bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted curation of the gut microbial gene content modulating human cardiovascular disease
Authors: Borton Mikayla A. , Shaffer Michael , Hoyt David W. , Jiang Ruisheng , Ellenbogen Jared , Purvine Samuel , Nicora Carrie D. , Eder Elizabeth K. , Wong Allison R. , Smulian A. George , Lipton Mary S. , Krzycki Joseph A. , Wrighton Kelly C. 
Published: June 2022

AbstractDespite the promise of the gut microbiome to forecast human health, few studies expose the microbial functions underpinning such predictions. To comprehensively inventory gut microorganisms and their gene content that control trimethylamine induced cardiovascular disease, we mined over 200,000 gut-derived genomes from cultivated and uncultivated microbial lineages. Creating MAGICdb (Methylated Amine Gene Inventory of Catabolism database), we designated an atherosclerotic profile for 6,341 microbial genomes that encoded metabolisms associated with heart disease. We used MAGICdb to evaluate diverse human fecal metatranscriptome and metaproteome datasets, demonstrating how this resource eases the recovery of methylated amine gene content previously obscured in microbiome datasets. From the feces of healthy and diseased subjects, we show MAGICdb gene markers predicted cardiovascular disease as effectively as traditional blood diagnostics. This functional microbiome catalog is a public, exploitable resource, enabling a new era of microbiota-based therapeutics.
Non-classical glycosylation determines intracellular trafficking of APP and Aβ production
Authors: Tachida Yuriko , Iijima Junko , Takahashi Kazuto , Suzuki Hideaki , Yamaguchi Yoshiki , Tanaka Katsunori , Nakano Miyako , Takakura Daisuke , Kawasaki Nana , Saito Yuko , Manya Hiroshi , Endo Tamao , Kitazume Shinobu 
Published: June 2022

AbstractA primary pathology of Alzheimer’s disease (AD) is Aβ deposition in brain parenchyma and blood vessels, the latter being called cerebral amyloid angiopathy (CAA). Parenchymal amyloid plaques presumably originate from neuronal Aβ precursor protein (APP), but vascular amyloid deposits’ origins remain unclear. Endothelial APP expression in APP-knock-in mice was recently shown to expand CAA pathology, highlighting endothelial APP’s importance. Furthermore, two types of endothelial APP—with and without O-glycans—have been biochemically identified, but only the former is cleaved for Aβ production, indicating the critical relationship between APP O-glycosylation and processing. Here, we analyzed APP glycosylation and its intracellular trafficking in neurons and endothelial cells. Although protein glycosylation is generally believed to precede cell surface trafficking, which was true for neuronal APP, we unexpectedly observed that APP lacking O-glycans is externalized to the endothelial cell surface and transported back to the Golgi apparatus, where it then acquires O-glycans. Knockdown of genes encoding enzymes initiating APP O-glycosylation significantly reduced Αβ production, suggesting this non-classical glycosylation pathway contributes to CAA pathology and is a novel therapeutic target.
The centrosomal protein 83 (CEP83) regulates human pluripotent stem cell differentiation towards the kidney lineage
Authors: Mansour Fatma , Hinze Christian , Telugu Narasimha Swamy , Kresoja Jelena , Shaheed Iman B. , Mosimann Christian , Diecke Sebastian , Schmidt-Ott Kai M. 
Published: June 2022

