bluuebunny/crossref_metadata_2025_split huggingface dataset:
Downregulation of PIK3IP1/TrIP on T cells is controlled by TCR signal strength, PKC and metalloprotease-mediated cleavage
Authors: Murter Benjamin M. , Robinson Sean C. , Banerjee Hridesh , Lau Louis , Uche Uzodinma U. , Szymczak-Workman Andrea L. , Kane Lawrence P. 
Published: May 2024

AbstractThe protein known as PI3K-interacting protein (PIK3IP1), or transmembrane inhibitor of PI3K (TrIP), is highly expressed by T cells and can modulate PI3K activity in these cells. Several studies have also revealed that TrIP is rapidly downregulated following T cell activation. However, it is unclear as to how this downregulation is controlled. Using a novel monoclonal antibody that robustly stains cell-surface TrIP, we demonstrate that TrIP is lost from the surface of activated T cells in a manner dependent on the strength of signaling through the T cell receptor (TCR) and specific downstream signaling pathways, in particular classical PKC isoforms. TrIP expression returns by 24 hours after stimulation, suggesting that it may play a role in resetting TCR signaling at later time points. We also provide evidence that ADAM family proteases are required for both constitutive and stimulation-induced downregulation of TrIP in T cells. Finally, by expressing truncated forms of TrIP in cells, we identify the region in the extracellular stalk domain of TrIP that is targeted for proteolytic cleavage.
Divergent gene expression patterns in alcohol and opioid use disorders lead to consistent alterations in functional networks within the Dorsolateral Prefrontal Cortex
Authors: MacDonald Martha , Fonseca Pablo A. S. , Johnson Kory , Murray Erin M , Kember Rachel L , Kranzler Henry , Mayfield Dayne , da Silva Daniel 
Published: May 2024

ABSTRACTSubstance Use Disorders (SUDs) manifest as persistent drug-seeking behavior despite adverse consequences, with Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) representing prevalent forms associated with significant mortality rates and economic burdens. The co-occurrence of AUD and OUD is common, necessitating a deeper comprehension of their intricate interactions. While the causal link between these disorders remains elusive, shared genetic factors are hypothesized. Leveraging public datasets, we employed genomic and transcriptomic analyses to explore conserved and distinct molecular pathways within the dorsolateral prefrontal cortex associated with AUD and OUD. Our findings unveil modest transcriptomic overlap at the gene level between the two disorders but substantial convergence on shared biological pathways. Notably, these pathways predominantly involve inflammatory processes, synaptic plasticity, and key intracellular signaling regulators. Integration of transcriptomic data with the latest genome-wide association studies (GWAS) for problematic alcohol use (PAU) and OUD not only corroborated our transcriptomic findings but also confirmed the limited shared heritability between the disorders. Overall, our study indicates that while alcohol and opioids induce diverse transcriptional alterations at the gene level, they converge on select biological pathways, offering promising avenues for novel therapeutic targets aimed at addressing both disorders simultaneously.
Network pharmacology, single gene survival analysis and molecular docking to study the mechanism of Sotetsuflavone in the treatment of pancreatic cancer
Authors: Chu Zi-Yong , Zi Xue-Jiao 
Published: May 2024

