bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measuring Multi-Joint Upper Limb Proprioceptive Position Sense in Children with Unilateral Spastic Cerebral Palsy using 3D Kinematics
Authors: Ratnadurai-Giridharan Shivakeshavan , Delfing Dalina , Robert Maxime T. , Kitago Tomoko , Gordon Andrew M. , Friel Kathleen M. 
Published: October 2024

AbstractBackgroundProprioceptive position sense (PPS), which provides the awareness of the positions of one’s limbs in space, is compromised in children with unilateral spastic cerebral palsy (USCP). Relationships between decreased PPS, skill acquisition, and performance are not well understood partly due to differences between measurement modalities of PPS. During assessments, individual joints are often constrained to a single plane of movement. We introduce ways to estimate PPS, simultaneously from multiple upper limb joints during unconstrained pose matching tasks, using 3D kinematics.MethodsNineteen children with USCP, 14 age-matched typically developing children (TDC) and, 16 typically developed adults (TDA) were recruited. Participants performed contralateral upper limb pose matching tasks while blindfolded. Using 3D kinematic data extracted by a VICON Nexus motion-capture system, three ways of measuring matching performance were calculated: joint angle symmetry, joint distance symmetry, and orientation symmetry. Mann-Whitney U tests were used to statistically compare scores between groups. Spearman’s rank correlation was used to investigate relationships between PPS symmetry measures and hand function in children with USCP.ResultsChildren with USCP presented significantly lower angle, distance, and orientation symmetries compared to TDC. TDA scores were not statistically significantly different compared to TDC. In children with USCP, orientation symmetry measures strongly correlated with several clinical hand function scores such as the box and blocks test.ConclusionsWe introduced a new way to conveniently measure multi-joint PPS. Children with USCP presented lower PPS estimates compared to TDC. We also observed that orientation symmetry (limb co-ordination) strongly correlates with hand function.
Artificial Intelligence Applied to Electrocardiographic Images for Scalable Screening of Transthyretin Amyloid Cardiomyopathy
Authors: Sangha Veer , Oikonomou Evangelos K , Khera Rohan 
Published: October 2024

ABSTRACTBackgroundTransthyretin amyloid cardiomyopathy (ATTR-CM) remains largely under-recognized, under-diagnosed, and under-treated. We hypothesized that the myocardial remodeling of ATTR-CM may be detectable through artificial intelligence (AI) applied to 12-lead electrocardiographic (ECG) images.MethodsAcross 5 hospitals of a large U.S.-based hospital system, we identified patients with ATTR-CM, defined by the presence of a positive nuclear scan with an approved bone radiotracer or pharmacotherapy with an approved transthyretin stabilizer between 2015 and the first half of 2023. The development cohort consisted of 1,011 ECGs from 234 patients (age 79 [IQR:70-85] years, n=176 [17.4%] women), who were age- and sex-matched in a 10:1 ratio to 10,110 ECGs from 10,110 controls (age 79 [IQR:70-85] years, n=1,800 [17.7%] female). A convolutional neural network (CNN) pre-trained using a bio-contrastive pretext on ECGs before 2015 was fine-tuned for ATTR-CM using 5-fold cross-validation and subsequently tested in an independent set of cases (139 ECGs in 47 patients; age 80 [75-86] years, n=44 (31.7% women)) and matched controls (1390 ECGs and patients) from the second half of 2023.ResultsThe AUROC (area under the receiver operating characteristic curve) of the AI-ECG model for discriminating ATTR-CM in the leave-out, temporally distinct dataset was 0.906 [95%CI: 0.89-0.94] (A), with a sensitivity of 0.85 [95%CI: 0.79-0.91] and specificity 0.80 [95%CI 0.78-0.82].ConclusionsWe demonstrate that AI applied directly to ECG images represents a promising and scalable approach for the screening of ATTR-CM.
MARLOWE: Taxonomic Characterization of Unknown Samples for Forensics UsingDe NovoPeptide Identification
Authors: Jenson Sarah C. , Chu Fanny , Barente Anthony S. , Crockett Dustin L. , Lamar Natalie C. , Merkley Eric D. , Jarman Kristin H. 
Published: October 2024

