bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective Translation Orchestrates Key Signaling Pathways in Primed Pluripotency
Authors: Okubo Chikako , Nakamura Michiko , Sato Masae , Shichino Yuichi , Mito Mari , Takashima Yasuhiro , Iwasaki Shintaro , Takahashi Kazutoshi 
Published: February 2024

AbstractPluripotent stem cell (PSC) identities, such as differentiation and infinite proliferation, have long been understood within the frameworks of transcription factor networks, epigenomes, and signal transduction, yet remain unclear and fragmented. Directing attention toward translational regulation, as a bridge between these events, promises to yield new insights into previously unexplained mechanisms. Our functional CRISPR interference screening-based approach revealed that EIF3D maintains primed pluripotency through selective translational regulation. The loss of EIF3D disrupts the balance of pluripotency-associated signaling pathways, impairing primed pluripotency. Moreover, we discovered that EIF3D ensures robust proliferation by controlling the translation of various p53 regulators, which maintain low p53 activity in the undifferentiated state. In this way, selective translation by EIF3D tunes the homeostasis of the primed pluripotency networks, ensuring the maintenance of an undifferentiated state with high proliferative potential. Therefore, this study establishes a paradigm for selective translational regulation as a defining feature of primed PSC identity.
SARS-COV-2 induces blood-brain barrier and choroid plexus barrier impairments and vascular inflammation in mice
Authors: Qiao Haowen , Deng Xiangxue , Qiu Lingxi , Qu Yafei , Chiu Yuanpu , Chen Feixiang , Xia Shangzhou , Muenzel Cheyene , Ge Tenghuan , Song Pengfei , Bonnin Alexandre , Zhao Zhen , Yuan Weiming 
Published: February 2024

AbstractThe coronavirus disease of 2019 (COVID-19) pandemic that has led to more than 700 million confirmed cases and near 7 million deaths. Although Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus mainly infects the respiratory system, neurological complications are widely reported in both acute infection and long-COVID cases. Despite the success of vaccines and antiviral treatments, neuroinvasiveness of SARS-CoV-2 remains as an important question, which is also centered on the mystery whether the virus is capable of breaching the barriers into the central nervous system. By studying the K18-hACE2 infection model, we observed clear evidence of microvascular damage and breakdown of the blood-brain barrier (BBB). Mechanistically, SARS-CoV-2 infection caused pericyte damage, tight junction loss, endothelial activation and vascular inflammation, which together drive microvascular injury and BBB impairment. In addition, the blood-cerebrospinal fluid barrier at the choroid plexus was also impaired after infection. Therefore, cerebrovascular and choroid plexus dysfunctions are important aspects of COVID-19 and may contribute to the neurological complications both acutely and in long COVID.
Identifying Reproducibly Important EEG Markers of Schizophrenia with an Explainable Multi-Model Deep Learning Approach
Authors: Sancho Martina Lapera , Ellis Charles A. , Miller Robyn L. , Calhoun Vince D. 
Published: February 2024

AbstractThe diagnosis of schizophrenia (SZ) can be challenging due to its diverse symptom presentation. As such, many studies have sought to identify diagnostic biomarkers of SZ using explainable machine learning methods. However, the generalizability of identified biomarkers in many machine learning-based studies is highly questionable given that most studies only analyze explanations from a small number of models. In this study, we present (1) a novel feature interaction-based explainability approach and (2) several new approaches for summarizing multi-model explanations. We implement our approach within the context of electroencephalogram (EEG) spectral power data. We further analyze both training and test set explanations with the goal of extracting generalizable insights from the models. Importantly, our analyses identify effects of SZ upon the α, β, and θ frequency bands, the left hemisphere of the brain, and interhemispheric interactions across a majority of folds. We hope that our analysis will provide helpful insights into SZ and inspire the development of robust approaches for identifying neuropsychiatric disorder biomarkers from explainable machine learning models.
A lentiviral toolkit to monitor airway epithelial cell differentiation using bioluminescence
Authors: Orr Jessica C. , Laali Asma , Durrenberger Pascal F. , Lazarus Kyren A. , Mdawar Marie-Belle El , Janes Sam M. , Hynds Robert E. 
Published: February 2024