AbstractPancreatic cancer is a highly lethal cancer with limited treatment options. The number of pancreatic cancer patients is increasing rapidly worldwide. Many natural products have been shown to have anticancer activity in a range of studies. Sotetsuflavone is derived fromCycas revolutaThunb. and exhibits anticancer activity. The present study incorporates network pharmacology, single gene survival analysis, gene expression analysis and molecular docking to reveal the mechanism of Sotetsuflavone in the treatment of pancreatic cancer. Initially, it was evaluated through multiple databases for a comprehensive pharmacological evaluation of Sotetsuflavone. Then, the target information of Sotetsuflavone and pancreatic cancer was searched and screened using public databases. According to the results of matching the potential targets of Sotetsuflavone with the targets of pancreatic cancer, the protein-protein interaction (PPI) network was constructed by using the STRING database and imported into Cytoscape 3.9.0 for the network analysis to screen the hub targets, and then classify and co-expression analysis was carried out on the hub targets. Then, we conducted Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of potential and hub targets and discovered that these targets were involved in pancreatic cancer-related signalling pathways. In addition, the GEPIA 2 platform was used to be performed for single gene survival analysis and gene expression analysis, and AutoDock Vina was employed for molecular docking analysis. In total, we have acquired 31 hub targets for the treatment of pancreatic cancer by Sotetsuflavone, namely ABCB1, AURKA, CDK1, and so on. Kaplan-Meier survival analyses demonstrated that ABCB1, AURKA, CDK1, HDAC6, MET, and MMP3 are promising hub targets that can be used as biomarkers for pancreatic cancer diagnosis and prognosis. These hub targets are highly expressed in pancreatic cancer tissues compared to normal tissues. The molecular docking results showed a strong binding capacity of Sotetsuflavone to these hub targets. In summary, it is proposed that Sotetsuflavone is a new anticancer drug, which can regulate cancer-related signalling pathways such as pancreatic cancer by inhibiting the activities of ABCB1, AURKA, CDK1, HDAC6, MET, and MMP3, which are hub targets with up-regulated expression in pancreatic cancer tissues, in order to treat pancreatic cancer. However, it also requires a series of in vivo and in vitro studies to ensure its safety and efficacy.
GDF15 knockout does not substantially impact perinatal body weight or neonatal outcomes in mice
Authors: Mulcahy Molly C. , Habbal Noura El , Redd JeAnna R. , Sun Haijing , Gregg Brigid E. , Bridges Dave 
Published: May 2024

AbstractGrowth differentiation factor-15 (GDF15) increases in circulation during pregnancy and has been implicated in food intake, weight loss, complications of pregnancy, and metabolic illness. We used aGdf15knockout mouse model (Gdf15-/-)to assess the role of GDF15 in body weight regulation and food intake during pregnancy. We found thatGdf15-/-dams consumed a similar amount of food and gained comparable weight during the course of pregnancy compared toGdf15+/+dams. Insulin sensitivity on gestational day 16.5 was also similar between genotypes. In the postnatal period, litter size, and survival rates were similar between genotypes. There was a modest reduction in birth weight ofGdf15-/-pups, but this difference was no longer evident postnatal day 3.5 to 14.5. We observed no detectable differences in milk volume production or milk fat percentage. These data suggest that GDF15 is dispensable for changes in food intake, and body weight as well as insulin sensitivity during pregnancy in a mouse model.
Machine learning-inferred and energy landscape-guided analyses reveal kinetic determinants of CRISPR/Cas9 gene editing
Authors: Jin Lei , Liyanage Risi , Duan Dongsheng , Chen Shi-Jie 
Published: May 2024

AbstractThe CRISPR/Cas nucleases system is widely considered the most important tool in genome engineering. However, current methods for predicting on/off-target effects and designing guide RNA (gRNA) rely on purely data-driven approaches or focus solely on the system’s thermal equilibrium properties. Nonetheless, experimental evidence suggests that the process is kinetically controlled rather than being in equilibrium. In this study, we utilized a vast amount of available data and combined random forest, a supervised ensemble learning algorithm, and free energy landscape analysis to investigate the kinetic pathways of R-loop formation in the CRISPR/Cas9 system and the intricate molecular interactions between DNA and the Cas9 RuvC and HNH domains. The study revealed (a) a novel three-state kinetic mechanism, (b) the unfolding of the activation state of the R-loop being the most crucial kinetic determinant and the key predictor for on- and off-target cleavage efficiencies, and (c) the nucleotides from positions +13 to +16 being the kinetically critical nucleotides. The results provide a biophysical rationale for the design of a kinetic strategy for enhancing CRISPR/Cas9 gene editing accuracy and efficiency.
Reinforcing Tunnel Network Exploration in Proteins Using Gaussian Accelerated Molecular Dynamics
Authors: Mandal Nishita , Surpeta Bartlomiej , Brezovsky Jan 
Published: May 2024

