-bet is both necessary and sufficient for generating resident memory T cells elicited by this combination therapy. In summary, our study reveals the role of Ang2 in resistance to PD1-blockade and provides a compelling rationale for clinical evaluation of blocking Ang2 along with VEGF and PD1 in GBM patients. Statement of Significance Our study is the first to demonstrate Ang2 as a resistance pathway for both αVEGF and αPD1 in GBM. Concomitant blockade of Ang2 reprograms endothelial cells to recruit, activate and retain CD8 T cells, overcomes resistance to αVEGF and αPD1, and imparts T cell memory formation via T-bet in GBM.
Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1: Preclinical Efficacy against Iron Overload and Safety Evaluation

Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of nonheme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or β-thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 inhibitors. Dimeric compounds were made to generate more potent compounds with low systemic exposure. Direct block of DMT1 was confirmed by voltage clamp measurements. The lead compound, XEN602, strongly inhibits dietary nonheme iron uptake in both rats and pigs yet has negligible systemic exposure. Efficacy is maintained for >2 weeks in a rat subchronic dosing assay. Doses that lowered iron content in the spleen and liver by >50% had no effect on the tissue content of other divalent cations except for cobalt. XEN602 represents a powerful pharmacological tool for understanding the physiologic function of DMT1 in the gut. SIGNIFICANCE STATEMENT This report introduces methodology to develop potent, gut-restricted inhibitors of divalent metal transporter 1 (DMT1) and identifies XEN602 as a suitable compound for in vivo studies. We also report novel animal models to quantify the inhibition of dietary uptake of iron in both rodents and pigs. This research shows that inhibition of DMT1 is a promising means to treat iron overload disorders.