ABSTRACTBasal cells are adult stem cells in the airway epithelium and regenerate differentiated cell populations, including the mucosecretory and ciliated cells that enact mucociliary clearance. Human airway basal cells can proliferate and produce differentiated epitheliumin vitro. However, studies of airway epithelial differentiation mostly rely on immunohistochemical or immunofluorescence-based staining approaches, meaning that a quantitative approach is lacking. Here, we use a lentiviral reporter gene approach to transduce primary human basal cells with bioluminescence-based reporter constructs to monitor airway epithelial differentiation longitudinally. We generated three constructs driven by promoter sequences from theTP63,MUC5ACandFOXJ1genes to quantitatively assess basal cell, ciliated cell and mucosecretory cell abundance, respectively. We validated these constructs by tracking differentiation of basal cells in air-liquid interface and organoid (‘bronchosphere’) cultures. Transduced cells also responded appropriately to stimulation with interleukin 13 (IL-13; to increase mucosecretory differentiation and mucus production) and IL-6 (to increase ciliated cell differentiation). We anticipate that these constructs will be a valuable resource for researchers monitoring airway epithelial cell differentiation in primary epithelial and/or induced pluripotent stem cell (iPSC) cell cultures.Graphical Abstract
Loss ofUBE3Aimpacts both neuronal and non-neuronal cells in human cerebral organoids
Authors: Estridge R. Chris , Yagci Z. Begum , Sen Dilara , Ptacek Travis S. , Simon Jeremy M. , Keung Albert J. 
Published: February 2024

AbstractAngelman syndrome is a neurodevelopmental disorder caused by (epi)genetic lesions of maternalUBE3A. Research has focused largely on the role ofUBE3Ain neurons due to its imprinting in that cell type. Yet, evidence suggests there may be broader neurodevelopmental impacts ofUBE3Adysregulation. Human cerebral organoids might reveal these understudied aspects ofUBE3Aas they recapitulate diverse cell types of the developing human brain. We performed scRNAseq on organoids to reveal the effects ofUBE3Adisruption on cell type-specific compositions and transcriptomic alterations. In the absence ofUBE3A, progenitor proliferation and structures were disrupted while organoid composition shifted away from proliferative cell types. We observed impacts on non-neuronal cells, including choroid plexus enrichment. Furthermore, EMX1+ cortical progenitors were negatively impacted, disrupting corticogenesis, and potentially delaying excitatory neuron maturation. This work reveals novel impacts ofUBE3Aon understudied cell types and related neurodevelopmental processes and elucidates potential new therapeutic targets.TeaserHuman cerebral organoids exhibit compositional and transcriptomic alterations in both neuronal and non-neuronal cells in the absence ofUBE3A.
Accessible chromatin maps of inflammatory bowel disease intestine nominate cell-type mediators of genetic disease risk
Authors: Wayman Joseph A. , Yang Zi , Angerman Elizabeth , Bonkowski Erin , Jurickova Ingrid , Chen Xiaoting , Bejjani Anthony T. , Parks Lois , Parameswaran Sreeja , Miethke Alexander G. , VanDussen Kelli L. , Dhaliwal Jasbir , Weirauch Matthew T. , Kottyan Leah C. , Denson Lee A. , Miraldi Emily R. 
Published: February 2024

