bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Ketamine Treatment on Social Withdrawal in Autism and Autism-Like Conditions
Authors: Ralston Megan , Osman Alim , Suryadevara Pavan , Cleland Elissa 
Published: May 2024

Objective
Ketamine and esketamine have been used in the field of psychiatry to alleviate conditions such as major depressive disorder. Our objective was to evaluate the current literature on the use of ketamine for symptoms of social withdrawal in autism spectrum disorder (ASD) and autism-like conditions.

Methods
A comprehensive search of PubMed and Web of Science was conducted to identify literature involving the use of ketamine to treat symptoms of autism and social withdrawal. Patients with comorbid disorders were also included.

Results
Two original studies were found, showing mixed results on the use of ketamine for ASD. The use of esketamine found no statistically significant results, whereas the use of intravenous ketamine was shown to alleviate symptoms of social withdrawal especially in the short term. Neither study reported a significant amount of serious adverse events. Five case reports were also included, showing decreased depressive symptoms and evidence of increased social condition.

Conclusions
Research on the use of ketamine for ASD and ASD-related conditions is limited. Evidence of improved social condition exists, but further studies should be conducted to increase sample power and test various doses and methods of administration.
Androgen receptor activity inversely correlates with immune cell infiltration and immunotherapy response across multiple cancer lineages
Authors: Hu Ya-Mei , Zhao Faming , Graff Julie N. , Chen Canping , Zhao Xiyue , Thomas George V. , Wu Hui , Kardosh Adel , Mills Gordon B. , Alumkal Joshi J. , Moran Amy E. , Xia Zheng 
Published: May 2024

AbstractThere is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects of AR activity on cancer immunity, we employed a computational approach to profile AR activity in 33 human tumor types using RNA-Seq datasets from The Cancer Genome Atlas. Our pan-cancer analysis revealed that the genes most negatively correlated with AR activity across cancers are involved in active immune system processes. Importantly, we observed a significant negative correlation between AR activity and IFNγ pathway activity at the pan-cancer level. Indeed, using a matched biopsy dataset from subjects with prostate cancer before and after AR-targeted treatment, we verified that inhibiting AR enriches immune cell abundances and is associated with higher IFNγ pathway activity. Furthermore, by analyzing immunotherapy datasets in multiple cancers, our results demonstrate that low AR activity was significantly associated with a favorable response to immunotherapy. Together, our data provide a comprehensive assessment of the relationship between AR signaling and tumor immunity.
Single-cell and spatial atlas of steatotic liver disease-related hepatocellular carcinoma
Authors: Prawira Aldo , Xu Hang , Leow Wei Qiang , Otsuka Masayuki , Chen Ziyao , Rahbari Mohammad , Hazirah Sharifah N. , Wasser Martin , Chung Alexander , Goh Brian K.P. , Chow Pierce K.H. , Albani Salvatore , Lee Joycelyn , Lim Tony K.H. , Zhai Weiwei , Dan Yock Young , Goh George , Tai David , DasGupta Ramanuj , Heikenwalder Mathias , Chen Jinmiao , Chew Valerie 
Published: May 2024

SummarySteatotic liver disease-related hepatocellular carcinoma (SLD-HCC) poses significant challenges in liver cancer management. Our current study investigates the tumor microenvironment (TME) of SLD-HCC using single-cell transcriptomic, proteomic and spatial transcriptomic analyses. We identified altered immune-related and lipid metabolism pathways, particularly in regulatory T cells (Tregs) and cancer-associated fibroblasts (CAFs) within the SLD-HCC microenvironment, suggesting distinct cellular adaptations to a high-fat TME and general immunosuppression. Cytometry by time-of-flight revealed a cold and immunosuppressive TME depleted with CD8+T cells and enriched with Tregs, while spatial transcriptomics uncovered a unique spatial architecture with Treg/CAF clusters specifically located at the tumor margins in SLD-HCC. Crucially, we identified Treg-CAF interactions as a key mediator associated with lack of response to immunotherapy in SLD-HCC. Our findings highlight the intricate immune dynamics of SLD-HCC, indicating potential therapeutic targets to counteract immune evasion and restore anti-tumor immunity in SLD-HCC.HighlightsThe TME of SLD-HCC exhibits altered immune and lipid pathwaysImmunosuppressive SLD-HCC TME is depleted with CD8+T cells and enriched with TregsSLD-HCC has a unique spatial architecture with Treg-CAF clusters at tumor marginsTreg-CAF interaction via TNFSF14-TNFRSF14 axis mediates immunotherapy resistance
Nutraceuticals Silybin B, resveratrol and epigallocatechin-3 gallate (EGCG) bind to cardiac muscle troponin to restore the loss of lusitropy caused by cardiomyopathy mutationsin vitro, in vivo, andin silico
Authors: Yang Zeyu , Sheehan Alice , Messer Andrew , Tsui Sharmane , Sparrow Alexander , Redwood Charles , Kren Vladimir , Gould Ian R. , Marston Steven B. 
Published: May 2024

