bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the link between T-regulatory cells and inflammatory cytokines in atherogenesis: findings from patients with stable angina pectoris
Authors: Tahtouh Zaatar Muriel , Othman Rima , Abou Samra Elias , Karam Marc
Published: August 2024

Background:

Atherosclerosis, a chronic inflammatory disease impacting arteries, is closely linked to cardiovascular conditions. Dyslipidemia, marked by high low-density lipoprotein (LDL), low high-density lipoprotein (HDL), and increased plasma triglycerides, is a key risk factor. Atherogenesis begins when modified lipoproteins like oxidized LDL (ox-LDL) activate the immune system. This study explores the roles of T-regulatory cells (Tregs) and interleukins 10 (IL-10), 6 (IL-6), and 17 (IL-17) in atherogenesis.

Methods:

Samples were collected from the Hospital patients with stable angina pectoris (SAP). Peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll density gradient and analyzed via flow cytometry. IL-10, IL-6, and IL-17 levels in cell culture supernatant were measured using ELISA. Data were expressed as mean ± SEM and analyzed with statistical software.

Results:

Results indicate that only patients exhibited reduced Treg and IL-10 levels after high-dose ox-LDL treatment. Significant IL-6 reduction was observed in both NCA and SA groups after high-dose n-LDL and low/high ox-LDL treatments compared to untreated PBMCs.

Conclusions and future directions:

Future research will explore n-LDL and ox-LDL effects on Th17/Treg immune responses within a specific cytokine environment known for inducing inflammation, assessing their potential role in atherosclerosis progression.
Optimizing serum electrolyte levels in stroke patients: a multimodal approach with soymilk supplementation
Authors: Esmealy Babak , Esmealy Leyla , Gholizadeh Leila , Nikookheslat Saeid , Sari-Sarraf Vahid
Published: August 2024

Introduction:

Electrolyte imbalances are common in stroke patients and can significantly impact their overall health, potentially leading to severe complications and even fatal outcomes. In this study, we investigated the impact of combining multiple exercise training modalities (METM) with soymilk supplementation on serum electrolyte levels in stroke patients.

Methods:

In a single-blind, four-arm randomized clinical trial, 120 stroke patients were randomly assigned to one of the following groups: (1) the METM group, (2) the soymilk group, (3) the METM plus soymilk group, and (4) the control group. Changes in serum electrolyte levels were compared both within and across groups over four consecutive weeks.

Results:

Upon admission, 38.3% of the participants presented with hyponatremia, 26.7% hypokalemia, and 73.3% hypocalcemia. Over time, there was an overall improvement in serum electrolyte imbalances across all study groups compared to the baseline. Between-group comparisons revealed that the METM plus soymilk group exhibited statistically significant improvements compared to the other groups with absolute reductions in the proportion of participants with hyponatremia, hypokalemia, and hypocalcemia by 43.3%, 33.3%, and 73.4%, respectively.

Conclusions:

The study findings substantiate the common occurrence of hyponatremia, hypokalemia, and hypocalcemia during the acute phase of stroke. Implementation of the METM alongside soymilk intake demonstrated potential in rectifying electrolyte imbalances among stroke patients, hinting at a promising intervention strategy.
Comparison of postoperative outcomes between tissue glue and suture for mesh fixation in open tension-free inguinal hernia repair: a prospective analytical study
Authors: Regmi Nabin , Rajthala Lilamani , Subedi Rojina , Shrestha Eruka , Gurung Narendra Vikram
Published: August 2024

Introduction:

A hernia is an abnormal protrusion of the viscus through the normal or abnormal opening of its containing cavity. Lichtenstein tension-free mesh repair is a commonly performed surgery for hernia. Various studies have revealed atraumatic fixation of the mesh produces less pain without compromising the outcomes.

Methods:

This is a prospective analytical study conducted in a tertiary hospital over a year. Eighty patients with primary inguinal hernia undergoing open mesh repair were enrolled and divided into two groups with 40 patients in each group. Mesh fixation was done with N-butyl 2 cyano-acrylate glue in one group, while polypropylene 2-0 suture in the other group. Postoperative pain, the number of dosages of analgesia required, the incidence of hematoma/seroma formation, surgical site infection, and length of hospital stay were compared between the two groups. Data were analyzed using SPSS 25.

Results:

Visual analog scores were significantly reduced in the glue group at 12 h and 24 h (P<0.05) with a reduction of the mean number of analgesic doses from 6.42±0.984 in the suture group to 5.95±0.597 in the glue group (P<0.05). The operating time was significantly reduced from 70.03±4.376 minutes in the suture group to 58.43±4.540 min in the glue group (P<0.05), while there was no significant difference in the length of hospital stay. Five percent of cases in the suture group developed seroma while no SSI was reported in this study.

