bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prioritizing genomic variants through neuro-symbolic, knowledge-enhanced learning
Authors: Althagafi Azza , Zhapa-Camacho Fernando , Hoehndorf Robert 
Published: May 2024

Abstract

Motivation
Whole-exome and genome sequencing have become common tools in diagnosing patients with rare diseases. Despite their success, this approach leaves many patients undiagnosed. A common argument is that more disease variants still await discovery, or the novelty of disease phenotypes results from a combination of variants in multiple disease-related genes. Interpreting the phenotypic consequences of genomic variants relies on information about gene functions, gene expression, physiology, and other genomic features. Phenotype-based methods to identify variants involved in genetic diseases combine molecular features with prior knowledge about the phenotypic consequences of altering gene functions. While phenotype-based methods have been successfully applied to prioritizing variants, such methods are based on known gene–disease or gene–phenotype associations as training data and are applicable to genes that have phenotypes associated, thereby limiting their scope. In addition, phenotypes are not assigned uniformly by different clinicians, and phenotype-based methods need to account for this variability.

Results
We developed an Embedding-based Phenotype Variant Predictor (EmbedPVP), a computational method to prioritize variants involved in genetic diseases by combining genomic information and clinical phenotypes. EmbedPVP leverages a large amount of background knowledge from human and model organisms about molecular mechanisms through which abnormal phenotypes may arise. Specifically, EmbedPVP incorporates phenotypes linked to genes, functions of gene products, and the anatomical site of gene expression, and systematically relates them to their phenotypic effects through neuro-symbolic, knowledge-enhanced machine learning. We demonstrate EmbedPVP’s efficacy on a large set of synthetic genomes and genomes matched with clinical information.

Availability and implementation
EmbedPVP and all evaluation experiments are freely available at https://github.com/bio-ontology-research-group/EmbedPVP.
Service Utilisation of an Innovative Mental Health Counselling Clinic
Authors: Fang Lin , Lung Yu , Hui Gilda , Pang Nelson , Smith Malik , Azizi Tamana 
Published: May 2024

Abstract
Responding to the increasing challenges to mental health equity, Talk It Out Counseling Clinic (the Clinic), an innovative, public-facing counselling service, was established at the University of Toronto during the pandemic. Operating on the principles of anti-oppression and trauma-informed care, the Clinic trains Master of Social Work students to deliver mental health counselling to populations encountering multiple barriers to mental health equity through phone or video. Guided by a quality improvement framework, this study used chart reviews to examine the demographic characteristics, initial mental health status and service utilisation of clients (N = 116) who completed services at the Clinic during its inaugural year. Three-quarters of the clients identified as Black or other racialised individuals, and over 70 per cent rated their general mental health as poor or fair. Nearly 80 per cent of clients referred to the Clinic proceeded to an intake, amongst whom 69.6 per cent successfully completed the services. Warm handoff was associated with service engagement, whilist men and older clients were more likely to terminate the services prematurely. The study underscores the mental health needs of communities confronting multiple challenges and illuminates the processes conducive to client engagement and service delivery within an innovative, school-run mental health clinic.
Sebaceous gland organoid engineering
Authors: Liu Yiqiong , Gao Huanhuan , Chen Huating , Ji Shuaifei , Wu Lu , Zhang Hongliang , Wang Yujia , Fu Xiaobing , Sun Xiaoyan 
Published: May 2024