ABSTRACTAdrenergic activation of protein kinase A (PKA) targets the thin filaments of the cardiac muscle, specifically phosphorylating cTroponin I Ser22 and Ser23, causing a higher rate of Ca2+dissociation from cTnC leading to a faster relaxation rate (lusitropy). This modulation is often suppressed by mutations that cause cardiomyopathy (uncoupling) and this could be sufficient to induce cardiomyopathy. A drug that could restore the phosphorylation-dependent modulation of relaxation rate could have the potential for treatment of these pathologies.We found, using single thin filamentin vitromotility assays that the small molecules including silybin B, resveratrol, and epigallocatechin-3 gallate (EGCG) can restore coupling.We performed molecular dynamics simulations of the unphosphorylated and phosphorylated cardiac Troponin core with the TNNC1 G159D mutation. We found that silybin B, EGCG, and resveratrol restored the phosphorylation-induced change in the TnC helix A/B angle and the interdomain angle to wild-type values, whilst silybin A and epicatechin gallate (ECG) did not. In unphosphorylated G159D the recoupling molecules were observed to be frequently intercalated between The N terminal peptide of Troponin I and troponin C. In contrast, the controls, silybin A, and ECG bound to the surface. All of the interactions were diminished when troponin I was phosphorylated.We also performed studies with intact transgenic ACTC E99K mouse cells and TNNT2 R92Q-transfected guinea pig cardiomyocytes. The mutations blunt the increase in relaxation speed due to dobutamine; resveratrol, EGCG, and silybin B could restore the dobutamine response whilst silybin A did not. Thus recoupling by small molecules is demonstratedin vitro, in vivo, andin silico.
Longitudinal Prediction of Drug Response in High-Grade Serous Ovarian Cancer Organoid Cultures Aligning with Clinical Responses
Authors: Cavarzerani Enrico , Caligiuri Isabella , Bartoletti Michele , Corona Giuseppe , Perin Tiziana , Palumbo Antonio , Canzonieri Vincenzo , Rizzolio Flavio 
Published: May 2024

ABSTRACTHigh-grade serous ovarian cancer (HGSOC) ranks among the most aggressive gynecological malignancies. Its high mortality stems from frequent recurrence post-primary treatments and development of platinum resistance. Since, traditional drug development via animal models is time-consuming and lacks reproducibility, in precision cancer medicine, primary patient-derived organoids (PDOs) offer a solution by replicating disease pathophysiology and expediting drug screening. We developed an expandable HGSOC organoid platform for rapid drug screening and resistance testing. Our study aimed to validate the stability of seven PDO pairs in predicting drug responses over time. Organoids underwent low- and high-passage drug screenings over nine months, involving 21 conventional and FDA-approved drugs and proteomic analyses. Comparison of in vitro outcomes with clinical data confirmed the platform’s predictive capacity. Notably, a PDO with BRCA1 mutation exhibited resistance to Carboplatin and PARP inhibitors, highlighting organoid models’ clinical relevance for novel targeted therapies such as the Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (Pin1), a valuable target for HGSOC patients.
Optimizing clinical interpretability of functional evidence in epilepsy-related ion channel variants
Authors: Parthasarathy Shridhar , Cohen Stacey R. , Fitch Eryn , Vaidiswaran Priya , Ruggiero Sarah , Lusk Laina , Chisari Victoria , Lewis-Smith David , Lauxmann Stephan , Boßelmann Christian M. , Thompson Christopher H. , Wengert Eric R. , Hedrich Ulrike , Ganesan Shiva , Balagura Ganna , Krause Roland , Xian Julie , Galer Peter , Pendziwiat Manuela , Perez-Palma Eduardo , Vihinen Mauno , Hart Jennifer , Landrum Melissa J. , Lal Dennis , Cooper Edward C. , Lerche Holger , Goldberg Ethan , Brunklaus Andreas , Vanoye Carlos G. , Schorge Stephanie , George Alfred L. , Helbig Ingo 
Published: May 2024

