bluuebunny/crossref_metadata_2025_split huggingface dataset:
PhenoID, a language model normalizer of physical examinations from genetics clinical notes
Authors: Weissenbacher Davy , Rawal Siddharth , Zhao Xinwei , Priestley Jessica R. C. , Szigety Katherine M. , Schmidt Sarah F. , Higgins Mary J. , Magge Arjun , O’Connor Karen , Gonzalez-Hernandez Graciela , Campbell Ian M. 
Published: October 2023

AbstractBackgroundPhenotypes identified during dysmorphology physical examinations are critical to genetic diagnosis and nearly universally documented as free-text in the electronic health record (EHR). Variation in how phenotypes are recorded in free-text makes large-scale computational analysis extremely challenging. Existing natural language processing (NLP) approaches to address phenotype extraction are trained largely on the biomedical literature or on case vignettes rather than actual EHR data.MethodsWe implemented a tailored system at the Children’s Hospital of Philadelpia that allows clinicians to document dysmorphology physical exam findings. From the underlying data, we manually annotated a corpus of 3136 organ system observations using the Human Phenotype Ontology (HPO). We provide this corpus publicly. We trained a transformer based NLP system to identify HPO terms from exam observations. The pipeline includes an extractor, which identifies tokens in the sentence expected to contain an HPO term, and a normalizer, which uses those tokens together with the original observation to determine the specific term mentioned.FindingsWe find that our labeler and normalizer NLP pipeline, which we call PhenoID, achieves state-of-the-art performance for the dysmorphology physical exam phenotype extraction task. PhenoID’s performance on the test set was 0.717, compared to the nearest baseline system (Pheno-Tagger) performance of 0.633. An analysis of our system’s normalization errors shows possible imperfections in the HPO terminology itself but also reveals a lack of semantic understanding by our transformer models.InterpretationTransformers-based NLP models are a promising approach to genetic phenotype extraction and, with recent development of larger pre-trained causal language models, may improve semantic understanding in the future. We believe our results also have direct applicability to more general extraction of medical signs and symptoms.FundingUS National Institutes of Health
A systematic review and meta-analysis of tau phosphorylation in mouse models of familial Alzheimer’s disease
Authors: Kourti Malamati , Metaxas Athanasios 
Published: October 2023

AbstractBackgroundTransgenic models of familial Alzheimer’s disease (AD) serve as valuable tools for probing the molecular mechanisms associated with amyloid-beta (Aβ)-induced pathology. Here, we sought to evaluate the levels of phosphorylated tau (p-tau) protein, and explore potential age-related variations in the hyperphosphorylation of tau, in mouse models of cerebral amyloidosis.MethodsThe PubMed and Scopus databases were searched for studies measuring soluble p-tau in 5xFAD,APPswe/PSEN1de9, J20 and APP23 mice. Data were extracted and analyzed using standardized procedures.ResultsFor the 5xFAD model, the search yielded 36 studies eligible for meta-analysis. Levels of p-tau were higher in 5xFAD mice relative to control, a difference that was evident in both the carboxy-terminal (CT) and proline-rich (PR) domains of tau. Age negatively moderated the effects of genotype on CT domain phosphorylated tau, particularly in studies using hybrid mice, female mice, and preparations from the cortex. For theAPPswe/PSEN1de9model, the search yielded 27 studies. Analysis showed tau hyperphosphorylation in transgenic vs. control animals, evident in both the CT and PR regions of tau. Age positively moderated the effects of genotype on PR domain phosphorylated tau in the cortex ofAPPswe/PSEN1de9mice. A meta-analysis was not performed for the J20 and APP23 models, due to the limited number of studies measuring p-tau levels in these mice (<10 studies).ConclusionsAlthough tau is hyperphosphorylated in both 5xFAD andAPPswe/PSEN1de9mice, the effects of ageing on p-tau are contingent upon the mouse model being examined. These observations emphasize the importance of tailoring model selection to the appropriate disease stage when assessing the relationship between Aβ and tau, and suggest that there are optimal intervention points for the administration of both anti-amyloid and anti-tau therapies.
Regulation of pupil size in natural vision across the human lifespan
Authors: Lazar Rafael , Degen Josefine , Fiechter Ann-Sophie , Monticelli Aurora , Spitschan Manuel 
Published: October 2023

