bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating effective population size trajectories from time-series Identity-by-Descent (IBD) segments
Authors: Huang Yilei , Carmi Shai , Ringbauer Harald 
Published: May 2024

AbstractLong, identical haplotypes shared between pairs of individuals, known as identity-by-descent (IBD) segments, result from recently shared co-ancestry. Various methods have been developed to utilize IBD sharing for demographic inference in contemporary DNA data. Recent methodological advances have enabled the screening for IBD in ancient DNA (aDNA) data, making demographic inference based on IBD also possible for aDNA. However, aDNA data typically have varying sampling times, but most demographic inference methods designed for modern data assume that sampling is contemporaneous. Here, we present TTNE (Time-Transect Ne), which models time-transect sampling to improve inference of recent effective population size trajectories. Using simulations, we show that utilizing IBD sharing in time series has increased resolution to infer recent fluctuations in effective population sizes compared to methods that only use contemporaneous samples. Finally, we developed an approach for estimating and modeling IBD detection errors in empirical IBD analysis. To showcase the practical utility of TTNE, we applied it to two time transects of ancient genomes, individuals associated with the Corded Ware Culture (CWC) and Medieval England. In both cases, we found evidence of a growing population, a signal consistent with archaeological records.
Proteomic and Lipidomic Plasma Evaluations Reveal Biomarkers for Domoic Acid Toxicosis in California Sea Lions
Authors: Solosky Amie M. , Claudio Iliana M. , Chappel Jessie R. , Kirkwood-Donelson Kaylie I. , Janech Michael G. , Bland Alison M. , Gulland Frances M.D. , Neely Benjamin A. , Baker Erin S. 
Published: May 2024

ABSTRACTDomoic acid is a neurotoxin secreted by the marine diatom genus,Pseudo-nitzschia, during toxic algal bloom events. California sea lions (Zalophus californianus) are exposed to domoic acid through ingestion of fish that feed on toxic diatoms, resulting in a domoic acid toxicosis (DAT), which can vary from mild to fatal. Sea lions with mild disease can be treated if toxicosis is detected early after exposure, therefore, rapid diagnosis of DAT is essential but also challenging. In this work, we performed multi-omics analyses, specifically proteomic and lipidomic, on blood samples from 31 California sea lions. Fourteen sea lions were diagnosed with DAT based on clinical signs and postmortem histological examination of brain tissue, and 17 had no evidence of DAT. Proteomic analyses revealed three apolipoproteins with statistically significant lower abundance in the DAT individuals compared to the non-DAT individuals. These proteins are known to transport lipids in the blood. Lipidomic analyses highlighted 29 lipid levels that were statistically different in the DAT versus non-DAT comparison, 28 of which were downregulated while only one was upregulated. Furthermore, of the 28 downregulated lipids, 15 were triglycerides, illustrating their connection with the perturbed apolipoproteins and showing their potential for use in rapid DAT diagnoses.SYNOPSISMulti-omics evaluations reveal blood apolipoproteins and triglycerides are altered in domoic acid toxicosis in California sea lions.GRAPHIC ABSTRACT
Flp-recombinase mouse line for genetic manipulation of ipRGCs
Authors: Contreras E , Liang C , Mahoney HL , Javier JL , Luce ML , Labastida Medina K , Bozza T , Schmidt TM 
Published: May 2024

