Miracle-dz/UniFAR-FTUs huggingface dataset:
Histone Demethylase Jumonji AT-rich Interactive Domain 1B (JARID1B) Controls Mammary Gland Development by Regulating Key Developmental and Lineage Specification Genes*

Background: Histone demethylase JARID1B is a potential oncoprotein, but its in vivo roles are not well understood. Results: Mice lacking JARID1B showed delayed mammary gland development and decreased female fertility. Conclusion: JARID1B promotes luminal lineage transcription programs in the mammary gland and fine-tunes systemic estrogen level. Significance: JARID1B functions in cancer are likely linked to its roles in gene regulation and mammary gland development. The JmjC domain-containing H3K4 histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) (also known as KDM5B and PLU1) is overexpressed in breast cancer and is a potential target for breast cancer treatment. To investigate the in vivo function of JARID1B, we developed Jarid1b−/− mice and characterized their phenotypes in detail. Unlike previously reported Jarid1b−/− strains, the majority of these Jarid1b−/− mice were viable beyond embryonic and neonatal stages. This allowed us to further examine phenotypes associated with the loss of JARID1B in pubertal development and pregnancy. These Jarid1b−/− mice exhibited decreased body weight, premature mortality, decreased female fertility, and delayed mammary gland development. Related to these phenotypes, JARID1B loss decreased serum estrogen level and reduced mammary epithelial cell proliferation in early puberty. In mammary epithelial cells, JARID1B loss diminished the expression of key regulators for mammary morphogenesis and luminal lineage specification, including FOXA1 and estrogen receptor α. Mechanistically, JARID1B was required for GATA3 recruitment to the Foxa1 promoter to activate Foxa1 expression. These results indicate that JARID1B positively regulates mammary ductal development through both extrinsic and cell-autonomous mechanisms.
Isolation and analysis of the C‐terminal signal directing export of Escherichia coli hemolysin protein across both bacterial membranes.

We have studied the C‐terminal signal which directs the complete export of the 1024‐amino‐acid hemolysin protein (HlyA) of Escherichia coli across both bacterial membranes into the surrounding medium. Isolation and sequencing of homologous hlyA genes from the related bacteria Proteus vulgaris and Morganella morganii revealed high primary sequence divergence in the three HlyA C‐termini and highlighted within the extreme terminal 53 amino acids the conservation of three contiguous sequences, a potential 18‐amino‐acid amphiphilic alpha‐helix, a cluster of charged residues, and a weakly hydrophobic terminal sequence rich in hydroxylated residues. Fusion of the C‐terminal 53 amino acid sequence to non‐exported truncated Hly A directed wild‐type export but export was radically reduced following independent disruption or progressive truncation of the three C‐terminal features by in‐frame deletion and the introduction of translation stop codons within the 3′ hlyA sequence. The data indicate that the HlyA C‐terminal export signal comprises multiple components and suggest possible analogies with the mitochondrial import signal. Hemolysis assays and immunoblotting confirmed the intracellular accumulation of non‐exported HlyA proteins and supported the view that export proceeds without a periplasmic intermediate. Comparison of cytoplasmic and extracellular forms of an independently exported extreme C‐terminal 194 residue peptide showed that the signal was not removed during export.
Thrombin-Induced Platelet-Fibrin Clot Strength Identified by Thrombelastography: A Novel Prothrombotic Marker of Coronary Artery Stent Restenosis.

