bluuebunny/crossref_metadata_2025 huggingface dataset:
RNase L-induced bodies sequester subgenomic flavivirus RNAs and re-establish host RNA decay
Authors: Watkins J. Monty , Burke James M.
Published: March 2024

Subgenomic flavivirus RNAs (sfRNAs) are structured RNA elements encoded in the 3’-UTR of flaviviruses that promote viral infection by inhibiting cellular RNA decay machinery. Herein, we analyze the production of sfRNAs using single-molecule RNA fluorescencein situhybridization (smRNA-FISH) and super-resolution microscopy during West Nile virus, Zika virus, or Dengue virus serotype 2 infection. We show that sfRNAs are initially localized diffusely in the cytosol or in processing bodies (P-bodies). However, upon activation of the host antiviral endoribonuclease, Ribonuclease L (RNase L), nearly all sfRNAs re-localize to antiviral biological condensates known as RNase L-induced bodies (RLBs). RLB-mediated sequestration of sfRNAs reduces sfRNA association with RNA decay machinery in P-bodies, which coincides with increased viral RNA decay. These findings establish a role of RLBs in promoting viral RNA decay, demonstrating the complex host-pathogen interactions at the level of RNA decay and biological condensation.

Highlights

Single-molecule imaging of sfRNA production and localization

sfRNAs localize to RNase L-induced bodies

RNase L-induced bodies sequester sfRNAs away from P-bodies

Sequestration of sfRNAs by RNase L-induced bodies enhances decay of viral genomes
The Evolutionary Origins and Ancestral Features of Septins
Authors: Delic Samed , Shuman Brent , Lee Shoken , Bahmanyar Shirin , Momany Michelle , Onishi Masayuki
Published: March 2024

Septins are a family of membrane-associated cytoskeletal GTPases that play crucial roles in various cellular processes, such as cell division, phagocytosis, and organelle fission. Despite their importance, the evolutionary origins and ancestral function of septins remain unclear. In opisthokonts, septins form five distinct groups of orthologs, with subunits from multiple groups assembling into heteropolymers, thus supporting their diverse molecular functions. Recent studies have revealed that septins are also conserved in algae and protists, indicating an ancient origin from the last eukaryotic common ancestor. However, the phylogenetic relationships among septins across eukaryotes remained unclear. Here, we expanded the list of non-opisthokont septins, including previously unrecognized septins from rhodophyte red algae and glaucophyte algae. Constructing a rooted phylogenetic tree of 254 total septins, we observed a bifurcation between the major non-opisthokont and opisthokont septin clades. Within the non-opisthokont septins, we identified three major subclades: Group 6 representing chlorophyte green algae (6A mostly for species with single septins, 6B for species with multiple septins), Group 7 representing algae in chlorophytes, heterokonts, haptophytes, chrysophytes, and rhodophytes, and Group 8 representing ciliates. Glaucophyte and some ciliate septins formed orphan lineages in-between all other septins and the outgroup. Combining ancestral-sequence reconstruction and AlphaFold predictions, we tracked the structural evolution of septins across eukaryotes. In the GTPase domain, we identified a conserved GAP-like arginine finger within the G-interface of at least one septin in most algal and ciliate species. This residue is required for homodimerization of the singleChlamydomonasseptin, and its loss coincided with septin duplication events in various lineages. The loss of the arginine finger is often accompanied by the emergence of the α0 helix, a known NC-interface interaction motif, potentially signifying the diversification of septin-septin interaction mechanisms from homo-dimerization to hetero-oligomerization. Lastly, we found amphipathic helices in all septin groups, suggesting that curvature-sensing is an ancestral trait of septin proteins. Coiled-coil domains were also broadly distributed, while transmembrane domains were found in some septins in Group 6A and 7. In summary, this study advances our understanding of septin distribution and phylogenetic groupings, shedding light on their ancestral features, potential function, and early evolution.
Heart failure admission characteristics in women with a history of sexual or physical abuse: a case-control study
Authors: Chan Alicia , Cosh Suzanne M. , Horowitz John , Tully Phillip J.
Published: March 2024

Introduction

An emerging body of epidemiological evidence links a history of exposure to sexual and physical abuse or assault with an increased risk of developing cardiovascular disease. Understanding adverse physical health outcomes including heart failure (HF) in persons exposed to sexual and physical abuse is of particular importance to help improve multidisciplinary approaches to mental and physical wellbeing, including cardiovascular management, among vulnerable populations.

Methods

This case-control study was performed at a tertiary hospital in metropolitan South Australia. At index HF admission 12 consecutive female patients with exposure to sexual and physical abuse or assault were identified from the trauma module of a structured psychiatric interview. Index admission data were classified into HF phenotype and aetiology using the criteria and definitions of the European Society of Cardiology. The presentation profile at index HF admission was compared to 12 gender and age-matched comparators.

Results

The clinical characteristics at index admission showed that most patients presented with pulmonary rales, peripheral oedema, and pulmonary congestion (67-75%), with diuretics the most common intervention (75%). By comparison to the non-exposed group, we observed differences between groups in HF severity determined by New York Heart Association class, diastolic blood pressure (BP), and heart rate (HR) but not systolic BP, saturation of peripheral oxygen (Sp02) or HF phenotypes. There were no differences in troponin, creatinine, sodium, admission use of inotropes, vasodilators or diuretics, post-traumatic stress disorder or comorbidities between the exposed patients and age-matched female controls.

