bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiomic approach and Mendelian randomization analysis identify causal associations between blood biomarkers and subcortical brain structure volumes
Authors: Jain Pritesh , Yates Madison , de Celis Carlos Rubin , Drineas Petros , Jahanshad Neda , Thompson Paul , Paschou Peristera 
Published: April 2023

AbstractAlterations in subcortical brain structure volumes have been found to be associated with several neurodegenerative and psychiatric disorders. At the same time, genome-wide association studies (GWAS) have identified numerous common variants associated with brain structure. In this study, we integrate these findings, aiming to identify proteins, metabolites, or microbes that have a putative causal association with subcortical brain structure volumes via a two-sample Mendelian randomization approach. This method uses genetic variants as instrument variables to identify potentially causal associations between an exposure and an outcome. The exposure data that we analyzed comprised genetic associations for 2,994 plasma proteins, 237 metabolites, and 103 microbial genera. The outcome data included GWAS data for seven subcortical brain structure volumes including accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Eleven proteins and six metabolites were found to have a significant association with subcortical structure volumes. We found causal associations between amygdala volume and granzyme A as well as association between accumbens volume and plasma protease c1 inhibitor. Among metabolites, urate had the strongest association with thalamic volume. No significant associations were detected between the microbial genera and subcortical brain structure volumes. We also observed significant enrichment for biological processes such as proteolysis, regulation of the endoplasmic reticulum apoptotic signaling pathway, and negative regulation of DNA binding. Our findings provide insights to the mechanisms through which brain volumes may be affected in the pathogenesis of neurodevelopmental and psychiatric disorders and point to potential treatment targets for disorders that are associated with subcortical brain structure volumes.
Homeobox Transcription Factor HbxA Influences Expression of over One Thousand Genes in the Model FungusAspergillus nidulans
Authors: Pandit S.S. , Zheng J. , Yi Y. , Lorber S. , Puel O. , Dhingra S. , Espeso E.A. , Calvo A.M 
Published: April 2023

ABSTRACTIn fungi, conserved homeobox-domain (HD) proteins are transcriptional regulators governing development. InAspergillusspecies, several HD transcription factor genes have been identified, among them,hbxA/hbx1. For instance, in the opportunistic human pathogenAspergillus fumigatus,hbxAis involved in conidial production and germination, as well as virulence and secondary metabolism (SM), including production of fumigaclavines, fumiquinazolines, and chaetominine. In the agriculturally important fungusAspergillus flavus,disruption ofhbx1results in fluffy aconidial colonies unable to produce sclerotia.hbx1also regulates production of aflatoxins, cyclopiazonic acid and aflatrem. Furthermore, transcriptome studies revealed thathbx1has a broad effect on theA. flavusgenome, including numerous genes involved in SM. These studies underline the importance of the HbxA/Hbx1 regulator, not only in developmental processes but also in the biosynthesis of a broad number of fungal natural products, including potential medical drugs and mycotoxins. To gain further insight into the regulatory scope of HbxA inAspergilli, we studied its role in the model fungusAspergillus nidulans. Our present study of theA. nidulans hbxA-dependent transcriptome revealed that more than one thousand genes are differentially expressed when this regulator was not transcribed at wild-type levels, among them numerous transcription factors, including those involved in development as well as in SM regulation. Furthermore, our metabolomics analyses revealed that production of several secondary metabolites, some of them associated withA. nidulans hbxA-dependent gene clusters, was also altered in deletion and overexpressionhbxAstrains compared to the wild type, including synthesis of nidulanins A, B and D, versicolorin A, sterigmatocystin, austinol, dehydroaustinol, and three unknown novel compounds.
XMAP: Cross-population fine-mapping by leveraging genetic diversity and accounting for confounding bias
Authors: Cai Mingxuan , Wang Zhiwei , Xiao Jiashun , Hu Xianghong , Chen Gang , Yang Can 
Published: April 2023