AbstractWe present a computational tool, MARLOWE, for source organism characterization of unknown, forensic biological samples. The intent of MARLOWE is to address a gap in applying proteomics data analysis to forensic applications. MARLOWE produces a list of potential source organisms given confident peptide tags derived fromde novopeptide sequencing and a statistical approach to assign peptides to organisms in a probabilistic manner, based on a broad sequence database. In this way, the algorithm assumes noa prioriknowledge of potential sources, and the probabilistic way peptides are taxonomically assigned and then scored enables results to be unbiased (within the constraints of the sequence database). In a proof-of-concept study, we examined MARLOWE’s performance on two datasets, the biodiversity dataset and theBacillus cereussuperspecies dataset. Not only did MARLOWE demonstrate successful characterization to true contributors in single source and binary mixtures in the biodiversity dataset, but also provided sufficient specificity to distinguish species within a bacterial superspecies group. These results suggest that MARLOWE is suitable for candidate- or lead-generation identification of single-organism and binary samples that can generate forensic leads and aid in selecting appropriate follow-on analyses in a forensic context.
Non-detection during excursions by citizen scientists modeled as a function of weather, season, list length, and individual preferences
Authors: Jacobusse Gert W. , Jongejans Eelke 
Published: October 2024

SUMMARYINTRODUCTIONCitizen science is an increasingly valuable source of information about biodiversity. It is challenging to use this information for analysis of distribution and trends. The lack of a protocol leads to bias in observations and therefore data are not representative. The bias is a consequence of unequal detection probabilities, caused by different preferences and habits of citizen scientists.METHODSWe propose to incorporate characteristics of these excursions in analyses of data collected by citizen scientists to improve estimates of the probability that a species is not detected and reported, even though it does occur. By limiting these models to areas that are known to be occupied, detection can be modeled separately without considering variation in occupancy. We apply this idea to 150 common species in the Southwest Delta of The Netherlands, and illustrate the data selection, the modeling process and the results using four species.RESULTSThe strongest features to predict detection are the number of species during a visit (list length), earlier observations of the target species by the same observer, and the day of year. We compare three approaches to predict the total non-detection probability that takes all visits to an area into account. Predictions based on only the number of visits were outperformed by predictions that also take the list length into account. Our predictions based on all features combined consistently beat both other approaches, across all 10 species groups that were compared.DISCUSSIONWe thus show that explicitly modelling the characteristics of all visits to an occupied area results in estimation of non-detection probabilities, while providing insight into the causes of detection and reporting bias. Furthermore, predictions of our model provide a basis for quantifying the sampling effort in each area, which is a promising first step to correct bias in citizen science data when aiming to map a species’ distribution.
Neuronal activity regulating the dauer entry decision inCaenorhabditis elegans
Authors: Prakash Sharan J. , Seyedolmohadesin Maedeh , Zhang Mark G. , Cohen Sarah M. , Gharib Shahla , Venkatachalam Vivek , Sternberg Paul W. 
Published: October 2024

AbstractThe model nematodeCaenorhabditis eleganscan choose between two alternative developmental trajectories. Larvae can either become reproductive adults or, under conditions of crowding or low food availability, enter a long-term, stress-resistant diapause known as the dauer stage. Previous studies showed that chemical signals from a secreted larval pheromone promote the dauer trajectory, and that their influence can be antagonised by increased availability of microbial food. The decision is known to be under neuronal control, involving both sensory and interneurons. To make an accurate decision, larvae must collect and compare complex patterns of environmental input over several hours of early larval development. The full composition of this circuit and the algorithm for decision-making are unknown. Here, we used cell-specific chemical silencing to systematically perturb several sensory and interneurons to further elucidate circuit composition. Our results suggest a role for gas-sensing neurons in regulating dauer entry. In addition, we quantitatively characterized the neuronal responses to food and pheromone inputs by measuring calcium traces from ASI and AIA neurons. We found that calcium in ASI increases linearly in response to food, and similarly decreases in response to pheromone, revealing a cellular site of antagonism between these key chemical inputs. Notably, the ASI response persists well beyond removal of the food stimulus, thus encoding a memory of recent food exposure. In contrast, AIA reports instantaneous food availability, and is unaffected by pheromone. We discuss how these findings may inform our understanding of this long-term decision-making process.
Reproductive and cognitive effects in carriers of recessive pathogenic variants
Authors: Fridman Hila , Khazeeva Gelana , Levy-Lahad Ephrat , Gilissen Christian , Brunner Han G. 
Published: October 2024