AbstractLight has myriad impacts on behavior, health, and physiology. These signals originate in the retina and are relayed to the brain by more than 40 types of retinal ganglion cells (RGCs). Despite a growing appreciation for the diversity of RGCs, how these diverse channels of light information are ultimately integrated by the ∼50 retinorecipient brain targets to drive these light-evoked effects is a major open question. This gap in understanding primarily stems from a lack of genetic tools that specifically label, manipulate, or ablate specific RGC types. Here, we report the generation and characterization of a new mouse line (Opn4FlpO), in which FlpO is expressed from theOpn4locus, to manipulate the melanopsin-expressing, intrinsically photosensitive retinal ganglion cells. We find that the Opn4FlpOline, when crossed to multiple reporters, drives expression that is confined to ipRGCs and primarily labels the M1-M3 subtypes. Labeled cells in this mouse line show the expected intrinsic, melanopsin-based light response and morphological features consistent with the M1-M3 subtypes. In alignment with the morphological and physiological findings, we see strong innervation of non-image forming brain targets by ipRGC axons, and weaker innervation of image forming targets in Opn4FlpOmice labeled using AAV-based and FlpO-reporter lines. Consistent with the FlpO insertion disrupting the endogenous Opn4 transcript, we find that Opn4FlpO/FlpOmice show deficits in the pupillary light reflex, demonstrating their utility for behavioral research in future experiments. Overall, the Opn4FlpOmouse line drives Flp-recombinase expression that is confined to ipRGCs and most effectively drives recombination in M1-M3 ipRGCs. This mouse line will be of broad use to those interested in manipulating ipRGCs through a Flp-based recombinase for intersectional studies or in combination with other, non-Opn4 Cre driver lines.
Multivalent modulation of endothelial LRP1 induces fast neurovascular amyloid-β clearance and cognitive function improvement in Alzheimer’s disease models
Authors: Chen Junyang , Xiang Pan , Duro-Castano Aroa , Cai Huawei , Guo Bin , Liu Xiqin , Yu Yifan , Lui Su , Luo Kui , Ke Bowen , Ruiz Perez Lorena , Wei Xiawei , Gong Qiyong , Tian Xiaohe , Battaglia Giuseppe 
Published: May 2024

AbstractThe blood-brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer’s disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques. We propose an AD therapeutic strategy targeting the BBB low-density lipoprotein receptor-related protein 1 (LRP1). We show that a multivalent scaffold with LRP1-specific peptide modulates the Aβ transport at the BBB. We show via detailed experimentation on AD model mice that this intervention markedly reduces Aβ deposits and prevents cognitive decline. This study marks a new approach to drug design, combining multivalent targeting with the regulation of membrane trafficking through advanced molecular engineering. Crucially, the therapeutic effects emerge from the multivalent nature of our proposed system. Furthermore, our findings underscore the paramount significance of the BBB in AD pathogenesis, particularly emphasizing the critical role of LRP1-mediated Aβ clearance in mitigating disease progression.
Altered markers of brain metabolism and excitability are associated with executive functioning in young children exposed to alcoholin utero
Authors: Perdue Meaghan V. , Ghasoub Mohammad , Long Madison , DeMayo Marilena M. , Bell Tiffany K. , McMorris Carly A. , Dewey Deborah , Gibbard W. Ben , Tortorelli Christina , Harris Ashley D. , Lebel Catherine 
Published: May 2024

AbstractPrenatal alcohol exposure (PAE) is the leading known cause of birth defects and cognitive disabilities, with impacts on brain development and executive functioning. Abnormalities in structural and functional brain features are well-documented in children with PAE, but the effects of PAE on brain metabolism in children have received less attention. Levels of brain metabolites can be measured non-invasively using magnetic resonance spectroscopy (MRS). Here, we present the first study of PAE-related brain metabolite differences in early childhood (ages 3-8 years) and their associations with cognitive performance, including executive functioning (EF) and pre-reading skills. We measured metabolites in two cohorts of children with PAE and unexposed children using MRS in the anterior cingulate cortex (ACC; cohort 1) and left temporo-parietal cortex (LTP; cohort 2). Total choline (tCho), a marker of membrane/myelin metabolism, was elevated in both regions in children with PAE compared to unexposed children, and glutamate+glutamine (Glx), a marker of excitability, was elevated in the ACC. The PAE group exhibited more difficulties with EF, and higher tCho was associated with better EF in both PAE and unexposed groups. In addition, elevated Glx in the ACC was associated with poorer inhibitory control within the PAE group only. LTP metabolites were not significantly associated with pre-reading skills in PAE or unexposed groups. Together, these findings point to altered membrane metabolism and excitability in young children with PAE. These findings provide new insight to potential mechanisms by which PAE disrupts brain development and cognitive functioning in early childhood.
Consensus Guideline for the Management of Colorectal Cancer with Peritoneal Metastases
Authors:   PSM Writing Group,   PSM Consortium Group, Turaga Kiran K. 
Published: May 2024