AbstractTunnels are structural conduits in biomolecules responsible for transporting chemical compounds and solvent molecules to and from the active site. They have been shown to be present in a wide variety of enzymes across all functional and structural classes. However, the study of such pathways is experimentally challenging because they are typically transient. Computational methods such as molecular dynamics (MD) simulations have been successfully proposed to explore tunnels. Conventional MD (cMD) provides structural details to characterize tunnels but suffers from sampling limitations to capture rare tunnel openings on longer timescales. Therefore, in this study, we explored the potential of Gaussian accelerated MD (GaMD) simulations to improve the exploration of complex tunnel networks in enzymes. We used the haloalkane dehalogenase LinB and its two variants with engineered transport pathways, which are not only well-known for their application potential but have also been extensively studied experimentally and computationally regarding their tunnel networks and their importance in multi-step catalytic reactions. Our study demonstrates that GaMD efficiently improves tunnel sampling and allows the identification of all known tunnels for LinB and its two mutants. Furthermore, the improved sampling provided insight into a previously unknown transient side tunnel (ST). The extensive conformational landscape explored by GaMD simulations allowed us to investigate in detail the mechanism of ST opening. We determined variant-specific dynamic properties of ST opening, which were previously inaccessible due to limited sampling of cMD. Our comprehensive analysis supports multiple indicators of the functional relevance of the ST, emphasizing its potential significance beyond structural considerations. In conclusion, our research proves that the GaMD method can overcome the sampling limitations of cMD for the effective study of tunnels in enzymes, providing further means for identifying rare tunnels in enzymes with potential for drug development, precision medicine, and rational protein engineering.
PEX39 facilitates the peroxisomal import of PTS2 proteins
Authors: Chen Walter W. , Rodrigues Tony A. , Wendscheck Daniel , Pedrosa Ana G. , Yang Chendong , Francisco Tânia , Möcklinghoff Till , Zografakis Alexandros , Nunes-Silva Bernardo , Avraham Reut Ester , Silva Ana R. , Ferreira Maria J. , Das Hirak , Bender Julian , Oeljeklaus Silke , Sondhi Varun , Schuldiner Maya , Zalckvar Einat , Hofmann Kay , Waterham Hans R. , DeBerardinis Ralph J. , Azevedo Jorge E. , Warscheid Bettina 
Published: May 2024

SUMMARYPeroxisomes are metabolic organelles essential for human health. Defects in peroxisomal biogenesis proteins (peroxins/PEXs) cause devastating disease. PEX7 binds newly synthesized proteins containing a type 2 peroxisomal targeting signal (PTS2) to enable their import from the cytosol into peroxisomes, although many aspects of this import pathway remain enigmatic. Utilizingin vitroassays, yeast, and human cells, we show that PEX39, a previously uncharacterized protein, is a cytosolic peroxin that facilitates PTS2-protein import by binding PEX7 and stabilizing its interaction with PTS2 cargo. PEX39 and PEX13, a peroxisomal membrane translocon protein, both possess a KPWE motif necessary for PEX7 binding. Sequential binding of PEX7 to this motif in PEX39 and PEX13 provides a novel paradigm for how PTS2 cargo engage the translocation machinery. Collectively, our work uncovers an ancient and functionally important relationship among PEX39, PEX7, and PEX13, offering insights that will advance our understanding of peroxisomal biogenesis and disease.
Metabolic immaturity of newborns and breast milk bile acid metabolites are the central determinants of heightened neonatal vulnerability to norovirus diarrhea
Authors: Peiper Amy M. , Aparicio Joyce Morales , Phophi Lufuno , Hu Zhengzheng , Helm Emily W. , Phillips Matthew , Williams Caroline G. , Subramanian Saravanan , Cross Michael , Iyer Neha , Nguyen Quyen , Newsome Rachel , Jobin Christian , Langel Stephanie N. , Bucardo Filemon , Becker-Dreps Sylvia , Tan Xiao-Di , Dawson Paul A. , Karst Stephanie M. 
Published: May 2024

