Miracle-dz/UniFAR-FTUs huggingface dataset:
mTORC1 is required for differentiation of germline stem cells in the Drosophila melanogaster testis

Metabolism participates in the control of stem cell function and subsequent maintenance of tissue homeostasis. How this is achieved in the context of adult stem cell niches in coordination with other local and intrinsic signaling cues is not completely understood. The Target of Rapamycin (TOR) pathway is a master regulator of metabolism and plays essential roles in stem cell maintenance and differentiation. We observe differential expression of the Tor kinase in the Drosophila male germline, which correlates with restriction of mTORC1 activity to germline stem cells (GSCs) and early germ cells. Targeted RNAi-mediated downregulation of Tor in early germ cells causes a block and/or a delay in differentiation, resulting in an accumulation of germ cells with GSC-like features. These early germ cells also contain unusually large and dysfunctional autolysosomes. In addition, downregulation of Tor in adult male GSCs and early germ cells causes non-autonomous activation of mTORC1 in neighboring cyst cells, which correlates with a disruption in the coordination of germline and somatic differentiation. Our study identifies a previously uncharacterized role of the TOR pathway in regulating male germline differentiation.
The Development of Sex Differences in Play in Wild White-Faced Capuchins (Cebus capucinus)

Many mammalian species display sex differences in the frequency of play behavior, yet the animal literature includes few longitudinal studies of play, which are important for understanding the developmental timing of sex differences and the evolutionary functions of play. We analyzed social play, solitary play, and grooming using an 18-year dataset on 38 wild white-faced capuchin monkeys (Cebus capucinus) followed since infancy. Rates of each behavior were measured as the proportion of point samples taken during focal follows in which the individual engaged in each behavior. To determine sex differences in these rates, we ran a series of generalized linear mixed models, considering both linear and quadratic effects of age, and chose the optimal model for each of the three behavioral outcomes based on information criteria. Rates of both social play and solitary play decreased with age, with the exception of social play in males, which increased in the early juvenile period before decreasing. Male and female capuchins had different temporal patterns of social play, with males playing more than females during most of the juvenile period, but they did not display meaningful sex differences in solitary play rates. Additionally, males and females had different patterns of grooming over the lifespan: males participated in grooming at low rates throughout their lives, while adult females participated in grooming at much higher rates, peaking around age 11 years before declining. We suggest that male and female white-faced capuchins may adopt alternative social bonding strategies, including different developmental timing and different behaviors (social play for males versus grooming for females). Our results were consistent with two functional hypotheses of play, the practice and bonding hypotheses. This study demonstrates that play behavior may be critical for the development of sex-specific social strategies and emphasizes the importance of developmental perspectives on social behaviors.
Characterization of Mechanics Driven Heterogeneity in Mesenchymal Stromal Cells

Mesenchymal stromal or stem cells (MSC) are one of the most promising candidates for a myriad of cell therapy applications because of their multipotency, trophic properties and immunomodulatory properties. Despite showing promises in numerous preclinical and clinical studies, MSC based therapy is not yet a reality for regenerative medicine due their suboptimal outcome at the clinical endpoint. Suboptimal function of MSC is often attributed to the monolayer expansion process on plastic which is a necessary condition to reach the therapeutically relevant number, and also to their response to a fibrotic environment post transplantation. In both scenarios of plastic culture and fibrotic conditions, the mechanical environment experienced by the MSC is completely different from the natural mechanical niche of the MSC. Accordingly, the role of mechanical environment has been shown to be a critical determinant of MSC gene expression and function. In this study we report that human bone marrow derived primary MSC population becomes phenotypically heterogenous when they experience an abnormal mechanical environment, compared to their native environment. Using a newly developed technique to quantify the heterogeneity, we provide the evidence of phenotypical heterogeneity of MSC through high resolution imaging and image analysis. Additionally, we provide mechanistic insight of the origin of such substrate mechanics driven heterogeneity, which is further determined by the cell-cell mechanical communication through the substrate. The outcome of this study might provide mechanism driven design principles to the molecular, cellular and tissue engineering researchers for rational design of MSC culture condition and biomaterials, thus improving their functional outcome.
Synthetic HNK-1 containing glycans provide insight into binding properties of serum antibodies from MAG-neuropathy patients