AbstractVision is mediated by light passing through the aperture of the eye, the pupil, which changes in diameter from ~2 to ~8 mm from the brightest to the darkest illumination. In addition, with age, mean pupil size declines. In laboratory experiments, factors affecting pupil size can be experimentally controlled or held constant, but how the pupil reflects changes in retinal input from the visual environment under natural viewing conditions is not clear. Here, we address this question in a field experiment (N=83, 43 female, age: 18-87 years) using a custom-made wearable video-based eye tracker with a spectroradiometer measuring spectral irradiance in the approximate corneal plane. Participants moved in and between indoor and outdoor environments varying in spectrum and engaged in a range of everyday tasks. Our real-world data confirm that light-adapted pupil size is determined by light intensity, with clear superiority of melanopic over photopic units, and that it decreases with increasing age, yielding steeper slopes at lower light levels. We find no indication that sex, iris colour or reported caffeine consumption affect pupil size. Taken together, the data provide strong evidence for considering age in personalised lighting solutions and for using melanopsin-weighted light measures to assess real-world lighting conditions.
Fluorescence dynamics of lysosomal-related organelle flashing in the intestinal cells ofCaenorhabditis elegans
Authors: Tan Chieh-Hsiang , Ding Keke , Zhang Mark G. , Sternberg Paul W. 
Published: October 2023

AbstractThe biological roles of the autofluorescent lysosome-related organelles (“gut granules”) in the intestinal cells of many nematodes, includingCaenorhabditis elegans, have been shown to play an important role in metabolic and signaling processes, but they have not been fully characterized. We report here a previously undescribed phenomenon in which the autofluorescence of these granules increased and then decreased in a rapid and dynamic manner that may be associated with nutrient availability. We observed that two distinct types of fluorophores are likely present in the gut granules. One displays a “flashing” phenomenon, in which fluorescence decrease is preceded by a sharp increase in fluorescence intensity that expands into the surrounding area, while the other simply decreases in intensity. Gut granule flashing was observed in the different life stages ofC. elegansand was also observed inSteinernema hermaphroditum, an evolutionarily distant nematode. We hypothesize that the “flashing” fluorophore is pH-sensitive, and the fluorescence intensity change results from the fluorophore being released from the lysosome-related organelles into the relatively higher pH environment of the cytosol. The visually spectacular dynamic fluorescence phenomenon we describe might provide a handle on the biochemistry and genetics of these lysosome-related organelles.
Mating-induced ecdysone in the testis disrupts soma-germline contacts and stem cell cytokinesis
Authors: Roach Tiffany V. , Lenhart Kari F. 
Published: October 2023

SummaryGermline maintenance relies on adult stem cells to continually replenish lost gametes over a lifetime and respond to external cues altering the demands on the tissue. Mating worsens germline homeostasis over time, yet a negative impact on stem cell behavior has not been explored. Using extended live imaging of theDrosophilatestis stem cell niche, we find that short periods of mating in young males disrupts cytokinesis in germline stem cells (GSCs). This defect leads to failure of abscission, preventing release of differentiating cells from the niche. We find that GSC abscission failure is caused by increased ecdysone hormone signaling induced upon mating, which leads to disrupted somatic encystment of the germline. Abscission failure is rescued by isolating males from females but recurs with resumption of mating. Importantly, reiterative mating also leads to increased GSC loss, requiring increased restoration of stem cells via symmetric renewal and de-differentiation. Together, these results suggest a model whereby acute mating results in hormonal changes that negatively impact GSC cytokinesis but preserves the stem cell population.Graphical Abstract
Revealing the spatial pattern of brain hemodynamic sensitivity to healthy aging through sparse DCM
Authors: Baron Giorgia , Silvestri Erica , Benozzo Danilo , Chiuso Alessandro , Bertoldo Alessandra 
Published: October 2023

AbstractAge-related changes in the BOLD response could reflect neuro-vascular coupling modifications rather than simply impairments in neural functioning. In this study, we propose the use of a generative dynamic causal model (DCM) to decouple neuronal and vascular factors in the BOLD signal, with the aim of characterizing the whole-brain spatial pattern of hemodynamic sensitivity to healthy aging, as well as to test the role of hemodynamic features as independent predictors in an age-classification model.In this view, DCM was applied to the resting-state fMRI data of a cohort of 126 healthy individuals in a wide age range, providing reliable estimates of the hemodynamic response function (HRF) for each subject and each region of interest. Then, some features characterizing each HRF curve were extracted and used to fit a multivariate logistic regression model to predict the age class of each individual. Ultimately, we tested the final predictive model on an independent dataset of 338 healthy subjects selected from the Human Connectome Project Aging (HCP-A) and Development (HCP-D) cohorts. Our results entail the spatial heterogeneity of the age effects on the hemodynamic component, since its impact resulted to be strongly region- and population-specific, discouraging any space-invariant corrective procedures that attempt to correct for vascular factors when carrying out functional studies involving groups with different ages. Moreover, we demonstrated that a strong interaction exists between some specific hemodynamic features and age, further supporting the essential role of the hemodynamic factor as independent predictor of biological aging, rather than a simple confounding variable.Significance statementBy inferring region-wise hemodynamic profiles at the individual level, this is the first study providing an exhaustive whole-brain characterization of the hemodynamic sensitivity to healthy aging, reporting further evidence of the vascular changes across the adult lifespan. Using a predictive framework, we analysed the statistical influence of advancing age on individual regional hemodynamic attributes, offering a quantitative evaluation of the diverse hemodynamic bias across different brain regions. We unveiled a specific set of hemodynamic predictors to discriminate young from elderly people, mainly describing vascular properties of right-hemispheric areas. This suggests the asymmetric nature of vascular degeneration processes affecting the human brain at the latest stage of life, other than a potential biomarker that could be relevant for brain-age prediction.
Human motor unit discharge patterns reveal differences in neuromodulatory and inhibitory drive to motoneurons across contraction levels
Authors: Škarabot Jakob , Beauchamp James A , Pearcey Gregory EP 
Published: October 2023