AbstractInflammatory Bowel Disease (IBD) is a chronic and often debilitating autoinflammatory condition, with an increasing incidence in children. Standard-of-care therapies lead to sustained transmural healing and clinical remission in fewer than one-third of patients. For children, TNFα inhibition remains the only FDA-approved biologic therapy, providing an even greater urgency to understanding mechanisms of response. Genome-wide association studies (GWAS) have identified 418 independent genetic risk loci contributing to IBD, yet the majority are noncoding and their mechanisms of action are difficult to decipher. If causal, they likely alter transcription factor (TF) binding and downstream gene expression in particular cell types and contexts. To bridge this knowledge gap, we built a novel resource: multiome-seq (tandem single-nuclei (sn)RNA-seq and chromatin accessibility (snATAC)-seq) of intestinal tissue from pediatric IBD patients, where anti-TNF response was defined by endoscopic healing. From the snATAC-seq data, we generated a first-time atlas of chromatin accessibility (putative regulatory elements) for diverse intestinal cell types in the context of IBD. For cell types/contexts mediating genetic risk, we reasoned that accessible chromatin will co-localize with genetic disease risk loci. We systematically tested for significant co-localization of our chromatin accessibility maps and risk variants for 758 GWAS traits. Globally, genetic risk variants for IBD, autoimmune and inflammatory diseases are enriched in accessible chromatin of immune populations, while other traits (e.g., colorectal cancer, metabolic) are enriched in epithelial and stromal populations. This resource opens new avenues to uncover the complex molecular and cellular mechanisms mediating genetic disease risk.
Gene regulatory network landscape of Group 3/4 medulloblastoma
Authors: Joshi Piyush , Stelzer Tamina , Okonechnikov Konstantin , Sarropoulos Ioannis , Sepp Mari , Pour-Jamnani Mischan V. , Rademacher Anne , Yamada-Saito Tetsuya , Schneider Céline , Schmidt Julia , Schäfer Philipp , Leiss Kevin , Bortolomeazzi Michele , Mallm Jan-Philipp , da Silva Patricia B.G. , Statz Britta , Wittmann Andrea , Schramm Kathrin , Blattner-Johnson Mirjam , Fiesel Petra , Jones Barbara , Milde Till , Pajtler Kristian , van Tilburg Cornelis M. , Witt Olaf , Rippe Karsten , Korshunov Andrey , Jones David T.W. , Hovestadt Volker , Northcott Paul A. , Thongjuea Supat , Jäger Natalie , Kaessmann Henrik , Pfister Stefan M. , Kutscher Lena M. 
Published: February 2024

AbstractResolving the molecular mechanisms driving childhood brain tumors will uncover tumor-specific vulnerabilities and advance mechanism-of-action-based therapies. Here we describe a continuum of cell-states in Group 3/4 medulloblastomas, the most frequent and fatal cerebellar embryonal tumor subgroups, based on the differential activity of transcription-factor-driven gene networks derived using a comprehensive single-nucleus multi-omic medulloblastoma atlas. We show that Group 3/4 tumor diversity stems from enriched cell-states along four molecular identity axes: photoreceptor, MYC, precursor, and unipolar brush cell-like. We identified a potential role ofPAX6in driving dual Group 3- and Group 4-like tumor trajectories in subtype VII tumors. Our study demonstrates how oncogenic events together with lineage determinants drive Group 3/4 tumor identity away from their original source in the cerebellar unipolar brush cell lineage.
The impact of bilateral versus unilateral anterior temporal lobe damage on face recognition, person knowledge and semantic memory
Authors: Rouse Matthew A. , Ramanan Siddharth , Halai Ajay D. , Volfart Angélique , Garrard Peter , Patterson Karalyn , Rowe James B. , Lambon Ralph Matthew A. 
Published: February 2024

AbstractIn recent years, the functional importance of the anterior temporal lobes (ATLs) has come to prominence in two active, albeit unconnected branches of the literature. In one branch, neuropsychology and functional neuroimaging evidence emphasises the role of the ATLs in face recognition and linking faces to biographical knowledge. In the other, cognitive and clinical neuroscience investigations have shown that the ATLs are critical to all forms of semantic memory. To draw these literatures together and generate a unified account of ATL function, we test the predictions arising from each literature and examine the effects of bilateralversusunilateral ATL damage on face recognition, person knowledge and semantic memory. Sixteen people with bilateral ATL atrophy from semantic dementia (SD), 17 people with unilateral ATL resection for temporal lobe epilepsy (TLE; left=10, right=7), and 14 controls completed a test battery encompassing general semantic processing, person knowledge and perceptual face matching. SD patients were severely impaired across all semantic tasks, including person knowledge. Despite commensurate total ATL damage, unilateral resection generated mild impairments, with minimal differences between left- and right-ATL resection. Face matching performance was largely preserved but slightly reduced in SD and right TLE. All groups displayed the classic familiarity effect in face matching; however, this benefit was reduced in SD and right TLE groups and was aligned with the level of item-specific semantic knowledge in all participants. We propose a unified neurocognitive framework whereby the ATLs underpin a resilient bilateral representation system that supports semantic memory, person knowledge and face recognition.
Larval protein restriction interacts with adult diet to increase fitness in an outbred multiparent population
Authors: Jones Andrew , Donnell De’anne , King Elizabeth G. , Ng’oma Enoch 
Published: February 2024