Anti-myelin-associated glycoprotein (anti-MAG) neuropathy is an autoimmune disease in which IgM autoantibodies target glycoconjugates of peripheral nerves resulting in progressive demyelination. To examine fine specificities of serum IgM autoantibodies and develop a more robust platform for diagnosis and disease monitoring, we describe here a chemoenzymatic approach that readily provided a panel of HNK-1 containing oligosaccharides presented on type 2 oligo-N-acetyl lactosamine (LacNAc) chains typical of glycosphingolipids. The compounds were prepared by a chemoenzymatic strategy in which an oligo-LacNAc structure was assembled enzymatically and then subjected to protecting group manipulation to chemically install a 3-O-sulfate glucuronic acid moiety. The synthetic strategy is highly divergent and made it possible to prepare from key precursors, additional compounds lacking sulfate of HNK-1 and derivatives in which the HNK-1 epitope is replaced by sulfate or sialic acid. The oligosaccharides were printed as a microarray to examine binding specificities of several monoclonal antibodies and serum antibodies of anti-MAG neuropathy patients. Surprisingly, three distinct patient subgroups were identified with variable dependance on the length of the LacNAc chain and sulfation of the glucuronyl moiety. In most cases, a lacto-neohexaose backbone was required for binding indicating the antibodies target corresponding glycosphingolipids. Significance statement A chemoenzymatic strategy is introduced in which a glycan backbone is assembled by glycosyltransferases to give a core oligosaccharide that is subjected to protecting group manipulations and chemical glycosylations to install terminal epitopes. It addresses limitations of enzymatic synthesis when specific glycosyltransferases or glycan-modifying enzymes for terminal epitope synthesis are not readily available. It provided an unprecedented panel of HNK-1 containing oligosaccharides, which was used to develop a glycan microarray that uncovered distinct binding preferences of serum antibodies of anti-MAG patients. The clinical spectrum of IgM monoclonal gammopathy varies substantially and an understanding of binding properties of IgM auto-antibodies will provide opportunities to monitor disease progression and develop personalized treatment options.
Title: T-cell targeted immunotherapy against the tumor associated antigen survivin (BIRC5) as a potential neoadjuvant immunotherapy for triple negative breast cancer.

Background Triple negative breast cancer (TNBC) cells are, by definition, estrogen and progesterone receptor negative and do not produce high levels of the HER2 protein. Checkpoint inhibitor immunotherapy has been approved for patients with TNBC, but the prognosis for these patients is poor compared with patients presenting with other common forms of breast cancer. Survivin (BIRC5) is a tumor-associated antigen (TAA) previously described to be overexpressed in triple negative breast cancer, but not expressed, or expressed at very low levels, in normal tissue, representing targets for cytotoxic T lymphocyte (CTL) immunotherapy. fixed Targeted T-cell immunotherapy triggering a T-cell immune response against neoadjuvant recurrence after surgical excision breast tumor tissue if the number of cells remaining after tumor debulking is low enough to result in CTL attack sufficient to blunt tumor-take and tumor growth rate. Previous studies have seen mixed efficacy with peptides used as immunotherapy A delivery system such may TAA cancer
Voting for authorship attribution applied to dark web data

This research is about authorship attribution (AA) within multiple Dark Web forums and the question of whether AA is possible beyond the boundaries of a single forum. AA can become a curse for users that try to protect their anonymity and simultaneously become a blessing for law enforcement groups that try to track users. In this paper, we explore AA within multiple Dark Web forums to determine whether AA is possible beyond the boundaries of a single forum. The analysis revealed that analyzing all features together with a single classifier does not achieve as good results as when they are classified separately and the final result is computed by a voting mechanism. The latter achieves an F1-Score that is up to 44% higher than in the former case. On top of that, the analyses show that the author of a post is at least 94% within the top three most likely candidates. This shows that AA can threaten the anonymity of Dark Web users across the boundaries of different forums.
Faster responses of photosynthesis to light transitions increase biomass and grain yield in transgenic Sorghum bicolor overexpressing Rieske FeS