Conclusions:

This study demonstrates mesh fixation with cyanoacrylate glue in open hernioplasty for primary groin hernias is associated with reduced immediate postoperative pain, dose of analgesia required, and operating time in comparison to fixation with suture.
Self-Reported Diagnosis of Autism Is Associated With a Lower Likelihood of HIV Testing
Authors: Morgan Ethan , Punches Brittany , Failla Michelle
Published: August 2024

Sexuality and sexual risk behaviors among autistic adults are often overlooked, resulting in inadequate sexual education courses and a reliance on peers or the internet as primary sources of information. Here, we plan to begin to fill this gap by assessing HIV and sexually transmitted infection (STI) outcomes among autistic adults. Data come from the 2007 NHIS data set, the only nationally representative and publicly available data set to host measures of HIV and autism alongside one another (and the only year of this survey to do so). Survey-weighted models were used to examine the association between self-reported measures of HIV/STIs and self-reported autism diagnosis. Compared with those who had not been told that they have autism, participants with an autism diagnosis had lower odds of ever having an HIV test in their lifetime (adjusted odds ratio [aOR] = 0.05; 95% confidence interval [CI]: 0.01 to 0.26). No association was observed between autism diagnosis and plans for an HIV test within the next year, nor did any autistic adults report testing positive for any STI within the past 5 years. These results suggest that further research is needed among the autism spectrum disorder community, particularly in terms of achieving the US goal of ending the HIV epidemic by 2030.
Disruption of Z-RNA–binding of ADAR1 induces Aicardi-Goutières syndrome–like encephalopathy in mice
Authors: Nakahama Taisuke , Kato Yuki , Shibuya Toshiharu , In Kim Jung , Vongpipatana Tuangtong , Todo Hiroyuki , Xing Yanfang , Kawahara Yukio
Published: August 2024

ADAR1 p150 is an enzyme responsible for adenosine-to-inosine RNA editing. Deletion of ADAR1 p150 results in embryonic lethality with a type I interferon (IFN) signature, caused by aberrant MDA5 sensing unedited transcripts. ADAR1 p150 contains a unique Z-DNA/RNA–binding domain α (Zα); however, the role of this domain remains unknown. A mutation has been identified in this domain in patients with Aicardi-Goutières syndrome (AGS), an inherited interferonopathy, suggesting an essential role in avoiding MDA5 activation. Here, we show that a mutation in the Zα domain reduces the editing activity of ADAR1 p150 by comparing activity between wild-type and mutated isoforms expressed inAdar1/Adar2knockout cells. Furthermore, we created Zα domain–mutated knock-in mice, which displayed severe growth retardation with abnormal organ development, including AGS-like encephalopathy with a type I IFN signature. These abnormalities were ameliorated by the concurrent deletion of MDA5. Collectively, Z-RNA–recognition contributes to ADAR1 p150–mediated RNA editing, which prevents MDA5 activation.
Adenovirus E1A Binding to DCAF10 Targets Degradation of AAA+ ATPases Required for Quaternary Assembly of Multiprotein Machines and Innate Immunity
Authors: Zemke NR , Barshop WD , Sha J , Hsu E , Wohlschlegel JA , Berk AJ
Published: August 2024

Adenovirus E1A early proteins modify host cell physiology to optimize virus replication. The N-terminal half of small e1a interacts with RB-family proteins to de-repress dNTP and DNA synthesis, and with p300/CBP to inhibit host anti-viral innate immune responses. These e1a N-terminal interactions activate a strong, late host anti-viral response due to stabilization and activation of interferon response factor 3 (IRF3). However, the C-terminal half of e1a inhibits this through interactions with three host proteins with seemingly unrelated functions. Proteomic analysis showed that all three C-terminal interactions are required for e1a-association into an ∼1 MDa multi-protein complex with scaffold subunits of a CRL4 E3 ubiquitin ligase and DCAF10, a presumed specificity subunit. This e1a-DCAF10-CRL4 prevents IRF3 stabilization indirectly by directing degradation of the essential AAA+ ATPases RUVBL1/2, subunits of several HSP90 co-chaperones required for quaternary assembly of cellular protein machines required for anti-viral defenses and responses to genotoxic and metabolic stress.
CoMPHI: A Novel Composite Machine Learning Approach Utilizing Multiple Feature Representation to Predict Hosts of Bacteriophages
Authors: Bodaka Shreyashi , Malgonde Onkar
Published: August 2024

Phage therapy has reemerged as a compelling alternative to antibiotics in treating bacterial infections, especially for superbugs that have developed antibiotic resistance. The challenge in the broader application of phage therapy is identifying host targets for the vast array of uncharacterized phages obtained through next-generation sequencing. To solve this issue, this paper introduces an innovative Composite Model for Phage Host Interaction, CoMPHI, to predict phage-host interactions by combining the accuracy of alignment-based methods with the efficiency and flexibility of machine learning techniques. The model initially generates multiple feature encodings from nucleotide and protein sequences of both phages and hosts to enhance prediction accuracies. It is further enriched by incorporating alignment scores between phage-phage, phage-host, and host-host, creating a composite model. During the 5-fold cross-validation, the composite model exhibited an Area Under the ROC Curve (AUC) of 94%, 96.4%, 96.5%, 96.6%, 96.6%, and 96.7% and accuracy of 92.3%, 93.3%, 93.6%, 94%, 94.9%, and 95.1% at the Species, Genus, Family, Order, Class, and Phylum levels, respectively. A comparative analysis revealed a 6-8% increase in model performance due to the inclusion of alignment scores. Additionally, an ablation study highlighted that including both nucleotide and protein sequences from both phages and hosts increased the prediction accuracy of the model. Another ablation study provided evidence that phage-host and host-host alignment scores, combined with phage-phage scores, equally contributed to enhancing the composite model’s performance. In conclusion, this paper presents a robust and comprehensive composite model advancing the use of phage therapy in modern medicine.
Inhibitory mechanisms in the prefrontal-cortex differentially mediate Putamen activity during valence-based learning
Authors: Finkelman Tal , Furman-Haran Edna , Aberg Kristoffer C. , Paz Rony , Tal Assaf
Published: August 2024