AbstractBackgroundThe peritoneum is a common site of metastases from colorectal cancer (CRC), yet controversy exists regarding optimal treatment strategies. These guidelines describe the results of a national consensus addressing the management of CRC with peritoneal metastases (CRC-PM).MethodsAn update of the 2018 Chicago Consensus Guidelines was conducted using a modified Delphi technique. Two rounds of voting were performed to assess agreement levels on two clinical management pathways regarding synchronous and metachronous CRC-PM. Supporting evidence was evaluated via rapid literature reviews.ResultsThe overall level of evidence was low in existing literature. Of 145 participants in the first round, 136 (96.8%) responded in the second round. Over 90% consensus was achieved in most pathway blocks. For both pathways, early referral to a peritoneal surface malignancy (PSM) center should be made for patients with CRC-PM. For the synchronous pathway, upfront cytoreductive surgery was de-emphasized in favor of systemic therapy. For the metachronous pathway, risk stratification via clinical and pathologic features was revised. For both pathways, surveillance strategies were added, including only a weak recommendation for circulating tumor DNA (ctDNA) testing given limited evidence of its utility in detecting and monitoring PM.ConclusionThe consensus-driven clinical pathways provide valuable guidance for the management of CRC-PM. There remains a need for high-quality evidence and prospective multicenter trials in this domain.SYNOPSISWe developed two consensus-driven clinical pathways for the management of colorectal cancer with peritoneal metastases (CRC-PM), using a modified Delphi approach. Rapid reviews evaluating the optimal systemic therapy and the role of plasma-based liquid-biopsy for CRC-PM were conducted.
A QUANTITATIVE ASSESSMENT OF VISUAL FUNCTION FOR YOUNG AND MEDICALLY COMPLEX CHILDREN WITH CEREBRAL VISUAL IMPAIRMENT: DEVELOPMENT AND INTER-RATER RELIABILITY
Authors: Weden Kathleen M. , Barstow Elizabeth A. , Oster Robert A. , DeCarlo Dawn K. 
Published: May 2024

ABSTRACTBackgroundCerebral Visual Impairment (CVI) is the most common cause of low vision in children. Standardized, quantifiable measures of visual function are needed.ObjectiveThis study developed and evaluated a new method for quantifying visual function in young and medically complex children with CVI using remote videoconferencing.MethodsChildren diagnosed with CVI who had been unable to complete clinic-based recognition acuity tests were recruited from a low-vision rehabilitation clinic(n=22)Video-based Visual Function Assessment (VFA) was implemented using videoconference technology. Three low-vision rehabilitation clinicians independently scored recordings of each child’s VFA. Interclass correlations for inter-rater reliability was analyzed using intraclass correlations (ICC). Correlations were estimated between the video-based VFA scores and both clinically obtained acuity measures and children’s cognitive age equivalence.ResultsInter-rater reliability was analyzed using intraclass correlations (ICC). Correlations were estimated between the VFA scores, clinically obtained acuity measures, and cognitive age equivalence. ICCs showed good agreement (ICC and 95% CI 0.835 (0.701-0.916)) on VFA scores across raters and agreement was comparable to that from previous, similar studies. VFA scores strongly correlated (r= -0.706, p=0.002) with clinically obtained acuity measures. VFA scores and the cognitive age equivalence were moderately correlated (r= 0.518, p=0.005), with notable variation in VFA scores for participants below a ten month cognitive age-equivalence. The variability in VFA scores among children with lowest cognitive age-equivalence may have been an artifact of the study’s scoring method, or may represent existent variability in visual function for children with the lowest cognitive age-equivalence.ConclusionsOur new VFA is a reliable, quantitative measure of visual function for young and medically complex children with CVI. Future study of the VFA intrarater reliability and validity is warranted.
A realist approach to implementation fidelity in a mixed-method evaluation of electronic decision support systems to improve the quality of antenatal care in Nepal
Authors: Radovich Emma , Karki Sulata , Das Seema , Shakya Rajani , McCarthy Ona L. , Shrestha Abha , Calvert Clara , Campbell Oona M. R. , Penn-Kekana Loveday 
Published: May 2024