Conclusion

Women with a history of experiencing sexual and physical abuse or assault presented with a unique HF admission profile characterised by lower BP and HR. The findings support previous work suggesting that persons experiencing sexual and physical abuse or assault have blunted cardiovascular reactivity to stressors such as hospital admission.
Unbiased metagenomic detection of RNA viruses for rapid identification of viral pathogens in clinical samples
Authors: Kappell Anthony D. , Scholes Amanda N. , Scholz Matthew B. , Keplinger Nicolette C. , Allen Leah W. , Murray Matthew C. , Ternus Krista L. , Hewitt F. Curtis
Published: March 2024

Unbiased long read sequencing approaches for clinical metagenomic sample analysis holds enormous potential for pathogen detection, including improved detection of unknown, novel or emerging viruses. However, the rapid rate of development in nanopore sequencing and library preparation methods complicates the process of selecting a standardized method for unbiased RNA virus detection. Here, we evaluate multiple sequencing approaches to identify a workflow with sufficient sensitivity, limits of detection, and throughput for potential utilization in a clinical laboratory setting. Four separate library preparation methods for the Oxford Nanopore Technologies MinION sequencer are compared, including direct RNA, direct cDNA, rapid cDNA, and double stranded cDNA. We also establish that depletion of host RNA is not required and can be deleterious for viral RNA detection in some instances when using samples in viral transport media (VTM) or plasma. Using unbiased whole genome amplification following reverse transcription, we achieve limits of detection on the order of 1.95E03 GE/mL of Venezuelan Equine Encephalitis Virus (VEEV) spiked in human plasma. We also report initial detection of 5.43E06 GE/mL of coronavirus 229E spiked into VTM samples containing human background RNA which are expected to decrease significantly during upcoming testing. These metrics were achieved within a 6-plex multiplex reaction, illustrating the potential to increase throughput and decrease costs for relevant sample analysis. Data analysis was performed using EPI2ME Labs framework and open access tools that are readily accessible to most clinical laboratories. Taken together, this work describes an optimized method for unbiased nanopore sequencing and analysis of RNA viruses present in two common clinical matrices.
Validation of an unbiased metagenomic detection assay for RNA viruses in viral transport media and plasma
Authors: Kappell Anthony D. , Schulte Kathleen Q. , Scheuermann Elizabeth A. , Scholz Matthew B. , Keplinger Nicolette C. , Scholes Amanda N. , Wolt Taylor A. , June Viviana M. , Schulte Cole J. , Allen Leah W. , Ternus Krista L. , Hewitt F. Curtis
Published: March 2024

Unbiased long read sequencing holds enormous potential for the detection of pathogen sequences in clinical samples. However, the untargeted nature of these methods precludes conventional PCR approaches, and the metagenomic content of each sample increases the challenge of bioinformatic analysis. Here, we evaluate a previously described novel workflow for unbiased RNA virus sequence identification in a series of contrived and real-world samples. The novel multiplex library preparation workflow was developed for the Oxford Nanopore Technologies (ONT) MinIONTMsequencer using reverse transcription, whole genome amplification, and ONT’s Ligation Sequencing Kit with Native Barcode Expansion. The workflow includes spiked MS2 Phage as an internal positive control and generates an 8-plex library with 6 samples, a negative control and agfptranscript positive control. Targeted and untargeted data analysis was performed using the EPI2ME Labs framework and open access tools that are readily accessible to most clinical laboratories. Contrived samples composed of common respiratory pathogens (Influenza A, Respiratory Syncytial Virus and Human Coronavirus 229E) in viral transport media (VTM) and bloodborne pathogens (Zika Virus, Hepatitis A Virus, Yellow Fever Virus and Chikungunya Virus) in human plasma were used to establish the limits of detection for this assay. We also evaluated the diagnostic accuracy of the assay using remnant clinical samples and found that it showed 100% specificity and 62.9% clinical sensitivity. More studies are needed to further evaluate pathogen detection and better position thresholds for detection and non-detection in various clinical sample metagenomic mixtures.
Prescribing of antipsychotics for people diagnosed with severe mental illness in UK primary care: A 20-year investigation of who receives treatment, with which agents, and at what doses
Authors: Richards-Belle Alvin , Launders Naomi , Hardoon Sarah , Man Kenneth K.C. , Bramon Elvira , Osborn David P.J. , Hayes Joseph F.
Published: March 2024

Background

Contemporary data relating to antipsychotic prescribing in UK primary care for patients diagnosed with severe mental illness (SMI) are lacking.

Aims

To describe contemporary patterns of antipsychotic prescribing in UK primary care for patients diagnosed with SMI.

Methods

Cohort study of patients with an SMI diagnosis (i.e., schizophrenia, bipolar disorder, other non-organic psychoses) first recorded in primary care between 2000-2017 derived from Clinical Practice Research Datalink. Patients were considered exposed to antipsychotics if prescribed at least one antipsychotic in primary care between 2000-2019. We compared characteristics of patients prescribed and not prescribed antipsychotics; calculated annual prevalence rates for antipsychotic prescribing; and computed average daily antipsychotic doses stratified by patient characteristics.