AbstractFine-mapping prioritizes risk variants identified by genome-wide association studies (GWASs), serving as a critical step to uncover biological mechanisms underlying complex traits. However, several major challenges still remain for existing fine-mapping methods. First, the strong linkage disequilibrium among variants can limit the statistical power and resolution of fine-mapping. Second, it is computationally expensive to simultaneously search for multiple causal variants. Third, the confounding bias hidden in GWAS summary statistics can produce spurious signals. To address these challenges, we develop a statistical method for cross-population fine-mapping (XMAP) by leveraging genetic diversity and accounting for confounding bias. By using cross-population GWAS summary statistics from global biobanks and genomic consortia, we show that XMAP can achieve greater statistical power, better control of false positive rate, and substantially higher computational efficiency for identifying multiple causal signals, compared to existing methods. Importantly, we show that the output of XMAP can be integrated with single-cell datasets, which greatly improves the interpretation of putative causal variants in their cellular context at single-cell resolution.
Activity-Guided Proteomic Profiling of Proteasomes Uncovers a Variety of Active (And Inactive) Proteasome Species
Authors: Sahoo Manisha Priyadarsini , Lavy Tali , Sahu Indrajit , Kleifeld Oded 
Published: April 2023

AbstractProteasomes are multi-subunit, multi-catalytic protein complexes present in eukaryotic cells that degrade misfolded, damaged, or unstructured proteins. In this study, we used an activity-guided proteomic methodology based on a fluorogenic peptide substrate to characterize the composition of proteasome complexes in WT yeast, and the changes these complexes undergo upon the deletion of Pre9 (Δα3) or of Sem1 (ΔSem1).A comparison of whole-cell proteomic analysis to activity-guided proteasome profiling indicates that the amounts of proteasomal proteins and proteasome interacting proteins in the assembled active proteasomes differ significantly from their total amounts in the cell as a whole. Using this activity-guided approach, we characterized the changes in the abundance of subunits of various active proteasome species in different strains, quantified the relative abundance of active proteasomes across these strains, and charted the overall distribution of different proteasome species within each strain. The distributions obtained by our mass spectrometry-based quantification were markedly higher for some proteasome species than those obtained by activity-based quantification alone, suggesting that the activity of some of these species is impaired. The impaired activity appeared mostly among 20SBlm10proteasome species which account for 20% of the active proteasomes in WT.To identify the factors behind this impaired activity, we mapped and quantified known proteasome-interacting proteins. Our results suggested that some of the reduced activity might be due to the association of the proteasome inhibitor Fub1. Additionally, we provide novel evidence for the presence of non-mature and therefore inactive proteasome protease subunits β2 and β5 in the fully assembled proteasomes.Significance StatementProteasomes, essential protein complexes in eukaryotic cells, degrade misfolded, damaged, or unstructured proteins. Here we present an activity-guided proteomic method to characterize the composition and abundance of proteasomes. When applied to yeast proteasomes, this method revealed discrepancies between proteasome distributions determined by mass spectrometry and peptidase activity. This implies that a substantial portion of the proteasomes may exhibit reduced activity. Our findings indicate that these changes in proteasome activity could be linked to proteasome inhibition by Fub1. Furthermore, we identified signature peptides that indicate incomplete maturation of some of the β2 and β5 proteolytic subunits in fully assembled proteasomes, suggesting that proteasome core particle assembly can proceed even without the complete maturation of all β subunits.
Race Corrections in Clinical Algorithms Can Help Correct for Racial Disparities in Data Quality
Authors: Zink Anna , Obermeyer Ziad , Pierson Emma 
Published: April 2023