AbstractBackgroundUnderstanding implementation fidelity, or adherence to the intervention-as-intended, is essential to interpreting the results of evaluations. In this paper, we propose a longitudinal, explanatory approach to implementation fidelity through a realist evaluation lens. We apply this approach to a mixed-method assessment of implementation fidelity to an electronic decision support system intervention to improve the quality of antenatal care in Nepal.MethodsThe tablet-based electronic decision support system was implemented in 19 primary care facilities in Nepal. As part of the project’s process evaluation, we used four data sources – monitoring visit checklists and fieldnotes, software backend data, and longitudinal case studies in four facilities – to examine three components of fidelity: use at the point of care, use for all antenatal visits, and quality of data entry. Quantitative data were analysed descriptively. Qualitative data were analysed thematically using template analysis to examine descriptive findings across the three fidelity components and later to develop and reflect on the causal mechanisms. Findings were synthesised, drawing on Normalization Process Theory, to understand the processes driving the different patterns of fidelity observed.ResultsFidelity to point-of-care use declined over time with healthcare providers often entering data after antenatal visits had ended because providers understood the intervention as primarily about recordkeeping rather than decision support. Even in facilities with higher fidelity to point-of-care use, software decision-support prompts were largely ignored. Low antenatal client caseloads and the suggestion by fieldworkers to practice back-entering data from previous antenatal visits undermined understanding of the intervention’s purpose for decision support.ConclusionsOur assessment explains how and why patterns of implementation fidelity occurred, yielding more nuanced understanding of the project evaluation’s null result that moves beyond intervention vs implementation failure. Our findings demonstrate the importance of discussing intervention theory in terms fieldworkers and participants understand so as not to undermine fidelity.
Genome-wide association meta-analysis of age at onset of walking
Authors: Gui Anna , Hollowell Anja , Wigdor Emilie M. , Morgan Morgan J. , Hannigan Laurie J. , Corfield Elizabeth C. , Odintsova Veronika , Hottenga Jouke-Jan , Wong Andrew , Pool René , Cullen Harriet , Wilson Siân , Warrier Varun , Eilertsen Espen M. , Andreassen Ole A. , Middeldorp Christel M. , Pourcain Beate St , Bartels Meike , Boomsma Dorret I. , Hartman Catharina A. , Robinson Elise B. , Arichi Tomoki , Edwards David , Johnson Mark H. , Dudbridge Frank , Sanders Stephan J. , Havdahl Alexandra , Ronald Angelica 
Published: May 2024

AbstractOnset of walking is a developmental milestone with wide individual differences and high heritability in humans. In this genome-wide association study meta-analysis of age at onset of walking (N=70,560 European-ancestry infants), SNP-based heritability was 24.13% (SE=1.16%) with ∼11.9K variants accounting for about 90% of it, suggesting high polygenicity. We identified 11 independent genome-wide significant loci, including a “double hit” haplotype in which both decreased expression ofRBL2and a potentially deleterious missense variant inRBL2are associated with delayed walking. Age at onset of walking (in months) was negatively genetically correlated with ADHD and BMI, and positively genetically correlated with intelligence, educational attainment, and adult brain gyrification. The polygenic score showed out-of-sample prediction of 3-5.6%, confirmed to be largely due to direct effects in sib-pair analyses, and was associated with volume of neonatal brain structures involved in motor control. This offers new biological insights of clinical relevance into neurodevelopment.
Diverging functional connectivity timescales: Capturing distinct aspects of cognitive performance in early psychosis
Authors: Hirsch Fabian , Bumanglag Ângelo , Zhang Yifei , Wohlschlaeger Afra 
Published: May 2024