Results

Of 309,378 patients first diagnosed with an SMI in primary care between 2000-2017, 212,618 (68.7%) were prescribed an antipsychotic between 2000-2019. Antipsychotic prescribing prevalence was 426 (95% CI, 420-433) per 1,000 patients in the year 2000, reaching a peak of 550 (547-553) in 2016, decreasing to 470 (468-473) in 2019. The proportion prescribed antipsychotics was higher amongst patients diagnosed with schizophrenia (81.0%) than with bipolar disorder (64.6%) and other non-organic psychoses (65.7%). Olanzapine, quetiapine, risperidone, and aripiprazole accounted for 78.8% of all prescriptions. Higher mean olanzapine equivalent total daily doses were prescribed to patients with the following characteristics: schizophrenia diagnosis, ethnic minority status, male sex, younger age, and greater deprivation.

Conclusions

Antipsychotic prescribing is dominated by olanzapine, quetiapine, risperidone, and aripiprazole. Two thirds of patients with diagnosed SMI were prescribed antipsychotics in primary care, but this proportion varied according to SMI diagnosis. There were disparities in both receipt and dose of antipsychotics across subgroups - further efforts are needed to understand why certain groups are prescribed higher doses and whether they require dose optimisation to minimise side effects.
An open-label, parallel-group, randomized clinical trial of different silver diamine fluoride application intervals to arrest dental caries
Authors: Schroth Robert J. , Bajwa Sukeerat , Lee Victor H. K. , Mittermuller Betty-Anne , Singh Sarbjeet , de Jesus Vivianne Cruz , Bertone Mary , Chelikani Prashen
Published: March 2024

Background

Non-surgical interventions are preferred to address the widespread issue of early childhood caries (ECC). Silver diamine fluoride (SDF) is an antimicrobial agent and alternative treatment option that can be used to arrest dental decay. While there is optimism with SDF with regard to caries management, there is no true consensus on the number and frequency of applications for children. The purpose of this study was to examine the effectiveness of 38% SDF to arrest ECC at three different application regimen intervals.

Methods

Children with ECC were recruited from community dental clinics into an open-label, parallel-group, randomized clinical trial. Participants were randomized to one of three groups: visits one month, four months, or six months apart. Participants received applications of 38% SDF, along with 5% sodium fluoride varnish (NaFV), at the first two visits to treat cavitated carious lesions. Lesions were followed and arrest rates were calculated. Lesions were considered arrested if they were hard on probing and black in colour. Statistics included descriptive and bivariate analyses. Ap-value of ≤ 0.05 was considered significant.

Results

Eighty-four children participated in the study (49 males and 35 females, mean age: 44.4 ± 14.2 months). Treatment groups were well matched with 28 participants per group. A total of 374 teeth and 505 lesions were followed. Posterior lesions represented only 29.1% of affected surfaces. Almost all SDF treated lesions were arrested for the one-month (98%) and four-month (95.8%) interval groups at the final visit. The six-month group experienced the lowest arrest rates; only 72% of lesions were arrested (p< 0.001). The duration of application intervals was inversely associated with improvements in arrest rates for all lesions.

Conclusions

Two applications of 38% SDF and 5% NaFV in one-month and four-month intervals were comparable and very effective in arresting ECC. Applications six months apart were less effective and could be considered inferior treatment.

Trial registration

ClinicalTrials.govNCT04054635(first registered 13/08/2019).
Misclassification of a frequent loss of function variant fromPMS2CLpseudogene as aPMS2variant in Brazilian patients
Authors: Campos Segura Anthony Vladimir , da Silva Sara Iolanda Oliveira , Santiago Karina Miranda , Brianese Rafael Canfield , Carraro Dirce Maria , Torrezan Giovana Tardin
Published: March 2024

PMS2, a Lynch Syndrome gene, presents challenges in genetic testing due to the existence of multiple pseudogenes. This study aims to describe a series of cases harboring a rare LoF variant in thePMS2CLpseudogene that has been incorrectly assigned toPMS2with different nomenclatures. We reviewed data from 647 Brazilian patients who underwent multigene genetic testing at a single center to identify those harboring thePMS2V1:c.2186_2187delTC or V2:c.2182_2184delACTinsG variants, allegedly located atPMS2exon 13. Gene-specific PCR and transcript sequencing was performed. Among the 647 individuals, 1.8% (12) carried the investigated variants, with variant allele frequencies ranging from 15 to 34%. By visually inspecting the alignments, we confirmed that both V1 and V2 represented the same variant and through gene-specific PCR andPMS2transcript analysis, we demonstrated that V1/V2 is actually located in thePMS2CLpseudogene. Genomic databases (ExAC and gnomAD) report an incidence of 2.5% - 5.3% of this variant in the African population. Currently, V1 is classified as “uncertain significance” and V2 as “conflicting” in ClinVar, with several laboratories classifying them as “pathogenic”. We identified a frequent AfricanPMS2CLLoF variant in the Brazilian population that is misclassified as aPMS2variant. It is likely that V1/V2 have been erroneously assigned toPMS2in several manuscripts and by clinical laboratories, underscoring a disparity-induced matter. Considering the limitations of short-read NGS differentiating between certain regions ofPMS2andPMS2CL, using complementary methodologies is imperative to provide an accurate diagnosis.
LCD Benchmark: Long Clinical Document Benchmark on Mortality Prediction for Language Models
Authors: Yoon WonJin , Chen Shan , Gao Yanjun , Zhao Zhanzhan , Dligach Dmitriy , Bitterman Danielle S. , Afshar Majid , Miller Timothy
Published: March 2024

Objective

The application of Natural Language Processing (NLP) in the clinical domain is important due to the rich unstructured information in clinical documents, which often remains inaccessible in structured data. When applying NLP methods to a certain domain, the role of benchmark datasets is crucial as benchmark datasets not only guide the selection of best-performing models but also enable the assessment of the reliability of the generated outputs. Despite the recent availability of language models (LMs) capable of longer context, benchmark datasets targeting long clinical document classification tasks are absent.