Learning from appetitive and aversive stimuli involves interactions between the prefrontal cortex and subcortical structures. Preclinical and theoretical studies indicate that inhibition is essential in regulating the relevant neural circuitry. Here, we demonstrate that GABA, the main inhibitory neurotransmitter in the central nervous system, differentially affects how the dACC interacts with subcortical structures during appetitive and aversive learning in humans. Participants engaged in tasks involving appetitive and aversive learning, while using functional magnetic resonance spectroscopy (MRS) at 7T to track GABA concentrations in the dACC, alongside whole-brain fMRI scans to assess BOLD activation. During appetitive learning, dACC GABA concentrations were negatively correlated with learning performance and BOLD activity measured from the dACC and the Putamen. These correlations were absent during aversive learning, where dACC GABA concentrations negatively correlated with the connectivity between the dACC and the Putamen. Our results show that inhibition in the dACC mediates appetitive and aversive learning in humans through distinct mechanisms.
Genome-Wide Analysis ofTCPFamily Genes and Their Constitutive Expression Pattern Analysis in the Melon (Cucumis melo)
Authors: Jone Md Jahid Hasan , Siddique Md Nure Adil , Biswas Manosh Kumar , Hossain Mohammad Rashed
Published: August 2024

TCPproteins are plant-specific transcription factors that play essential roles in various developmental processes, including leaf morphogenesis and senescence, flowering, lateral branching, hormone crosstalk, and stress responses. However, the specific functions ofTCPgenes in melon remain largely unknown. This study identified and characterized 29 putativeTCPgenes in melon. These genes were classified into two classes: Class-I (13 genes) and Class-II (16 genes). The chromosomal location, gene structure, conserved motifs, structural homology, cis-regulating elements, transcript expression patterns, and potential protein-protein interactions were further analyzed. The results revealed that the putativeCmTCPgenes are distributed across nine of the twelve melon chromosomes and exhibit diverse expression patterns in different tissues and during floral organ development. Phylogenetic analysis suggests that someCmTCPgenes may have similar functions to their homologs in other plant species, while others may have undergone functional diversification. This study provides a valuable resource for future investigations into the specific roles of individualCmTCPgenes in melon development and paves the way for elucidating the mechanisms by whichTCPproteins regulate leaf elongation, floral development, and lateral branching.
Epidermal Growth Factor in the Brain: A Promising Biomarker for Depression
Authors: Xu Shu-xian , Lyu Honggang , Chen Mian-mian , Li Kun , Yao Lihua , Wang Chao , Xie Xin-hui , Liu Zhongchun
Published: August 2024

Background

This study aimed to examine the neurotrophic factors secreted from brain in depression by analyzing astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma, and to explore the causal relationship between the expression of neurotrophic factors in the brain and depression.

Methods

A total of 40 patients with treatment-resistant depression (TRD) and 35 matched healthy controls (HCs) were recruited at baseline, and 34 TRD patients completed the post-electroconvulsive therapy (ECT) visits. The concentrations of five neurotrophic factors in ADEVs were measured. A correlation analysis was performed between neurotrophic factors in ADEVs and neurogenesis marker doublecortin (DCX) in neuron-derived extracellular vesicles (NDEVs). Subsequently, Mendelian randomization (MR) study and cell experiments were conducted.

Results

Our findings revealed a decrease in the level of epidermal growth factor (EGF) in ADEVs among TRD patients, with an increase observed post-ECT. The corrected area under the curve for EGF were larger than those for other neurotrophic factors: 0.99 (95% CI: 0.98-1.00). MR suggested that decreased expression levels of theEGFgene in the cortex constitute a risk factor for depression. We observed a positive correlation between the levels of EGF in ADEVs and DCX in NDEVs. Subsequently, cell experiments suggested that EGF can activate EGF receptor (EGFR) to trigger the PI3K-Akt pathway, participating in the promotion of DCX.