Sorghum is one of the most important crops providing food and feed in many of the world’s harsher environments. Sorghum utilises the C4 pathway of photosynthesis in which a biochemical carbon concentrating mechanism results in high CO2 assimilation rates. Overexpressing the Rieske subunit of the Cytochrome b6f complex was previously shown to increase the rate of photosynthetic electron transport and stimulate CO2 assimilation in the model C4 plant Setaria viridis. To test whether productivity of C4 crops could be improved by Rieske overexpression, we created transgenic Sorghum bicolor plants with increased Rieske content. The transgenic plants showed no marked changes in abundance of other photosynthetic proteins or chlorophyll content. Increases in yield of Photosystem II and CO2 assimilation rate as well as faster responses of non-photochemical quenching during transient photosynthetic responses were observed as a result of an elevated in vivo Cytochrome b6f activity in plants overexpressing Rieske. The steady-state rates of electron transport and CO2 assimilation did not differ between transgenic and control plants, suggesting that Cytochrome b6f is not the only factor limiting electron transport in sorghum at high light and high CO2. Nevertheless, more agile responses of photosynthesis to light transitions led to increases in biomass and grain yield in plants overexpressing Rieske. Our results indicate that increasing Rieske content could boost productivity of C4 crops by improving the efficiency of light utilisation and conversion to biomass.
On the Functional Role of Gamma Synchronization in the Retinogeniculate System of the Cat

Fast gamma oscillations, generated within the retina, and transmitted to the cortex via the lateral geniculate nucleus (LGN), are thought to carry information about stimulus size and continuity. This hypothesis relies mainly on studies conducted under anesthesia and the extent to which it holds under more naturalistic conditions remains unclear. Using multielectrode recordings of spiking activity in the retina and the LGN of both male and female cats, we show that visually driven gamma oscillations are absent for awake states and are highly dependent on halothane (or isoflurane). Under ketamine, responses were nonoscillatory, as in the awake condition. Response entrainment to the monitor refresh was commonly observed up to 120 Hz and was superseded by the gamma oscillatory responses induced by halothane. Given that retinal gamma oscillations are contingent on halothane anesthesia and absent in the awake cat, such oscillations should be considered artifactual, thus playing no functional role in vision. SIGNIFICANCE STATEMENT Gamma rhythms have been proposed to be a robust encoding mechanism critical for visual processing. In the retinogeniculate system of the cat, many studies have shown gamma oscillations associated with responses to static stimuli. Here, we extend these observations to dynamic stimuli. An unexpected finding was that retinal gamma responses strongly depend on halothane concentration levels and are absent in the awake cat. These results weaken the notion that gamma in the retina is relevant for vision. Notably, retinal gamma shares many of the properties of cortical gamma. In this respect, oscillations induced by halothane in the retina may serve as a valuable preparation, although artificial, for studying oscillatory dynamics.
Algebraic & definable closure in free groups

We study algebraic closure and its relation with definable closure in free groups and more generally in torsion-free hyperbolic groups. Given a torsion-free hyperbolic group G and a nonabelian subgroup A of G, we describe G as a constructible group from the algebraic closure of A along cyclic subgroups. In particular, it follows that the algebraic closure of A is finitely generated, quasiconvex and hyperbolic. Suppose that G is free. Then the definable closure of A is a free factor of the algebraic closure of A and the rank of these groups is bounded by that of G. We prove that the algebraic closure of A coincides with the vertex group containing A in the generalized cyclic JSJ-decomposition of G relative to A. If the rank of G is bigger than 4, then G has a subgroup A such that the definable closure of A is a proper subgroup of the algebraic closure of A. This answers a question of Sela.
Dysfunction of the Polycomb protein RYBP and of 5-methylcytosine oxidases leads to widespread CpG island hypermethylation and cell transformation