ABSTRACTNoroviruses are the leading global cause of acute gastroenteritis, responsible for 685 million annual cases. While all age groups are susceptible to noroviruses, children are vulnerable to more severe infections than adults, underscored by 200 million pediatric cases and up to 200,000 deaths in children annually. Understanding the basis for the increased vulnerability of young hosts is critical to developing effective treatments. The pathogenic outcome of any enteric virus infection is governed by a complex interplay between the virus, intestinal microbiota, and host immune factors. A central mediator in these complex relationships are host- and microbiota-derived metabolites. Noroviruses bind a specific class of metabolites, bile acids, which are produced by the host and then modified by commensal bacterial enzymes. Paradoxically, bile acids can have both proviral and antiviral roles during norovirus infections. Considering these opposing effects, the microbiota-regulated balance of the bile acid pool may be a key determinant of the pathogenic outcome of a norovirus infection. The bile acid pool in newborns is unique due to immaturity of host metabolic pathways and developing gut microbiota, which could underlie the vulnerability of these hosts to severe norovirus infections. Supporting this concept, we demonstrate herein that microbiota and their bile acid metabolites protect from severe norovirus diarrhea whereas host-derived bile acids promote disease. Remarkably, we also report that maternal bile acid metabolism determines neonatal susceptibility to norovirus diarrhea during breastfeeding by delivering proviral bile acids to the newborn. Finally, directed targeting of maternal and neonatal bile acid metabolism can protect the neonatal host from norovirus disease. Altogether, these data support the conclusion that metabolic immaturity in newborns and ingestion of proviral maternal metabolites in breast milk are the central determinants of heightened neonatal vulnerability to norovirus disease.
Floral Cues and Flower Handling Tactics Affect Switching Decisions by Nectar-Foraging Bumble Bees
Authors: Baek Minjung , Garcia Jonathan S. , Papaj Daniel R. 
Published: May 2024

AbstractNectar foraging bees change their use of floral resources as plant species appear in the environment and disappear over their lifetimes. The new flowers used may involve different cues and different nectar extraction tactics. Although bumble bees can adapt to changes in floral cues and required tactics, little is known about whether bees prioritize switching tactics or floral cues when deciding which plant species to switch to. In a laboratory assay, we forcedBombus impatiens(common eastern bumble bee) workers either to switch the handling tactic they were using or to continue using the tactic but to switch the colour of artificial flowers foraged on. We examined whether bees’ tendency to change their tactics was influenced by how similar in colour novel flowers were to familiar ones. We conducted a 2 × 2 factorial experiment using artificial flowers, manipulating the handling tactic that bees were initially trained (legitimate visitation or nectar robbing) and the similarity between novel and trained colours (similar or distinct). We found that under most conditions bees preferred to switch flower colours and retain handling tactics. However, when given experience with legitimate visitation and when novel flowers were markedly different in colour from those they had experienced previously, bees tended to switch tactic while continuing to forage on flowers of the same colour. These findings suggest that the similarity in colour of a new floral resource to the currently exploited resource, along with the flower handling tactic employed by bees, jointly plays an important role in decision-making by foraging bumble bees.
Transient hypoxia followed by progressive reoxygenation is required for efficient skeletal muscle repair through Rev-ERBα modulation
Authors: Quétin Marie , Vartanian Audrey Der , Dubois Christelle , Berthier Juliette , Ledoux Marine , Michineau Stéphanie , Drayton-Libotte Bernadette , Sotiropoulos Athanassia , Relaix Frédéric , Gervais Marianne 
Published: May 2024

SUMMARYMuscle stem cells (MuSCs) are essential for skeletal muscle repair. Following injury, MuSCs reside in low oxygen environments until muscle fibers and vascularization are restablished. The dynamics of oxygen levels during the regenerative process and its impact on muscle repair has been underappreciated. We confirm that muscle repair is initiated in a low oxygen environment followed by gradual reoxygenation. Strikingly, when muscle reoxygenation is limited by keeping mice under systemic hypoxia, muscle repair is impaired and leads to the formation of hypotrophic myofibers.In vivo, sustained hypoxia decreases the ability of MuSCs to differentiate and fuse independently of HIF-1α. Prolonged hypoxia specifically affects the circadian clock by increasingRev-erbαexpression in MuSCs. Using pharmacological tools, we demonstrate that Rev-ERBα negatively regulates myogenesis by reducing late myogenic cell fusion under prolonged hypoxia. Our results underscore the critical role of progressive muscle reoxygenation after transient hypoxia in coordinating proper myogenesis through Rev-ERBα.
Hedgehog-dependent and Hedgehog-independent roles for Growth Arrest Specific 1 in mammalian kidney morphogenesis
Authors: Franks Nicole E. , Allen Benjamin L. 
Published: May 2024