Conclusions

This study provides thein vivoevidences supporting that a reduction in EGF levels in the central nervous system could potentially contribute to depression and serve as a biomarker for it. Additionally, the EGF/EGFR signaling pathway may be involved in regulating early neurogenesis traits in depression.
Bacteriocin production facilitates nosocomial emergence of vancomycin-resistantEnterococcus faecium
Authors: Mills Emma G. , Smith Alexander B. , Griffith Marissa P. , Hewlett Katharine , Pless Lora , Sundermann Alexander J. , Harrison Lee H. , Zackular Joseph P. , Van Tyne Daria
Published: August 2024

Vancomycin-resistantEnterococcus faecium(VREfm) is a prevalent healthcare-acquired pathogen. Gastrointestinal colonization can lead to difficult-to-treat bloodstream infections with high mortality rates. Prior studies have investigated VREfm population structure within healthcare centers. However, little is known about how and why hospital-adapted VREfm populations change over time. We sequenced 710 healthcare-associated VREfm clinical isolates from 2017-2022 from a large tertiary care center as part of the Enhanced Detection System for Healthcare-Associated Transmission (EDS-HAT) program. Although the VREfm population in our center was polyclonal, 46% of isolates formed genetically related clusters, suggesting a high transmission rate. We compared our collection to 15,631 publicly available VREfm genomes spanning 20 years. Our findings describe a drastic shift in lineage replacement within nosocomial VREfm populations at both the local and global level. Functional and genomic analysis revealed, antimicrobial peptide, bacteriocin T8 may be a driving feature of strain emergence and persistence in the hospital setting.

This study shows local and global lineage replacement of vancomycin-resistantEnterococcus faecium. Bacteriocin T8 is enriched in emergent lineages and provides a strong competitive advantagein vitroandin vivo.
Integrity and miss-grouping as support for clusters in agglomerative hierarchical methods—the r-package octopucs
Authors: MacGregor-Fors Ian , Guevara Roger
Published: August 2024

The hierarchical clustering of communities based on species’compositional similarity (and abundance or frequency) is standard in community ecology to unveil large-scale patterns and underlay environmental causes of differentiation among communities. Often, the threshold to discretize clusters is arbitrary despite the existence of methods that minimize this bias. Most available techniques use the exact repeatability of clusters’ memberships under resampling protocols to define robust groups. Here, we propose a novel method to yield cluster support throughout the topology of hierarchical analyses. We acknowledge that the observed dataset may be biased. Instead of using the observed topology as a reference to work out the groups’ support, we compiled a consensus topology. Then, we borrowed the ecological concepts of reciprocal complementarities between a pair of communities and translated them into cluster integrity and contamination. This procedure allows for building support for groups even when there is a partial membership match after resampling the dataset. In addition, we present the R package octopucs in which we implemented the method reported here. Compared with other methods, the new proposal robustly detected changes in the group memberships, resulting in considerable differences in the pattern of supported clusters.
Buzz Pollination: Investigations of Pollen Expulsion using the Discrete Element Method
Authors: Boucher-Bergstedt Caelen , Jankauski Mark , Johnson Erick
Published: August 2024

Buzz pollination involves the release of pollen from, primarily, poricidal anthers through vibrations generated by certain bee species. Despite previous experimental and numerical studies, the intricacies of pollen dynamics within vibrating anthers remain elusive due to the challenges in observing these small-scale, opaque systems. This research employs the discrete element method (DEM) to simulate the pollen expulsion process in vibrating anthers. By exploring various frequencies and displacement amplitudes, a correlation between the maximum jerk of anther walls and the initial rate of pollen expulsion is observed under translating oscillations. This study highlights that while increased vibration intensity enhances pollen release, the rate of increase diminishes at higher intensities. Our findings also reveal the significant role of pollen-pollen interactions, which account for upwards of one-third of the total collisions. Comparisons between poricidal and pseudoporicidal anther geometries suggest that pore size and shape also influence expulsion rates. This research provides a foundation for more comprehensive models that can incorporate additional factors such as cohesion, adhesion, and Coulomb forces, paving the way for deeper insights into the mechanics of buzz pollination and its variability across different anther types and vibration parameters.
Factors affecting the individual probability of infection with a prevalent pathogen (Mycoplasma) and the effect on Griffon vultures’ movement behavior
Authors: Anglister Nili , Crafton Miranda May , Avraham On , Acácio Marta , Vaadia Gideon , Hatzofe Ohad , Miller Yigal , Mikula Inna , Pinter-Wollman Noa , Lysnyansky Inna , Spiegel Orr
Published: August 2024

Mycoplasmas are known as commensals and pathogenic bacteria of various raptor species causing clinical or subclinical infections. However, little is known about the prevalence of mycoplasma in captive and wild raptors and its significance to their health. In Israel, the Griffon vulture (Gyps fulvus; hereafter Griffons) is considered critically endangered, and its intensive management program includes population monitoring and restocking (captive-born or imported rehabilitated wild Spanish Griffons). Here we survey the prevalence ofMycoplasmaspecies in both the wild and captive populations. During 2019-2020, we collected 244 tracheal swab samples from 167 unique individuals. We used PCR analysis to identifyMycoplasmaspecies. First, we identified nine spp., including species not yet described in Israel or for Griffon vultures. Second, imported Griffons showed a higher prevalence and a different diversity of species in comparison to the local ones, suggesting that at least oneMycoplasmaspecies (Sp 18b) was introduced into the native population. Third, juvenile Griffons had a higher prevalence, different species composition, and stronger reduction in movement compared to adults, confirming the susceptibility of this group to mycoplasma infections. GPS-tracking of 60 free-ranging individuals showed that even in the absence of apparent clinical signs, Griffons infected with mycoplasma, and especially sub-adults flew less (shorter distances and periods). These findings underscore the importance of considering potential pathogen introductions in population reinforcement and reintroduction initiatives, providing valuable insights for similar conservation programs globally. Further, they demonstrate the potential of long-term tracking for detecting subclinical effects that are unnoticeable in clinical examination.
SeuratExtend: Streamlining Single-Cell RNA-Seq Analysis Through an Integrated and Intuitive Framework
Authors: Hua Yichao , Weng Linqian , Zhao Fang , Rambow Florian
Published: August 2024