AbstractVariants in genes encoding the voltage-gated ion channels are among the most common monogenic causes of epilepsy and neurodevelopmental disorders. Functional effects of a variant are increasingly important for diagnosis and therapeutic decisions. To incorporate knowledge regarding functional consequences in formal clinical variant interpretation, we developed an approach for evaluating multiple functional measurements within the Bayesian framework of the modified ACMG/AMP guidelines. We analyzed 216 functional assessments of 191 variants inSCN1A(n=74),SCN2A(n=66),SCN3A(n=18), andSCN8A(n=33). Of 20 commonly measured biophysical parameters, the most frequent drivers of overall functional consequence were persistent current (f=0.54), voltage dependence of activation (f=0.51), and voltage dependence of fast inactivation (f=0.40) for gain-of-function and peak current (f=0.87) for loss-of-function. By comparing measurements of 23 benign variants, we determined thresholds by which published data on these four parameters conferStrongevidence of variant pathogenicity (likelihood ratio > 18.7) under the ACMG/AMP rubric. Similarly, we delineated evidence weights for the most common epilepsy-related potassium channel gene,KCNQ2, through reports of 80 pathogenic and 24 benign variants, accounting for heterozygous and homozygous experimental conditions. We collected the resulting categorization of functional data into FENICS, a biomedical ontology of 152 standardized terms for coherent annotation of electrophysiological results. Across 271 variants inSCN1A/2A/3A/8AandKCNQ2, 1,731 annotations are available in ClinVar, facilitating use of this evidence in variant classification. In summary, we introduce and apply an ACMG/AMP-calibrated framework for electrophysiological studies in epilepsy-related channelopathies to delineate the impact of functional evidence on clinical variant interpretation.
Distinct genome architecture underlies fine-scale population differentiation in two common European bumblebees (Bombus pascuorumandBombus lapidarius)
Authors: Cobb Lauren , Sydenham Markus A. K. , Nielsen Anders , Star Bastiaan 
Published: May 2024

AbstractBumblebees are keystone pollinators which facilitate the reproduction of a wide range of wild and agricultural plants. Their abundance and diversity have been severely reduced by anthropogenic stressors such as land-use change and widespread habitat fragmentation. However, we lack a comprehensive understanding of bumblebee population structure and local adaptation in response to human-altered landscapes. We here discover surprisingly fine-scaled population structure (e.g. ∼300km) within two widely occurring bumblebee species,Bombus lapidariusandBombus pascuorum, by analysing whole genome data of 106 specimens from 7 sites in Northern Europe. Our sample range encompasses a mosaic of land-use types with varying levels of habitat fragmentation and natural oceanic barriers. While the observed population structure is largely associated with reduced gene flow across natural barriers, we also detect significant divergence between populations sampled from more fragmented, agricultural landscapes. Furthermore, we identify species-specific patterns of population structure which are underpinned by distinct genomic architecture. Whereas genetic divergence inB. lapidariusis spread relatively evenly across the genome, divergence inB. pascuorumis concentrated within several megabase-sized genomic regions with significantly elevated differentiation – including a putative chromosomal inversion – which may underlie well-known colour polymorphisms across its range. Our observations reveal unexpectedly high levels of inter- and intraspecific genomic diversity within the bumblebee genus, and highlight the necessity of increasing our understanding of bumblebee population structure and connectivity to design optimal bumblebee conservation strategies.Significance statementAnthropogenic stressors such as habitat fragmentation have severe impacts on bumblebee abundance and diversity, yet little is known about how bumblebee populations are structured in human-altered landscapes. We analyse whole-genome data from two common bumblebee species (Bombus lapidariusandBombus pascuorum) across Northern Europe to uncover species-specific patterns of spatial population differentiation and local adaptation, including a chromosomal rearrangement inB. pascuorum. Importantly, our results imply that many of the fragmented bumblebee habitats in Europe comprise locally distinct populations with limited gene flow in between. These findings are therefore of major importance for our overall understanding of bumblebee genomic variation, connectivity and adaptation, offering fundamental insights that are required to effectively mitigate the effects of human activities on wild bee biodiversity.
Supervised and unsupervised deep learning-based approaches for studying DNA replication spatiotemporal dynamics
Authors: Ng-Kee-Kwong Julian , Philps Ben , Smith Fiona N. C. , Sobieska Aleksandra , Chen Naiming , Alabert Constance , Bilen Hakan , Buonomo Sara C. B. 
Published: May 2024