AbstractBackgroundDuring embryonic development, the mesoderm undergoes patterning into diverse lineages including axial, paraxial, and lateral plate mesoderm (LPM). Within the LPM, the so-called intermediate mesoderm (IM) forms kidney and urogenital tract progenitor cells, while remaining LPM forms cardiovascular, hematopoietic, mesothelial and additional progenitor cells. The signals that regulate these early lineage decisions are incompletely understood. Here, we found that the centrosomal protein 83 (CEP83), a centriolar component necessary for primary cilia formation and mutated in pediatric kidney disease, influences the differentiation of human induced pluripotent stem cells (hiPSCs) towards intermediate mesoderm.MethodsWe induced inactivating deletions of CEP83 in hiPSCs and applied a 7 day in vitro protocol of intermediate mesoderm kidney progenitor differentiation, based on timed application of WNT and FGF agonists. We characterized induced mesodermal cell populations using single cell and bulk transcriptomics and tested their ability to form kidney structures in subsequent organoid culture.ResultsWhile hiPSCs with homozygous CEP83 inactivation were normal regarding morphology and transcriptome, their induced differentiation into IM progenitor cells was perturbed. Mesodermal cells induced after 7 days of monolayer culture of CEP83-deficient hiPCS exhibited absent or elongated primary cilia, displayed decreased expression of critical IM genes (PAX8, EYA1, HOXB7) and an aberrant induction of LPM markers (e. g. FOXF1, FOXF2, FENDRR, HAND1, HAND2). Upon subsequent organoid culture, wildtype cells differentiated to form kidney tubules and glomerular-like structures, whereas CEP83-deficient cells failed to generate kidney cell types, instead upregulating cardiomyocyte, vascular, and more general LPM progenitor markers.ConclusionOur data suggest that CEP83 regulates the balance of intermediate mesoderm and lateral plate mesoderm formation from human pluripotent stem cells, identifying a potential link between centriolar or ciliary function and mesodermal lineage induction.
Purely STDP-based assembly dynamics: stability, learning, overlaps, drift and aging
Authors: Manz Paul , Memmesheimer Raoul-Martin 
Published: June 2022

AbstractMemories may be encoded in the brain via strongly interconnected groups of neurons, called assemblies. The concept of Hebbian plasticity suggests that these assemblies are generated through synaptic plasticity, strengthening the recurrent connections within select groups of neurons that receive correlated stimulation. To remain stable in absence of such stimulation, the assemblies need to be self-reinforcing under the plasticity rule. Previous models of such assembly maintenance require additional mechanisms of fast homeostatic plasticity often with biologically implausible timescales. Here we provide a model of neuronal assembly generation and maintenance purely based on spike-timing-dependent plasticity (STDP) between excitatory neurons. It uses irregularly and stochastically spiking neurons and STDP that depresses connections of uncorrelated neurons. We find that assemblies do not grow beyond a certain size, because temporally imprecisely correlated spikes dominate the plasticity in large assemblies. Assemblies in the model can be learned or spontaneously emerge. The model allows for prominent, stable overlap structures between static assemblies. Further, assemblies can drift, particularly according to a novel, transient overlap-based mechanism. Finally the model indicates that assemblies grow in the aging brain, where connectivity decreases.Author summaryIt is widely assumed that memories are represented by ensembles of nerve cells that have strong interconnections with each other. It is to date not clear how such strongly interconnected nerve cell ensembles form, persist, change and age. Here we show that already a basic rule for activity-dependent synaptic strength plasticity can explain the learning or spontaneous formation and the stability of assemblies. In particular, it is not necessary to explicitly keep the overall total synaptic strength of a neuron nearly constant, a constraint that was incorporated in previous models in a manner inconsistent with current experimental knowledge. Furthermore, our model achieves the challenging task of stably maintaining many overlaps between assemblies and generating the experimentally observed drift of memory representations. Finally, the model predicts that if the number of synaptic connections in the brain decreases, as observed during aging, the size of the neuron ensembles underlying memories increases. This may render certain memories in the aging brain more robust and prominent but also less specific.
Obesogenic diet induces circuit-specific memory deficits in mice
Authors: Bakoyiannis Ioannis , Ducourneau Eva-Gunnel , N’diaye Matéo , Fermigier Alice , Ducroix-Crepy Céline , Bosch-Bouju Clémentine , Coutureau Etienne , Trifilieff Pierre , Ferreira Guillaume 
Published: June 2022

