bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatially Aware Transformer Networks for Contextual Prediction of Diabetic Nephropathy Progression from Whole Slide Images
Authors: Shickel Benjamin , Lucarelli Nicholas , Rao Adish S. , Yun Donghwan , Moon Kyung Chul , Han Seung Seok , Sarder Pinaki 
Published: February 2023

ABSTRACTDiabetic nephropathy (DN) in the context of type 2 diabetes is the leading cause of end-stage renal disease (ESRD) in the United States. DN is graded based on glomerular morphology and has a spatially heterogeneous presentation in kidney biopsies that complicates pathologists’ predictions of disease progression. Artificial intelligence and deep learning methods for pathology have shown promise for quantitative pathological evaluation and clinical trajectory estimation; but, they often fail to capture large-scale spatial anatomy and relationships found in whole slide images (WSIs). In this study, we present a transformer-based, multi-stage ESRD prediction framework built upon nonlinear dimensionality reduction, relative Euclidean pixel distance embeddings between every pair of observable glomeruli, and a corresponding spatial self-attention mechanism for a robust contextual representation. We developed a deep transformer network for encoding WSI and predicting future ESRD using a dataset of 56 kidney biopsy WSIs from DN patients at Seoul National University Hospital. Using a leave-one-out cross-validation scheme, our modified transformer framework outperformed RNNs, XGBoost, and logistic regression baseline models, and resulted in an area under the receiver operating characteristic curve (AUC) of 0.97 (95% CI: 0.90-1.00) for predicting two-year ESRD, compared with an AUC of 0.86 (95% CI: 0.66-0.99) without our relative distance embedding, and an AUC of 0.76 (95% CI: 0.59-0.92) without a denoising autoencoder module. While the variability and generalizability induced by smaller sample sizes are challenging, our distance-based embedding approach and overfitting mitigation techniques yielded results that suggest opportunities for future spatially aware WSI research using limited pathology datasets.
Assessing the Value of ChatGPT for Clinical Decision Support Optimization
Authors: Liu Siru , Wright Aileen P. , Patterson Barron L. , Wanderer Jonathan P. , Turer Robert W. , Nelson Scott D. , McCoy Allison B. , Sittig Dean F. , Wright Adam 
Published: February 2023

ABSTRACTObjectiveTo determine if ChatGPT can generate useful suggestions for improving clinical decision support (CDS) logic and to assess noninferiority compared to human-generated suggestions.MethodsWe supplied summaries of CDS logic to ChatGPT, an artificial intelligence (AI) tool for question answering that uses a large language model, and asked it to generate suggestions. We asked human clinician reviewers to review the AI-generated suggestions as well as human-generated suggestions for improving the same CDS alerts, and rate the suggestions for their usefulness, acceptance, relevance, understanding, workflow, bias, inversion, and redundancy.ResultsFive clinicians analyzed 36 AI-generated suggestions and 29 human-generated suggestions for 7 alerts. Of the 20 suggestions that scored highest in the survey, 9 were generated by ChatGPT. The suggestions generated by AI were found to offer unique perspectives and were evaluated as highly understandable and relevant, with moderate usefulness, low acceptance, bias, inversion, redundancy.ConclusionAI-generated suggestions could be an important complementary part of optimizing CDS alerts, can identify potential improvements to alert logic and support their implementation, and may even be able to assist experts in formulating their own suggestions for CDS improvement. ChatGPT shows great potential for using large language models and reinforcement learning from human feedback to improve CDS alert logic and potentially other medical areas involving complex, clinical logic, a key step in the development of an advanced learning health system.
The allotetraploidNicotiana tabacumgenome and GenBank genomics highlight the genomic features, genetic diversity and regulation of morphological, metabolic and disease-resistance traits
Authors: Zan Yanjun , Chen Shuai , Ren Min , Liu Guoxiang , Liu Yutong , Si Huan , Liu Zhengwen , Liu Dan , Zhang Xingwei , Tong Ying , Li Yuan , Jiang Caihong , Wen Liuying , Xiao Zhiliang , Sun Yangyang , Geng Ruimei , Feng Quanfu , Wang Yuanying , Ye Guoyou , Fang Lingzhao , Chen Yong , Cheng Lirui , Yang Aiguo 
Published: February 2023