Single-cell RNA sequencing (scRNA-seq) has revolutionized the study of cellular heterogeneity, but the rapid expansion of analytical tools has proven to be both a blessing and a curse, presenting researchers with significant challenges. Here, we present SeuratExtend, a comprehensive R package built upon the widely adopted Seurat framework, which streamlines scRNA-seq data analysis by integrating essential tools and databases. SeuratExtend offers a user-friendly and intuitive interface for performing a wide range of analyses, including functional enrichment, trajectory inference, gene regulatory network reconstruction, and denoising. The package seamlessly integrates multiple databases, such as Gene Ontology and Reactome, and incorporates popular Python tools like scVelo, Palantir, and SCENIC through a unified R interface. SeuratExtend enhances data visualization with optimized plotting functions and carefully curated color schemes, ensuring both aesthetic appeal and scientific rigor. We demonstrate SeuratExtend’s performance through case studies investigating tumor-associated high-endothelial venules and autoinflammatory diseases, and showcase its novel applications in pathway-Level analysis and cluster annotation. SeuratExtend empowers researchers to harness the full potential of scRNA-seq data, making complex analyses accessible to a wider audience. The package, along with comprehensive documentation and tutorials, is freely available at GitHub, providing a valuable resource for the single-cell genomics community.

Practitioner Points

SeuratExtend streamlines scRNA-seq workflows by integrating R and Python tools, multiple databases (e.g., GO, Reactome), and comprehensive functional analysis capabilities within the Seurat framework, enabling efficient, multi-faceted analysis in a single environment.

Advanced visualization features, including optimized plotting functions and professional color schemes, enhance the clarity and impact of scRNA-seq data presentation.

A novel clustering approach using pathway enrichment score-cell matrices offers new insights into cellular heterogeneity and functional characteristics, complementing traditional gene expression-based analyses.
Patient-specific therapeutic benefit of MuSK agonist antibody ARGX-119 in MuSK myasthenia gravis passive transfer models
Authors: Lim Jamie L. , Jensen Stine Marie , Plomp Jaap J. , Vankerckhoven Bernhardt , Kneip Christa , Coppejans Rani , Steyaert Christophe , Moens Kathleen , De Clercq Lieselot , Tannemaat Martijn R. , Ulrichts Peter , Silence Karen , van der Maarel Silvère M. , Vergoossen Dana L.E. , Vanhauwaert Roeland , Verschuuren Jan. J. , Huijbers Maartje G.
Published: August 2024

Muscle-specific kinase (MuSK) orchestrates establishment and maintenance of neuromuscular synapses, which enable muscle contraction. Autoantibodies targeting MuSK cause myasthenia gravis (MG), a disease characterized by fatigable skeletal muscle weakness which requires chronic immunosuppressive treatment and ventilatory support at some point in ∼30% of patients. MuSK autoantibodies are predominantly IgG4 and are bispecific, functionally monovalent antibodies due to Fab-arm exchange. Through monovalent binding, MuSK IgG4 autoantibodies act as antagonists on the MuSK signalling pathway, impairing neuromuscular synaptic function. In contrast, bivalent MuSK antibodies act as agonists of the MuSK signalling pathway. Since symptoms in MuSK MG are largely caused by antagonistic monovalent MuSK antibodies, we hypothesized that a bivalent MuSK agonist could rescue MuSK MG, bypassing the need for generalized immunosuppression. In this study, we investigated whether an agonist antibody targeting the Frizzled-like domain of MuSK, ARGX-119, can ameliorate disease in MuSK MG models induced by passive transfer of polyclonal IgG4 from unrelated patients. For each patient material we first established the minimal dose for a progressive MG phenotype based on muscle function tests. ARGX-119 significantly improved survival and muscle weakness in a mouse model induced by one patient material, but not by three others. Mechanistically, this patient-specific efficacy could not be explained by autoantibody epitope specificity, titer or competition for ARGX-119 binding, but rather correlated to the presence of MuSK activating antibodies in some patients. We further provide evidence that anin vitroassay may predict which patients potentially benefit from ARGX-119 and that this treatment, when effective in MuSK MG mice, follows a bell-shaped dose-effect curve. These results provide first proof of concept of a MuSK agonist in a clinically relevant model for MuSK MG. We anticipate this to be a starting point for investigating the therapeutic benefit of ARGX-119 in MuSK MG and other neuromuscular diseases hallmarked by neuromuscular synaptic dysfunction.