Materials and Methods

To address this issue, we propose LCD benchmark, a benchmark for the task of predicting 30-day out-of-hospital mortality using discharge notes of MIMIC-IV and statewide death data. We evaluated this benchmark dataset using baseline models, from bag-of-words and CNN to instruction-tuned large language models. Additionally, we provide a comprehensive analysis of the model outputs, including manual review and visualization of model weights, to offer insights into their predictive capabilities and limitations.

Results and Discussion

Baseline models showed 28.9% for best-performing supervised models and 32.2% for GPT-4 in F1-metrics. Notes in our dataset have a median word count of 1687. Our analysis of the model outputs showed that our dataset is challenging for both models and human experts, but the models can find meaningful signals from the text.

Conclusion

We expect our LCD benchmark to be a resource for the development of advanced supervised models, or prompting methods, tailored for clinical text.

The benchmark dataset is available athttps://github.com/Machine-Learning-for-Medical-Language/long-clinical-doc
Hyperspectral imaging for chloroplast movement detection
Authors: Hermanowicz Paweł , Łabuz Justyna
Published: March 2024

We employed hyperspectral imaging to detect chloroplast positioning inNicotiana benthamianaandArabidopsis thalianaleaves and assess its influence on commonly used vegetation indices. In low light, chloroplasts move to cell walls perpendicular to the direction of the incident light. In high light, they move to cell walls parallel to the light direction. Chloroplast movements result in significant changes in leaf transmittance and reflectance. The changes in leaf reflectance offer a way to examine chloroplast positioning in a non-contact way. At the same time, they may confound remote sensing of other physiological traits. The shape of reflectance spectra recorded on irradiated and non-irradiated parts ofN. benthamianaandA. thalianaleaves indicated the specific position of chloroplasts. Low blue light resulted in a decrease in leaf reflectance in the green-yellow region of the spectrum. High blue light irradiation caused an increase in leaf reflectance in the visible range. The differential spectra, showing the effect of high light on leaf reflectance, exhibited a characteristic saddle in the green-yellow region and a peak at around 695 nm. Results obtained for A. thaliana mutants with disrupted chloroplast movements suggest that the observed spectral changes are mostly due to the chloroplast relocations. The reflectance spectra were used to train machine learning methods in the classification of leaves according to the chloroplast positioning. The convolutional network showed low levels of misclassification of leaves irradiated with high light even when different species were used for training and testing. This suggests that reflectance spectra may be used to detect the chloroplast avoidance response in heterogeneous patches of vegetation. We also examined the correlation between chloroplast positioning and values of indices of normalized-difference type for various combinations of wavelengths and proposed a chloroplast movement index for validation of chloroplast positions in leaves. The analysis of commonly used vegetation indices showed that their values may be altered due to chloroplast rearrangements. Our work indicates that changes in leaf reflectance due to chloroplast movements may be substantial and should be taken into account in remote sensing studies.
Morphoregulatory ADD3 underlies glioblastoma growth and formation of tumor-tumor connections
Authors: Barelli Carlotta , Kaluthantrige Don Flaminia , Iannuzzi Raffaele M , Bertani Ilaria , Osei Isabella , Sorrentino Simona , Villa Giulia , Sokolova Viktoria , Iorio Francesco , Kalebic Nereo
Published: March 2024

Glioblastoma is a major unmet clinical need characterized by striking inter- and intra-tumoral heterogeneity and a population of glioblastoma stem cells (GSCs), conferring aggressiveness and therapy resistance. GSCs communicate through a network of tumor-tumor connections (TTCs), including nanotubes and microtubes, promoting tumor progression. However, very little is known about the mechanisms underlying TTC formation and overall GSC morphology. As GSCs closely resemble neural progenitor cells during neurodevelopment, we hypothesized that GSCs' morphological features affect tumor progression. We identified GSC morphology as a new layer of tumoral heterogeneity with important consequences on GSC proliferation. Strikingly, we showed that the neurodevelopmental morphoregulator ADD3, is sufficient and necessary for maintaining proper GSC morphology, TTC abundance and cell cycle progression as well as required for cell survival. Remarkably, both the effects on cell morphology and proliferation depend on the stability of actin cytoskeleton. Hence, cell morphology and its regulators play a key role in tumor progression by mediating cell-cell communication. We thus propose that GSC morphological heterogeneity holds the potential to identify new therapeutic targets and diagnostic markers.
Whole-genome resequencing revealed the Origin and Domestication of Chinese Domestic Rabbits
Authors: Xie Kerui , Song Zichen , Wang Yanyan , Di Yan , Li Wenqang , Wang Yubin , Yang Aiguo , Qiao Xibo , Wang Bo , Li Mingyong , Xie Xiping , Xie Xiaohong , Liu Lie , Ning Chao , Tang Hui , Li Xianyao , Wu Xinsheng , Zhang Qin , Wang Dan , Fan Xinzhong
Published: March 2024