AbstractDespite ethical and historical arguments for removing race corrections from clinical algorithms, the consequences of removal remain unclear. An important and underdiscussed consideration in this debate is the fact that medical data quality frequently varies across race groups. For example, family history of cancer is an essential predictor in cancer risk prediction algorithms but is less reliably documented for Black patients and may therefore be less predictive of cancer outcomes. We assessed whether race corrections could allow risk prediction models to capture varying data quality by race, focusing on colorectal cancer risk prediction. Using data from the Southern Community Cohort Study, we analyzed 77,836 adults with no history of colorectal cancer at baseline. We assessed whether the predictive relationship between self-reported family history of colorectal cancer and 10-year colorectal cancer risk differed by race. We then compared two cancer risk prediction algorithms -- a race-blind algorithm which included standard colorectal cancer risk factors but not race, and a race-corrected algorithm which additionally included race. Family history predicted 10-year colorectal cancer risk among White patients (OR: 1.74, 95% CI 1.25-2.38), but not Black patients (OR: 0.98, 95% CI 0.72-1.29). Relative to the race-blind algorithm, the race-corrected algorithm improved predictive performance, as measured by goodness of fit in a likelihood ratio test (p-value <0.001) and AUROC among Black patients (0.611 versus 0.608, p-value 0.006). Because the race-blind algorithm underpredicted risk for Black participants, the race-corrected algorithm increased the fraction of Black participants among the predicted high-risk group, potentially increasing access to screening. Race corrections can allow risk prediction algorithms to model varying data quality by race group, which frequently occurs in clinical settings.
Infusing behavior science into large language models for activity coaching
Authors: Vardhan Madhurima , Hegde Narayan , Nathani Deepak , Rosenzweig Emily , Karthikesalingam Alan , Seneviratne Martin 
Published: April 2023

AbstractLarge language models (LLMs) have shown promise for task-oriented dialogue across a range of domains. The use of LLMs in health and fitness coaching is under-explored. Behavior science frameworks such as COM-B, which conceptualizes behavior change in terms of capability (C), Opportunity (O) and Motivation (M), can be used to architect coaching interventions in a way that promotes sustained change. Here we aim to incorporate behavior science principles into an LLM using two knowledge infusion techniques: coach message priming (where exemplar coach responses are provided as context to the LLM), and dialogue re-ranking (where the COM-B category of the LLM output is matched to the inferred user need). Simulated conversations were conducted between the primed or unprimed LLM and a member of the research team, and then evaluated by 8 human raters. Ratings for the primed conversations were significantly higher in terms of empathy and actionability. The same raters also compared a single response generated by the unprimed, primed and re-ranked models, finding a significant uplift in actionability from the re-ranking technique. This is a proof of concept of how behavior science frameworks can be infused into automated conversational agents for a more principled coaching experience.Institutional Review Board (IRB)The study does not involve human subjects beyond the volunteer annotators. IRB approval was not sought for this research.
Lower delayed but comparable working memory performance in patients with Parkinson disease
Authors: Lee Eun-Young 
Published: April 2023

AbstractIntruductionThe present study examined nature of memory deficits and its associations with MRI structural metrics in patients with Parkinson disease (PD).MethodsNineteen PD and 23 matched controls underwent two memory experiments. In experiment 1 (delayed memory task), subjects were asked to remember an array of colored rectangles with varying memory set sizes [Low-Load (2 items), Low-Load with distractors, & High-Load (5 items)]. After a 7s delay period, they reported whether the orientation of any relevant figures had changed (test period). In experiment 2 (working memory task), memory arrays were presented in varying set sizes (2 to 6 items) but with no distractors and they were followed by a 2s delay period and subsequent test period. Brain MRI data were acquired to assess morphological differences (volumes and cortical thickness) in brain areas related to attentional filtering (middle frontal gyrus and basal ganglia) and memory storage and consolidation (intraparietal sulcus and medial temporal corticies).ResultsCompared to controls, PD patients had lower memory capacity scores in all memory conditions for the experiment 1 (p <0.021) whereas there were no memory score group differences in any memory set sizes for the experiment 2 (p>0.06). In addition, there were no group differences in structural metrics for any ROI and no asccociations of strucrutal metrics with delayed memory scores (p>0.056).DiscussionThe present findings suggest that both lower attentional filtering and memory storage may contribute to lower delayed memory scores in PD. Memory storage capacity for visuospatial working memory in PD, however, appeared to be comparable to that of controls at least in the absence of apparent distractors. In addition, lower delayed memory in PD may partly be associated with early brain structural or functional changes that may occur before morphological changes.
Mycobacterial Metabolic Model Development for Drug Target Identification
Authors: Bannerman Bridget P. , Oarga Alex , Júlvez Jorge 
Published: April 2023

