bluuebunny/crossref_metadata_2025_split huggingface dataset:
ENCoDE – a skin tone and clinical dataset from a prospective trial on acute care patients
Authors: Hao Sicheng , Matos Joao , Dempsey Katelyn , Alwakeel Mahmoud , Houghtaling Jared , Hong Chuan , Gichoya Judy , Kibbe Warren , Pencina Michael , Cox Christopher E. , Ian Wong A. 
Published: August 2024

AbstractBackgroundAlthough hypothesized to be the root cause of the pulse oximetry disparities, skin tone and its use for improving medical therapies have yet to be extensively studied. Studies previously used self-reported race as a proxy variable for skin tone. However, this approach cannot account for skin tone variability within race groups and also risks the potential to be confounded by other non-biological factors when modeling data. Therefore, to better evaluate health disparities associated with pulse oximetry, this study aimed to create a unique baseline dataset that included skin tone and electronic health record (EHR) data.MethodsPatients admitted to Duke University Hospital were eligible if they had at least one pulse oximetry value recorded within 5 minutes before an arterial blood gas (ABG) value. We collected skin tone data at 16 different body locations using multiple devices, including administered visual scales, colorimetric, spectrophotometric, and photography via mobile phone cameras. All patients’ data were linked in Duke’s Protected Analytics Computational Environment (PACE), converted into a common data model, and then de-identified before publication in PhysioNet.ResultsSkin tone data were collected from 128 patients. We assessed 167 features per skin location on each patient. We also collected over 2000 images from mobile phones measured in the same controlled environment. Skin tone data are linked with patients’ EHR data, such as laboratory data, vital sign recordings, and demographic information.ConclusionsMeasuring different aspects of skin tone for each of the sixteen body locations and linking them with patients’ EHR data could assist in the development of a more equitable AI model to combat disparities in healthcare associated with skin tone. A common data model format enables easy data federation with similar data from other sources, facilitating multicenter research on skin tone in healthcare.DescriptionA prospectively collected EHR-linked skin tone measurements database in a common data model with emphasis on pulse oximetry disparities.
Transferability of polygenic risk scores depending on demography and dominance coefficients
Authors: Fohler Leonie , Mayr Andreas , Maj Carlo , Staerk Christian , Klinkhammer Hannah , Krawitz Peter M. 
Published: August 2024

The genetic liability to a complex phenotype is calculated as the sum of genotypes, weighted by effect size estimates derived from summary statistics of genome-wide association study (GWAS) data. Due to different allele frequencies (AF) and linkage disequilibrium (LD) patterns across populations, polygenic risk scores (PRS) that were developed on one population drop drastically in predictive performance when transferred to another. One of the major factors contributing to AF and LD heterogeneity is genetic drift, which acts strongly during population bottlenecks and is influenced by the dominance of certain alleles. In particular, since the causal variants on empirical data are typically not known, the presence of population specific LD-patterns will strongly affect transferability of PRS models. In this work, we therefore conducted demographic simulations to investigate the influence of the dominance coefficient on the transferability of PRS among European, African and Asian populations. By modifying the length and size of the bottleneck leading to the split of Eurasian and African populations, we gain a deeper understanding of the underlying dynamics. Finally, we illustrate that PRS models that are adapted to the underlying dominance coefficient can substantially increase their prediction performance in out-of-target populations.Significance StatementPolygenic risk scores (PRS) are increasingly used in clinical care for the management of many complex disorders such as breast cancer or cardiovascular diseases. Since heritability should be independent of ancestry so should be the predictability of the models. This is, however, currently not the case and the missing transferability of PRS is favoring individuals from European descent, who represent the largest population to train PRS. In this work we study on simulated populations what degree of transferability is theoretically achievable under different demographic models and dominance coefficients of the pathogenic variants. The results of our work are twofold: the effect of genetic drift and selection on the transferability can be quantified in simulations and recessive traits are more conserved.
Incidence of cardiovascular-kidney-metabolic syndrome and its risk factors for progression in China
Authors: Chen Aomiao , He Qiuyu , Wu Yichuan , Chen Jiaqi , Ma Xiaoqin , Wang Geningyue , Hu Lingyuan , Wang Zhuotong , Huang Jinming , Xie Xinran , Xue Yaoming , Zheng Zongji , Jia Yijie 
Published: August 2024