AbstractIn eukaryotic cells, DNA replication is organised both spatially and temporally, as evidenced by the stage-specific spatial distribution of replication foci in the nucleus. Despite the genetic association of aberrant DNA replication with numerous human diseases, the labour-intensive methods employed to study DNA replication have hindered large-scale analyses of its roles in pathological processes. In this study, we first demonstrate that a convolutional neural network trained to classify S-phase stages based on DAPI and EdU patterns could identify altered replication dynamics inRif1-deficient mouse embryonic stem cells (mESCs), revealing a skewed distribution across the various S-phase stages. Given the possible practical limitations associated with a supervised framework, we proceed to show that the abnormal replication profile ofRif1-deficient mESCs could further be detected by an unsupervised approach (based on self-supervised representation learning), which could additionally reconstruct progression through S-phase. Finally, we extend our approach to a well-characterised cellular model of inducible deregulated origin firing, involving cyclin E overexpression. Through parallel EdU- and PCNA-based analyses, we demonstrate the potential applicability of our method to patient samples, offering a means to identify the contribution of deregulated DNA replication to a plethora of pathogenic processes.
TOR signaling regulates GPCR levels on the plasma membrane and suppresses theSaccharomyces cerevisiaemating pathway
Authors: Leclerc Nicholas R. , Dunne Toby M. , Shrestha Sudati , Johnson Cory P. , Kelley Joshua B. 
Published: May 2024

AbstractSaccharomyces cerevisiaerespond to mating pheromone through the GPCRs Ste2 and Ste3, which promote growth of a mating projection in response to ligand binding. This commitment to mating is nutritionally and energetically taxing, and so we hypothesized that the cell may suppress mating signaling during starvation. We set out to investigate negative regulators of the mating pathway in nutritionally depleted environments. Here, we report that nutrient deprivation led to loss of Ste2 from the plasma membrane. Recapitulating this effect with nitrogen starvation led us to hypothesize that it was due to TORC1 signaling. Rapamycin inhibition of TORC1 impacted membrane levels of all yeast GPCRs. Inhibition of TORC1 also dampened mating pathway output. Deletion analysis revealed that TORC1 repression leads to α-arrestin-directed CME through TORC2-Ypk1 signaling. We then set out to determine whether major downstream effectors of the TOR complexes also downregulate pathway output during mating. We found that autophagy contributes to pathway downregulation through analysis of strains lackingATG8. We also show that Ypk1 significantly reduced pathway output. Thus, both autophagy machinery and TORC2-Ypk1 signaling serve as attenuators of pheromone signaling during mating. Altogether, we demonstrate that the stress-responsive TOR complexes coordinate GPCR endocytosis and reduce the magnitude of pheromone signaling, in ligand-independent and ligand-dependent contexts.One Sentence SummaryTOR signaling regulates the localization of allSaccharomyces cerevisiaeGPCRs during starvation and suppress the mating pathway in the presence and absence of ligand.
Identification of the potential function-specific sites in subunits of vertebrate neuronal nicotinic acetylcholine receptors
Authors: Zhu Zhouhai , Zhang Fengyu , Guan Ying , Pan Zhenhua , Li Meng , Wang Ju 
Published: May 2024