AbstractObesity is associated with neurocognitive dysfunction, including memory deficits. This is particularly worrisome during adolescence, which represents a crucial period for maturation of brain structures, such as the hippocampus which are crucial for cognition. In rodent models, we recently reported that memory impairments induced by obesogenic high-fat diet (HFD) intake during the periadolescent period can be reversed by chemogenetic manipulation of the ventral hippocampus (vHPC). Here, we used an intersectional viral approach in HFD-fed male mice to chemogenetically inactivate specific vHPC efferent pathways to nucleus accumbens or medial prefrontal cortex during memory tasks. We first demonstrated that HFD enhanced activation of both pathways after training and that our chemogenetic approach was effective in normalising this activation. Inactivation of the vHPC-nucleus accumbens pathway rescued HFD-induced deficits in recognition but not location memory. Conversely, inactivation of the vHPC-medial prefrontal cortex pathway restored location but not recognition memory impairments produced by HFD. Either pathway manipulation did not affect exploration, locomotion or anxiety-like behaviour. These findings suggest that HFD intake throughout adolescence impairs different types of memory through overactivation of specific hippocampal efferent pathways and that targeting these overactive pathways has therapeutic potential.
Super-enhancers require a combination of classical enhancers and novel facilitator elements to drive high levels of gene expression
Authors: Blayney Joseph , Francis Helena , Camellato Brendan , Mitchell Leslie , Stolper Rosa , Boeke Jef , Higgs Douglas , Kassouf Mira 
Published: June 2022

AbstractSuper-enhancers (SEs) are a class of compound regulatory elements which control expression of key cell-identity genes. It remains unclear whether they are simply clusters of independent classical enhancers or whether SEs manifest emergent properties and should therefore be considered as a distinct class of element. Here, using synthetic biology and genome editing, we engineered the well characterised erythroid α-globin SE at the endogenous α-globin locus, removing all SE constituent elements in a mouse embryonic stem cell-line, to create a “blank canvas”. This has allowed us to re-build the SE through individual and combinatorial reinsertion of its five elements (R1, R2, R3, Rm, R4), to test the importance of each constituent’s sequence and position within the locus. Each re-inserted element independently creates a region of open chromatin and binds its normal repertoire of transcription factors; however, we found a high degree of functional interdependence between the five constituents. Surprisingly, the two strongest α-globin enhancers (R1 and R2) act sub-optimally both on their own and in combination, and although the other three elements (R3, Rm and R4) exhibit no discernible enhancer activity, they each exert a major positive effect in facilitating the activity of the classical enhancers (R1 and R2). This effect depends not simply on the sequence of each element but on their positions within the cluster. We propose that these “facilitators” are a novel form of regulatory element, important for ensuring the full activity of SEs, but distinct from conventional enhancer elements.
Optimizing insect metabarcoding using replicated mock communities
Authors: Iwaszkiewicz-Eggebrecht Elzbieta , Granqvist Emma , Buczek Mateusz , Prus Monika , Roslin Tomas , Tack Ayco J.M. , Andersson Anders F. , Miraldo Andreia , Ronquist Fredrik , Łukasik Piotr 
Published: June 2022