The evolutionary and genetic origins of Chinese indigenous rabbits (Oryctolagus cuniculus) remain largely unclear, despite being among the most recently domesticated animals. We sequenced the whole genomes of 142 individual rabbits and collected 25 resequencing accessions from the NCBI, representing six Chinese indigenous breeds, three other domesticated breeds (serving as a bridge between European wild-type and Chinese domestic populations), and two wild rabbit populations from the Iberian Peninsula and Southern France. Population and demographic analyses suggest that Chinese domestic rabbits are most likely descendants of O. c. cuniculus, native to France 800-1500 years ago. These rabbits likely first arrived in the southeast coastal areas of China through trade before spreading to inland regions. Additionally, there may be other origins for Chinese domestic rabbits. We observed considerable variation in the genetic makeup of maternal ancestry between Chinese domestic rabbits and European wild populations, with Chinese rabbits possessing unique mitochondrial haplotypes. Our analysis also highlights selective sweeps on genes affecting brain and neuronal development, which may have been under strong positive selection during domestication; genes related to starch digestion and fat metabolism, suggesting an evolutionary adaptation to digest high-starch diets; and the white coat phenotype in rabbits, resulting from selection at the melanogenesis-associated transcription factor locus. Overall, our data provide comprehensive insights into the origin and domestication of rabbits and lay the foundation for genome-based breeding.
FLIGHTED: Inferring Fitness Landscapes from Noisy High-Throughput Experimental Data
Authors: Sundar Vikram , Tu Boqiang , Guan Lindsey , Esvelt Kevin
Published: March 2024

Machine learning (ML) for protein design requires large protein fitness datasets generated by high-throughput experiments for training, fine-tuning, and benchmarking models. However, most models do not account for experimental noise inherent in these datasets, harming model performance and changing model rankings in benchmarking studies. Here we develop FLIGHTED, a Bayesian method of accounting for uncertainty by generating probabilistic fitness landscapes from noisy high-throughput experiments. We demonstrate how FLIGHTED can improve model performance on two categories of experiments: single-step selection assays, such as phage display and SELEX, and a novel high-throughput assay called DHARMA that ties activity to base editing. We then compare the performance of standard machine-learning models on fitness landscapes generated with and without FLIGHTED. Accounting for noise significantly improves model performance, especially of CNN architectures, and changes relative rankings on numerous common benchmarks. Based on our new benchmarking with FLIGHTED, data size, not model scale, currently appears to be limiting the performance of protein fitness models, and the choice of top model architecture matters more than the protein language model embedding. Collectively, our results indicate that FLIGHTED can be applied to any high-throughput assay and any machine learning model, making it straightforward for protein designers to account for experimental noise when modeling protein fitness.
CYRI-B loss promotes enlarged mature focal adhesions and restricts microtubule and ERC1 access to the cell leading edge
Authors: Whitelaw Jamie A. , Lilla Sergio , Nikolaou Savvas , Tweedy Luke , Fort Loic , Paul Nikki R. , Zanivan Sara , Gadegaard Nikolaj , Insall Robert H. , Machesky Laura M.
Published: March 2024

CYRI proteins promote lamellipodial dynamics by opposing Rac1-mediated activation of the Scar/WAVE complex. This activity also supports resolution of macropinocytic cups, promoting internalisation of surface proteins, including integrins. Here, we show that CYRI-B also promotes focal adhesion maturation and dynamics. Focal adhesions in CYRI-B-depleted cells show accelerated maturation and become excessively large. We probed the composition of these enlarged focal adhesions, using a Bio-ID screen, with paxillin as bait. Our screen revealed changes in the adhesome suggesting early activation of stress fibre contraction and depletion of the integrin internalisation mediator ERC1. Lack of CYRI-B leads to more stable lamellipodia and accumulation of polymerised actin in stress fibres. This actin acts as a barrier to microtubule targeting for adhesion turnover. Thus, our studies reveal an important connection between lamellipodia dynamics controlled by CYRI-B and microtubule targeting of ERC1 to modulate adhesion maturation and turnover.
The 24-Hour Time Course of Integrated Molecular Responses to Resistance Exercise in Human Skeletal Muscle ImplicatesMYCas a Hypertrophic Regulator That is Sufficient for Growth
Authors: Edman Sebastian , Jones Ronald G. , Jannig Paulo R. , Fernandez-Gonzalo Rodrigo , Norrbom Jessica , Thomas Nicholas T. , Khadgi Sabin , Koopmans Pieter Jan , Morena Francielly , Peterson Calvin S. , Scott Logan N. , Greene Nicholas P. , Figueiredo Vandre C. , Fry Christopher S. , Zhengye Liu , Lanner Johanna T. , Wen Yuan , Alkner Björn , Murach Kevin A. , von Walden Ferdinand
Published: March 2024