ABSTRACTAll motor commands converge onto motor units (MUs), which transduce the signals into mechanical actions of muscle fibres. This process is highly non-linear due to combinations of ionotropic (excitatory/inhibitory) and metabotropic (neuromodulatory) inputs. Neuromodulatory inputs facilitate dendritic persistent inward currents, which introduce non-linearities in MU discharge patterns and provide insights into the structure of motor commands. Here, we investigated the relative contribution of neuromodulation and the pattern of inhibition to modulate human MU discharge patterns with contraction forces up to 70% maximum. Leveraging MU discharge patterns identified from three human muscles (tibialis anterior – TA, and vastus lateralis and medialis), we show that with increased contraction force, the onset-offset discharge rate hysteresis (ΔF) increased whilst ascending MU discharge patterns become more linear, with lower slopes. In a follow-up experiment, we demonstrated that the observations of increased ΔF and more linear ascending MU discharge patterns with greater contraction force are maintained even when accounting for contraction duration and rate of force increase. We then reverse-engineered TA MU discharge patterns using highly realistic in silico motoneuron pools to substantiate the inferred physiological mechanisms from human recordings. We demonstrate a sharply restricted solution space, whereby the contraction force-induced changes in experimentally obtained MU discharge patterns can only be recreated with increased neuromodulation and a more reciprocal (i.e. push-pull) inhibitory pattern. In summary, our experimental and computational data suggest that neuromodulation and inhibitory patterns are uniquely shaped to generate discharge patterns that support force increases across a large proportion of the motor pool’s recruitment range.Significance statementHow the structure of motor commands is modified to scale motor output is largely speculative despite its critical role in the neural control of movement. Here, we demonstrate that human motor unit discharge patterns become more linear and exhibit greater discharge rate hysteresis with greater contraction force. These experimentally observed patterns can only be replicated in silico with biophysical models of spinal motoneurons by increasing neuromodulation and shifting inhibitory commands to be more reciprocal to excitation (i.e., push-pull excitation-inhibition synaptic control). Collectively, these results suggest that the structure of motor commands is uniquely orchestrated to support increases in contraction force.
Neural correlates of crowding in macaque area V4
Authors: Kim Taekjun , Pasupathy Anitha 
Published: October 2023