AbstractMetabarcoding (high-throughput sequencing of marker gene amplicons) has emerged as a promising and cost-effective method for characterizing insect community samples. Yet, the methodology varies greatly among studies and its performance has not been systematically evaluated to date. In particular, it is unclear how accurately metabarcoding can resolve species communities in terms of presence-absence, abundances, and biomass. Here we use mock community experiments and a simple probabilistic model to evaluate the performance of different metabarcoding protocols. Specifically, we ask four questions: (Q1) How consistent are the recovered community profiles across replicate mock communities?; (Q2) How does the choice of lysis buffer affect the recovery of the original community?; (Q3) How are community estimates affected by differing lysis times and homogenization?; and (Q4) Is it possible to obtain adequate species abundance estimates through the use of biological spike-ins? We show that estimates are quite variable across community replicates. In general, a mild lysis protocol is better at reconstructing species lists and approximate counts, while homogenization is better at retrieving biomass composition. Tiny insects are more likely to be detected in lysates, while some tough species require homogenization to be detected. Results are less consistent across biological replicates for lysates than for homogenates. Some species are associated with strong PCR amplification bias, which complicates the reconstruction of species counts. Yet, with adequate spike-in data, species abundance can be determined with roughly 40% standard error for homogenates, and with roughly 50% standard error for lysates, under ideal conditions. In the latter case, however, this often requires species-specific reference data, while spike-in data generalizes better across species for homogenates. We conclude that a non-destructive, mild lysis approach shows the highest promise for presence/absence description of the community, while also allowing future morphological or molecular work on the material. However, homogenization protocols perform better for characterizing community composition, in particular in terms of biomass.
WITHDRAWN: Nucleic acid biomarkers of immune response and cell and tissue damage in COVID-19 and MIS-C
Authors: Loy Conor J. , Sotomayor-Gonzalez Alicia , Servellita Venice , Nguyen Jenny , Lenz Joan , Bhattacharya Sanchita , Williams Meagan , Cheng Alexandre P. , Bliss Andrew , Saldhi Prachi , Brazer Noah , Streithorst Jessica , Suslovic William , Hsieh Charlotte , Bahar Burak , Wood Nathan , Foresythe Abiodun , Gliwa Amelia , Bhakta Kushmita , Perez Maria A. , Hussaini Laila , Anderson Evan J. , Chahroudi Ann , Delaney Meghan , Butte Atul J. , DeBiasi Roberta , Rostad Christina A. , De Vlaminck Iwijn , Chiu Charles Y. 
Published: June 2022

Withdrawal StatementThe authors have withdrawn their manuscript owing to data from patients who had not been consented being inadvertently used in the preprint. This has been corrected in the version of the study published in Cell Reports Medicine. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID
Authors: Peluso Michael J. , Deveau Tyler-Marie , Munter Sadie E. , Ryder Dylan , Buck Amanda , Beck-Engeser Gabriele , Chan Fay , Lu Scott , Goldberg Sarah A. , Hoh Rebecca , Tai Viva , Torres Leonel , Iyer Nikita S. , Deswal Monika , Ngo Lynn H. , Buitrago Melissa , Rodriguez Antonio , Chen Jessica Y. , Yee Brandon C. , Chenna Ahmed , Winslow John W. , Petropoulos Christos J. , Deitchman Amelia N. , Hellmuth Joanna , Spinelli Matthew A. , Durstenfeld Matthew S. , Hsue Priscilla Y. , Kelly J. Daniel , Martin Jeffrey N. , Deeks Steven G. , Hunt Peter W. , Henrich Timothy J. 
Published: June 2022

ABSTRACTThe presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. In a cohort of 280 adults with prior SARS-CoV-2 infection, we observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4 months following initial diagnosis were independently associated with serological evidence of recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen IgG levels, but not with ongoing EBV viremia. Evidence of EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52) and tended to have less severe (>5 symptoms reported) LC (OR 0.44). Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.SUMMARYThe authors found that Long COVID symptoms in a post-acute cohort were associated with serological evidence of recent EBV reactivation and pre-existing HIV infection when adjusted for participant factors, sample timing, comorbid conditions and prior hospitalization, whereas underlying CMV infection was associated with a decreased risk of Long COVID.
Antenatal depressive symptoms are strongly predicted by the severity of pre-menstrual syndrome: results of partial least squares analysis
Authors: Abe Yoshiko , Sirichokchatchawan Wandee , Sangkomkamhang Ussanee , Satthapisit Sirina , Suwimonteerabutr Junpen , Maes Michael 
Published: June 2022