Molecular control of recovery after exercise in muscle is temporally dynamic. A time course of biopsies around resistance exercise (RE) combined with -omics is necessary to better comprehend the molecular contributions of skeletal muscle adaptation in humans. Vastus lateralis biopsies before and 30 minutes, 3-, 8-, and 24-hours after acute RE were collected. A time-point matched biopsy-only group was also included. RNA-sequencing defined the transcriptome while DNA methylomics and computational approaches complemented these data. The post-RE time course revealed: 1) DNA methylome responses at 30 minutes corresponded to upregulated genes at 3 hours, 2) a burst of translation- and transcription-initiation factor-coding transcripts occurred between 3 and 8 hours, 3) global gene expression peaked at 8 hours, 4) ribosome-related genes dominated the mRNA landscape between 8 and 24 hours, 5) methylation-regulatedMYCwas a highly influential transcription factor throughout the 24-hour recovery and played a primary role in ribosome-related mRNA levels between 8 and 24 hours. The influence of MYC in human muscle adaptation was strengthened by transcriptome information from acute MYC overexpression in mouse muscle. To test whether MYC was sufficient for hypertrophy, we generated a muscle fiber-specific doxycycline inducible model of pulsatile MYC induction. Periodic 48-hour pulses of MYC over 4 weeks resulted in higher muscle mass and fiber size in the soleus of adult female mice. Collectively, we present a temporally resolved resource for understanding molecular adaptations to RE in muscle and reveal MYC as a regulator of RE-induced mRNA levels and hypertrophy.
A Hollow TFG Condensate Spatially Compartmentalizes the Early Secretory Pathway
Authors: Wegeng William R. , Bogus Savannah M. , Ruiz Miguel , Chavez Sindy R. , Noori Khalid S. M. , Niesman Ingrid R. , Ernst Andreas M.
Published: March 2024

In the early secretory pathway, endoplasmic reticulum (ER) and Golgi membranes form a nearly spherical interface. In this ribosome-excluding zone, bidirectional transport of cargo coincides with a spatial segregation of anterograde and retrograde carriers by an unknown mechanism. We show that at physiological conditions, Trk-fused gene (TFG) self-organizes to form a hollow, anisotropic condensate that matches the dimensions of the ER-Golgi interface. Regularly spaced hydrophobic residues in TFG control the condensation mechanism and result in a porous condensate surface. We find that TFG condensates act as a molecular sieve, enabling molecules corresponding to the size of anterograde coats (COPII) to access the condensate interior while restricting retrograde coats (COPI). We propose that a hollow TFG condensate structures the ER-Golgi interface to create a diffusion-limited space for bidirectional transport. We further propose that TFG condensates optimize membrane flux by insulating secretory carriers in their lumen from retrograde carriers outside TFG cages.
Recognition of specific PIP2-subtype composition triggers the allosteric control mechanism for selective membrane targeting of cargo loading and release functions of the intracellular sterol transporter StarD4
Authors: Xie Hengyi , Weinstein Harel
Published: March 2024

StarD4 is an intracellular cholesterol trafficking protein that facilitates the crucial non-vesicular sterol transport between the plasma membrane and the endoplasmic reticulum. It targets both sterol donor and acceptor membranes via interactions with anionic lipids. Experiments have illuminated the kinetics of this sterol transfer and shown it to be modulated by specific phosphatidylinositol phosphates (PIPs) on the target membrane. The distinct subtype distribution of PIPs in the membranes of cellular organelles serves as a guide to direct StarD4 to recognized cell components. However, little is known about the molecular mechanism of the recognition of the PIP2 subtype by StarD4, and how this affects the direction and kinetics of cholesterol transport, as the reaction pathways of the cholesterol uptake and release processes in StarD4 have never been observed. Here, we investigated 1)-how StarD4 transports a cholesterol from/to membranes; 2)-how StarD4 recognizes PIP2-subtypes in membranes; and 3)-how the PIP2-subtype recognition impacts cholesterol transport kinetics, using extensive molecular dynamics (MD) sampling with advanced machine learning and information theory methods for trajectory analysis. The findings revealed function-related allosteric dynamics of StarD4, connecting the identified PIP2-subtype-specific conformational states to the cholesterol binding modes in the pocket, which steers the dynamics of the gates towards conformations that support either cholesterol release or uptake. This reveals the crucial role of PIP2 subtypes in shaping functional StarD4 motifs responsible for organelle selectivity of the cholesterol trafficking, providing fundamental insights into cellular cholesterol regulation.
The Scribble/SGEF/Dlg1 complex regulates the stability of apical junctions in epithelial cells
Authors: Rabino Agustin , Awadia Sahezeel , Ali Nabaa , Edson Amber , Garcia-Mata Rafael
Published: March 2024

SGEF, a RhoG specific GEF, can form a ternary complex with the Scribble polarity complex proteins Scribble and Dlg1, which regulates the formation and maintenance of adherens junctions and barrier function of epithelial cells. Notably, silencing SGEF results in a dramatic downregulation of the expression of both E-cadherin and ZO-1. However, the molecular mechanisms involved in the regulation of this pathway are not known. Here, we describe a novel signaling pathway governed by the Scribble/SGEF/Dlg1 complex. Our results show that an intact ternary complex is required to maintain the stability of the apical junctions, the expression of ZO-1, and TJ permeability. In contrast, only SGEF is necessary to regulate E-cadherin expression. The absence of SGEF destabilizes the E-cadherin/catenin complex at the membrane, triggering a positive feedback loop that exacerbates the phenotype through the repression of E-cadherin transcription in a process that involves the internalization of E-cadherin by endocytosis, β-catenin signaling and the transcriptional repressor Slug.
The Outer Kinetochore Proteins KNL-1 and Ndc80 complex are Required to Pattern the Central Nervous System
Authors: Ouzounidis Vasileios R. , Green Mattie , de Ceuninck van Capelle Charlotte , Gebhardt Clara , Crellin Helena , Finlayson Cameron , Prevo Bram , Cheerambathur Dhanya K.
Published: March 2024