DNA hypermethylation is a hallmark of cancer and predominantly affects CpG island regions. Although this phenomenon was first described more than three decades ago, its mechanisms have remained unknown. Since CpG island hypermethylation is strongly biased towards Polycomb target genes, we reasoned that dysfunction of Polycomb repression complexes (PRCs) may underlie CpG island hypermethylation. We observed that a few genes coding for components of the PRC1 complex are downregulated in many cancer types. We focused on RYBP, a key activator of variant PRC1 complexes responsible for H2AK119 monoubiquitylation. We inactivated RYBP in nontumorigenic bronchial epithelial cells and observed a limited extent of DNA hypermethylation. Considering that tumors are deficient in 5-methylcytosine oxidase (TET protein) function as documented by substantially reduced levels of 5-hydroxymethylcytosine in all solid tumors, we then inactivated TET1, TET2, and TET3 in bronchial cells, individually and in combination. Using quadruple knockouts of RYBP and all three TET proteins, we observed widespread hypermethylation of H2AK119Ub1-marked CpG islands affecting almost 4,000 target genes. This hypermethylation closely mirrored the DNA hypermethylation landscape observed in human lung tumors. These cells showed aberrant methylation and dysregulation of several cancer-relevant pathways including cell cycle control genes, defects in the Hippo pathway and overexpression of AP-1 transcription factor genes. As a result, the quadruple knockout bronchial cells acquired properties of a transformed phenotype, including efficient growth in soft agar and formation of squamous cell carcinomas in immune-compromised mice. Our data provide a long- sought mechanism for DNA hypermethylation in cancer and explain how such hypermethylation leads to cell transformation. Cancer formation, therefore, is achievable by misregulation of two epigenetic pathways without introduction of cancer driver mutations.
Contrast subgraphs allow comparing homogeneous and heterogeneous networks derived from omics data

Biological networks are often used to describe the relationships between relevant entities, in particular genes and proteins, and are a powerful tool for functional genomics. Many important biological problems can be investigated by comparing biological networks between different conditions, or networks obtained with different techniques. We show that contrast subgraphs, a recently introduced technique to identify the most important structural differences between two networks, provide a versatile tool for comparing gene and protein networks of diverse origin. We show in three concrete examples how contrast subgraphs can provide new insight in functional genomics by extracting the gene/protein modules whose connectivity is most altered between two conditions or experimental techniques.
Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB

The nuclear factor-κB (NFκB) pathway is a major thoroughfare for skeletal muscle atrophy and is driven by diverse stimuli. Targeted inhibition of NFκB through its canonical mediator IKKβ effectively mitigates loss of muscle mass across many conditions, from denervation to unloading to cancer. In this study, we used gain- and loss-of-function mouse models to examine the role of NFκB in muscle atrophy following rotator cuff tenotomy – a model of chronic rotator cuff tear. IKKβ was knocked down or constitutively activated in muscle-specific inducible transgenic mice to elicit a 2-fold gain or loss of NFκB signaling. Surprisingly, neither knockdown of IKKβ nor overexpression of caIKKβ significantly altered the loss of muscle mass following tenotomy. This finding was consistent across measures of architectural adaptation (fiber cross-sectional area, fiber length, fiber number), tissue pathology (fibrosis and fatty infiltration) and intracellular signaling (ubiquitin-proteasome, autophagy). Intriguingly, late-stage tenotomy-induced atrophy was exacerbated in male mice compared to female mice. This sex specificity was driven by ongoing decreases in fiber cross-sectional area, which paralleled the accumulation of large autophagic vesicles in male, but not female muscle. These findings suggest that tenotomy-induced atrophy is not dependent on NFκB and instead may be regulated by autophagy in a sex-specific manner.
Targeting oncogenic KRasG13C with nucleotide-based covalent inhibitors

Mutations within Ras proteins represent major drivers in human cancer. In this study, we report the structure-based design, synthesis, as well as biochemical and cellular evaluation of nucleotide-based covalent inhibitors for KRasG13C, an important oncogenic mutant of Ras that has not been successfully addressed in the past. Mass spectrometry experiments and kinetic studies reveal promising molecular properties of these covalent inhibitors, and X-ray crystallographic analysis has yielded the first reported crystal structures of KRasG13C covalently locked with these GDP analogues. Importantly, KRasG13C covalently modified with these inhibitors can no longer undergo SOS-catalysed nucleotide exchange. As a final proof-of-concept, we show that in contrast to KRasG13C, the covalently locked protein is unable to induce oncogenic signalling in cells, further highlighting the possibility of using nucleotide-based inhibitors with covalent warheads in KRasG13C-driven cancer.
Stromal Interaction Molecule 1 Maintains β Cell Identity and Function in Female Mice through Preservation of G Protein-Coupled Estrogen Receptor 1 Signaling

