bluuebunny/crossref_metadata_2025_split huggingface dataset:
An avidity-driven mechanism of extracellular BMP regulation by Twisted gastrulation
Authors: Moore Gareth , Revici Raluca , Forbes Beadle Lauren , Birchenough Holly , Baldock Clair , Ashe Hilary L 
Published: July 2024

AbstractBone Morphogenetic Protein (BMP) signalling is tightly regulated extracellularly by specific protein-protein interactions. During dorsoventral patterning of vertebrate and invertebrate embryos, the conserved regulator Twisted gastrulation (Tsg) precisely modulates BMP signalling by binding Chordin/Short gastrulation (Sog) to promote formation of the inhibitory Tsg-Sog/Chordin-BMP ternary complex. Here we elucidate the mechanism by which Tsg interacts with Sog/Chordin to modulate BMP signalling extracellularly. Using AlphaFold predictions, we identify a Chordin binding epitope in the Tsg C-terminal domain, which we validate usingin vitrobinding studies with targeted point mutants. Introduction of the equivalent point mutation intoDrosophilaTsg, to disrupt Tsg-Sog interaction, results in an unexpectedly mild perturbation to embryonic dorsoventral patterningin vivo, in the form of a shallower BMP gradient. Using binding assays, we provide a molecular explanation for this mild phenotype by showing that the BMP ligand can partially rescue ternary complex formation when the Tsg-Sog interaction is disrupted. Additionally, we show that an evolutionary divergent Tsg C-terminal extension is essential for full Tsg function inDrosophilaembryos. Based on these findings we propose that Tsg promotes formation of a Tsg-Sog/Chordin-BMP complex by an avidity-driven mechanism, which will be relevant to a broad range of developmental contexts.
Proteomic Aging Clocks and the Risk of Mortality among Longer-Term Cancer Survivors in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Wang Shuo , Rao Zexi , Blaes Anne H. , Coresh Josef , Joshu Corinne E. , Pankow James S. , Thyagarajan Bharat , Ganz Peter , Guan Weihua , Platz Elizabeth A. , Prizment Anna 
Published: July 2024

AbstractBackgroundWe constructed a new proteomic aging clock (PAC) and computed the published Lehallier’s PAC to estimate biological age. We tested PACs’ associations with mortality in longer-term cancer survivors and cancer-free participants.MethodsARIC measured 4,712 proteins using SomaScan in plasma samples collected at multiple visits, including Visit 5 (2011-13), from 806 cancer survivors and 3,699 cancer-free participants (aged 66-90). In the training set (N=2,466 randomly selected cancer-free participants), we developed the new PAC using elastic net regression and computed Lehallier’s PAC. Age acceleration was calculated as residuals after regressing each PAC on chronological age after excluding the training set. We used multivariable-adjusted Cox proportional hazards regression to examine the associations of age acceleration with all-cause, cardiovascular disease (CVD), and cancer mortality.ResultsBoth PACs were correlated with chronological age [r=0.70-0.75]. Age acceleration for these two PACs was similarly associated with all-cause mortality in cancer survivors [hazard ratios (HRs) per 1 SD=1.40-1.42, p<0.01]. The associations with all-cause mortality were similar in cancer survivors and cancer-free participants for both PACs [p-interactions=0.20-0.62]. There were also associations with all-cause mortality in breast cancer survivors for both PACs [HRs=1.54-1.72, p<0.01] and colorectal cancer survivors for the new PAC [HR=1.96, p=0.03]. Additionally, the new PAC was associated with cancer mortality in all cancer survivors. Finally, HRs=1.42-1.61 [p<0.01] for CVD mortality in cancer-free participants for two PACs but the association was insignificant in cancer survivors perhaps due to a limited number of outcomes.ConclusionPACs hold promise as potential biomarkers for premature mortality in cancer survivors.
Correlation between Mid-Upper Arm Circumference and Body Mass Index in the assessment of adults’ nutritional status in Malawi
Authors: Mzumara Thokozani , Lubanga Adriano Focus , Afonne Joseph , Munthali George , Kaonga Byenala , Harawa Gracian , Bwanali Akim Nelson 
Published: July 2024