The KMN (Knl1/Mis12/Ndc80) network at the kinetochore, primarily known for its role in chromosome segregation, has been shown to be repurposed during neurodevelopment. Here, we investigate the underlying neuronal mechanism and show that the KMN network is essential to establish the proper axonal organization within theC. eleganshead nervous system. Post-mitotic degradation of KNL-1, which acts as a scaffold for signaling and has microtubule-binding activities at the kinetochore, led to disorganized ganglia and aberrant placement and organization of axons in the nerve ring - an interconnected axonal network. Through gene-replacement approaches, we demonstrate that the signaling motifs within KNL-1, responsible for recruiting the protein phosphatase 1, and activating the spindle assembly checkpoint are required for neurodevelopment. Interestingly, while the microtubule-binding activity is crucial to KMN’s neuronal function, microtubule dynamics and organization were unaffected in the absence of KNL-1. Instead, the NDC-80 microtubule-binding mutant displayed notable defects in axon bundling during nerve ring formation, indicating its role in facilitating axon-axon contacts. Overall, these findings provide evidence for a non-canonical role for the KMN network in shaping the structure and connectivity of the nervous system inC. elegansduring brain development.
Respiratory pauses highlight sleep architecture in mice
Authors: Casali Giulio , Miermon Camille , Terral Geoffrey , Ravassard Pascal , Dolique Tiphaine , Harrell Evan , Lesburguères Edith , Jarriault David , Gambino Frédéric , Chenouard Nicolas , Roux Lisa
Published: March 2024

Brain activity and breathing rate influence each other but it remains unclear how fine respiratory features vary across vigilance states. Using simultaneous nasal pressure and hippocampal local field potential recordings in freely-moving mice, we show that the position of respiratory pauses within breathing cycles distinguish Wake, Rapid Eye Movement (REM) and non-REM (NREM) sleep states. Model-based predictions of vigilance states based on respiratory features perform well even on animals outside of the training set, suggesting the rules are generalized. Respiratory features underwent specific changes at state transitions, such as progressive elimination of pauses after inhalation foreshadowing REM. During NREM, respiratory changes predicted moment-to moment sigma power variations beyond movement-defined packets delineated by micro-arousals, as pauses after inhalation fragmented NREM sleep into ∼30s windows of high sigma power. Overall, our findings reveal that respiratory features structure the macro- and micro-architecture of sleep, opening new windows into brain states through respiration.
Dynamics of the
O(4)
critical point in QCD: Critical pions and diffusion in model G
Authors: Florio Adrien , Grossi Eduardo , Teaney Derek
Published: March 2024

We present a detailed study of the finite momentum dynamics of the O(4) critical point of QCD, which lies in the dynamic universality class of “model G.” The critical scaling of the model is analyzed in multiple dynamical channels. For instance, the finite momentum analysis allows us to precisely extract the pion dispersion curve below the critical point. The pion velocity is in striking agreement with the predictions relation and static universality. The pion damping rate and velocity are both consistent with the dynamical critical exponent ζ=3/2 of model G. Similarly, although the critical amplitude for the diffusion coefficient of the conserved O(4) charges is small, it is clearly visible both in the restored phase and with finite explicit symmetry breaking, and its dynamical scaling is again consistent with ζ=3/2. We determine a new set of universal dynamical critical amplitude ratios relating the diffusion coefficient to a suitably defined order parameter relaxation time. We also show that in a finite volume simulation, the chiral condensate diffuses on the coset manifold in a manner consistent with dynamical scaling, and with a diffusion coefficient that is determined by the transport coefficients of hydrodynamic pions. Finally, the amplitude ratios (together with other nonuniversal amplitudes also reported here) compile all relevant information for further studies of model G both in and out of equilibrium.

Published by the American Physical Society
2024
Linear response theory for spin alignment of vector mesons in thermal media
Authors: Dong Wen-Bo , Yin Yi-Liang , Sheng Xin-Li , Yang Shi-Zheng , Wang Qun
Published: March 2024

We present a calculation of the spin alignment for unflavored vector mesons in thermalized quark-gluon plasma based on the Kubo formula in linear response theory. This is achieved by expanding the system to the first order of the coupling constant and the spatial gradient. The effect strongly relies on the vector meson’s spectral functions which are determined by the interaction and medium properties. The spectral functions are calculated for the one-quark-loop self-energy with meson-quark interaction. The numerical results show that the correction to the spin alignment from the thermal shear tensor is of the order 10−4∼10−5 for the chosen values of quark-meson coupling constant, if the magnitude of thermal shear tensor is 10−2.