AbstractBackgroundCardiovascular-kidney-metabolic syndrome (CKM syndrome) has become one of the leading causes of death. However, its prevalence and factors associated with its progression are unknown. In this study, we investigate the incidence of CKM syndrome in middle-aged and elderly individuals, identify the risk factors for CKM syndrome progression via 4 years of follow-up data, explore CKM syndrome prevalence and identify prevention strategies.MethodsThis was a retrospective cohort study using China Health and Retirement Longitudinal Study (CHARLS) data with a four-year follow-up period (2011--2015), which is a multilevel complex sampling design survey of the Chinese population used to represent the national population. We retrospectively included 4821 participants (27.2% of all participants, mean age = 58 years, 54.1% were female) with sufficient CKM indicator data from CHARLS. We investigated the incidence and progression of CKM syndrome in Chinese adults by building a multivariate logistic regression model to analyze the additional risk factors for CKM progression, focusing on the potential social determinants of health (SDOHs).ResultsIn the baseline survey, after weighting, the proportions of patients with stages 0-4 CKM syndrome were 10.5%, 17.0%, 46.3%, 12.1%, and 14.1%, respectively. During the 4-year follow-up, 27.20% of patients experienced CKM deteriorated. A higher CRP (OR =1.55, 95% CI: 1.06-2.28, P = 0.02), Chinese visceral obesity index (CVAI) (OR = 1.81, 95% CI: 1.31-2.52, P < 0.001), and conicity index (CI) (OR = 1.34, 95% CI: 1.01-1.79, P = 0.04) were identified as risk factors for CKM deterioration.ConclusionCKM syndrome incidence is extremely high in middle-aged and elderly people in China, with rapid and severe progression. Additional risk factors and predictive indications related to the staged progression of CKM syndrome should be actively explored to achieve the slowing and reversal of CKM syndrome deterioration.Key PointsThis cohort study investigated the prevalence of CKM syndrome and explored the factors related to its progression and recovery.QuestionWhat is the prevalence of CKM syndrome, and what factors affect its progression?FindingsIn this cohort study of 4821 participants with 4 years of follow-up, a high incidence of CKM syndrome and a high risk of CKM deterioration were observed in the Chinese middle-aged and elderly population.MeaningThe findings of this study support the recommendations of the AHA that additional risk factors and predictive indicators for the progression of CKM should be actively explored.
Coevolving Residues Distant from the Ligand Binding Site are Involved in GAF Domain Function
Authors: Ahmed Wesam S. , Geethakumari Anupriya M , Sultana Asfia , Tiwari Anmol , Altamash Tausif , Arshad Najla , Visweswariah Sandhya S , Biswas Kabir H 
Published: August 2024

AbstractLigand binding to GAF domains regulates the activity of associated catalytic domains in a wide variety of proteins. For instance, cGMP binding to the GAFa domain of phosphodiesterase 5 (PDE5) activates the cGMP-hydrolyzing catalytic domain in the protein. However, the residues involved and the mechanism of GAF domain function are not entirely clear. Here, combining computational and experimental analysis, we show that two highly coevolving residues distant from the ligand binding site play a critical role in GAF domain allostery. Specifically, Statistical Coupling Analysis (SCA) of GAF domain sequences revealed the highest coevolution score for residues L267 and F295. Molecular dynamics (MD) simulations of both apo and holo forms of the wild type and mutant (L267A and F295A) PDE5 GAFa domains revealed significant alterations in structural dynamics and interaction with cGMP. Incorporation of the mutations in a Bioluminescence Resonance Energy Transfer (BRET)-based biosensor, which reports a ligand-induced conformational change, revealed a change in the conformation of the GAF domain and an increase in the EC50of cGMP-induced conformational change. Similar results were obtained regarding cGMP-induced conformational change in the full-length PDE5 and in the fluorescence of the GAF domain fluorescent protein, miRFP670nano3. Finally, structural analysis of conformers observed in MD simulations revealed a possible mechanism underlying the impact of mutations of these two coevolving residues in the PDE5 GAFa domain. Our results provide insight into the role of distant, coevolving residues in GAF domain allostery, and may aid in understanding evolution of allostery in proteins.
Adenosine signaling in glia modulates metabolic state-dependent behavior inDrosophila
Authors: Backer Jean-François De , Karges Thomas , Papst Julia , Coman Cristina , Ahrends Robert , Xu Yanjun , García-Cáceres Cristina , Grunwald Kadow Ilona C. 
Published: August 2024