Abstract
Sebaceous glands (SGs), as holocrine-secreting appendages, lubricate the skin and play a central role in the skin barrier. Large full-thickness skin defects cause overall architecture disruption and SG loss. However, an effective strategy for SG regeneration is lacking. Organoids are 3D multicellular structures that replicate key anatomical and functional characteristics of in vivo tissues and exhibit great potential in regenerative medicine. Recently, considerable progress has been made in developing reliable procedures for SG organoids and existing SG organoids recapitulate the main morphological, structural and functional features of their in vivo counterparts. Engineering approaches empower researchers to manipulate cell behaviors, the surrounding environment and cell–environment crosstalk within the culture system as needed. These techniques can be applied to the SG organoid culture system to generate functionally more competent SG organoids. This review aims to provide an overview of recent advancements in SG organoid engineering. It highlights some potential strategies for SG organoid functionalization that are promising to forge a platform for engineering vascularized, innervated, immune-interactive and lipogenic SG organoids. We anticipate that this review will not only contribute to improving our understanding of SG biology and regeneration but also facilitate the transition of the SG organoid from laboratory research to a feasible clinical application.
Follow-up of immune response in patients with common variable immunodeficiency following SARS-CoV-2 vaccination
Authors: Gutiérrez-Bautista Juan Francisco , Díaz-Alberola Irene , Tarriño María , Aguilera María , Cobo Fernando , Reguera Juan Antonio , Rodríguez-Granger Javier , Mendoza Joaquín , López-Nevot Miguel Ángel , Sampedro Antonio 
Published: May 2024

Abstract
The COVID-19 pandemic highlighted the importance of effective vaccination strategies in controlling the spread of infectious diseases. SARS-CoV-2 vaccine has demonstrated high efficacy in preventing COVID-19 infection in the general population. However, the efficacy of this vaccine in patients with predominantly antibody deficiencies, such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA), should be closely monitored. CVID and XLA are rare genetic disorders that impair the immune system’s ability to produce antibodies, which are crucial for fighting infections. Patients with these disorders have a higher risk of severe disease and mortality from COVID-19 due to their compromised immune systems. In this study, we evaluated the humoral and cellular immune responses after four doses of mRNA-1273 and one BNT162b2 bivalent vaccine in a cohort of patients with CVID and XLA. The response in this population was lower than in the control group. However, the administration of the third dose improved the number of patients with seroconversion and the intensity of the humoral response, as well as the number of patients with a positive cellular response. Finally, the administration of the fourth and fifth doses improves the antibody titer and neutralization against wild type variant, but not against the prevalent XBB1.5 variant.
Cortical dysmorphology and reduced cortico-collicular projections in an animal model of autism spectrum disorder
Authors: Kosmer Kara , Kulesza Randy 
Published: May 2024

Abstract
Autism spectrum disorder is a neurodevelopmental disability that includes sensory disturbances. Hearing is frequently affected and ranges from deafness to hypersensitivity. In utero exposure to the antiepileptic valproic acid is associated with increased risk of autism spectrum disorder in humans and timed valproic acid exposure is a biologically relevant and validated animal model of autism spectrum disorder. Valproic acid-exposed rats have fewer neurons in their auditory brainstem and thalamus, fewer calbindin-positive neurons, reduced ascending projections to the midbrain and thalamus, elevated thresholds, and delayed auditory brainstem responses. Additionally, in the auditory cortex, valproic acid exposure results in abnormal responses, decreased phase-locking, elevated thresholds, and abnormal tonotopic maps. We therefore hypothesized that in utero, valproic acid exposure would result in fewer neurons in auditory cortex, neuronal dysmorphology, fewer calbindin-positive neurons, and reduced connectivity. We approached this hypothesis using morphometric analyses, immunohistochemistry, and retrograde tract tracing. We found thinner cortical layers but no changes in the density of neurons, smaller pyramidal and non-pyramidal neurons in several regions, fewer neurons immunoreactive for calbindin-positive, and fewer cortical neurons projecting to the inferior colliculus. These results support the widespread impact of the auditory system in autism spectrum disorder and valproic acid-exposed animals and emphasize the utility of simple, noninvasive auditory screening for autism spectrum disorder.
Quantitative proteomics of dorsolateral prefrontal cortex reveals an early pattern of synaptic dysmaturation in children with idiopathic autism
Authors: Fatemi S Hossein , Eschenlauer Arthur , Aman Justin , Folsom Timothy D , Chekouo Thierry 
Published: May 2024