Published by the American Physical Society
2024
Charge Conservation beyond Uniformity: Spatially Inhomogeneous Electromagnetic Response in Periodic Solids
Authors: McKay Robert C. , Mahmood Fahad , Bradlyn Barry
Published: March 2024

Nonlinear electromagnetic response functions have reemerged as a crucial tool for studying quantum materials, due to recently appreciated connections between optical response functions, quantum geometry, and band topology. Most attention has been paid to responses to spatially uniform electric fields, relevant to low-energy optical experiments in conventional solid state materials. However, magnetic and magnetoelectric phenomena are naturally connected by responses to spatially varying electric fields due to Maxwell’s equations. Furthermore, in the emerging field of moiré materials, characteristic lattice scales are much longer, allowing spatial variation of optical electric fields to potentially have a measurable effect in experiments. In order to address these issues, we develop a formalism for computing linear and nonlinear responses to spatially inhomogeneous electromagnetic fields. Starting with the continuity equation, we derive an expression for the second-quantized current operator that is manifestly conserved and model independent. Crucially, our formalism makes no assumptions on the form of the microscopic Hamiltonian and so is applicable to model Hamiltonians derived from tight-binding or calculations. We then develop a diagrammatic Kubo formalism for computing the wave vector dependence of linear and nonlinear conductivities, using Ward identities to fix the value of the diamagnetic current order by order in the vector potential. We apply our formula to compute the magnitude of the Kerr effect at oblique incidence for a model of a moiré-Chern insulator and demonstrate the experimental relevance of spatially inhomogeneous fields in these systems. We further show how our formalism allows us to compute the (orbital) magnetic multipole moments and magnetic susceptibilities in insulators. Turning to nonlinear response, we use our formalism to compute the second-order transverse response to spatially varying transverse electric fields in our moiré-Chern insulator model, with an eye toward the next generation of experiments in these systems.

Published by the American Physical Society
2024
Digital transformation and governance heterogeneity as determinants of CSR disclosure: insights from Chinese A-share companies
Authors: Jin Xiaoyan , Mirza Sultan Sikandar , Huang Chengming , Zhang Chengwei
Published: March 2024

Purpose

In this fast-changing world, digitization has become crucial to organizations, allowing decision-makers to alter corporate processes. Companies with a higher corporate social responsibility (CSR) level not only help encourage employees to focus on their goals, but they also show that they take their social responsibility seriously, which is increasingly important in today’s digital economy. So, this study aims to examine the relationship between digital transformation and CSR disclosure of Chinese A-share companies. Furthermore, this research investigates the moderating impact of governance heterogeneity, including CEO power and corporate internal control (INT) mechanisms.

Design/methodology/approach

This study used fixed effect estimation with robust standard errors to examine the relationship between digital transformation and CSR disclosure and the moderating effect of governance heterogeneity among Chinese A-share companies from 2010 to 2020. The whole sample consists of 17,266 firms, including 5,038 state-owned enterprise (SOE) company records and 12,228 non-SOE records. The whole sample data is collected from the China Stock Market and Accounting Research, the Chinese Research Data Services and the WIND databases.

Findings

The regression results lead us to three conclusions after classifying the sample into non-SOE and SOE groups. First, Chinese A-share businesses with greater levels of digitalization have lower CSR disclosures. Both SOE and non-SOE are consistent with these findings. Second, increasing CEO authority creates a more centralized company decision-making structure (Breuer et al., 2022; Freire, 2019), which improves the negative association between digitalization and CSR disclosure. These conclusions, however, also apply to non-SOE. Finally, INT reinforces the association between corporate digitization and CSR disclosure, which is especially obvious in SOEs. These findings are robust to alternative HEXUN CSR disclosure index. Heterogeneity analysis shows that the negative relationship between corporate digitalization and CSR disclosures is more pronounced in bigger, highly levered and highly financialized firms.

Originality/value

Digitalization and CSR disclosure are well studied, but few have examined their interactions from a governance heterogeneity perspective in China. Practitioners and policymakers may use these insights to help business owners implement suitable digital policies for firm development from diverse business perspectives.
Reading habits of undergraduate students in the digital environment: a gender perspective
Authors: Mog Rajesh Kumar , Gayan Mithu Anjali
Published: March 2024

Purpose

The purpose of this study is to understand the role and impact of gender on reading habits. It is an attempt to explore the probable reason why or why not gender differences take place concerning reading time, reading purpose, reading resources and digital devices among undergraduate students in the digital environment.

Design/methodology/approach

For this study, the researcher used a survey-based approach. To accomplish the study’s goals, a meticulously designed questionnaire has been disseminated among undergraduate students in selected colleges located in the western district of Tripura, a northeastern state in India.

Findings

The study found that female respondents have a slightly higher level of liking for reading than males. For both genders, the major purpose of reading is to enhance their knowledge unvaryingly. Furthermore, it has been observed that female respondents read electronic and print reading material more frequently compared to their male counterparts. Female respondents read fiction more frequently than males in print form. Both genders have more ease in reading print resources than digital resources. Among all digital devices, respondents are most competent at using mobile devices and prefer them for digital reading.

Research limitations/implications

As part of the pilot study, investigators surveyed a limited sample population, where the participation of students was further lower because of the unavailability of students.

Originality/value

The gender-based level of competency with digital devices is studied as a variable among the adult population to measure its correlation with reading habits.