ABSTRACTBackgroundBody Mass Index (BMI) is a widely used and accepted indicator of nutritional status in adults. Mid-Upper-Arm-Circumference (MUAC) is another anthropometric measure used primarily among children. While BMI remains the best indicator of nutritional status, it can sometimes be impractical because of logistical requirements for weight and height measurement, especially for large population-based studies and bed-ridden patients. Therefore, we analyzed anthropometric data collected from the Malawi Epidemiology and Intervention Research Unit (MEIRU) Non-Communicable Disease (NCD) survey to determine the correlation between BMI and MUAC in the assessment of adult nutritional status in Malawi.MethodsA secondary data analysis utilizing descriptive and correlational statistical research methods was used to determine the relationship between BMI and MUAC in the assessment of adults’ nutritional status in Malawi. The data was analyzed using SPSS version 27. The independent t test and Chi-square were employed. Furthermore, the study included the Pearson correlation test to assess the relationship between variables. A p-value of <0.05 was considered statistically significant.ResultsThe study assessed 30,575 participants, of whom the majority (61.8%) were females. The mean MUAC was 27.2 (SD = 3.300), and the mean BMI was 23.5 (SD = 4.55). The study found a strong positive statistically significant correlation between MUAC and BMI among Malawians (r = 0.836, CI = (0.832-0.839) such that for each additional centimeter increase in MUAC, BMI is expected to increase by approximately 1.153 units (BMI = -7.797 + 1.153 (MUAC)). There was a significant positive correlation between BMI and MUAC in both males and females and in rural and urban residents (P<0.01). The ROC curve was excellent for BMI in the overweight range (AUC = 0.87), and the findings were superior in the obese range (AUC = 0.956).ConclusionThe correlation between MUAC and BMI is positive regardless of sex or rural/urban residence. Therefore, the MUAC can be used as a clinical test to predict BMI.
Machine-Learning based Prediction Models for Healthcare Outcomes in Patients Participating in Cardiac Rehabilitation: A Systematic Review
Authors: Tieliwaerdi Xiarepati , Manalo Kathryn , Abuduweili Abulikemu , Khan Sana , Appiah-kubi Edmund , Oehler Andrew 
Published: July 2024

AbstractPurposeCR has been proven to reduce mortality and morbidity in patients with CVD. ML techniques are increasingly used to predict healthcare outcomes in various fields of medicine including CR. This systemic review aims to perform critical appraisal of existing ML based prognosis predictive model within CR and identify key research gaps in this area.Review methodsA systematic literature search was conducted in Scopus, PubMed, Web of Science and Google Scholar from the inception of each database to 28th January 2024. The data extracted included clinical features, predicted outcomes, model development and validation as well as model performance metrics. Included studies underwent quality assessments using the IJMEDI.Summary22 ML-based clinical models from 7 studies across multiple phases of CR were included. Most models were developed using smaller patient cohorts from 41 to 227, with one exception involving 2280 patients. The prediction objectives ranged from patient intention to initiate CR to graduate from outpatient CR along with interval physiological and psychological response to CR. The best-performing ML models reported AUC between 0.82 and 0.91, sensitivity from 0.77 to 0.95, indicating good prediction capabilities. However, none of them underwent calibration or external validation. Most studies raised concerns for bias. Readiness of these models for implement into practice is questionable. External validation of existing models and development of new models with robust methodology based on larger populations and targeting diverse clinical overcomes in CR are needed.
Developing a natural language processing system using transformer-based models for adverse drug event detection in electronic health records
Authors: Wu Jingyuan , Ruan Xiaodi , McNeer Elizabeth , Rossow Katelyn M. , Choi Leena 
Published: July 2024