Abstract
Autism spectrum disorder (ASD) is a developmental disorder with a rising prevalence and unknown etiology presenting with deficits in cognition and abnormal behavior. We hypothesized that the investigation of the synaptic component of prefrontal cortex may provide proteomic signatures that may identify the biological underpinnings of cognitive deficits in childhood ASD. Subcellular fractions of synaptosomes from prefrontal cortices of age-, brain area-, and postmortem-interval-matched samples from children and adults with idiopathic ASD vs. controls were subjected to HPLC-tandem mass spectrometry. Analysis of data revealed the enrichment of ASD risk genes that participate in slow maturation of the postsynaptic density (PSD) structure and function during early brain development. Proteomic analysis revealed down regulation of PSD-related proteins including AMPA and NMDA receptors, GRM3, DLG4, olfactomedins, Shank1-3, Homer1, CaMK2α, NRXN1, NLGN2, Drebrin1, ARHGAP32, and Dock9 in children with autism (FDR-adjusted P &lt; 0.05). In contrast, PSD-related alterations were less severe or unchanged in adult individuals with ASD. Network analyses revealed glutamate receptor abnormalities. Overall, the proteomic data support the concept that idiopathic autism is a synaptopathy involving PSD-related ASD risk genes. Interruption in evolutionarily conserved slow maturation of the PSD complex in prefrontal cortex may lead to the development of ASD in a susceptible individual.
Neuroanatomy of autism: what is the role of the cerebellum?
Authors: Baizer Joan S 
Published: May 2024

Abstract
Autism (or autism spectrum disorder) was initially defined as a psychiatric disorder, with the likely cause maternal behavior (the very destructive “refrigerator mother” theory). It took several decades for research into brain mechanisms to become established. Both neuropathological and imaging studies found differences in the cerebellum in autism spectrum disorder, the most widely documented being a decreased density of Purkinje cells in the cerebellar cortex. The popular interpretation of these results is that cerebellar neuropathology is a critical cause of autism spectrum disorder. We challenge that view by arguing that if fewer Purkinje cells are critical for autism spectrum disorder, then any condition that causes the loss of Purkinje cells should also cause autism spectrum disorder. We will review data on damage to the cerebellum from cerebellar lesions, tumors, and several syndromes (Joubert syndrome, Fragile X, and tuberous sclerosis). Collectively, these studies raise the question of whether the cerebellum really has a role in autism spectrum disorder. Autism spectrum disorder is now recognized as a genetically caused developmental disorder. A better understanding of the genes that underlie the differences in brain development that result in autism spectrum disorder is likely to show that these genes affect the development of the cerebellum in parallel with the development of the structures that do underlie autism spectrum disorder.
Differences in mid-gestational and early postnatal neonatal cytokines and chemokines are associated with patterns of maternal autoantibodies in the context of autism
Authors: McLellan Janna , Croen Lisa A , Iosif Ana-Maria , Ashwood Paul , Yoshida Cathleen , Berger Kimberly , Van de Water Judy 
Published: May 2024

Abstract
Associations between maternal immune dysregulation (including autoimmunity and skewed cytokine/chemokine profiles) and offspring neurodevelopmental disorders such as autism have been reported. In maternal autoantibody-related autism, specific maternally derived autoantibodies can access the fetal compartment to target eight proteins critical for neurodevelopment. We examined the relationship between maternal autoantibodies to the eight maternal autoantibody-related autism proteins and cytokine/chemokine profiles in the second trimester of pregnancy in mothers of children later diagnosed with autism and their neonates’ cytokine/chemokine profiles. Using banked maternal serum samples from 15 to 19 weeks of gestation from the Early Markers for Autism Study and corresponding banked newborn bloodspots, we identified three maternal/offspring groups based on maternal autoantibody status: (1) mothers with autoantibodies to one or more of the eight maternal autoantibody-related autismassociated proteins but not a maternal autoantibody-related autism-specific pattern, (2) mothers with a known maternal autoantibody-related autism pattern, and (3) mothers without autoantibodies to any of the eight maternal autoantibody-related autism proteins. Using a multiplex platform, we measured maternal second trimester and neonatal cytokine/chemokine levels. This combined analysis aimed to determine potential associations between maternal autoantibodies and the maternal and neonatal cytokine/chemokine profiles, each of which has been shown to have implications on offspring neurodevelopment independently.
Infants’ reorienting efficiency depends on parental autistic traits and predicts future socio-communicative behaviors
Authors: Ronconi Luca , Cantiani Chiara , Riva Valentina , Franchin Laura , Bettoni Roberta , Gori Simone , Bulf Herman , Valenza Eloisa , Facoetti Andrea 
Published: May 2024