AbstractBackgroundPsychosis spectrum disorders (PSDs) are marked by cognitive impairments, the neurobiological correlates of which remain poorly understood. Here, we investigate the entropy of time-varying functional connectivity (TVFC) patterns from resting-state fMRI (rfMRI) as potential biomarker for cognitive performance in PSDs. By combining our results with multimodal reference data, we hope to generate new insights into the mechanisms underlying cognitive dysfunction in PSDs. We hypothesized that low-entropy TVFC patterns (LEN) would be more behaviorally informative than high-entropy TVFC patterns (HEN), especially for tasks that require extensive integration across diverse cognitive subdomains.MethodsrfMRI and behavioral data from 97 patients in the early phases of psychosis and 53 controls were analyzed. Positron-Emission Tomography (PET) and magnetoencephalography (MEG) data were taken from a public repository (Hansen et al., 2022). Multivariate analyses were conducted to examine relationships between TVFC patterns at multiple spatial scales and cognitive performance in patients.ResultsCompared to HEN, LEN explained significantly more cognitive variance on average in PSD patients, driven by superior encoding of information on psychometrically more integrated tasks. HEN better captured information in specific subdomains of executive functioning. Nodal HEN-LEN transitions were spatially aligned with neurobiological gradients reflecting monoaminergic transporter densities and MEG beta power. Exploratory analyses revealed a close statistical relationship between LEN and positive PSD symptoms.ConclusionOur entropy-based analysis of TVFC patterns dissociates distinct aspects of cognition in PSDs. By linking topographies of neurotransmission and oscillatory dynamics with cognitive performance, it enhances our understanding of the mechanisms underlying cognitive deficits in PSDs.CRediT Authorship Contribution StatementFabian Hirsch:Conceptualization, Methodology, Software, Formal analysis, Writing - Original Draft, Writing - Review & Editing, Visualization;Ângelo Bumanglag:Methodology, Software, Formal analysis, Writing - Review & Editing;Yifei Zhang:Methodology, Software, Formal analysis, Writing - Review & Editing;Afra Wohlschlaeger:Methodology, Writing - Review & Editing, Supervision, Project administration
Automated Identification of Thrombectomy Amenable Vessel Occlusion on Computed Tomography Angiography using Deep Learning
Authors: Han Jung Hoon , Lee Hoyeon , Park Gi-Hoon , Hong Hotak , Kim Dongmin , Kim Jae Guk , Kim Joon-Tae , Sunwoo Leonard , Kim Chi Kyung , Ryu Wi-Sun 
Published: May 2024

AbstractObjectivesRecent advancements have extended the treatment window for large vessel occlusion in acute ischemic stroke, prompting a shift in the standard of care for patients presenting within 6 to 24 hours. We developed and externally validated an automated deep learning algorithm for detecting thrombectomy amenable vessel occlusion (TAVO) in computed tomography angiography (CTA).MethodsThe algorithm was trained on 2,045 acute ischemic stroke patients who underwent CTA, and validation was conducted using two external datasets comprising 64 (external 1) and 313 (external 2) patients with ischemic stroke. TAVO was defined as occlusion in the intracranial internal carotid artery (ICA), or M1/M2 segment of the middle cerebral artery (MCA). Utilizing U-Net for vessel segmentation and EfficientNetV2 for TAVO prediction, the algorithm’s diagnostic performance was assessed using the area under the receiver operating characteristics curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).ResultsThe mean age in the training and validation dataset was 68.7±12.6; 56.3% were men, and 18.0% had TAVO. The algorithm achieved AUC of 0.950 (95% CI, 0.915–0.971) in the internal test. For the external datasets 1 and 2, the AUCs were 0.970 (0.897–0.997) and 0.971 (0.924–0.990), respectively. Notably, the algorithm demonstrated robust sensitivity and specificity (approximately 0.95) for intracranial ICA or M1-MCA occlusion, but a slight reduction in performance for isolated M2-MCA occlusion.ConclusionThis validated algorithm has potential applications in identifying TAVO and could aid less-experienced clinicians, potentially expediting the treatment process for eligible patients.
Circulating microRNAs are related to cognitive domains in the general population
Authors: Melas Konstantinos , Talevi Valentina , Etteldorf Rika , Estrada Santiago , Krüger Dennis M. , Pena Tonatiuh , Aziz N. Ahmad , Fischer André , Breteler Monique M.B. 
Published: May 2024

ABSTRACTINTRODUCTIONCirculating microRNAs have been suggested as candidates for detecting and preventing subclinical cognitive dysfunction. However, replication of previous findings and identification of novel microRNAs associated with cognitive domains, including their relation to brain structure and the pathways they regulate, are still lacking.METHODSWe examined circulating microRNAs and microRNAco-expressionclusters in relation to cognitive domains, structural MRI measures, and target gene expression in 2869 participants of a population-based cohort.RESULTSFive previously identified and 10 novel microRNAs were associated with cognitive domains. Importantly, seven of these microRNAs were also associated with cortical thickness and two with hippocampal volume. Functional genomics analysis showed that the identified microRNAs regulated genes in pathways like neurogenesis, axon guidance, and synapse assembly.DISCUSSIONWe identified microRNAs associated with cognitive domains, brain regions, and neuronal processes affected by aging and neurodegeneration, making them promising candidate blood-based biomarkers or therapeutic targets of subclinical cognitive dysfunction.