ABSTRACTAntibiotic resistance is increasing at an alarming rate, and three related mycobacteria are the source of widespread infections in humans. According to the World Health Organization,Mycobacterium leprae, which causes leprosy, is still endemic in tropical countries; Mycobacterium tuberculosis is the second largest infectious disease killer worldwide after COVID-19;Mycobacteroides abscessus, a group of non-tuberculous mycobacteria, causes lung infections and other health-care-associated infections in humans. Due to the rise in resistance to common antibacterial drugs, it is critical to develop alternatives to traditional treatment procedures. Furthermore, an understanding of the biochemical mechanisms underlying pathogenic evolution is important for the treatment and management of these diseased conditions.In this study, metabolic models have been developed for two bacterial pathogens,M. leprae, andM. abscessus, and a new computational tool has been used to identify potential drug targets, which are referred to as bottleneck reactions. The genes, reactions, and pathways in each of these organisms have been highlighted; the potential drug targets can be further explored as broad-spectrum antibacterials and the unique drug targets to each pathogen are significant for precision medicine initiatives.The models and associating datasets are available in GigaScience and the following repositories:M. abscessusBiomodels:https://www.ebi.ac.uk/biomodels/MODEL2203300002https://www.patmedb.org/Bacteria/MabscessusM. lepraeBiomodels:https://www.ebi.ac.uk/biomodels/MODEL2203300001https://www.patmedb.org/Bacteria/Mleprae
Radial askew endodermal cell divisions reveal IRK functions in division orientation
Authors: Rony R. M. Imtiaz Karim , Campos Roya , Perez-Henriquez Patricio , Van Norman Jaimie M. 
Published: April 2023

ABSTRACTOriented cell divisions establish plant tissue and organ patterning and produce different cell types; this is particularly true of the highly organized Arabidopsis root meristem. Mutant alleles ofINFLORESCENCE AND ROOT APICES RECEPTOR KINASE(IRK) exhibit excess cell divisions in the root endodermis. IRK is a transmembrane receptor kinase that localizes to the outer polar domain of these cells, which suggests directional signal perception is necessary to repress endodermal cell division. Here, a detailed examination revealed many of the excess endodermal divisions inirkhave division planes that specifically skew towards the outer lateral side, therefore we termed them ‘radial askew’ divisions. Expression of an IRK truncation, lacking the kinase domain, retains polar localization and rescues these radial askew divisions, but the roots exhibit excess periclinal endodermal divisions. Using markers of cell identity, we show that the daughters of radial askew divisions transition from endodermal to cortex identity similar to those of periclinal divisions. These results extend the requirement for IRK beyond repression of cell division activity to include cell division plane positioning. Based on its polarity, we propose that IRK at the outer lateral endodermal cell face participates in division plane positioning to ensure normal root ground tissue patterning.
Engineering living immunotherapeutic agents for improved cancer treatment
Authors: Gwisai Tinotenda , Günther Sina , Vizovisek Matej , Jacobs Mira , Schuerle Simone 
Published: April 2023

AbstractBacteria-based biohybrid agents are emerging as a promising strategy for cancer therapy due to their ability to actively target tumors, trigger localized inflammation and induce tumor regression. There has been growing interest in using bacteria that are responsive to external cues, such as magnetic fields, to facilitate the formation of robust colonies in tumor the achieve the threshold for clinical efficacy. Several studied have demonstrated the potential of innately magnetically responsive bacteria, known as magnetotactic bacteria (MTB), as steerable agents, however, their immunostimulatory properties and therapeutic effects are yet to be explored. Here, we characterize key properties of human immune cell responses and the behavior of the MTB strainMagnetospirillum magneticumAMB-1 in physiological environments. This work investigates the ability of MTB to maintain magnetic properties, viability in whole blood, cytokine production by macrophages, and the ability to increase uptake of cancer cell material by dendritic cells. This study also explores the use of MTB-liposome complexes for effective delivery of therapeutic payloads. Overall, this study establishes the potential of MTB as a versatile, combined drug delivery platform for immune-mediated cancer therapy.
Event-related potential (ERP) evidence of early visual processing differences in cystinosis
Authors: Horsthuis Douwe J. , Molholm Sophie , Foxe John J. , Francisco Ana A. 
Published: April 2023