ABSTRACTObjectiveTo develop a transformer-based natural language processing (NLP) system for detecting adverse drug events (ADEs) from clinical notes in electronic health records (EHRs).Materials and MethodsWe fine-tuned BERT Short-Formers and Clinical-Longformer using the processed dataset of the 2018 National NLP Clinical Challenges (n2c2) shared task Track 2. We investigated two data processing methods, window-based and split-based approaches, to find an optimal processing method. We evaluated the generalization capabilities on a dataset extracted from Vanderbilt University Medical Center (VUMC) EHRs.ResultsOn the n2c2 dataset, the best average macro F-scores of 0.832 and 0.868 were achieved using a 15-word window with PubMedBERT and a 10-chunk split with Clinical-Longformer. On the VUMC dataset, the best average macro F-scores of 0.720 and 0.786 were achieved using a 4-chunk split with PubMedBERT and Clinical-Longformer.DiscussionOur study provided a comparative analysis of data processing methods. The fine-tuned transformer models showed good performance for ADE-related tasks. Especially, Clinical-Longformer model with split-based approach had a great potential for practical implementation of ADE detection. While the token limit was crucial, the chunk size also significantly influenced model performance, even when the text length was within the token limit.ConclusionWe provided guidance on model development, including data processing methods for ADE detection from clinical notes using transformer-based models. Our results on two datasets indicated that data processing methods and models should be carefully selected based on the type of clinical notes and the allocation trade-offs of human and computational power in annotation and model fine-tuning.
High incidence and geographic distribution of cleft palate cases in Finland are associated with a regulatory variant inIRF6
Authors: Rahimov Fedik , Nieminen Pekka , Kumari Priyanka , Juuri Emma , Nikopensius Tiit , Paraiso Kitt , German Jakob , Karvanen Antti , Kals Mart , Elnahas Abdelrahman G. , Karjalainen Juha , Kurki Mitja , Palotie Aarno ,   FinnGen, Estonian Biobank Research Team, Heliövaara Arja , Esko Tõnu , Jukarainen Sakari , Palta Priit , Ganna Andrea , Patni Anjali P. , Mar Daniel , Bomsztyk Karol , Mathieu Julie , Ruohola-Baker Hannele , Visel Axel , Fakhouri Walid D. , Schutte Brian C. , Cornell Robert A. , Rice David P. 
Published: July 2024

AbstractIn Finland the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We performed a genome-wide association study for orofacial clefts, which include CL/P and CP, in the Finnish population. We identified rs570516915, a single nucleotide polymorphism that is highly enriched in Finns and Estonians, as being strongly associated with CP (P= 5.25 × 10−34, OR = 8.65, 95% CI 6.11–12.25), but not with CL/P (P= 7.2 × 10−5), with genome-wide significance. The risk allele frequency of rs570516915 parallels the regional variation of CP prevalence in Finland, and the association was replicated in independent cohorts of CP cases from Finland (P= 8.82 × 10−28) and Estonia (P= 1.25 × 10−5). The risk allele of rs570516915 disrupts a conserved binding site for the transcription factor IRF6 within a previously characterized enhancer upstream of theIRF6gene. Through reporter assay experiments we found that the risk allele of rs570516915 diminishes the enhancer activity. Oral epithelial cells derived from CRISPR-Cas9 edited induced pluripotent stem cells demonstrate that the CP-associated allele of rs570516915 concomitantly decreases the binding of IRF6 and the expression level ofIRF6, suggesting impairedIRF6autoregulation as a molecular mechanism underlying the risk for CP.
Rapid loss of genetic variation and increased inbreeding in small and isolated populations of Norwegian wild reindeer
Authors: Hansen Brage B. , Peeters Bart , Flagstad Øystein , Røed Knut , Martin Michael D. , Jensen Henrik , Burnett Hamish A. , Bieker Vanessa C. , Mysterud Atle , Sun Xin , Côté Steeve D. , Robert Claude , Rolandsen Christer M. , Strand Olav 
Published: July 2024