Graphical abstract

Highlights

MuSK agonist ARGX-119 can rescue MuSK MG in a patient-specific manner

MuSK agonism follows a bell-shaped efficacy curve in this MuSK MG mouse model

Variation in ARGX-119 efficacy between patient models is not explained by competition for binding on MuSK, but rather appears related to an agonistic fraction of patient antibodies

Anin vitroassay is potentially predictive for treatment efficacy of the MuSK agonist
Socially driven negative feedback regulates activity and energy use in ant colonies
Authors: Porfiri Maurizio , Abaid Nicole , Garnier Simon
Published: August 2024

Despite almost a century of research on energetics in biological systems, we still cannot explain energy regulation in social groups, like ant colonies. How do individuals regulate their collective activity without a centralized control system? What is the role of social interactions in distributing the workload amongst group members? And how does the group save energy by avoiding being constantly active? We offer new insight into these questions by studying an intuitive compartmental model, calibrated with and compared to data on ant colonies. The model describes a previously unexplored balance between positive and negative social feedback driven by individual activity: when activity levels are low, the presence of active individuals stimulates inactive individuals to start working; when activity levels are high, however, active individuals inhibit each other, effectively capping the proportion of active individuals at any one time. Through the analysis of the system stability, we demonstrate that this balance results in energetic spending at the group level growing proportionally slower than the group size. Our finding is reminiscent of Kleiber’s law of metabolic scaling in unitary organisms and highlights the critical role of social interactions in driving the collective energetic efficiency of group-living organisms.
Rapid reprogramming and stabilisation of homoeolog expression bias in hexaploid wheat biparental populations
Authors: Glombik Marek , Arunkumar Ramesh , Burrows Samuel , Mogg Sophie Louise , Wang Xiaoming , Borrill Philippa
Published: August 2024

Differences in the relative level of expression of homoeologs, known as homoeolog expression bias (HEB), are widely observed in allopolyploids. While the evolution of homoeolog expression bias through hybridisation has been characterised, on shorter timescales the extent to which homoeolog expression bias is preserved or altered between generations remains elusive.

Here we use biparental mapping populations of hexaploid wheat (Triticum aestivum) with a common Paragon parent to explore the inheritance of homoeolog expression bias in the F5generation.

We found that homoeolog expression bias is inherited for 26-27% of triads in both populations. Most triads (∼70%) conserved a similar homoeolog expression bias pattern as one or both parents. Inherited patterns were largely driven by changes in the expression of one homoeolog, allowing homoeolog expression bias in subsequent generations to match parental expression. Novel patterns of homoeolog expression bias occurred more frequently in the biparental population from a landrace x elite cross, than in the population with two elite parents.

These results demonstrate that there is significant reprogramming and stabilisation of homoeolog expression bias within a small number of generations that differs significantly based on the parental lines used in the crossing.
Involvement of OsS40-14 in ROS and plastid organization related regulatory networks of dark-induced leaf senescence in rice
Authors: Habiba  , Fan Chunlan , Hong Wuqiang , Shi Ximiao , Wang Xiaowei , Wang Weiqi , Lin Wenfang , Li Yanyun , Ain Noor ul , Miao Ying , Zheng Xiangzi
Published: August 2024

Dark-induced senescence triggers significant metabolic changes that recycle resources and ensure plant survival. In this study, we identified a transcription factor OsS40-14 in rice, which can form homo-oligomers. Theoss40-14knockout mutants exhibited stay-green phenotype of primary leaf and flag leaf during dark-induced condition, with substantial retention of chlorophylls and photosynthetic capacity as well as remarkably reduced reactive oxygen species (ROS), whileOsS40-14overexpressing transgenic lines (oeOsS40-14) showed an accelerated senescence phenotype under dark-induced leaf senescence conditions. Transcriptome analysis revealed that when the detached leaves ofoss40-14and WT were treated in darkness condition for 72 hours, 1585 DEGs (|Log2FC| ≥1, P value<0.05) were reprogrammed inoss40-14relative to WT. CUT&Tag-seq analysis in protoplast transient expression of OsS40-14 system showed that OsS40-14 was 40.95% enriched in the transcription start site (TSS) of the genome. Sequence clustering analysis showed that OsS40-14 protein was mainly enriched and bound to TACCCACAAGACAC conserved elements. The seed region “ACCCA” of OsS40 proteins was identified by single nucleotide mutagenesis EMSA. The integrative analysis of transcriptome and CUT&Tag-seq datasets showed 153 OsS40-14-targeted DEGs, they mainly enriched in plastid organization and photosynthesis process at dark-induced condition inoss40-14relative to WT. Among them, eleven candidate targets of OsS40-14 such as Glucose 6-phosphate/phosphate translocator, Na+/H+ antiporter, Catalase, Chitinase 2, Phosphate transporter 19, OsWAK32, and OsRLCK319 were directly targeted and upregulated confirmed by ChIP-PCR and RT-qPCR. It demonstrates a novel model of OsS40-14 mediating macromolecule metabolism and nutrient recycling controls the plastid organization during dark-induced leaf senescence.