AbstractThe genetic landscape of human Mendelian diseases is shaped by mutation and selection. Selection is mediated by phenotypic effects which interfere with health and reproductive success. Although selection on heterozygotes is well-established in autosomal dominant disorders, convincing evidence for selection in carriers of pathogenic variants associated with recessive conditions is limited, with only a few specific cases documented.We studied heterozygous pathogenic variants in 1,929 genes, which cause recessive diseases when bi-allelic, in a cohort of 378,751 unrelated European individuals from the UK Biobank1. We assessed the impact of these pathogenic variants on reproductive success. We find evidence for fitness effects in heterozygous carriers for recessive genes, especially for variants in constrained genes across a broad range of diseases. Our data suggest reproductive effects at the population level, and hence natural selection, for autosomal recessive disease variants. We further show that variants in genes that underlie intellectual disability are associated with reduced cognition measures in carriers. In concordance with this, we observe an altered genetic landscape, characterized by a threefold reduction in the calculated frequency of biallelic intellectual disability in the population relative to other recessive disorders. The existence of phenotypic and selective effects of pathogenic variants in constrained recessive genes is consistent with a gradient of heterozygote effects, rather than a strict dominant-recessive dichotomy2.
Lamins regulate nuclear mechanics and shape to control glioblastoma cell proliferation, migration and invasion
Authors: Wang Xiuyu , Pereira David , Perfettini Isabelle , Péglion Florent , Wimmers Ryszard , Roy Ananya , Forsberg-Nilsson Karin , Baffet Alexandre , Etienne-Manneville Sandrine , Manneville Jean-Baptiste 
Published: October 2024

AbstractGlioblastoma (GBM) is known as the most aggressive brain tumor and is characterized by a high heterogeneity and a median patient survival time around 15 months. Phenotyping based on cell mechanics is increasingly recognized as a potential prognostic marker for tumor aggressiveness. We have previously shown that cell and nuclear mechanical properties vary between different grades of gliomas and may be used to differentiate between GBM of different aggressiveness. Here, we find that the levels of lamin proteins can serve as an indicator of GBM aggressiveness. In patient-derived GBM cell lines, we found that cells from different GBM express different lamin levels. Nuclear size correlates positively with the ratio between lamin A and lamin B1 while nuclear stiffness increases with the levels of both lamin A and lamin B1. A simple mechanical model suggests that lamin A and lamin B1 act like springs in series. We also show that cells proliferate faster in GBM cell lines expressing higher lamin A levels. Downregulating lamin A expression in these cells reverse the aggressive phenotype. In contrast with breast cancer cells for which reduced lamin A levels favor cell migration in a confined environment, increased levels of lamin A may facilitate the invasion of more aggressive GBM cell lines in the soft environment of the brain. Furthermore, since nuclear deformation is a hallmark of malignancy in cancer cells, our results suggest that nuclear shape and mechanics may serve as prognosis biomarkers for GBM.
Impact of biosolids amendment on the soil resistome and microbiome – a greenhouse study
Authors: Marie John Ste. , Mays Catherine , Guo Bing , Radniecki Tyler S. , Waite-Cusic Joy , Navab-Daneshmand Tala 
Published: October 2024

