bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Diagnosis Is Highly Predictive of Laboratory-Confirmed Mpox in a Sexual Health Clinic
Authors: Cannon Chase A. , Karmarkar Ellora N. , Ramchandani Meena S. , Dombrowski Julia C. , Golden Matthew R.
Published: February 2024

Background

Promptly recognizing mpox can facilitate earlier diagnosis and appropriate treatment. How accurately clinicians can diagnose mpox based on clinical data and before receiving molecular test results is not known.

Methods

Leveraging public health and clinical data collected in Seattle–King County's Sexual Health Clinic (SHC) from July 29, 2022, to September 30, 2022, we analyzed the proportion of patients who received presumptive versus results-based tecovirimat when clinicians had a high, intermediate, or low suspicion for mpox after clinical evaluation. We calculated the sensitivity, specificity, and positive (PPV) and negative predictive value (NPV) of this approach against criterion standard mpox polymerase chain reaction (PCR) results.

Results

Of 321 patients evaluated for mpox in the SHC, median age was 34.5 years and 88% were cisgender men. Overall, 121 of 319 (38%) tested positive by mpox PCR. Clinicians had high suspicion for mpox in 122 patients and offered empiric tecovirimat to 92 (88%), of whom 85 (92%) tested PCR positive. Of 13 intermediate suspicion patients offered presumptive therapy, all accepted but none tested positive by PCR. The sensitivity, specificity, PPV, and NPV of high/intermediate clinical suspicion for mpox were 99%, 90%, 86%, and 99%, respectively. A higher proportion of people with HIV were diagnosed with mpox (57% vs. 36%, P = 0.01, χ
2 test), and sensitivity and PPV of high/intermediate clinical suspicion in this subgroup were 100% and 86%, respectively.

Conclusions

Clinical providers working in a high-volume, public SHC were able to both accurately identify and rule out mpox based on clinical examination before receiving PCR test results.
Comparison of Ultrasound Guided Saline Enema and X-ray-Guided Air Enema in the Treatment of Intussusception Reduction in Children
Authors: Lian Dan-Dan , Sun Chen
Published: February 2024

To compare the effect of ultrasound guided saline enema (USGSE) and x-ray fluoroscopic air enema in the reduction of intussusception in children, 80 children with intussusception were randomly divided into ultrasonic-guided saline enema reduction in 40 cases (USGSE group) and x-ray air enema reduction in 40 cases (air enema group). The enema pressure, success rate, average time, and cost of the 2 methods were compared. The average operation time of the USGSE group was lower than that of the air group ([5.35 ± 1.79] min vs [6.03 ± 2.41] min, P = 0.159), the average pressure of the air group was higher than that of the air group ([10.95 ± 1.54] kPa vs [9.6 ± 1.26] kPa; P < 0.001), the success rate of resetting was higher than that of the air group (87.5% vs 85.0%; P = 0.745), and the cost of USGSE was lower than that of the air group ([339.23 ± 10.73] yuan vs [378.23 ± 18.20] yuan, P < 0.001). Subgroup analysis showed that the success rate of enema treatment in children with onset time <48 hours was significantly higher than that in children with onset time ≥48 hours (98.30% vs 54.50%, continuous correction χ2 = 22.16; P < 0.001). The success rate and operation time of USGSE in pediatric intussusception reduction are similar to that of air enema, and the advantages of low cost and no radiation are worthy of popularization. For children with onset time ≥48 hours, enema reduction is safe and effective, but the conversion rate to open is high. It is necessary to carefully identify the symptoms of intestinal perforation and necrosis on the basis of strictly following the indications to avoid delayed treatment.
Reasons for Removal of Rigid Internal Fixation Devices in Craniofacial Surgery: A 20-year Update
Authors: Lynn Jeremy V. , Daniel Melissa C. , Jackson Charlotte M. K. , Ulma Raquel M. , Vercler Christian J. , Kasten Steven J. , Buchman Steven R.
Published: February 2024

The hardware utilized for rigid internal fixation of the craniofacial skeleton has evolved over time. Thus, the reasons for the unplanned removal of hardware continue to change. The purpose of this study is to compare past (1989–1995) and present (2000–2020) patient cohorts to establish trends related to unplanned removal of craniofacial hardware. A retrospective review study was designed. Data from our institution’s original publication describing the unplanned removal of craniofacial hardware (1989-1995) was obtained. Data related to patients who underwent unplanned removal of hardware from 2000 to 2020 was collected from the electronic medical record. A descriptive statistical analysis was performed to compare demographics, reasons for hardware placement, and reasons for unplanned hardware removal between cohorts. This study includes 55 patients treated from 1989 to 1995 and 184 patients treated from 2000 to 2020. The average age at hardware placement decreased from 32 years (1989–1995) to 28 years (2000–2020). The most common reason for hardware placement changed from motor vehicle accident (1989–1995) to congenital deformity (2000–2020). The length of time with hardware in situ increased from 13 months (1989–1995) to 25 months (2000–2020). The most common reason for hardware removal changed from prominent hardware (1989–1995) to hardware exposure (2000–2020). In summary, patients who underwent rigid internal fixation of the craniofacial skeleton from 2000 to 2020 retained their hardware 2 times longer than patients treated from 1989 to 1995. Factors potentially contributing to increased retention include improved surgical technique, decreased profile of hardware, and increased surgeon experience. Further studies are warranted to define preoperative risk factors for unplanned hardware removal.
Salvage of Extensive Skin Graft Necrosis After Auricle Reconstruction by Using Modified Nagata Method
Authors: Lu Peng , Qian Jin , Wang Yue , Liu Tun , Wang Bingqing , Zhang Qingguo
Published: February 2024