Abstract
Attentional reorienting is dysfunctional not only in children with autism spectrum disorder (ASD), but also in infants who will develop ASD, thus constituting a potential causal factor of future social interaction and communication abilities. Following the research domain criteria framework, we hypothesized that the presence of subclinical autistic traits in parents should lead to atypical infants’ attentional reorienting, which in turn should impact on their future socio-communication behavior in toddlerhood. During an attentional cueing task, we measured the saccadic latencies in a large sample (total enrolled n = 89; final sample n = 71) of 8-month-old infants from the general population as a proxy for their stimulus-driven attention. Infants were grouped in a high parental traits (HPT; n = 23) or in a low parental traits (LPT; n = 48) group, according to the degree of autistic traits self-reported by their parents. Infants (n = 33) were then longitudinally followed to test their socio-communicative behaviors at 21 months. Results show a sluggish reorienting system, which was a longitudinal predictor of future socio-communicative skills at 21 months. Our combined transgenerational and longitudinal findings suggest that the early functionality of the stimulus-driven attentional network—redirecting attention from one event to another—could be directly connected to future social and communication development.
Atypical functional connectivity between the amygdala and visual, salience regions in infants with genetic liability for autism
Authors: Liu Janelle , Girault Jessica B , Nishino Tomoyuki , Shen Mark D , Kim Sun Hyung , Burrows Catherine A , Elison Jed T , Marrus Natasha , Wolff Jason J , Botteron Kelly N , Estes Annette M , Dager Stephen R , Hazlett Heather C , McKinstry Robert C , Schultz Robert T , Snyder Abraham Z , Styner Martin , Zwaigenbaum Lonnie , Pruett Jr John R , Piven Joseph , Gao Wei 
Published: May 2024

Abstract
The amygdala undergoes a period of overgrowth in the first year of life, resulting in enlarged volume by 12 months in infants later diagnosed with ASD. The overgrowth of the amygdala may have functional consequences during infancy. We investigated whether amygdala connectivity differs in 12-month-olds at high likelihood (HL) for ASD (defined by having an older sibling with autism), compared to those at low likelihood (LL). We examined seed-based connectivity of left and right amygdalae, hypothesizing that the HL and LL groups would differ in amygdala connectivity, especially with the visual cortex, based on our prior reports demonstrating that components of visual circuitry develop atypically and are linked to genetic liability for autism. We found that HL infants exhibited weaker connectivity between the right amygdala and the left visual cortex, as well as between the left amygdala and the right anterior cingulate, with evidence that these patterns occur in distinct subgroups of the HL sample. Amygdala connectivity strength with the visual cortex was related to motor and communication abilities among HL infants. Findings indicate that aberrant functional connectivity between the amygdala and visual regions is apparent in infants with genetic liability for ASD and may have implications for early differences in adaptive behaviors.
CED-6/GULP and components of the clathrin-mediated endocytosis machinery act redundantly to correctly display CED-1 on the cell membrane in Caenorhabditis elegans
Authors: Harders Rikke Hindsgaul , Morthorst Tine H , Landgrebe Line E , Lande Anna D , Fuglsang Marie Sikjær , Mortensen Stine Bothilde , Feteira-Montero Verónica , Jensen Helene Halkjær , Wesseltoft Jonas Bruhn , Olsen Anders 
Published: May 2024