AbstractDevelopmental conditions including temperature, diet, and parasites can shape adult fitness phenotypes in many species. Studies typically focus on the additive effects of early-life and adult life conditions on life history response in the context of competing models of developmental plasticity (i.e. environmental matching and silver spoon). These models continue to yield mixed results in the same or different species. Here, we characterize interaction effects of larval vs adult diet on lifespan and fecundity in a high diversity outbred population ofDrosophila melanogaster. We compare fitness proxies of matched vs mismatched early-to-late nutritional conditions differing in protein content. Diet interactions significantly affected both traits, albeit differently. We find no consistent evidence for either model. Rather, several patterns emerged including age and sex effects, survival differences in the post-median life phase, regime-specific timing of peak fecundity, and substantial fecundities in older post-median flies. Surprisingly, lower adult protein delayed egg-laying by about 2 weeks, compared to treatments with higher protein in adult diet. Our results underscore the extent to which adult life history expression depends significantly on developmental conditions. Results further highlight the need for assessing possible adult life phase patterns which might potentially reveal trade-offs between adult life stages than traits.
Clearance of protein aggregates during cell division
Authors: Du Shoukang , Wang Yuhan , Chen Bowen , Xie Shuangshuang , Chan Kuan Yoow , Hay David C. , Chew Ting Gang 
Published: February 2024

AbstractProtein aggregates are spatially organized and regulated in cells to prevent deleterious effects of proteostatic stress. Misfolding of proteins in the endoplasmic reticulum (ER) result in aggregate formation, but how the aggregates are processed especially during cell division is not well understood. Here, we induced proteostatic stress and protein aggregation using a proteostasis reporter, which is prone to misfolding and aggregation in the ER. Unexpectedly, we detected solid-like protein aggregates deposited mainly in the nucleus and surrounded by the ER membrane. The membrane-bound aggregates were then cleared as cells progressed through mitosis and cytokinesis. Aggregate clearance depended on Hsp70 family chaperones in the ER, particularly BiP, and proteasomal activity. The clearance culminated at mitotic exit and required cyclin-dependent kinase 1 (Cdk1) inactivation and ER reorganization but was independent of the anaphase-promoting complex (APC/C). Thus, dividing cells have the capacity to clear protein aggregates to maintain proteostasis in the newly divided cells, which could have implications for human disease development and aging.
Abatacept treatment in LRBA deficient patients results in an increase in circulating FoxP3+Helios+natural Treg
Authors: Donhauser Sabine , Salzmann-Manrique Emilia , Lueck Leon Maximilian , Fekadu-Siebald Julia , Königs Christoph , Schubert Ralf , Kaffenberger Celia , Moser Laura M. , Bader Peter , Huenecke Sabine , Bakhtiar Shahrzad 
Published: February 2024

AbstractBackgroundMutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene were identified to cause autoimmunity and immunodeficiency with a broad spectrum of clinical manifestations. Increased lysosomal degradation of the CTLA-4 due to the lack of recylcing by LRBA protein has been described resulting in a reduced suppressive capacity of regulatory T cells (Treg).>ObjectiveWe sought to explore the extended Treg profile of patients with LRBA deficiency (N=6) compared to reference values for Treg subpopulations from an age-matched healthy cohort (N=39) prior and during abatacept treatment as well as after allogeneic haematopoietic stem cell transplantation. In parallel we assessed the feasibility and robustness of the CHAI and the IDDA2.1 scores for this cohort.MethodsUsing a flow cytometric approach with a pre-formulated antibody panel in peripheral blood samples, we analyzed Treg subsets including CD4+CD25hiFoxP3+Treg, Helios+natural Treg, Helios-induced Treg, CD39+Treg, CD62L+CD45RA+naïve Treg, CD62L+CD45RA-memory Treg, and FoxP3hiCD45RA-effector Treg as well as CD4+CD25hiCD127lowTreg. Longitudinal data were collected while patients were receiving abatacept and in three patients after alloHSCT. CHAI and IDDA2.1 scores were performed.ResultsThe healthy cohort including individuals from the ages of 2 to 40 years showed a steady total CD25hiFoxP3+Treg population around 5%, while there was a significant age-dependent increase in Helios+natural Treg (P=0.003), Helios-induced Treg (P=0.046), CD62L+CD45RA-memory Treg (P=0.020) with a continuous decrease in CD62L+CD45RA+naïve Treg (P=0.015) and CD4+CD25hiCD127lowTreg (P=0.024) over time. LRBA deficient patients showed a significant lack in FoxP3+Helios+natural Treg (P=0.003), CD62L+CD45RA+naïve Treg (P<0.001), FoxP3hiCD45RA+effector Treg (P=0.001) and CD4+CD25hiCD127lowTreg (P=0.005), while their CD62L+CD45RA+memory Treg (P=0.016) were significantly elevated. Abatacept treatment led to a significant increase in natural Treg (P=0.003) in patients without having a measurable effect on the other subpopulations. This was accompanied by a decrease in sIL2R levels. The IDDA2.1 score was feasible for this mainly pediatric cohort and correlated with patients’ clinical course of the disease.ConclusionWithin the Treg subsets in peripheral blood of LRBA deficient patients, there is a significant lack of natural, naïve, effector and CD4+CD25hiCD127lowTreg, while memory Treg are elevated. During abatacept treatment we observe a significant increase in circulating Helios+natural Treg levels. IDDA2.1 scoring system is feasible for pediatric patients to assess the severity of their disease and the response to the treatment.
A Phase II Study Integrating a Single-Blind Safety Phase with a Double-Blind, Placebo-Controlled Randomized Phase, Assessing Single-Dose Intramuscular or Intranasal Administration to Evaluate the Safety and Immunogenicity of the Recombinant Vaccine Against COVID-19 (AVX/COVID-12 “Patria”) Based on an Active Newcastle Disease Viral Vector as a Heterologous Booster in Subjects with Evidence of Previous Immunity to SARS-CoV-2
Authors: López-Macías Constantino , Torres Martha , Armenta-Copca Brenda , Wacher Niels , Castro-Castrezana Laura , Colli-Domínguez Andrea Alicia , Rivera-Hernández Tania , Torres-Flores Alejandro , Ramírez-Martínez Luis , Paz-De la Rosa Georgina , Rojas-Martínez Oscar , Suárez-Martínez Alejandro , Peralta-Sánchez Gustavo , Carranza Claudia , Juárez Esmeralda , Zamudio-Meza Horacio , Carreto-Binaghi Laura E. , Viettri Mercedes , Romero-Rodríguez Damaris , Palencia Andrea , Reyna-Rosas Edgar , Márquez-García José E. , Sarfati-Mizrahi David , Sun Weina , Chagoya-Cortés Héctor Elías , Castro-Peralta Felipa , Palese Peter , Krammer Florian , García-Sastre Adolfo , Lozano-Dubernard Bernardo 
Published: February 2024

AbstractBackgroundThe global inequity in coronavirus disease 2019 (COVID-19) vaccine distribution, primarily affecting low- and middle-income countries (LMICs), highlights the urgent need for innovative and cost-effective vaccine technologies to address availability disparities. This is crucial for achieving and sustaining widespread immunity and protecting vulnerable populations during future booster campaigns.MethodsTo address this need, we conducted a phase II clinical trial evaluating the safety and immunogenicity of the AVX/COVID-12 “Patria” vaccine as a booster dose. The vaccine was administered through both intramuscular (IM) and intranasal (IN) routes to participants who had previously received severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines based on adenoviral technology, inactivated virus, or mRNA technology. The inclusion criterion involved individuals with initial anti-spike IgG titers below 1,200 U/mL, allowing observation of the booster effect induced by vaccination.ResultsImmunization with AVX/COVID-12 resulted in a significant (>2.5 times) increase in neutralizing antibodies against the original Wuhan strain and variants of concern (VOCs) such as Alpha, Beta, Delta, and Omicron (BA.2 and BA.5). This immune response was accompanied by cellular interferon-gamma (IFN-γ) production, indicating a robust and multifaceted reaction.ConclusionsThe administration of AVX/COVID-12 as a booster dose, whether through IM or IN routes, was safe and well-tolerated. The vaccine extended immune responses not only against the original Wuhan-1 strain but also against various VOCs. Its ability to enhance preexisting immune responses suggests a potential contribution to expanding and sustaining herd immunity within the population.