AbstractNicotiana tabacumis a model organism in plant molecular and pathogenic research and has significant potential in the production of biofuels and active pharmaceutical compounds in synthetic biology. Because of the large allotetraploid genome of tobacco, its genomic features, genetic diversity and genetic regulation of many complex traits remain unknown. In this study, we present a nearly complete chromosome-scale assembly ofN. tabacumand provide evidence that homoeologous exchange between subgenomes and epigenetic remodelling are likely mechanisms of genome stabilization and subgenome coordination following polyploidization. By leveraging GenBank-scale sequencing and phenotyping data from 5196 lines, geography at the continent scale, rather than types assigned on the basis of curing crop practices, was found to be the most important correlate of genetic structure. Using 178 marker□trait associations detected in genome-wide association analysis, a reference genotype-to-phenotype map was built for 39 morphological, developmental, and disease-resistance traits. A novel gene, auxin response factor 9 (Arf9), associated with wider leaves after being knocked out, was fine-mapped to a single nucleotide polymorphism (SNP). This point mutation alters the translated amino acid from Ala203to Pro203, likely preventing homodimer formation during DNA binding. Our analysis also revealed signatures of positive and polygenic selection for multiple traits during the process of selective breeding. Overall, this study demonstrated the power of leveraging GenBank genomics to gain insights into the genomic features, genetic diversity, and regulation of complex traits inN. tabacum, laying a foundation for future research on plant functional genomics, crop breeding, and the production of biopharmaceuticals and biofuels.
The clinical impact of serious respiratory disease in children under the age of two during the 2021-2022 bronchiolitis season in the United Kingdom and Ireland
Authors: Williams Thomas C. , Marlow Robin , Hardelid Pia , Lyttle Mark D. , Lewis Kate M. , Mpamhanga Chengetai D. ,   PERUKI, Cunningham Steve , Roland Damian 
Published: February 2023

AbstractBackgroundInterventions introduced in 2020 to reduce the spread of SARS-CoV-2 led to a widespread reduction in childhood infections, including respiratory syncytial virus (RSV), in the subsequent year. However, from the spring of 2021 onwards the United Kingdom and Ireland began to experience an unusual out of season epidemic of childhood respiratory disease.MethodsWe conducted a prospective observational cohort study (BronchStart), enrolling children aged 0-23 months presenting with clinician-diagnosed bronchiolitis, lower respiratory tract infection or first episode of wheeze in 59 Emergency Departments (ED) across England, Scotland and Ireland from 1 May 2021 to 30 April 2022. We collected baseline data on patient demographics and clinical presentation, and follow-up data at 7 days. We used high-granularity BronchStart clinical data together with national English and Scottish admission datasets to infer the impact of RSV disease in a typical year before the Covid-19 pandemic, and to provide an up-to-date estimate of the annual impact of disease to inform implementation of anti-RSV interventions.FindingsThe BronchStart study collected data on 17,899 ED presentations for 17,179 children. Of these, 6,825 (38.1%) were admitted to hospital for further observation or treatment, 458 (2.6%) required care in a high dependency unit (HDU), and 154 (0.9%) were admitted to a paediatric intensive care unit (PICU). Of the 5,788 children admitted and tested for RSV, 41.8% of the overall study cohort, and 48.7% of those 0-11 months of age, were positive. Risk factors for hospital admission included prematurity and congenital cardiac disease. Patients with these risk factors were also more likely to receive oxygen therapy, or be admitted to a HDU or PICU. However, 84.5% of those admitted to an observation unit, 78.1% of those admitted to a ward, 67.7% of those admitted to HDU and 50.0 % of those admitted to PICU had no identified comorbidity. Using admissions data for England and Scotland we estimate that every year 12,167 infants with RSV infection receive low flow oxygen, 4,998 high flow oxygen and 6,198 a course of antibiotic therapy in secondary care.InterpretationAlthough RSV was the major pathogen in this cohort, 51.3% of admissions for serious respiratory viral infections in those aged <1 year of age were not associated with the virus. Whilst prematurity and congenital cardiac disease were risk factors for admission to hospital, HDU and PICU, the majority of these admissions, for all levels of care except PICU, were in previously healthy term born infants.
Stress in autism (STREAM): A study protocol on the role of circadian activity, sleep quality and sensory reactivity
Authors: Gernert Clara C. , Falter-Wagner Christine M. , Noreika Valdas , Jachs Barbara , Jassim Nazia , Gibbs Kathryn , Streicher Joaquim , Betts Hannah , Bekinschtein Tristan A. 
Published: February 2023