Extensive skin graft necrosis after auricle reconstruction surgery is a thorny problem for plastic surgeons. Four unilateral microtia patients were enrolled for extensive skin graft necrosis after ear elevation surgery. Early debridement and daily dressing changes were important for preoperative preparation. Surgical treatments involved local flaps and secondary split-thickness skin graft. After 3 to 12 months of follow-up, clear surface structures and obvious auricular sulcus were shown in all 4 patients. No cartilage exposure, skin necrosis, healing impairment, or other complications were found. We attribute the cause of extensive skin graft necrosis to subcutaneous hematoma. Local skin flaps and split-thickness skin grafting can be effective treatments for such situations. The use of temporoparietal fascial flap is unnecessary when poor graft survival is caused by subcutaneous hematoma.
Belonging in Surgery
Authors: Acker Rachael C. , Sharpe James , Shea Judy A. , Ginzberg Sara P. , Bakillah Emna , Rosen Claire B. , Finn Caitlin B. , Roberts Sanford E. , Ajmera Sonia , Kelz Rachel R.
Published: February 2024

Objective:

The aim of this study was to develop and validate an instrument to measure Belonging in Surgery among surgical residents.

Background:

Belonging is the essential human need to maintain meaningful relationships and connections to one’s community. Increased belongingness is associated with better well-being, job performance, and motivation to learn. However, no tools exist to measure belonging among surgical trainees.

Methods:

A panel of experts adapted a belonging instrument for use among United States surgery residents. After administration of the 28-item instrument to residents at a single institution, a Cronbach alpha was calculated to measure internal consistency, and exploratory principal component analyses were performed. Multiple iterations of analyses with successively smaller item samples suggested the instrument could be shortened. The expert panel was reconvened to shorten the instrument. Descriptive statistics measured demographic factors associated with Belonging in Surgery.

Results:

The overall response rate was 52% (114 responses). The Cronbach alpha among the 28 items was 0.94 (95% CI: 0.93−0.96). The exploratory principal component analyses and subsequent Promax rotation yielded 1 dominant component with an eigenvalue of 12.84 (70% of the variance). The expert panel narrowed the final instrument to 11 items with an overall Cronbach alpha of 0.90 (95% CI: 0.86, 0.92). Belonging in Surgery was significantly associated with race (Black and Asian residents scoring lower than White residents), graduating with one’s original intern cohort (residents who graduated with their original class scoring higher than those that did not), and inversely correlated with resident stress level.

Conclusions:

An instrument to measure Belonging in Surgery was validated among surgical residents. With this instrument, Belonging in Surgery becomes a construct that may be used to investigate surgeon performance and well-being.
SHIP-1 differentially regulates IgE-induced IL-10 and antiviral responses in human monocytes
Authors: Solleti Siva Kumar , Matthews Bailey E. , Rowe Regina K.
Published: February 2024

IgE-mediated stimulation of monocytes regulates multiple cellular functions including cellular maturation, cytokine release, antiviral responses, and T cell priming and differentiation. The high affinity IgE receptor, FcεRI, is closely linked to serum IgE levels and atopic disease. The signaling molecules which regulate effector functions of this receptor have been well studied in mast cells and basophils, however, less is known about the signaling components, regulatory molecules, and mechanisms downstream of receptor activation in monocytes. This study sought to identify regulators of IgE-mediated cytokine release in human monocytes. SHIP-1 was identified as a negative regulator of IgE-induced IL-10 production. It was also determined that IgE-mediated stimulation and SHIP-1 inhibition decreased antiviral IP-10 production after liposomal poly(I:C) stimulation, indicating differential regulation by SHIP-1 in IgE-driven and antiviral response pathways. Both SHIP-1 and NF-κB were activated following IgE-mediated stimulation of primary monocytes, and NF-κB activation was related to both SHIP-1 and FcεRIα expression levels in monocytes. To our knowledge this is the first study to identify a role for SHIP-1 in regulating IgE-driven responses and antiviral responses in human monocytes. Given the importance of monocytes in inflammation and immune responses, a better understanding of the signaling and regulatory mechanisms downstream of FcεRI receptor could lead to new therapeutic targets in allergic disease.
CoCoPyE: feature engineering for learning and prediction of genome quality indices
Authors: Birth Niklas , Leppich Nicolina , Schirmacher Julia , Andreae Nina , Steinkamp Rasmus , Blanke Matthias , Meinicke Peter
Published: February 2024