AbstractObjectiveAntenatal depression (AD) is the commonest morbidity during pregnancy. There is evidence that premenstrual syndrome (PMS) and AD share common immune-inflammatory pathways. Few studies have assessed the relation between the affective symptoms of PMS and AD. The present study aims to evaluate the association between the severity of depressive PMS and AD in early and late pregnancy.MethodsWomen in early pregnancy (<=16 weeks) were recruited and followed until late pregnancy (>=20 weeks). The Premenstrual Symptoms Screening Tool (PSST) was used to assess PMS and AD symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). Results: The PSST score was significantly and positively associated with the EPDS scores both in early and late pregnancy. Up to 57.6% of the variance in the early EPDS score was explained by the regression on the first factor extracted from 10 depression and anxiety PSST items (dubbed the DepAnx PSST domain), PSST item insomnia, relation dissatisfaction, and the Abuse Assessment Screen item 1 (partner abuse). Additionally, 6.3% of the variance in the PSST DepAnx domain was explained by the regression on the mental-physical neglect score of the Adverse Childhood Experiences Questionnaire. There were specific indirect effects of PSST DepAnx (p<0.001), insomnia (p=0.041), relation dissatisfaction (p=0.023) and partner abuse (p=0.007) on the late EPDS which were mediated by the early EPDS score.ConclusionThe affective, but not psychosomatic, symptoms of PMS strongly predict depressive symptoms during pregnancy suggesting that the pathophysiology of affective PMS symptoms overlap with those of AD.
Development of a new DHFR-based destabilizing domain with enhanced basal turnover and applicability in mammalian systems
Authors: Nakahara Emi , Mullapudi Vishruth , Joachimiak Lukasz A. , Hulleman John D. 
Published: June 2022

ABSTRACTDestabilizing domains (DDs) are an attractive strategy allowing for positive post-transcriptional small molecule-regulatable control of a fusion protein’s abundance. Yet in many instances, the currently available DDs suffer from higher-than-desirable basal levels of the fusion protein. Accordingly, we redesigned the E. coli dihydrofolate reductase (ecDHFR) DD by introducing a library of ~1200 random ecDHFR mutants fused to YFP into CHO cells. Following successive rounds of FACS sorting, we identified six new ecDHFR DD clones with significantly enhanced proteasomal turnover in the absence of a stabilizing ligand, trimethoprim (TMP). One of these clones, designated as ‘C12’, contained four unique missense mutations (W74R/T113S/E120D/Q146L) and demonstrated a significant 2.9-fold reduction in basal levels compared to the conventional ecDHFR DD YFP. This domain was similarly responsive to TMP with respect to dose-response and maximal stabilization, indicating an overall enhanced dynamic range. Interestingly, both computational and wet-lab experiments identified the W74R and T113S mutations of C12 as the main contributors towards its basal destabilization. Yet, the combination of all the C12 mutations were required to maintain both its enhanced degradation and TMP stabilization. We further demonstrate the utility of C12 by fusing it to IκBα and Nrf2, two stress-responsive proteins that have previously been challenging to regulate. In both instances, C12 significantly enhanced the basal turnover of these proteins and improved the dynamic range of regulation post stabilizer addition. These advantageous features of the C12 ecDHFR DD variant highlight its potential for replacing the conventional N-terminal ecDHFR DD, and overall improving the use of destabilizing domains, not only as a chemical biology tool, but for gene therapy avenues as well.
Damaged mitochondria recruit the effector NEMO to activate NF-κB signaling
Authors: Harding Olivia , Holzbaur Erika L.F. 
Published: June 2022

AbstractFailure to clear damaged mitochondria via mitophagy disrupts physiological function and may initiate damage signaling via inflammatory cascades. However, signaling mechanisms leading from impaired mitophagy to neuro-inflammation are unclear. We discovered that NF-κB essential regulator NEMO is recruited to damaged mitochondria in a Parkin- and p62/SQSTM1-dependent manner in a time-course similar to recruitment of the structurally-related mitophagy receptor, OPTN. NEMO and p62 colocalize, partitioning into distinct domains from OPTN. Either depletion of p62 or mutation of NEMO’s ubiquitin-binding domain abolishes NEMO recruitment, indicating multifactorial interactions. The active catalytic IKK component phospho-IKKβ colocalizes with NEMO on damaged mitochondria, initiating NF-κB signaling and the upregulation of inflammatory cytokines. These findings suggest that damaged mitochondria serve as an intracellular platform for innate immune signaling by promoting the formation of activated IKK complexes in a Parkin-dependent manner. We propose that mitophagy and NF-κB signaling are competing pathways regulating the response to cellular stress.