Loss of pancreatic β cell mass, identity, and function contribute to the development of diabetes. Here, we show that the endoplasmic reticulum (ER) calcium sensor, stromal interaction molecule 1 (STIM1), is critical for the maintenance of β cell function in female mice. When mice with β cell-specific deletion of STIM1 (STIM1Δβ) were challenged with high-fat diet, β cell dysfunction was observed in female, but not male, mice. Impaired glucose tolerance was accompanied by reductions in β cell mass, a concomitant increase in α cell mass, and significant reductions in the expression of markers of β cell maturity, including MafA and UCN3. Mechanistic assays demonstrated that the sexually dimorphic phenotype observed in STIM1Δβ mice was due in part to loss of signaling through the noncanonical 17-β estradiol receptor, GPER1. Together, these data suggest that STIM1 orchestrates pancreatic β cell function and identity through GPER1-mediated estradiol signaling.
Combined sensor-based monitoring of mycothiol redox potential and DNA-damage response in Corynebacterium glutamicum

Excessive amounts of reactive oxygen species (ROS) can cause irreversible damages to essential cellular components such as DNA. Genetically encoded biosensors targeting oxidative stress and DNA-stress have emerged to a powerful analytical tool to assess physiological states in a non-invasive manner. In this study, we aimed to combine the redox biosensor protein Mrx1-roGFP2 with a transcriptional biosensor for DNA-damage based on the PrecA promoter fused to a reporter gene (e2-crimson) in Corynebacterium glutamicum. Therefore, the redox biosensor strains C. glutamicum WT_Mrx1-roGFP2 and the mycothiol (MSH)-deficient mutant strain C. glutamicum ΔmshC_Mrx1-roGFP2 were equipped with the DNA-stress reporter plasmid pJC1_PrecA_e2-crimson. Exposure of the double-sensor equipped C. glutamicum WT strain to hypochlorite resulted in an oxidative redox shift, accompanied by an induction of the DNA-stress reporter system. In absence of the major non-enzymatic antioxidant MSH, the induction of the DNA-stress response was even more pronounced. This confirms the linkage of oxidative stress and DNA-damage response, and therefore making antioxidants a crucial player to protect DNA. Furthermore, exposure of the double biosensor strains to a DNA-damage inducing agent resulted in an oxidative redox shift. These results suggest a direct link of DNA-damage and oxidative stress response in C. glutamicum. Finally, we observed that inhibition of cell wall biosynthesis by penicillin caused both an oxidative redox shift and a DNA-damage response in C. glutamicum. The excellent compatibility of Mrx1-roGFP2 with E2-Crimson shown here provides a powerful combinatorial biosensor concept for in-depth studies of redox-related physiology in future studies.
Asymmetric dimethylarginine positively modulates Calcium-Sensing Receptor signalling to promote lipid accumulation and adiposity

Irreversible methylation of arginine residues generates asymmetric dimethylarginine (ADMA). ADMA is a competitive inhibitor of nitric oxide (NO) synthase and an independent risk factor for cardiovascular disease. Plasma ADMA concentrations increase with obesity and fall following weight loss. Here, we demonstrate that ADMA drives lipid accumulation through a newly identified NO-independent pathway via the amino-acid sensitive calcium-sensing receptor (CaSR). ADMA treatment of 3T3-L1 and HepG2 cells activates mTOR signalling and upregulates a suite of lipogenic genes with an associated increase in triglyceride content. Pharmacological blockade of CaSR inhibits ADMA driven lipid accumulation and ADMA treatment potentiates CaSR signalling via both Gq and Gi/o pathways. Impairment of ADMA metabolism in adipocytes in vivo, by dimethylamine dimethylaminohydrolase-1 (DDAH1) deletion, increases visceral adiposity and adipocyte hypertrophy. This study identifies a signalling mechanism for ADMA as an endogenous ligand of the G protein-coupled receptor CaSR that potentially contributes to the impact of ADMA in cardiometabolic disease.