AbstractGrowth arrest specific 1 (GAS1) is a key regulator of mammalian embryogenesis, best known for its role in Hedgehog (HH) signaling, but with additional described roles in the FGF, RET, and NOTCH pathways. Previous work indicated a later role for GAS1 in kidney development through FGF pathway modulation. Here, we demonstrate that GAS1 is essential for both mesonephrogenesis and metanephrogenesis– most notably,Gas1deletion in mice results in renal agenesis in a genetic background-dependent fashion. Mechanistically, GAS1 promotes mesonephrogenesis in a HH-dependent fashion, performing a unique co-receptor function, while promoting metanephrogenesis in a HH-independent fashion, acting as a putative secreted RET co-receptor. Our data indicate thatGas1deletion leads to renal agenesis through a transient reduction in metanephric mesenchyme proliferation– a phenotype that can be rescued by exogenous RET pathway stimulation. Overall, this study indicates that GAS1 contributes to early kidney development through the integration of multiple different signaling pathways.
Quantum spin liquid ground state in the trimer rhodate
Ba4NbRh3O12
Authors: Bandyopadhyay Abhisek , Lee S. , Adroja D. T. , Stenning G. B. G. , Berlie Adam , Lees M. R. , Saha R. A. , Takegami D. , Meléndez-Sans A. , Poelchen G. , Yoshimura M. , Tsuei K. D. , Hu Z. , Kao Cheng-Wei , Huang Yu-Cheng , Chan Ting-Shan , Choi Kwang-Yong 
Published: May 2024

Frustrated magnets offer a plethora of exotic magnetic ground states, including quantum spin liquids (QSLs), in which enhanced quantum fluctuations prevent a long-range magnetic ordering of the strongly correlated spins down to lowest temperature. Here we have investigated the trimer based mixed valence hexagonal rhodate Ba4NbRh3O12 using a combination of dc and ac magnetization, electrical resistivity, specific heat, and muon spin rotation/relaxation (μSR) measurements. Despite the substantial antiferromagnetic exchange interactions, as evident from the Weiss temperature (θW∼−35 to −45K), among the Rh-local moments, neither long-range magnetic ordering nor spin freezing is observed down to at least 50 mK, in ac-susceptibility, specific heat, and zero-field μSR measurements (down to 0.26 K). We ascribe the absence of any magnetic transition to enhanced quantum fluctuations as a result of geometrical frustration arising out of the edge-sharing equilateral Rh-triangular network in the structure. Our longitudinal-field μSR result evidences persistent spin fluctuations down to 0.26 K, thus stabilizing a dynamic QSL ground state in Ba4NbRh3O12. Furthermore, the magnetic specific heat data at low T reveal a significant T-linear contribution plus a quadratic T dependence, which may indicate the gapless Dirac QSL phenomenology of the spinon excitations with a linear dispersion.

Published by the American Physical Society
2024
Does information matter? Online discourse on the Yemenite children’s affair in Israel after release of archival documents
Authors: Peled Roy , Yavetz Gal 
Published: May 2024

PurposeThis study evaluates how publicly available archival documents shaped online discussions about allegations that thousands of children were kidnapped during the 1950s in Israel, known as the Yemenite children’s affair. It examines if access to historical records leads to more informed and rational public discourse, especially on social media.Design/methodology/approachUsing content analysis, this study examines Facebook posts from media outlets, politicians, NGOs and public groups between 2016 and 2021 to understand how the Israeli State Archives’ release of over 300,000 documents affected support of the kidnapping.FindingsDespite extensive archival information debunking the kidnapping theory, public opinion and discourse largely continued to support it. This suggests a complex interaction between information availability, preexisting beliefs, echo chambers and group allegiances, suggesting that access to factual data alone may not effectively challenge established beliefs in online public settings.Research limitations/implicationsSince data were collected only from Facebook, our conclusions cannot be generalized to other platforms. The study relies only on publicly accessible data and does not establish causality between exposure to information and shifts in opinion. Our findings show that disclosing archival information does not significantly benefit public political discourse on contentious topics but also point to the advantages of mediating information by politicians, NGOs and journalists.Originality/valueAs a unique case study, this research contributes to understanding the role of historical archives in digital-age public discourse. It highlights their potential and limitations in facilitating informed debate and deliberation, emphasizing the complexity of influencing established beliefs with factual data.