AbstractThe spread of antibiotic resistance poses a significant challenge to public health worldwide. Wastewater treatment utilities are reservoirs of antibiotic-resistant bacteria and antibiotic resistance genes (ARGs). This study investigates the impact of biosolids amendment on the soil microbiome, resistome, virulence factors, and ESKAPE pathogens during carrot cultivation in a replicated greenhouse study. Metagenomic sequencing revealed that biosolids amendment increased the richness of microbial genera, ARGs, and virulence factors in soil. The relative abundance of ESKAPE pathogens, includingEnterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, andEnterobacterspp., was notably higher in biosolids-amended soils. These pathogens persisted throughout the 11-week cultivation period, raising concerns about the potential for horizontal gene transfer and the spread of antibiotic resistance. The study also identified significant co-occurrences between microbial genera and ARGs, which can suggest the possibility of the microbial taxa harboring the co-occurring ARGs. These findings highlight the importance of continued research and monitoring to ensure the safe and effective use of biosolids in agriculture.
Titin-dependent biomechanical feedback tailors sarcomeres to specialised muscle functions in insects
Authors: Loreau Vincent , Koolhaas Wouter , Chan Eunice HoYee , De Boissier Paul , Brouilly Nicolas , Avosani Sabina , Sane Aditya , Pitaval Christophe , Reiter Stefanie , Luis Nuno Miguel , Mangeol Pierre , von Philipsborn Anne C. , Rupprecht Jean-François , Görlich Dirk , Habermann Bianca H. , Schnorrer Frank 
Published: October 2024

AbstractSarcomeres are the contractile units of muscles that enable animals to move. Insect muscles are remarkable examples because they use extremely different contraction frequencies (ranging from ∼1 to 1000 Hz) and amplitudes for flying, walking and crawling. This is puzzling because sarcomeres are built from essentially the same actin-myosin components. We show here that the giant protein titin is the key to this functional specialisation. I-band titin spans and determines the length of the sarcomeric I-band, and occurs in muscle-type-specific isoforms. Surprisingly, it also rules the length of the force-generating myosin filament in a force feedback mechanism, even though it is not present there. We provide evidence for this model and its validity beyond insects.SummaryHere we identified a mechanical mechanism that instructs sarcomeres to fulfill the specific needs of different muscle types.
Actomyosin Contractility is a Potent Suppressor of Mesoderm Induction by Human Pluripotent Stem Cells
Authors: Fort Loic , Wang Wenjun , Macara Ian 
Published: October 2024

AbstractThe activation of WNT signaling in human pluripotent stem cells drives efficient conversion to lateral mesoderm, which can be further differentiated into cardiomyocytes. Stabilization of the WNT effector β-catenin promotes expression of mesoderm-specifying genes such as Brachyury (encoded byTBXT) and Eomesodermin and drives an epithelial-mesenchymal transition (EMT) that occurs at 49-52 hrs post WNT activation. Interestingly, WNT activation also triggers an early contraction of stem cell colonies, with increased myosin light chain (MLC) phosphorylation, resulting in cellular morphological changes. Small molecule inhibitors and genetic approaches were applied to determine if contractility is related to mesoderm differentiation. Contrary to expectation, suppressing contractility accelerated differentiation; Brachyury induction was enhanced, and EMT initiated as early as 24 hrs post WNT activation. Conversely, expression of constitutively active Rho kinase or myosin light chain kinase, to increase contractility, efficiently blocked any induction of mesoderm, and cells fail to undergo EMT. Mechanistically, reduced contractility promoted active β-catenin levels in the cytoplasm and nucleus. We propose that the early contraction of human pluripotent stem cell colonies in response to WNT activation initially delays mesoderm induction by restraining accumulation of active β-catenin, suggesting a role for contractility as a temporal gate.
Pulsatile basal gene expression as a fitness determinant in bacteria
Authors: Jain Kirti , Hauschild Robert , Bochkareva Olga O , Roemhild Roderich , Tkačik Gasper , Guet Calin C 
Published: October 2024