AbstractMental health issues are markedly increased in individuals with autism, making it the number one research priority by stakeholders. There is a crucial need to use personalized approaches to understand the underpinnings of mental illness in autism and consequently, to address individual needs. Based on the risk factors identified in typical mental research, we propose the following themes central to mental health issues in autism: sleep difficulties and stress. Indeed, the prevalence of manifold circadian disruptions and sleep difficulties in autism, alongside stress related to sensory overload, forms an integral part of autistic symptomatology.This proof-of-concept study protocol outlines an innovative, individualised approach towards investigating the interrelationships between stress indices, sleep and circadian activation patterns, and sensory sensitivity in autism. Embracing an individualized methodology, we aim to collect 14 days of data per participant from 20 individuals with autism diagnoses and 20 without. Participants’ sleep will be monitored using wearable EEG headbands and a sleep diary. Diurnal tracking of heart rate and electrodermal activity through wearables will serve as proxies of stress. Those objective data will be synchronized with subjective experience traces collected throughout the day using the Temporal Experience Tracing (TET) method. TET facilitates the quantification of relevant aspects of individual experience states, such as stress or sensory sensitivities, by providing a continuous multidimensional description of subjective experiences. Capturing the dynamics of subjective experiences phase-locked to neural and physiological proxies both between and within individuals, this approach has the potential to contribute to our understanding of critical issues in autism, including sleep problems, sensory reactivity and stress. The planned strives to provide a pathway towards developing a more nuanced and individualized approach to addressing mental health in autism.
Intensive Systolic Blood Pressure Treatment Remodels Brain Perivascular Spaces: A Secondary Analysis of SPRINT
Authors: Kern Kyle C. , Nasrallah Ilya M. , Bryan Robert Nick , Reboussin David M. , Wright Clinton B. 
Published: February 2023

AbstractBackgroundBrain perivascular spaces (PVS) are part of the glymphatic system and facilitate clearance of metabolic byproducts. Since enlarged PVS are associated with vascular health, we tested whether intensive systolic blood pressure (SBP) treatment affects PVS structure.MethodsThis is a secondary analysis of the Systolic PRessure INTervention (SPRINT) Trial MRI Substudy: a randomized trial of intensive SBP treatment to goal < 120 mm Hg vs. < 140 mm Hg. Participants had increased cardiovascular risk, pre-treatment SBP 130-180, and no clinical stroke, dementia, or diabetes. Brain MRIs acquired at baseline and follow-up were used to automatically segment PVS in the supratentorial white matter and basal ganglia using a Frangi filtering method. PVS volumes were quantified as a fraction of the total tissue volume. The effects of SBP treatment group and major antihypertensive classes on PVS volume fraction were separately tested using linear mixed-effects models while covarying for MRI site, age, sex, black race, baseline SBP, history of cardiovascular disease (CVD), chronic kidney disease, and white matter hyperintensities (WMH).ResultsFor 610 participants with sufficient quality MRI at baseline (mean age 67±8, 40% female, 32% black), greater PVS volume fraction was associated with older age, male sex, non-Black race, concurrent CVD, WMH, and brain atrophy. For 381 participants with MRI at baseline and at follow-up (median = 3.9 years), intensive treatment was associated with decreased PVS volume fraction relative to standard treatment (interaction coefficient: -0.029 [-0.055 to -0.0029] p=0.029). Reduced PVS volume fraction was also associated with exposure to calcium channel blockers (CCB) and diuretics.ConclusionsIntensive SBP lowering partially reverses PVS enlargement. The effects of CCB use suggests that improved vascular compliance may be partly responsible. Improved vascular health may facilitate glymphatic clearance.Clincaltrials.gov:NCT01206062
Macroscopic waves, biological clocks and morphogenesis driven by light in a giant unicellular green alga
Authors: Afik Eldad , Liu Toni J.B. , Meyerowitz Elliot M. 
Published: February 2023