AbstractWildlife responses to habitat loss and fragmentation are a central concern in the management and conservation of biodiversity. Small and isolated populations are vulnerable, both due to demographic and genetic mechanisms, which are often linked. Thus, understanding how (changes in) genetic diversity, effective population sizes, and levels of inbreeding relate to population size and degree of isolation is key for developing effective conservation strategies. High-density Single Nucleotide Polymorphism (SNP) arrays represent an increasingly cost-efficient tool to achieve the data needed for such analysis. Here, we present the development of a novel 625k SNP array for reindeerRangifer tarandusand apply this array to assess conservation genetic issues across thirteen Norwegian wild reindeer populations of varying size, isolation, and genetic origin (i.e., semi-domesticated reindeer origin or a mix of wild reindeer and semi-domesticated reindeer origins). Many of these populations are currently completely isolated, with no gene flow from other populations. We genotyped n = 510 individuals sampled by hunters and found that variation in population size across the populations largely predicted their (recent loss of) genetic variation (observed heterozygosity, Ho), as well as effective population size (Ne) and (change in) level of recent inbreeding. For the smallest and most isolated populations, with total population sizes of <50-100 individuals and a high and increasing level of recent inbreeding, estimated loss of genetic variation was as high as 3-10% over the time span of a generation or less, and estimated Newas as low as six individuals. With the current level of isolation and associated lack of gene flow, and considering their already low genetic diversity, these populations are hardly viable – neither demographically nor genetically – in the long term. These results have direct relevance for the management of Norwegian wild reindeer, recently red-listed as ‘Near Threatened’. Yet, these genetic challenges, characterizing many of the small ‘wild reindeer’ populations in Norway, have been largely ignored by management thus far. Mitigation efforts such as reducing barriers would introduce substantial conservation dilemma due to the aim of avoiding further spread of chronic wasting disease (CWD), as well as potential further domestic introgression into populations with genetically wild reindeer (or mixed) origin. Nevertheless, our cost-efficient and high-density SNP array especially designed for reindeer and caribou offers a powerful genetic tool to include in future monitoring, providing important contributions to management and conservation decisions.
Spatial transcriptomics unveils landscape of resistance to concurrent chemo-radiotherapy in hypopharyngeal squamous cell carcinoma: the role ofSPP1+macrophages
Authors: Ohn Jungyoon , Bae Sungwoo , Choi Hongyoon , Kim In Gul , Na Kwon Joong , Chung Eun-Jae 
Published: July 2024

AbstractHypopharyngeal squamous cell carcinoma (SCC) is a highly aggressive cancer with a poor prognosis, particularly in advanced stages where concurrent chemoradiotherapy (CCRT) is used for treatment. However, resistance to CCRT poses a significant challenge, often leading to treatment failure and disease progression. This study explores the tumor microenvironment (TME) of hypopharyngeal SCC to understand the molecular mechanisms underlying CCRT resistance. Using spatial transcriptomics (ST), we analyzed tissue samples from patients with locally advanced hypopharyngeal SCC, distinguishing between those who were CCRT-resistant and those who were CCRT-naive. The analysis revealed six distinct cellular clusters within the TME, including a prominent epithelio-immune cellular area in CCRT-resistant tissues. SPP1 was identified as a key gene with significantly higher expression in CCRT-resistant samples, specifically within macrophages. Further investigation showed that SPP1+ macrophages interacted with malignant epithelial cells through SPP1-CD44 and SPP1-ITGB1 ligand-receptor pairs. These interactions were primarily localized in the peri-tumoral and intra-tumoral regions, highlighting their potential role in driving CCRT resistance. Our findings suggest that SPP1+ macrophages contribute to the resistant phenotype in hypopharyngeal SCC by modulating the TME and interacting with cancer cells. Understanding these interactions offers valuable insights into the mechanisms of CCRT resistance and may inform the development of targeted therapies to improve patient outcomes.
Age-dependent predictors of effective reinforcement motor learning across childhood
Authors: Hill Nayo M. , Tripp Haley M. , Wolpert Daniel M. , Malone Laura A. , Bastian Amy J. 
Published: July 2024

AbstractAcross development, children must learn motor skills such as eating with a spoon and drawing with a crayon. Reinforcement learning, driven by success and failure, is fundamental to such sensorimotor learning. It typically requires a child to explore movement options along a continuum (grip location on a crayon) and learn from probabilistic rewards (whether the crayon draws or breaks). Here, we studied the development of reinforcement motor learning using online motor tasks to engage children aged 3 to 17 and adults (cross-sectional sample, N=385). Participants moved a cartoon penguin across a scene and were rewarded (animated cartoon clip) based on their final movement position. Learning followed a clear developmental trajectory when participants could choose to move anywhere along a continuum and the reward probability depended on final movement position. Learning was incomplete or absent in 3 to 8-year-olds and gradually improved to adult-like levels by adolescence. A reinforcement learning model fit to each participant identified three age-dependent factors underlying improvement: amount of exploration after a failed movement, learning rate, and level of motor noise. We predicted, and confirmed, that switching to discrete targets and deterministic reward would improve 3 to 8-year-olds’ learning to adult-like levels by increasing exploration after failed movements. Overall, we show a robust developmental trajectory of reinforcement motor learning abilities under ecologically relevant conditions i.e., continuous movement options mapped to probabilistic reward. This learning appears to be limited by immature spatial processing and probabilistic reasoning abilities in young children and can be rescued by reducing the demands in these domains.
Lacticaseibacillus rhamnosusP118 enhances host tolerance toSalmonellainfection by promoting microbe-derived indole metabolites
Authors: Wang Baikui , Peng Xianqi , Zhou Xiao , Jin Xiuyan , Siddique Abubakar , Yao Jiayun , Zhang Haiqi , Li Weifen , Li Yan , Yue Min 
Published: July 2024