Significant statement

Involvement of OsS40-14 in macromolecule catabolism, nutrient recycling, and ROS homeostasis revealed a plastid organization defection of dark-induced senescence in rice
Resources modulate developmental shifts but not infection tolerance upon coinfection in an insect system
Authors: Schulz Nora K.E. , Asgari Danial , Liu Siqin , Birnbaum Stephanie S.L. , Williams Alissa M. , Prakash Arun , Tate Ann T.
Published: August 2024

Energetic resources fuel immune responses and parasite growth within organisms, but it is unclear whether energy allocation is sufficient to explain changes in infection outcomes under the threat of multiple parasites. We manipulated diet in flour beetles (Tribolium confusum) infected with two natural parasites to investigate the role of resources in shifting metabolic and immune responses after single and co-infection. Our results suggest that gregarine parasites alter the within-host energetic environment, and by extension juvenile development time, in a diet- dependent manner. Gregarines do not affect host resistance to acute bacterial infection but do stimulate the expression of an alternative set of immune genes and promote damage to the gut, ultimately contributing to reduced survival regardless of diet. Thus, energy allocation is not sufficient to explain the immunological contribution to coinfection outcomes, emphasizing the importance of mechanistic insight for predicting the impact of coinfection across levels of biological organization.
Per- and Poly-fluoroalkyl Substances (PFAS) in Circulation in a Canadian Population: Their Association with Serum Liver Enzyme Biomarkers and Piloting a Novel Method to Reduce Serum PFAS
Authors: Schlezinger Jennifer J. , Bello Anila , Mangano Kelsey M. , Biswas Kushal , Patel Paridhiben P. , Pennoyer Emily H. , Wolever Thomas M.S. , Heiger-Bernays Wendy J. , Bello Dhimiter
Published: August 2024

Extensive use of per- and polyfluoroalkyl substances (PFAS) has resulted in their ubiquitous presence in human blood. PFAS exposures have been associated with multiple adverse human health effects including increased risk of liver damage, elevated serum lipids, impaired vaccine response, adverse birth outcomes and cancer. Biomonitoring studies have focused on measuring long-chain PFAS, but these are being replaced by shorter chain PFAS and PFAS with alternative structures, resulting in incomplete understanding of human exposures. Here, we take advantage of serum samples collected as part of a clinical trial testing the efficacy of a dietary fiber intervention to reduce serum cholesterol to investigate exposure to legacy and replacement PFAS chemicals in Canadian participants. Serum samples were collected from 72 participants in 2019-2020 at baseline and after 4 weeks of the intervention and were analyzed for 17 PFAS species. The highest geometric mean concentrations of PFAS measured at baseline corresponded to PFOSA (7.1 ng/ml), PFOS (4.2, ng/ml), PFOA (1.8 ng/ml) and PFHxS (1.3 ng/ml). Short chain PFAS including PFBuA, PFHxS and/or PFHpA were detected in 100% of participants and GenX was detected in 70% of participants. Analyses of associations between PFAS serum concentrations and biomarkers of adverse health outcomes showed the PFBuA, PFHxA, PFDA and PFOSA were associated with higher serum gamma-glutamyl transferase concentrations but not with measures of serum total or low-density lipoprotein cholesterol. Comparison of PFAS concentrations at baseline and after a 4-week follow-up showed that total PFAS concentrations decreased in both the control and cholesterol intervention groups. However, the suite of PFAS of concern identified by the United States National Academies of Sciences, Engineering, and Medicine, significantly decreased only in the cholesterol intervention group. This observation suggests that a dietary fiber intervention may reduce PFAS body burden, but future intervention studies need to control for PFAS exposure sources and extend beyond 4 weeks. Overall, the results show that exposures to short-chain and alternative PFAS are common in this Canadian population.
Improving Tuberculosis Detection in Chest X-ray Images through Transfer Learning and Deep Learning: A Comparative Study of CNN Architectures
Authors: Mirugwe Alex , Tamale Lillian , Nyirenda Juwa
Published: August 2024

Introduction

Tuberculosis remains a significant global health challenge, necessitating more efficient and accurate diagnostic methods.

Methods

This study evaluates the performance of various convolutional neural network (CNN) architectures— VGG16, VGG19, ResNet50, ResNet101, ResNet152, and Inception-ResNet-V2—in classifying chest X-ray (CXR) images as either normal or TB-positive. The dataset comprised 4,200 CXR images, with 700 labeled as TB-positive and 3,500 as normal. We also examined the impact of data augmentation on model performance and analyzed the training times and the number of parameters for each architecture.

Results

Our results showed that VGG16 outperformed the other models across all evaluation metrics, achieving an accuracy of 99.4%, precision of 97.9%, recall of 98.6%, F1-score of 98.3%, and AUC-ROC of 98.25%. Surprisingly, data augmentation did not improve performance, suggesting that the original dataset’s diversity was sufficient. Furthermore, models with large numbers of parameters, such as ResNet152 and Inception-ResNet-V2, required longer training times without yielding proportionally better performance.

Discussion

These findings highlight the importance of selecting the appropriate model architecture based on task-specific requirements. While more complex models with larger parameter counts may seem advantageous, they do not necessarily offer superior performance and often come with increased computational costs.