AbstractThe nicotinic acetylcholine receptors (nAChR) are complexes that are composed of subunits evolved from common ancestor. Although the subunits are similar in sequences and structures, their molecular function varies significantly. Therefore, detecting the molecular sites specific to each subunit is important to understand the property of the subunits and the receptors formed by them. As we know, the molecular sites critical to the structure and molecular function of a protein family usually are conserved in evolution, and those specific to each member of the family are often closely related to its structural and functional specificity. In this study, we analyzed the sequence specific sites in nAChR subunits by adopting the evolutionary trace method and the two-state model, and explored the relationship between structure and function in combination with the spatial location of the sites. The results showed that the detected sites in α7 subunit were closely related to ligand binding and conformational changes of the energetic coupling pathway. The conserved sites tended to be distributed in the interior of the spatial structure of protein molecules, and the sites potentially related to new functions were distributed on the surface of the spatial structure. In summary, our results could be helpful to understanding the molecular features related to the function specificity and diversity of the nAChR subunits.
An early, novel arginine methylation of KCa3.1 attenuates subsequent T cell exhaustion
Authors: Sharma Piyush , Guo Ao , Poudel Suresh , Boada-Romero Emilio , Verbist Katherine C. , Palacios Gustavo , Immadisetty Kalyan , Chen Mark J. , Haydar Dalia , Mishra Ashutosh , Peng Junmin , Babu M. Madan , Krenciute Giedre , Glazer Evan S. , Green Douglas R. 
Published: May 2024

ABSTRACTT cell receptor (TCR) engagement initiates the activation process, and this signaling event is regulated in multifaceted ways. Nutrient availability in the immediate niche is one such mode of regulation1–3. Here, we investigated how the availability of an essential amino acid methionine (Met) and TCR signaling might interplay in the earliest events of T cell activation to affect subsequent T cell fate and function. We found that limiting Met during only the initial 30 minutes of CD8+T cell activation increased Ca2+influx, Ca2+-mediated NFAT1 (Nfatc2) activation, NFAT1 promoter occupancy, and T cell exhaustion. We identified changes in the protein arginine methylome during the initial 30 min of TCR engagement and discovered a novel arginine methylation of a Ca2+-activated potassium transporter, KCa3.1, which regulates Ca2+-mediated NFAT1 signaling to ensure optimal activation. Ablation of arginine methylation in KCa3.1 led to increased NFAT1 activation, rendering T cells dysfunctional in murine tumour and infection models. Furthermore, acute Met supplementation at early stages reduced nuclear NFAT1 in tumour-infiltrating T cells and augmented their anti-tumour activity. Our findings identify a metabolic event occurring early after T cell activation that influences the subsequent fate of the cell.
Automated muscle path calibration with gradient-specified optimization based on moment arm
Authors: Chen Ziyu , Hu Tingli , Haddadin Sami , Franklin David W. 
Published: May 2024

AbstractMuscle path modeling is more than just routing a cable that visually represents the muscle, but rather it defines how moment arms vary with different joint configurations. The muscle moment arm is the factor that translates muscle force into joint moment, and this property has an impact on the accuracy of musculoskeletal simulation. However, it is not easy to calibrate muscle path based on moment arm, because each path is configured by various parameters while the relations between moment arm and both the parameters and joint configuration are complicated. Here, we tackle this challenge in the simple fashion of optimization, but with an emphasis on the gradient; when specified in its analytical form, optimization speed and accuracy will be improved. We explain in detail how to differentiate the enormous cost function and how our optimization is configured, then we demonstrate the performance of this method by fast and accurate replication of muscle paths from a state-of-the-art shoulder–arm model. As long as the muscle is represented as a cable wrapping around obstacles, our method could overcome difficulties in path calibration, both for developing generic models and for customizing subject-specific models.