SummaryAn animal’s metabolic state strongly influences its behavior. Hungry animals prioritize food seeking and feeding behaviors, while sated animals suppress these behaviors to engage in other activities. Additionally, neuronal activity and synaptic transmission are among the most energy expensive processes. Yet neurons do not uptake nutrients from the circulation. Instead, glia fulfill this highly evolutionary conserved function. Recent studies have shown that glia can modulate neuronal activity and behavior. However, how different glia subtypes sense metabolic state and modulate neurons and behavior is incompletely understood. Here, we unravel two types of glia-mediated modulation of metabolic state-dependent behavior. In food-deprived flies, astrocyte-like and perineurial glia promote foraging and feeding, respectively, while cortex glia suppress these behaviors. We further show that adenosine and adenosine receptor modulate intracellular calcium levels in these glia subtypes, which ultimately controls behavior. This study reveals a new mechanism how different glia subtypes sense the metabolic state of the animal and modulate its behavior accordingly.
Genomic sequencing to detect cross-breeding quality in dogs: an example studying disorders in sexual development
Authors: de Gennaro Luciana , Burgio Matteo , Lacalandra Giovanni Michele , Petronella Francesco , L’Abbate Alberto , Ravasini Francesco , Trombetta Beniamino , Rizzo Annalisa , Ventura Mario , Cicirelli Vincenzo 
Published: August 2024

AbstractBackgroundDisorders of Sexual Development (DSD) in dogs, similar to humans, arise from irregularities in genetic determinants, gonadal differentiation, or phenotypic sex development. The French Bulldog, a breed that has seen a surge in popularity and demand, has also shown a marked increase in DSD incidence. This study aims to characterize the genetic underpinnings of DSD in a French Bulldog named Brutus, exhibiting ambiguous genitalia and internal sexual anatomy, and to explore the impact of breeding practices on genetic diversity within the breed.MethodsWe utilized a comprehensive approach combining conventional cytogenetics, molecular techniques, and deep sequencing to investigate the genetic profile of Brutus. The sequence data were compared to three other male French Bulldogs genome sequences with typical reproductive anatomy, including Brutus’s father, and the canine reference genome (CanFam6).FindingsOur findings revealed a 22% mosaicism (78, XX/77, XX), the absence of the SRY gene, and the presence of 43 unique Single Nucleotide Variants (SNVs) not inherited from the father. Notably, the Run of Homozygosity (ROH) analysis showed Brutus has a significantly higher number of homozygous segments compared to other Bulldogs, with a total length of these fragments 50% greater than the average, strongly suggesting this dog is the product of the mating between siblings. While no direct causative genes for the DSD phenotype were identified four candidate loci warranting further investigation were highlighted.ConclusionsOur study highlighted the need for a better annotated and curated reference dog genome to define genes causative of any specific phenotype, suggests a potential genetic basis for the DSD phenotype in dogs, and underscores the consequences of uncontrolled breeding practices in French Bulldogs. These findings highlight the importance of implementing strategic genetic management to preserve genetic health and diversity in canine populations.
Extensively acquired antimicrobial resistant bacteria restructure the individual microbial community in post-antibiotic conditions
Authors: Baek Jae Woo , Lim Songwon , Park Nayeon , Song Byeongsop , Kirtipal Nikhil , Nielsen Jens , Mardinoglu Adil , Shoaie Saeed , Kim Jae-il , Son Jang Won , Koh Ara , Lee Sunjae 
Published: August 2024