ABSTRACTCystinosis, a rare lysosomal storage disease, is characterized by cystine crystallization and accumulation within tissues and organs, including the kidneys and brain. Its impact on neural function appears mild relative to its effects on other organs, but therapeutic advances have led to substantially increased life expectancy, necessitating deeper understanding of its impact on neurocognitive function.Behavioral difficulties have been reported in cystinosis in the visual and visual-processing domain. Very little is known, however, about how the brains of people living with cystinosis process visual information, although cysteamine accumulation in the retina is a prominent feature of cystinosis. Here, electrophysiology was recorded during a Go/No-Go task to investigate early visual processing in cystinosis, compared to an age-matched control group. Analyses focused on early stages of cortical visual processing.The groups differed in their initial cortical response, with individuals with cystinosis exhibiting a significantly larger visual evoked potential (VEP) in the 130 to 150 ms time window. The timing and topography of this response suggested an enhanced P1 in cystinosis that could be the result of cortical hyperexcitability and/or differences in attentional engagement and explain, at least partially, the visual and visual-spatial difficulties described in this population. The groups also differed in the associations between neural responses and verbal abilities: While controls with higher IQ scores presented larger neural responses, that relationship was not observed in cystinosis.
A collection ofTrichodermaisolates from natural environments in Sardinia, a biodiversity hotspot, reveals a complex virome that includes negative-stranded mycoviruses with unprecedented genome organizations
Authors: Pagnoni Saul , Oufensou Safa , Balmas Virgilio , Bulgari Daniela , Gobbi Emanuela , Forgia Marco , Migheli Quirico , Turina Massimo 
Published: April 2023

SUMMARYTheTrichodermagenus includes soil-inhabiting fungi that provide important ecological services in their interaction with plants and other fungi. They are exploited for biocontrol. A collection ofTrichodermaisolates from the Sardinia island (a biodiversity hotspot) had been previously characterized. Here we started a characterization of the viral components associated to 113 selectedTrichodermaisolates, representatives of the collection. We carried out NGS sequencing of ribosome depleted total RNA following a bioinformatic pipeline that detects virus RNA-dependent RNA polymerases (RdRP) and other conserved virus protein sequences. This pipeline detected 17 viral RdRPs. Two of them correspond to viruses already detected in other regions of the world. The remaining 15 represent isolates of new virus species: surprisingly, eight of them are from new negative stranded RNA viruses, which for the first time are reported in the genusTrichoderma. Among them is a cogu-like virus, very closely related to plant-infecting viruses. Regarding the positive strand viruses, it is noticeable the presence of an ormycovirus belonging to a recently characterized group of bi-segmented ssRNA genome viruses with still uncertain phylogenetic assignment. Finally, for the first time we report a bipartite mononegavirales-infecting fungi: the proteins encoded by the second genomic RNA were used to re-evaluate a number of viruses in thePenicillimonavirusandPlasmopamonavirusgenera, here shown to be bipartite and to encode a conserved polypeptide having structural conservation with the nucleocapsid (NC) domain of members of the Rabhdoviridae.IMPORTANCETrichodermais a genus of fungi of great biotechnological impact in multiple industrial fields. The possibility to investigate a diverse collection ofTrichodermaisolates allowed us to characterize both double-stranded and single-stranded virus genomes belonging to three of the major phyla that constitute the RNA viral kingdom, thus further increasing the taxa of viruses infecting this genus. To our knowledge here we report for the first time negative-stranded RNA viruses infectingTrichodermaspp. and throughin silicostructural analysis a new conserved domain of nucleocapsids common among some mymonavirids. Obtaining such a library of mycoviruses could be the basis for further development of targeted virus-induced gene silencing or gene editing (VIGS/VIGE) tools; in addition, the many biotechnological applications of this fungus, will require to assess the qualitative (commercial) stability of strains, linked to positive or negative effects caused by mycovirus infections.