AbstractA hallmark of self-organisation in living systems is their capacity to stabilise their own dynamics, often appearing to anticipate and act upon potential outcomes.Caulerpa brachypusis a marine green alga consisting of differentiated organs resembling leaves, stems and roots. While an individual can exceed a metre in size, it is a single multinucleated giant cell. ThusCaulerpapresents the mystery of morphogenesis on macroscopic scales in the absence of cellularization. The experiments reported here reveal self-organised waves of greenness — chloroplasts — that propagate throughout the alga in anticipation of the day-night light cycle. Using dynamical systems analysis we show that these waves are coupled to a self-sustained oscillator, and demonstrate their entrainment to light. Under constant conditions light intensity affects the natural period and drives transition to temporal disorder. Moreover, we find distinct morphologies depending on light temporal patterns, suggesting waves of chlorophyll could link biological oscillators to metabolism and morphogenesis in this giant single-celled organism.
The balance between growth and resistance is shifted to the latter by over-accumulation of chloroplast-nucleus located WHIRLY1 in barley
Authors: Nia Monireh Saeid , Frank Susann , Schäfer Anke , Desel Christine , Mulisch Maria , Voigt Ulrike , Nowara Daniela , Tandron Moya Yudelsy Antonia , Bilger Wolfgang , Wiren Nicolaus von , Hensel Götz , Krupinska Karin 
Published: February 2023

SUMMARYWHIRLY1 is a chloroplast-nucleus located DNA/RNA-binding protein with functions in development and stress tolerance. By overexpression ofHvWHIRLY1in barley, lines with a 10-and two lines with a 50-fold accumulation of the protein were obtained. In these lines, the relative abundance of the nuclear form exceeded that of the chloroplast form indicating that over-accumulating WHIRLY1 exceeded the amount that chloroplasts can sequester. Growth of the plants was shown to be compromised in a WHIRLY1 abundance-dependent manner. Over-accumulation of WHIRLY1 in chloroplasts had neither an evident impact on nucleoid morphology nor on the composition of the photosynthetic apparatus. Nevertheless, oeW1 plants were found to be compromised in the efficiency of photosynthesis. The reduction in growth and photosynthesis was shown to be accompanied by a decrease in the levels of cytokinins and an increase in the level of jasmonic acid. Gene expression analyses revealed that already in non-stress conditions the oeW1 plants had enhanced levels of pathogen response (PR) gene expression indicating activation of constitutive defense. During growth in continuous light of high irradiance,PR1expression further increased in addition to an increase in the expression ofPR10and of the gene encoding phenylalanine lyase (PAL), the key enzyme of salicylic acid biosynthesis in barley. The activation of defense gene expression in oeW1 plants coincided with an enhanced resistance towards powdery mildew, which in barley is independent of salicylic acid. Taken together, the results show that over-accumulation of WHIRLY1 in barley to levels of 10 or more, amplified the tradeoff between growth and stress resistance.
A NovelC. elegansMemory Type Mediated by an Insulin/Phospholipase C Pathway
Authors: Merritt Daniel M. , Udachina Alexandra , Freidel Ninon , Almeida Sylvia M. T. , Anson Lau Yan Ming , Lee Matthew , van der Kooy Derek 
Published: February 2023