BACKGROUND AND OBJECTIVE In-stent restenosis (ISR) is a limitation of percutaneous coronary intervention and has been linked to specific clinical and angiographic variables. We aimed to simultaneously assess thrombosis biomarkers and lipid levels in patients with and without ISR. METHODS Consecutive patients (n = 170) with a history of coronary stenting undergoing elective angiography were studied. Blood samples for thrombelastography, light transmittance aggregometry, and lipid levels were obtained prior to cardiac catheterization. RESULTS Sixty-nine patients (41%) had ISR (>50% luminal diameter stenosis). Among patients with ISR, 40 (58%) had ISR in more than one stent bed. Patients with ISR were more often female (37.7% vs. 21.8%, P = 0.04), had higher thrombin-induced platelet-fibrin clot strength (TIP-FCS) (69.9 mm vs. 65.6 mm, P < 0.001), and a higher ApoB/A1 ratio (0.65 vs. 0.59, P = 0.03). In patients on dual antiplatelet therapy (n = 86), there were no differences in ADP-, arachidonic acid-, and collagen-induced platelet aggregation between groups. The frequency of patients with ISR increased with TIP-FCS quartiles and by ROC analysis, TIP-FCS = 67.0 mm was the cutpoint for identification of ISR (AUC = 0.80 (95%CI 0.73-0.87, P < 0.0001). By multivariate analysis, TIP-FCS ≥67.0 mm strongly associated with ISR (OR = 7.3, P = 0.004). CONCLUSION Patients with ISR identified at the time of cardiac catheterization have a prothrombotic phenotype indicated by high TIP-FCS, a novel marker. Studies to confirm the prognostic utility of high TIP-FCS for the development of ISR are ongoing.
EFFECT OF CYCLOSPORIN A ON NITRIC OXIDE PRODUCTION IN CULTURED LLC-PK1 CELLS

The effect of Cyclosporin A on nitric oxide production was studied in cultured LLC- PK1 cells. For this purpose the cells were incubated with vehicle (olive oil, 10 μg/ml in DMSO), Cyclosporin A (CsA, 10 μg/ml), tumor necrosis factor (TNF-α, 150 U/ml) + interferon (IFN-γ, 500 U/ml) to upregulate NOS synthesis, and therefore NO production (used as a positive control), or CsA + TNF-α + IFN-γ. After 72 hours the culture medium was collected and nitrite was determined by the Griess method. The results were normalized to the protein harvested from these cells as measured by the Lowry method. Viability was determined by the exclusion of the fluorescent dyes (acridine orange and ethidium bromide). Intracellular calcium was measured spectrophotometrically using the fluorescent calcium indicator fura-2 AM. In CsA treated cells, the nitrite (pmoles/mg of protein) was decreased when compared to control (12.8 ± 0.5 vs. 18.3 ± 0.6; p < 0.05; both n = 8). TNF-α + IFN-γ increased the nitrite synthesis (52.0 ± 0.2; p < 0.05 vs. control; n = 6). This effect was decreased significantly by the simultaneous treatment with CsA (38.8 ± 0.3; p <0.05; n = 6). Cell viability in CsA group was decreased when compared to the control (84.7 ± 0.2% vs. 93.6 ± 0.1%; p < 0.05; both n = 10). TNF-α + IFN-γ had no effect on viability (93.0 ± 0.3%; n = 10). However, when combined with CsA, viability was decreased relative to the control (85.0 ± 0.2%; p < 0.05; n = 10). Acute (1 h) or chronic (72 h) treatment of LLC- PK1 cells with CsA had no effect on basal calcium levels. Our results demonstrate a reduced level of nitric oxide production in LLC- PK1 cells treated with CsA. There was no effect of the drug on intracellular calcium levels, however CsA treatment did reduce cellular viability. We suggest that, in part, the decreased levels of NO production are a secondary consequence of direct cell damage. However, CsA may also be exerting direct effects on NO synthesis through its interactions with both iNOS and cNOS. These results also provide a dual mechanism of action for CsA induced nephrotoxicity, that is, direct cell damage and interference with the NO system within the nephron.
THE ASSASSINATION OF MILITARY COMMANDERS IN LESOTHO: TRIGGERS AND REACTIONS

This article investigates civil-military relations (CMR) in Lesotho and its impact on political and security stability. The nature of CMR is unmasked by tracing the evolution of the Lesotho Defence Force (LDF) and the history of its politicisation. The assassinations of LDF commanders, Lt-Gen Maaparankoe Mahao in 2015 and Lt-Gen Khoantle Motšomotšo in 2017, respectively, by members from within their ranks, are explored to illustrate how the undue involvement of the military in politics has contributed to instability in Lesotho. Other triggers contributing to the unstable situation are highlighted. The enquiry of this article is not only about the nature of CMR but how the regional body, the Southern African Development Community (SADC) has sought to intervene in Lesotho with the aim of firstly stabilising the politics and security of the country. SADC’s other aim has been the facilitating of security sector reforms that will, amongst other things, configure CMR such that the armed forces are accountable to civilian authority and they do not meddle in political contest.
Evaluating the association between CACNA1C rs1006737 and schizophrenia risk: A meta‐analysis

