bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can social prescribing reach patients most in need? Patterns of (in)equalities in referrals in a representative cohort of older adults in England
Authors: Fancourt Daisy , Steptoe Andrew 
Published: March 2024

AbstractImportanceSocial prescribing (SP) is a mechanism of care referring people to non-clinical forms of support and services in local communities to improve health and wellbeing. But there is much contention over whether SP is in fact provided disproportionately more to individuals who are less disadvantaged. However, a comprehensive analysis of who is receiving SP from both medical and non-medical referral routes has never been undertaken.ObjectiveTo incorporate bespoke novel questions on SP into a nationally-representative cohort study to assess whether SP is truly reaching individuals most in need.DesignWe used data from Wave 10 (2021/23) of the English Longitudinal Study of Ageing (ELSA) involving richly-phenotyped adults aged 50+ living in England. We explored how SP was patterned according to social and health inequalities, all measured in Wave 9 (2018/19; prior to the reported engagement in SP). Multiple ordinal regression models were used to explore predictors of receiving a SP referral.SettingCommunity-dwelling older adults living in EnglandParticipants7,283 adults aged 50+ answered the self-completion questionnaire at wave 10 so were included in analyses.Main outcomes and measuresParticipants were asked if they had received a referral to a wide range of community-based activities by a doctor, social worker or other health professionalResults495 adults (6.8%) reported receiving a SP referral, and 435 (88%) accepted. Age was a significant predictor of referrals (OR 1.02, CI 1.01-1.03), but being female was not (OR 1.05, CI 0.84-1.30). Receiving benefits increased referral odds two-fold (OR 2.03, CI 1.53-2.70) and being in the lowest wealth tertile (relative to middle tertile) by 55% (CI 1.13-2.13). Education and employment status did not predict referrals. Referrals were most common for individuals with depression (OR=1.60, CI 1.20-2.12), diabetes (OR=1.52, CI 1.11-2.10), chronic pain (OR=1.57, CI 1.22-2.02), multiple long-term conditions (4+ conditions, OR=2.8, CI 1.41-5.51), and who were physically inactive (OR=1.63, CI 1.10-2.41).Conclusions and relevanceThere is some initial evidence of SP referrals occurring amongst older adults in England, with high uptake amongst those referred. Promisingly, those with highest socio-economic need and most long-term health conditions particularly appear to be receiving support.Key pointsQuestionWho is receiving referrals to social prescribing programmes?FindingsIn this analysis of a nationally representative cohort study of 7,283 richly-phenotyped adults aged 50+ living in England, SP was offered most to individuals experiencing socio-economic adversity with health needs including depression, diabetes, chronic pain, multiple long-term conditions, and those who were physically inactive.MeaningPromisingly, older adults with highest socio-economic need and most long-term health conditions particularly appear to be receiving support through social prescribing.
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

ABSTRACTBackgroundNon-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.MethodsChildren 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.ResultsEighty-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.ConclusionsTwo 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 registrationClinicalTrials.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

AbstractPMS2, 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

ABSTRACTObjectiveThe 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 MethodsTo 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 DiscussionBaseline 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.ConclusionWe 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

SummaryWe 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.
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

AbstractThe 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

ABSTRACTMachine 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

AbstractCYRI 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

AbstractMolecular 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

SummaryIn 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

ABSTRACTStarD4 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

AbstractSGEF, 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.