AbstractIn recent years, the overuse of antibiotics has led to the emergence of antimicrobial resistant (AMR) bacteria. To evaluate the spread of AMR bacteria, the reservoir of AMR genes (resistome) has traditionally been identified from environmental samples, hospital environments, and human populations; however, the functional role of AMR bacteria in the human gut microbiome and their persistency within individuals has not been fully investigated. Here, we performed a strain-resolved in-depth analysis of the resistome changes by reconstructing a large number of metagenome-assembled genomes (MAGs) of antibiotics- treated individual’s gut microbiome. Interestingly, we identified two bacterial populations with different resistome profiles, extensively acquired antimicrobial resistant bacteria (EARB) and sporadically acquired antimicrobial resistant bacteria (SARB), and found that EARB showed broader drug resistance and a significant functional role in shaping individual microbiome composition after antibiotic treatment. Furthermore, longitudinal strain analysis revealed that EARB bacteria were inherently carried by individuals and can reemerge through strain switching in the human gut microbiome. Our data on the presence of AMR bacteria in the human gut microbiome provides a new avenue for controlling the spread of AMR bacteria in the human community.
Transposable elements impact the human regulatory landscape through cell type specific epigenomic associations
Authors: Hyacinthe Jeffrey , Bourque Guillaume 
Published: August 2024

AbstractTransposable elements (TEs) are DNA sequences able to create copies of themselves within the genome. Despite their limited expression due to silencing, TEs still manage to impact the host genome. For instance, some TEs have been shown to act as cis-regulatory elements and be co-opted in the human genome. This highlights that the contributions of TEs to the host might come from their relationship with the epigenome rather than their expression. However, a systematic analysis that relates TEs in the human genome directly with chromatin histone marks across distinct cell types remains lacking. Here we leverage a new dataset from the International Human Epigenome Consortium with 4867 uniformly processed ChIP-seq experiments for 6 histone marks across 175 annotated cell labels and show that TEs have drastically different enrichments levels across marks. Overall, we find that TEs are generally depleted in H3K9me3 histone modification, except for L1s, while MIRs were highly enriched in H3K4me1, H3K27ac and H3K27me3 and Alus were enriched in H3K36me3. Furthermore, we present a generalised profile of the relationship between TEs enrichment and TE age which reveals a few TE families (Alu, MIR, L2) as diverging from expected dynamics. We also find significant differences in TE enrichment between cell types and that in 20% of the cases, these enrichments were cell-type specific. Moreover, we report that at least 4% of cell types-histone-TE combinations featured significant differences in enrichment between healthy and cancer samples. Notably, we identify 456 cell type-histone-TE triplets with strong cell-type specific enrichments. We show that many of these triplets are associated with relevant biological processes and genes expressed in the relevant cell type. These results further support a role for TE in genome regulation and highlight novel associations between TEs and histone marks across cell types.
Canonical and non-canonical PRC1 differentially contribute to the regulation of neural stem cell fate
Authors: Hoffmann Janine , Schütze Theresa M. , Kolodziejczyk Annika , Kränkel Annekathrin , Reinhardt Susanne , Derihaci Razvan P. , Birdir Cahit , Wimberger Pauline , Koseki Haruhiko , Albert Mareike 
Published: August 2024

AbstractNeocortex development is characterized by sequential phases of neural progenitor cell (NPC) expansion, neurogenesis and gliogenesis. Polycomb-mediated epigenetic mechanisms are known to play important roles in regulating the lineage potential of NPCs during development. The composition of Polycomb Repressive Complex 1 (PRC1) is highly diverse in mammals and was hypothesized to contribute to context-specific regulation of cell fate. Here, we have performed side-by-side comparison of the role of canonical PRC1.2/1.4 and non-canonical PRC1.3/1.5, all of which are expressed in the developing neocortex, in NSC proliferation and differentiation. We found that the deletion ofPcgf2/4in NSCs led to a strong reduction in proliferation and to altered lineage fate, both during the neurogenic and gliogenic phase, whereasPcgf3/5played a minor role. Mechanistically, genes encoding stem cell and neurogenic factors were bound by PRC1 and differentially expressed uponPcgf2/4deletion. Thus, rather than different PRC1 sub-complexes contributing to different phases of neural development, we found that canonical PRC1 played a more significant role in NSC regulation during proliferative, neurogenic and gliogenic phases compared to non-canonical PRC1.
Latent generative modeling of long genetic sequences with GANs
Authors: Szatkownik Antoine , Furtlehner Cyril , Charpiat Guillaume , Yelmen Burak , Jay Flora 
Published: August 2024