Genetic analyses including genome‐wide association studies have reported an intronic single nucleotide polymorphism (SNP) rs1006737 in CACNA1C gene (encoded calcium channel, voltage‐dependent, L type, alpha 1C subunit) as a risk factor for schizophrenia in European populations. The replications in other ethnic populations such as East Asians have also been conducted, but the results were inconsistent, either likely due to the limited sample size of single study or genetic heterogeneity between continental populations on this locus.
Partitioning of current‐use and legacy pesticides in salmon habitat in British Columbia, Canada

Current regulatory paradigms have favored a shift from persistent pesticides that amplify in aquatic food webs to pesticides with reduced persistence and bioaccumulative potential (low log KOW). Although these new generation pesticides preferentially partition away from food web–associated lipids, aquatic biota may nonetheless be exposed to them via other environmental compartments. To characterize pesticide patterns in coho salmon (Oncorhynchus kisutch) habitat, we studied two salmon‐bearing watersheds (agricultural and urban) in British Columbia, Canada's Fraser River valley and one in a remote area of the province's central coast. The agricultural and remote sites exhibited pesticide patterns dominated by current‐use pesticides, whereas the urban site was largely dominated by legacy organochlorine pesticides. When adjusted to trans‐chlordane concentrations across environmental matrices, correlations were observed between water to sediment ratios for the pesticides and their octanol:water partitioning coefficients (log KOW; r2 = 0.48, p < 0.0001); between air to water ratios and Henry's Law coefficients (r2 = 0.55, p < 0.0001); and between fish to water ratios and log KOW (r2 = 0.74, p < 0.0001). These relationships underscore the importance of physicochemical properties in determining the fate of pesticides in freshwater salmon habitat, and highlight the need for research on the nature of health risks associated with exposure where little or no accumulation occurs.
Epidermal Viral Immunity Induced by CD8α+ Dendritic Cells But Not by Langerhans Cells

The classical paradigm for dendritic cell function derives from the study of Langerhans cells, which predominate within skin epidermis. After an encounter with foreign agents, Langerhans cells are thought to migrate to draining lymph nodes, where they initiate T cell priming. Contrary to this, we show here that infection of murine epidermis by herpes simplex virus did not result in the priming of virus-specific cytotoxic T lymphocytes by Langerhans cells. Rather, the priming response required a distinct CD8α+ dendritic cell subset. Thus, the traditional view of Langerhans cells in epidermal immunity needs to be revisited to accommodate a requirement for other dendritic cells in this response.
The RNA Polymerase Omega Factor RpoZ Is Regulated by PhoP and Has an Important Role in Antibiotic Biosynthesis and Morphological Differentiation in Streptomyces coelicolor

ABSTRACT The RNA polymerase (RNAP) omega factor (ω) forms a complex with the α2ββ′ core of this enzyme in bacteria. We have characterized the rpoZ gene of Streptomyces coelicolor, which encodes a small protein (90 amino acids) identified as the omega factor. Deletion of the rpoZ gene resulted in strains with a slightly reduced growth rate, although they were still able to sporulate. The biosynthesis of actinorhodin and, particularly, that of undecylprodigiosin were drastically reduced in the ΔrpoZ strain, suggesting that expression of these secondary metabolite biosynthetic genes is dependent upon the presence of RpoZ in the RNAP complex. Complementation of the ΔrpoZ mutant with the wild-type rpoZ allele restored both phenotype and antibiotic production. Interestingly, the rpoZ gene contains a PHO box in its promoter region. DNA binding assays showed that the phosphate response regulator PhoP binds to such a region. Since luciferase reporter studies showed that rpoZ promoter activity was increased in a ΔphoP background, it can be concluded that rpoZ is controlled negatively by PhoP, thus connecting phosphate depletion regulation with antibiotic production and morphological differentiation in Streptomyces.
Expression of nitric oxide synthase isoforms and arginase in normal human skin and chronic venous leg ulcers