Conclusion

The study demonstrates the potential of simpler models such as VGG16 to effectively diagnose TB from CXR images, providing a balance between performance and computational efficiency. This insight can guide future research and practical implementations in medical image classification.
Relative income and its relationship with mental health in UK employees: a conceptual and methodological review
Authors: Croak Bethany , Grover Laura E. , Wessely Simon , Kharicha Kalpa , Lamb Danielle , Stevelink Sharon A.M.
Published: August 2024

The relative income hypothesis theorises that one’s earnings relative to others exert a greater influence on subjective wellbeing than absolute income. Understanding the relationship between relative income and mental health could contribute to employee wellbeing. This review narratively synthesised the defining features and measurement of relative income, and its impact on mental health among UK employees. Systematic searches of qualitative and quantitative research evidence identified 13 studies. A conceptualisation of relative income revealed that an income comparison is either researcher-defined using averages or self-assessed based on a person’s perception. Having a lower income than the reference group was commonly associated with diminished wellbeing, though moderating factors (gender, income inequality and composition of reference group) are discussed.

Implications for practice and policy are considered amidst the UK’s ‘cost of living crisis’ and ongoing pay disputes in various sectors.
From Big Data to the clinic: methodological and statistical enhancements to implement the UK Biobank imaging framework in a memory clinic
Authors: Gillis Grace , Bhalerao Gaurav , Blane Jasmine , Mitchell Robert , Pretorius Pieter M , McCracken Celeste , Nichols Thomas E , Smith Stephen M , Miller Karla L , Alfaro-Almagro Fidel , Raymont Vanessa , Martos Lola , Mackay Clare E , Griffanti Ludovica
Published: August 2024

Introduction

The analysis tools and statistical methods used in large neuroimaging research studies differ from those applied in clinical contexts, making it unclear whether these techniques can be translated to a memory clinic setting. The Oxford Brain Health Clinic (OBHC) was established in 2020 to bridge this gap between research studies and memory clinics.

Methods

We optimised the UK Biobank imaging framework for the memory clinic setting by integrating enhanced quality control (QC) processes (MRIQC, QUAD, and DSE decomposition) and supplementary dementia-informed analyses (lobar volumes, NBM volumes, WMH classification, PSMD, cortical diffusion MRI metrics, and tract volumes) into the analysis pipeline. We explored associations between resultant imaging-derived phenotypes (IDPs) and clinical phenotypes in the OBHC patient population (N=213), applying hierarchical FDR correction to account for multiple testing.

Results

14-24% of scans were flagged by automated QC tools, but upon visual inspection, only 0-2.4% of outputs were excluded. The pipeline successfully generated 5683 IDPs aligned with UK Biobank and 110 IDPs targeted towards dementia-related changes. We replicated established associations and found novel associations between brain metrics and age, cognition, and dementia-related diagnoses.

Conclusion

The imaging protocol is feasible, acceptable, and yields high-quality data that is usable for both clinical and research purposes. We validated the use of this methodology in a real-world memory clinic population, which demonstrates the potential of this enhanced pipeline to bridge the gap between big data studies and clinical settings.

Key Points

The imaging methods, analysis techniques, and population characteristics in research studies often differ to those in traditional clinical settings.

To bridge this gap, we optimised the UK Biobank imaging framework for memory clinic use by integrating enhanced quality control (QC) and supplementary analyses targeted towards dementia-related changes.

We generated 5683 imaging-derived phenotypes (IDPs) aligned with UK Biobank and 110 supplementary dementia-informed IDPs that captured both established and novel associations between brain metrics and dementia-related clinical phenotypes, highlighting the value of integrating UK Biobank-aligned imaging and analyses in a real-world memory clinic population.
Clinical Advancement Forecasting
Authors: Czech Eric , Wojdyla Rafal , Himmelstein Daniel , Frank Daniel , Miller Nick , Milwid Jack , Kolom Adam , Hammerbacher Jeff
Published: August 2024

Abstract

Choosing which drug targets to pursue for a given disease is one of the most impactful decisions made in the global development of new medicines. This study examines the extent to which the outcomes of clinical trials can be predicted based on a small set of longitudinal (temporally labeled) evidence and properties of drug targets and diseases. We demonstrate a novel statistical learning framework for identifying the top 2% of target-disease pairs that are as much as 4-5x more likely to advance beyond phase 2 trials. This framework is 1.5-2x more effective than an Open Targets composite score based on the same set of evidence. It is also 2x more effective than a common measure for genetic support that has been observed previously, as well as in this study, to confer a 2x higher likelihood of success. Utilizing a subset of our biomedical evidence base, non-negative linear models resulting from this framework can produce simple weighting schemes across various types of human, animal, and cell model genomic, transcriptomic, proteomic, and clinical evidence to identify previously undeveloped target-disease pairs poised for clinical success. In this study we further explore: i) how longitudinal treatment of evidence relates to leakage and reverse causality in biomedical research and how temporalized evidence can mitigate common forms of potential biases and inflation ii) the relative impact of different types of features on our predictions; and iii) an analysis of the space of currently undeveloped, tractable targets predicted with these methods to have the highest likelihood of clinical success. To ease reproduction and deployment, no data is used outside of Open Targets and the described methods require no expert knowledge, and can support expansion of lines of evidence to further improve performance.