AbstractSalmonellais one of the most common foodborne pathogens, resulting in inflammatory gastroenteritis and frequently accompanied by dysbiosis. Gut commensals, such asLactobacillusspecies, have been proven to exhibit broad anti-bacterial activities and protect hosts against pathogenic infections. Here,Lacticaseibacillus rhamnosusstrain P118, screened from 290 isolates recovered from fermented yoghurts and healthy piglet intestines using traditional andC. elegans-infection screening strategies, exerts great probiotic properties. Notably, P118 and its supernatant exhibited great antibacterial activities and attenuatedCaenorhabditis eleganssusceptibility toSalmonellainfection. We found that P118 protected mice againstSalmonellalethal infections by enhancing colonization resistance, reducing pathogen invasion, alleviating intestinal pro-inflammatory response, and improving microbial dysbiosis and fecal metabolite changes. Microbiota and fecal metabolome analyses suggested P118 administration significantly decreased the relative abundances of potentially harmful microbes (e.g.,Salmonella,Anaeroplasma,Klebsiella) and increased the fecal levels of tryptophan and its derivatives (indole, indole-3-acrylic acid, 5-hydroxytryptophan, 5-methoxyindoleacetate). Deterministic processes determined the gut microbial community assembly of P118-pretreated mice. Integrated omics further demonstrated that P118 probiotic activities in enhancing host tolerance toSalmonellainfection were mediated by microbe-derived tryptophan/indole metabolites (e.g., indole-3-acrylic acid, indole, tryptophan, 5-methoxyindoleacetic acid, and 5-hydroxytryptophan). Collective results demonstrate thatL. rhamnosusP118 could enhance host tolerance toSalmonellainfections via various pathways, including direct antibacterial actions, inhibitingSalmonellacolonization and invasion, attenuating pro-inflammatory responses of intestinal macrophages, and modulating gut microbiota mediated by microbe-derived indole metabolites.
Efficient Genome Editing with Chimeric Oligonucleotide-Directed Editing
Authors: Nguyen Long T. , Rakestraw Noah R. , Pizzano Brianna L.M. , Young Cullen B. , Huang Yujia , Beerensson Kate T. , Fang Anne , Antal Sydney G. , Anamisis Katerina V. , Peggs Coleen M.D. , Yan Jun , Jing Yangwode , Burdine Rebecca D. , Adamson Britt , Toettcher Jared E. , Myhrvold Cameron , Jain Piyush K. 
Published: July 2024

AbstractPrime editing has emerged as a precise and powerful genome editing tool, offering a favorable gene editing profile compared to other Cas9-based approaches. Here we report new nCas9-DNA polymerase fusion proteins to create chimeric oligonucleotide-directed editing (CODE) systems for search-and-replace genome editing. Through successive rounds of engineering, we developed CODEMax and CODEMax(exo+) editors that achieve efficient genome modifications in human cells with low unintended edits. CODEMax and CODEMax(exo+) contain an engineered Bst DNA polymerase derivative known for its robust strand displacement ability. Additionally, CODEMax(exo+) features a 5’ to 3’ exonuclease activity that promotes effective strand invasion and repair outcomes favoring the incorporation of the desired edit. We demonstrate CODEs can perform small insertions, deletions, and substitutions with improved efficiency compared to PEMax at many loci. Overall, CODEs complement existing prime editors to expand the toolbox for genome manipulations without double-stranded breaks.