Chronic venous ulcers, an example of abnormal wound healing, show chronic inflammation with defective matrix deposition which together with the underlying vascular pathology, result in delayed healing. L‐arginine is known to be metabolized by one of two pathways: nitric oxide synthase (NOS), producing nitric oxide (NO), or arginase, producing ornithine. NO is involved in many pathological conditions including vascular and inflammatory disorders. This study therefore investigated the distribution, level and activity of NOS and arginase in chronic venous ulcers in comparison with normal skin, using immunocytochemistry, western blotting, and enzyme assays. The results demonstrated an increased distribution of both NOS and arginase in chronic venous ulcer tissue compared with normal skin, with inflammatory cells and vascular endothelial cells as the main sources. These data were confirmed by western blot analysis, which showed increased levels of both enzymes in chronic venous ulcers. Moreover, there was significantly increased activity of both total NOS (p<0.04) and inducible NOS (p<0.05) in chronic venous ulcer tissue compared with normal skin, and significantly increased activity of arginase (p<0.01) in chronic venous ulcer tissue in comparison with normal skin. NO is known to combine with hydroxyl free radicals forming peroxynitrite, a potent free radical which causes tissue destruction. NO overexpression in chronic venous ulcers may be involved directly or indirectly (through production of peroxynitrite) in the pathogenesis and delayed healing of chronic venous ulcers, through its effects on vasculature, inflammation, and collagen deposition. Arginase is known to enhance matrix deposition. Thus, increased levels of arginase in chronic venous ulcers could contribute to the pathogenesis of lipodermatosclerosis associated with chronic venous insufficiency, predisposing to the formation of chronic venous ulcers and also to matrix cuff formation around blood vessels. Copyright © 2000 John Wiley & Sons, Ltd.
Demonstration of innate immune responses in the thyroid gland: potential to sense danger and a possible trigger for autoimmune reactions.

BACKGROUND Autoimmune thyroid disease is an archetypal organ-specific autoimmune disorder that is characterized by the production of thyroid autoantibodies and lymphocytic infiltration into the thyroid. However, the underlying mechanisms by which specific thyroid antibodies are produced are largely unknown. Recent studies have shown that innate immune responses affect both the phenotype and the severity of autoimmune reactions. Moreover, it appears that even non-immune cells, including thyroid cells, have an ability to launch such responses. The aim of this study was to conduct a more detailed analysis of innate immune responses of the thyroid upon stimulation with various "non-self" and "self" factors that might contribute to the initiation of autoimmune reactions. METHODS We used rat thyroid FRTL-5 cells, human thyroid cells, and mice to investigate the effects of various pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and iodide on gene expression and function that were related to innate immune responses. RESULTS RT-PCR analysis showed that both rat and human thyroid cells expressed mRNAs for Toll-like receptors (TLRs) that sensed PAMPs. Stimulation of thyrocytes with TLR ligands resulted in activation of the interferon-beta (IFN-β) promoter and the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)-dependent promoter. As a result, pro-inflammatory cytokines, chemokines, and type I interferons were produced. Similar activation was observed when thyroid cells were stimulated with double-stranded DNA, one of the typical DAMPs. In addition to these PAMPs and DAMPs, treatment of thyroid cells with high concentrations of iodide increased mRNA expression of various cytokines. CONCLUSION We show that thyroid cells express functional sensors for exogenous and endogenous dangers, and that they are capable of launching innate immune responses without the assistance of immune cells. Such responses may relate to the development of thyroiditis, which in turn may trigger autoimmune reactions.
Partitioning the Genetic Diversity of a Virus Family: Approach and Evaluation through a Case Study of Picornaviruses