Abstract
CED-1 (cell death abnormal) is a transmembrane receptor involved in the recognition of “eat-me” signals displayed on the surface of apoptotic cells and thus central for the subsequent engulfment of the cell corpse in Caenorhabditis elegans. The roles of CED-1 in engulfment are well established, as are its downstream effectors. The latter include the adapter protein CED-6/GULP and the ATP-binding cassette family homolog CED-7. However, how CED-1 is maintained on the plasma membrane in the absence of engulfment is currently unknown. Here, we show that CED-6 and CED-7 have a novel role in maintaining CED-1 correctly on the plasma membrane. We propose that the underlying mechanism is via endocytosis as CED-6 and CED-7 act redundantly with clathrin and its adaptor, the Adaptor protein 2 complex, in ensuring correct CED-1 localization. In conclusion, CED-6 and CED-7 impact other cellular processes than engulfment of apoptotic cells.
Genome-wide patterns of noncoding and protein-coding sequence variation in the major fungal pathogen Aspergillus fumigatus
Authors: Brown Alec , Steenwyk Jacob L , Rokas Antonis 
Published: May 2024

Abstract
Aspergillus fumigatus is a deadly fungal pathogen, responsible for &gt;400,000 infections/year and high mortality rates. A. fumigatus strains exhibit variation in infection-relevant traits, including in their virulence. However, most A. fumigatus protein-coding genes, including those that modulate its virulence, are shared between A. fumigatus strains and closely related nonpathogenic relatives. We hypothesized that A. fumigatus genes exhibit substantial genetic variation in the noncoding regions immediately upstream to the start codons of genes, which could reflect differences in gene regulation between strains. To begin testing this hypothesis, we identified 5,812 single-copy orthologs across the genomes of 263 A. fumigatus strains. In general, A. fumigatus noncoding regions showed higher levels of sequence variation compared with their corresponding protein-coding regions. Focusing on 2,482 genes whose protein-coding sequence identity scores ranged between 75 and 99%, we identified 478 total genes with signatures of positive selection only in their noncoding regions and 65 total genes with signatures only in their protein-coding regions. Twenty-eight of the 478 noncoding regions and 5 of the 65 protein-coding regions under selection are associated with genes known to modulate A. fumigatus virulence. Noncoding region variation between A. fumigatus strains included single-nucleotide polymorphisms and insertions or deletions of at least a few nucleotides. These results show that noncoding regions of A. fumigatus genes harbor greater sequence variation than protein-coding regions, raising the hypothesis that this variation may contribute to A. fumigatus phenotypic heterogeneity.
Does Social Intelligence Training Improve Daily Well-Being and Responsiveness to Daily Negative and Positive Events in Custodial Grandmothers?
Authors: Infurna Frank J , Castro Saul A , Webster Britney A , Dolbin-MacNab Megan L , Smith Gregory C , Crowley D Max , Musil Carol 
Published: May 2024

Abstract

Objectives
Custodial grandparents are grandparents who raise grandchildren on a full-time basis in absence of the grandchild’s birth parents. Compared to noncaregiving grandparents, custodial grandparents report poorer mental and physical health and stronger changes in daily well-being when experiencing negative and positive events. We examine whether an online social intelligence training (SIT) program improves custodial grandmothers’ (CGM) daily well-being, socioemotional skills, and changes in well-being when confronted with daily negative and positive events.

Methods
Multilevel models were applied to 200 CGM who were recruited from across the United States and completed a daily survey for 14 consecutive days prior to and following participation in a randomized clinical trial. Participants were randomized into the SIT program or an attention control condition focusing on healthy living habits. The outcomes of interest were daily well-being, social connectedness, emotional awareness, and perspective-taking.

Results
Multilevel analyses revealed that participants who participated in the SIT program, compared to the attention control condition, exhibited stronger emotional responsiveness (i.e., improvements) to daily positive events in the outcomes of positive affect, social engagement, and perspective-taking.

Discussion
Our findings illustrate that SIT improves key components of daily functioning in CGM, which may serve as a pathway linking the demands of custodial grandparenting to poorer mental and physical health. Our discussion focuses on the utility and accessibility of the SIT program for helping improve outcomes for this disadvantaged population.
Clinical Trials Registration Number: NCT03239977