AbstractVisual crowding refers to the phenomenon where a target object that is easily identifiable in isolation becomes difficult to recognize when surrounded by other stimuli (distractors). Extensive psychophysical studies support two alternative possibilities for the underlying mechanisms. One hypothesis suggests that crowding results from the loss of visual information due to pooled encoding of multiple nearby stimuli in the mid-level processing stages along the ventral visual pathway. Alternatively, crowding may arise from limited resolution in decoding object information during recognition and the encoded information may remain inaccessible unless it is salient. To rigorously test these alternatives, we studied the responses of single neurons in macaque area V4, an intermediate stage of the ventral, object-processing pathway, to parametrically designed crowded displays and their texture-statistics matched metameric counterparts. Our investigations reveal striking parallels between how crowding parameters, e.g., number, distance, and position of distractors, influence human psychophysical performance and V4 shape selectivity. Importantly, we found that enhancing the salience of a target stimulus could reverse crowding effects even in highly cluttered scenes and such reversals could be protracted reflecting a dynamical process. Overall, we conclude that a pooled encoding of nearby stimuli cannot explain the observed responses and we propose an alternative model where V4 neurons preferentially encode salient stimuli in crowded displays.Significance StatementPsychophysicists have long studied the phenomena of visual crowding, but the underlying neural mechanisms are unknown. Our results reveal striking correlations between the responses of neurons in mid-level visual cortical area V4 and psychophysical demonstrations, revealing that crowding is influenced not only by the number and spatial arrangement of distractors but also by the similarity of features between target and distractors, as well as among the distractors themselves. Overall, our studies provide strong evidence that the visual system uses strategies to preferentially encode salient features in a visual scene presumably to process visual information efficiently. When multiple nearby stimuli are equally salient, the phenomenon of crowding ensues.
Accelerated Aging after Traumatic Brain Injury: an ENIGMA Multi-Cohort Mega-Analysis
Authors: Dennis Emily L , Vervoordt Samantha , Adamson Maheen M , Amiri Houshang , Bigler Erin D , Caeyenberghs Karen , Cole James H , Dams-O’Connor Kristen , Deutscher Evelyn M , Dobryakova Ekaterina , Genova Helen M , Grafman Jordan H , Håberg Asta K , Hollstrøm Torgeir , Irimia Andrei , Koliatsos Vassilis E , Lindsey Hannah M , Livny Abigail , Menon David K , Merkley Tricia L , Mohamed Abdalla Z , Mondello Stefania , Monti Martin M , Newcome Virginia FJ , Newsome Mary R , Ponsford Jennie , Rabinowitz Amanda , Smevik Hanne , Spitz Gershon , Vankatesan Umesh M , Westlye Lars T , Zafonte Ross , Thompson Paul M , Wilde Elisabeth A , Olsen Alexander , Hillary Frank G 
Published: October 2023

AbstractObjectiveThe long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. In light of current evidence that even a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using MRI data. Complicated mild, moderate and severe TBI (cmsTBI) is associated with a higher predicted (brain) age difference (PAD), but the progression of PAD over time remains unclear. Here we sought to examine whether PAD increases as a function of time since injury (TSI).MethodsAs part of the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n=343), along with controls, for a total sample size of 540, to reproduce and extend prior findings in the study of TBI brain age. T1w-MRI data were aggregated across 7 cohorts and brain age was established using a similar brain age algorithm to prior work in TBI.ResultsFindings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find evidence supporting a link between PAD and cognitive performance.InterpretationThis work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability, eventually leading to further changes in the decades after a single cmsTBI.
Mining the Health Disparities and Minority Health Bibliome: A Computational Scoping Review and Gap Analysis of 200,000+ Articles
Authors: Reyes Nieva Harry , Bakken Suzanne , Elhadad Noémie 
Published: October 2023

AbstractWithout comprehensive examination of available literature on health disparities and minority health (HDMH), the field is left vulnerable to disproportionately focus on specific populations or conditions, curtailing our ability to fully advance health equity. Using scalable open-source methods, we conducted a computational scoping review of more than 200,000 articles to investigate major populations, conditions, and themes in the literature as well as notable gaps. We also compared trends in studied conditions to their relative prevalence in the general population using insurance claims (42MM Americans). HDMH publications represent 1% of articles in MEDLINE. Most studies are observational in nature, though randomized trial reporting has increased five-fold in the last twenty years. Half of all HDMH articles concentrate on only three disease groups (cancer, mental health, endocrine/metabolic disorders), while hearing, vision, and skin-related conditions are among the least well represented despite substantial prevalence. To support further investigation, we also present HDMH Monitor, an interactive dashboard and repository generated from the HDMH bibliome.
Investigation of the genetic aetiology of Lewy body diseases with and without dementia
Authors: Wu Lesley , Real Raquel , Martinez Alejandro , Chia Ruth , Lawton Michael A , Shoai Maryam , Bresner Catherine , Hubbard Leon , Blauwendraat Cornelis , Singleton Andrew B , Ryten Mina , Scholz Sonja W. , Traynor Bryan J , Williams Nigel , Hu Michele T M , Ben-Shlomo Yoav , Grosset Donald G , Hardy John , Morris Huw R ,   International LBD Genomic Consortium
Published: October 2023

AbstractUp to 80% of Parkinson’s disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson’s disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson’s disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be key to understanding disease pathways and ultimately therapy development. Previous genome-wide association studies in Parkinson’s disease and dementia with Lewy bodies/Parkinson’s disease dementia have identified risk loci differentiating patients from controls. We collated data for 7,804 patients of European ancestry from Tracking Parkinson’s (PRoBaND), The Oxford Discovery Cohort, and AMP-PD. We conducted a discrete phenotype genome-wide association studies comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk alleles rs429358 taggingAPOEe4and rs7668531 near theMMRN1and SNCA-AS1 genes, increase the odds of developing dementia and that an intronic variant rs17442721 taggingLRRK2G2019S, on chromosome 12 is protective against dementia. These results should be validated in autopsy confirmed cases in future studies.