ABSTRACT The recent advent of genome sequences as the only source available to classify many newly discovered viruses challenges the development of virus taxonomy by expert virologists who traditionally rely on extensive virus characterization. In this proof-of-principle study, we address this issue by presenting a computational approach (DEmARC) to classify viruses of a family into groups at hierarchical levels using a sole criterion—intervirus genetic divergence. To quantify genetic divergence, we used pairwise evolutionary distances (PEDs) estimated by maximum likelihood inference on a multiple alignment of family-wide conserved proteins. PEDs were calculated for all virus pairs, and the resulting distribution was modeled via a mixture of probability density functions. The model enables the quantitative inference of regions of distance discontinuity in the family-wide PED distribution, which define the levels of hierarchy. For each level, a limit on genetic divergence, below which two viruses join the same group, was objectively selected among a set of candidates by minimizing violations of intragroup PEDs to the limit. In a case study, we applied the procedure to hundreds of genome sequences of picornaviruses and extensively evaluated it by modulating four key parameters. It was found that the genetics-based classification largely tolerates variations in virus sampling and multiple alignment construction but is affected by the choice of protein and the measure of genetic divergence. In an accompanying paper (C. Lauber and A. E. Gorbalenya, J. Virol. 86:3905–3915, 2012), we analyze the substantial insight gained with the genetics-based classification approach by comparing it with the expert-based picornavirus taxonomy.
Role of SUMO in the dynamics of telomere maintenance in fission yeast

The sheltering of chromosome ends from illegitimate DNA repair reactions and telomere length homeostasis are critical for preserving genomic integrity. Growing evidence implicates covalent protein modification by SUMO (small ubiquitin-like modifier) (sumoylation) in the regulation of numerous DNA transactions, including DNA repair and transcription, as well as heterochromatin formation and maintenance. We have recently shown that fission yeast Pli1p is a SUMO E3 ligase and that pli1 mutants, which are impaired for global sumoylation, are viable, but exhibit de-regulated homologous recombination and marked defects in chromosome segregation and centromeric silencing, as well as a consistent increase in telomere length. In this work, we explore the mechanisms underlying sumoylation-dependent telomere maintenance. We show that Pli1p, but not the related Nse2p, is the principal SUMO E3 ligase enzyme involved. Using both a pli1 mutation and a physiological “knockdown” of sumoylation, achieved by inducible expression of a dominant negative form of the conjugating enzyme Ubc9p, we further show that telomere lengthening induced by lack of sumoylation is not due to unscheduled telomere–telomere recombination. Instead, sumoylation increases telomerase activity, therefore suggesting that this modification controls the activity of a positive or negative regulator of telomerase.
Regulatory CD4+ T Cells Promote B Cell Anergy in Murine Lupus

To prevent autoimmunity, anergy of autoreactive B cells needs to be maintained, together with the suppression of hyperactive B cells. We previously reported that CD4+CD25+Foxp3+ regulatory T cells (Tregs) can directly suppress autoantibody-producing autoreactive B cells in systemic lupus erythematosus. In this article, we show that Tregs can also reduce the production of autoantibodies in (NZB × NZW)F1 mouse lupus B cells by promoting B cell anergy, both in vitro and in vivo. This phenomenon associated with a reduction in Ca2+ flux in B cells, and CTLA-4 blockade inhibited the effects of Tregs on anergic lupus B cells. These findings identify a new mechanism by which Tregs can control production of autoantibodies in lupus B cells and, more generally, B cell activity in physiopathological conditions.
Unified modeling of the mammalian and fish proton-dependent oligopeptide transporter PepT1

The partial and complete cycle of the intestinal pH-dependent oligopeptide transporter PepT1 from three species (seabass, zebrafish and rabbit) were studied using an electrophysiological approach and a biophysical analysis, in order to identify similarities and differences. On the whole the presteady state currents of the fish transporters were similar to each other, while presenting some quantitative differences with respect to rabbit PepT1: this last form showed slower decaying currents and the charge vs. potential (Q/V) and time constant vs. potential (τ/V) curves shifted to more positive potentials. All isoforms were similarly affected by external pH, showing acidity-induced slowing of the transients and positive shifts in the Q/V and τ/V curves. Analysis of the pH dependence of the unidirectional rates of the intramembrane charge movement suggested that external protonation of the protein limits the speed of this process in both directions. The complete cycle of the transporter was studied using the neutral dipeptide Gly-Gln. Michaelis-Menten analysis confirmed that in all species the apparent affinity for the substrate is significantly increased by acidity, while the maximal transport current is not strongly affected. Simulations using a kinetic model incorporating the new findings show good agreement with experimental data for all three species both with respect to the presteady-state and transport currents.