AbstractActive regulation of gene expression, orchestrated by complex interactions of activators and repressors at promoters, controls the fate of organisms. In contrast, basal expression at uninduced promoters is considered to be a dynamically inert mode of non-functional “promoter leakiness”, merely a byproduct of transcriptional regulation. Here, we investigate the basal expression mode of themaroperon, the main regulator of intrinsic multiple antibiotic resistance inEscherichia coli, and link its dynamic properties to the non-canonical, yet highly conserved start codon ofmarRacrossEnterobacteriaceae. Real-time single-cell measurements across tens of generations, reveal that basal expression consists of rare stochastic gene expression pulses, which maximize variability in wildtype and, surprisingly, transiently accelerate cellular elongation rates. Competition experiments show that basal expression confers fitness advantages to wildtype across several transitions between exponential and stationary growth by shortening lag times. The dynamically rich basal expression of themaroperon, has likely been evolutionarily maintained for its role in growth homeostasis ofEnterobacteriawithin the gut environment, thereby allowing other ancillary gene regulatory roles to evolve, e.g. control of costly-to-induce multi-drug efflux pumps. Understanding the complex selection forces governing genetic systems involved in intrinsic multi-drug resistance is crucial for effective public health measures.
Tissue-specific and spatially dependent metabolic signatures perturbed by injury in skeletally mature male and female mice
Authors: Welhaven Hope D. , Welfley Avery H. , Brahmachary Priyanka P. , Smith Donald F. , Bothner Brian , June Ronald K. 
Published: October 2024

AbstractJoint injury is a risk factor for post-traumatic osteoarthritis. However, metabolic and microarchitectural changes within the joint post-injury in both sexes remain unexplored. This study identified tissue-specific and spatially-dependent metabolic signatures in male and female mice using matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and LC-MS metabolomics. Male and female C57Bl/6J mice were subjected to non-invasive joint injury. Eight days post-injury, serum, synovial fluid, and whole joints were collected for metabolomics. Analyses compared between injured, contralateral, and naïve mice, revealing local and systemic responses. Data indicate sex influences metabolic profiles across all tissues, particularly amino acid, purine, and pyrimidine metabolism. MALDI-MSI generated 2D ion images of bone, the joint interface, and bone marrow, highlighting increased lipid species in injured limbs, suggesting physiological changes across injured joints at metabolic and spatial levels. Together, these findings reveal significant metabolic changes after injury, with notable sex differences.Significance statementOsteoarthritis, the leading cause of disability worldwide, disproportionately affects females with sex being one of the strongest predictors of disease. This disparity is partly driven by sex-specific differences in injury susceptibility, increasing the likelihood of traumatic injury to the anterior cruciate ligament (ACL), other ligaments, and menisci. Using a non-invasive injury model, we demonstrate that injury perturbs the local joint environment and has systemic effects in a sex-specific manner. Furthermore, by leveraging matrix-assisted laser desorption ionization-mass spectrometry imaging of the joint, we provide new insight into the composition of osteochondral tissue at the metabolite level. These sexually dimorphic metabolic responses to joint injury advance current understanding of the complex sexual dimorphism in OA pathogenesis providing a foundation for targeted therapeutic strategies and improved patient outcomes for female patients.
The multimodal transcriptional response of denervated skeletal muscle involves alterations in cholesterol homeostasis impacting muscle size
Authors: Calvo Cristofer , Swoboda Casey O. , Montecino Morales Fabian , Nagar Siddhant , Petrany Michael J. , Sun Chengyi , Durumutla Hima Bindu , Quattrocelli Mattia , Millay Douglas P. 
Published: October 2024

AbstractThe development and maintenance of the neuromuscular junction (NMJ) requires reciprocal signals between the nerve terminals and the multinucleated skeletal muscle fiber (myofiber). This interaction leads to highly specialized transcription in the sub-synaptic or NMJ myonuclei within mature myofibers leading to clustering of acetylcholine receptors (AChRs). Here, we utilized single-nucleus RNA sequencing (snRNA-seq) to delineate the transcriptional response of myonuclei to denervation. Through snRNA-seq on skeletal muscle from two independent mouse models of denervation, sciatic nerve transection and amyotrophic lateral sclerosis, we identify a multimodal transcriptional response of NMJ-enriched genes and an alteration in cholesterol homeostasis in both slow and fast myofibers.Gramd1, a family of genes involved in non-vesicular cholesterol transport, are enriched at the NMJ in innervated muscle and upregulated in both models of denervation by the NMJ and extrasynaptic myonuclei.In vivogain and loss of function studies indicate that NMJ-enrichedGramd1 genesregulate myofiber sizes independent of an obvious impact on AChR clustering. We uncovered a dynamic transcriptional response of myonuclei to denervation and highlight a critical role for cholesterol transport to maintain myofiber sizes.