AbstractSynthetic data generation via generative modeling has recently become a prominent research field in genomics, with applications ranging from functional sequence design to high-quality, privacy-preserving artificial in silico genomes. Following a body of work on Artificial Genomes (AGs) created via various generative models trained with raw genomic input, we propose a conceptually different approach to address the issues of scalability and complexity of genomic data generation in very high dimensions. Our method combines dimensionality reduction, achieved by Principal Component Analysis (PCA), and a Generative Adversarial Network (GAN) learning in this reduced space. Using this framework, we generated genomic proxy datasets for very diverse human populations around the world. We compared the quality of AGs generated by our approach with AGs generated by the established models and report improvements in capturing population structure, linkage disequilibrium, and metrics related to privacy leakage. Furthermore, we developed a frugal model with orders of magnitude fewer parameters and comparable performance to larger models. For quality assessment, we also implemented a new evaluation metric based on information theory to measure local haplotypic diversity, showing that generative models yield higher diversity than real genomes. In addition, we addressed the shrinkage issue associated with PCA and generative modeling, examined its relation to the nearest neighbor resemblance metric, and proposed a resolution. Finally, we evaluated the effect of different binarization methods on the quality of the output AGs.
Repetition effects reveal the sub-sequence representation of actions
Authors: Shahbazi Mahdiyar , Pruszynski J. Andrew , Diedrichsen Jörn 
Published: August 2024

AbstractWhen a movement sequence is repeated, the second execution is faster than the first. This demonstrates that the brain retains some trace of the just-executed sequence, the earliest form of sequence memory. Currently, it is unclear whether this memory trace is represented at the level of (a) transitions between movements, (b) chunks of multiple movements, or (c) the entire sequence. To answer this question, we instructed human participants to generate sequences of 11 finger presses in a delayed response paradigm. From one trial to the next, segments of variable length (1, 2, 4, 6, 11) could be repeated from the previous trial. We observed that repetition benefits appeared when a segment of 4 consecutive finger presses or longer was repeated from the previous trial. This suggests that the benefit of repetition is not merely the sum of improvements in individual transitions, nor does it require the entire sequence to be repeated. The repetition benefit was small for the first transition of a repeated segment and increased with additional repetitions. This suggests that the memory supporting the repetition effect is mainly activated when a series of past movements matches the memory trace. Planned future movements had less of an effect on the repetition effect. Our results provide insight into the structure of the earliest memory traces for motor sequences.Significance StatementMany motor skills involve concatenating single movements into complex sequences. Already after a single execution of a sequence, humans retain a memory trace that accelerates the execution of the sequence if it is repeated in the next trial. Our results show a repetition benefit even when only a small portion of movements from the previous trial is repeated, suggesting that full sequence repetition is not necessary. Detailed analyses indicate that the memory trace is activated when the last 2-3 movements match the current execution. Our work, therefore, sheds light on the structure of the earliest sequence memory and will interest researchers studying motor skill learning and the neural basis of movement control.
The synaptonemal complex aligns meiotic chromosomes by wetting
Authors: Gordon Spencer G. , Rodriguez Alyssa A. , Gu Yajie , Corbett Kevin D. , Lee Chiu Fan , Rog Ofer 
Published: August 2024

AbstractDuring meiosis, the parental chromosomes are drawn together to enable exchange of genetic information. Chromosomes are aligned through the assembly of a conserved interface, the synaptonemal complex, composed of a central region that forms between two parallel chromosomal backbones called axes. Here we identify the axis-central region interface inC. elegans, containing a conserved positive patch on the axis component HIM-3 and the C-terminus of the central region protein SYP-5. Crucially, the canonical ultrastructure of the synaptonemal complex is altered upon weakening this interface. We developed a thermodynamic model that recapitulates our experimental observations, indicating that the liquid-like central region can assemble by wetting the axes without active energy consumption. More broadly, our data show that condensation drives tightly regulated nuclear reorganization during sexual reproduction.