AbstractMemories are often categorized into types, reflecting their behavioral, anatomical and molecular diversity: these classifications both aid understanding of the differences among varieties of memory and help delineate the unifying cross-species principles underlying them. In the nematode wormCaenorhabditis elegans,we find that an associative memory of the pairing of the normally attractive odorant benzaldehyde and starvation depends onde novotranslation, is independent of CREB, and is produced by massed training: a pattern which does not correspond to any of the well-characterized molecular categories of invertebrate memory. Further, as has been shown for many memories in vertebrates, but not previously in nematodes, we find that formation of this memory continues after removal of the stimuli initially causing it, and that it is labile to disruption through protein synthesis inhibition following training, but that inhibition of proteasomal activity does not extend the duration of the memory. Previous findings have implicated insulin pathway signaling, which canonically regulates the transcription factor DAF- 16, as a key component of this benzaldehyde/starvation memory, however our results suggest that transcriptional inhibition has, at most, only moderate effects on memory formation. We find that insulin signaling instead acts to regulate phospholipase C, which in turn regulates memory through diacylglycerol signaling. These findings better characterize this model associative memory in relation to other invertebrate memory types and identify ways in which it both shares their traits and differs from them, as well as revealing a more complete picture of the molecular pathway underlying it.
Functional traits shape plant-plant interactions and recruitment in a hotspot of woody plant diversity
Authors: Cooksley Huw , Dreyling Lukas , Esler Karen J. , Griebenow Stian , Neumann Günter , Valentine Alex , Schleuning Matthias , Schurr Frank M. 
Published: February 2023

SummaryUnderstanding and predicting recruitment in species-rich plant communities requires identifying the functional determinants of both density-independent performance and interactions.In a common-garden field experiment with 25 species of the woody plant genusProtea, we varied the initial spatial and taxonomic arrangement of seedlings and followed their survival and growth during recruitment. Neighbourhood models quantified how six key functional traits affect density-independent performance, interaction effects and responses.Trait-based neighbourhood models accurately predicted individual survival and growth from the initial spatial and functional composition of species-rich experimental communities. Functional variation among species caused substantial variation in density-independent survival and growth that was not correlated with interaction effects and responses. Interactions were spatially-restricted but had important, predominantly competitive, effects on recruitment. Traits increasing the acquisition of limiting resources (water for survival, soil P for growth) mediated a trade-off between competitive effects and responses. Moreover, resprouting species had higher survival but reduced growth, likely reinforcing the survival-growth trade-off in adult plants.The combination of field experiments and trait-based neighbourhood analyses holds substantial potential for community ecology. It permits the identification of traits that mediate performance trade-offs promoting coexistence in species-rich communities and contributes key knowledge to guide conservation and restoration of biodiversity hotspots.
Error-corrected Duplex Sequencing enables direct detection and quantification of mutations in human TK6 cells with remarkable inter-laboratory consistency
Authors: Cho Eunnara , Swartz Carol D. , Williams Andrew , Rivas Miriam , Recio Leslie , Witt Kristine L. , Schmidt Elizabeth K. , Yaplee Jeffry , Smith Thomas H. , Van Phu , Lo Fang Yin , Valentine Charles C. , Salk Jesse J. , Marchetti Francesco , Smith-Roe Stephanie L. , Yauk Carole L. 
Published: February 2023

ABSTRACTError-corrected Duplex Sequencing (DuplexSeq) enables direct quantification of low-frequency mutations and offers tremendous potential for chemical mutagenicity assessment. We investigated the utility of DuplexSeq to quantify induced mutation frequency (MF) and spectrum in human lymphoblastoid TK6 cells exposed to a prototypical DNA alkylating agent,N-ethyl-N-nitrosourea (ENU). Furthermore, we explored appropriate experimental parameters for this application, and assessed inter-laboratory reproducibility. In two independent experiments in two laboratories, TK6 cells were exposed to ENU (25-200 µM) and DNA was sequenced 48, 72, and 96 h post-exposure. A DuplexSeq mutagenicity panel targeting twenty 2.4-kb regions distributed across the genome was used to sample diverse, genome-representative sequence contexts. A robust increase in MF that was unaffected by time was observed in both laboratories. Concentration-response in the MF from the two laboratories was strongly positively correlated (R2=0.95). C:G>T:A, T:A>C:G, T:A>A:T, and T:A>G:C mutations increased in consistent, concentration-dependent manners in both laboratories, with high proportions of C:G>T:A at all time points. The target sites responded similarly between the two laboratories and revealed a higher average MF in intergenic regions. These results, demonstrating remarkable reproducibility across time and laboratory for both MF and spectrum, support the high value of DuplexSeq for characterizing chemical mutagenicity in both research and regulatory evaluation.