The exploration of the microbial world has been greatly advanced by the reconstruction of genomes from metagenomic sequence data. However, the rapidly increasing number of metagenome-assembled genomes has also resulted in a wide variation in data quality. It is therefore essential to quantify the achieved completeness and possible contamination of a reconstructed genome before it is used in subsequent analyses. The classical approach for the estimation of quality indices solely relies on a relatively small number of universal single copy genes. Recent tools try to extend the genomic coverage of estimates for an increased accuracy. CoCoPyE is a fast tool based on a novel two-stage feature extraction and transformation scheme. First it identifies genomic markers and then refines the marker-based estimates with a machine learning approach. In our simulation studies, CoCoPyE showed a more accurate prediction of quality indices than the existing tools.
scGrapHiC : Deep learning-based graph deconvolution for Hi-C using single cell gene expression
Authors: Murtaza Ghulam , Butaney Byron , Wagner Justin , Singh Ritambhara
Published: February 2024

Single-cell Hi-C (scHi-C) protocol helps identify cell-type-specific chromatin interactions and sheds light on cell differentiation and disease progression. Despite providing crucial insights, scHi-C data is often underutilized due the high cost and the complexity of the experimental protocol. We present a deep learning framework, scGrapHiC, that predicts pseudo-bulk scHi-C contact maps using pseudo-bulk scRNA-seq data. Specifically, scGrapHiC performs graph deconvolution to extract genome-wide single-cell interactions from a bulk Hi-C contact map using scRNA-seq as a guiding signal. Our evaluations show that scGrapHiC, trained on 7 cell-type co-assay datasets, outperforms typical sequence encoder approaches. For example, scGrapHiC achieves a substantial improvement of 23.2% in recovering cell-type-specific Topologically Associating Domains over the baselines. It also generalizes to unseen embryo and brain tissue samples. scGrapHiC is a novel method to generate cell-type-specific scHi-C contact maps using widely available genomic signals that enables the study of cell-type-specific chromatin interactions.

Availability

https://github.com/rsinghlab/scGrapHiC

Contact

ritambhara@brown.edu
A common set of structurally distinct endogenous retroviruses predict survival in multiple human tumor types
Authors: Massa Alexandra L. , Chintalapudi Himanshu , Coppenbarger Evelyn C. , Peterson Jake M. , Moss Walter N. , Frost H. Robert , Leach Steven D.
Published: February 2024

Accumulating evidence suggests that viral mimicry induction in cancer cells through the expression of human endogenous retroviral elements (ERVs) enhances tumor immunogenicity and improves response to immunotherapy. However, the characterization of ERV expression across multiple tumor types, their clinical relevance, and their role in tumor immunity remain limited. Here, we assessed the prognostic and immune-related consequences of ERV expression across 8 different tumor types from The Cancer Genome Atlas (TCGA). We applied a recently developed tool, Telescope, to quantify the expression of 14,968 ERVs in bulk tumor RNA-sequencing data. Approximately 15-22% of Telescope’s ERVs (navg= 2,736) were expressed in each tumor cohort. We identified both tissue-specific and commonly expressed ERVs across cohorts. Over 50% of tissue-specific ERVs were ubiquitously expressed (n = 1,709) across all 8 tumor types. Using patient clinical data, we identified a subset of 94 ERVs whose expression levels were significantly associated with overall survival, of which 42 were favorably prognostic. Prognostic ERVs displayed unique structural characteristics, including more frequent inverted repeats and more stable secondary structures. Patients were classified based on ERV expression, allowing identification of patient cohorts with greater than 6-fold differences in overall survival. We also found that expression of positively prognostic ERVs was associated with enrichment for selected anti-tumor immune response gene expression signatures. This analysis extends previous results identifying patterns of ERV expression in bulk tumor RNA-seq datasets, providing further insight into the role of ERVs in tumor clinicopathology and immunogenicity.
Marine phytoplankton and heterotrophic bacteria rapidly adapt to future pCO2conditions in experimental co-cultures
Authors: Lu Zhiying , Entwistle Elizabeth , Kuhl Matthew D. , Durrant Alexander R. , Filho Marcelo Malisano Barreto , Goswami Anuradha , Morris J. Jeffrey
Published: February 2024

The CO2content of Earth’s atmosphere is rapidly increasing due to human consumption of fossil fuels. Models based on short-term culture experiments predict that major changes will occur in marine phytoplankton communities in the future ocean, but these models rarely consider how the evolutionary potential of phytoplankton or interactions within marine microbial communities may influence these changes. Here we experimentally evolved representatives of four phytoplankton functional types (silicifiers, calcifiers, coastal cyanobacteria, and oligotrophic cyanobacteria) in co-culture with a heterotrophic bacterium,Alteromonas, under either present-day or predicted future pCO2conditions. Growth rates of cyanobacteria generally increased under both conditions, and the growth defects observed in ancestralProchlorococcuscultures at elevated pCO2and in axenic culture were diminished after evolution, possibly due to regulatory mutations in antioxidant genes. Except forProchlorococcus, mutational profiles suggested phytoplankton experienced primarily purifying selection, but mostAlteromonaslineages showed evidence of directional selection, especially when co-cultured with eukaryotic phytoplankton, where evolution appeared to favor a broad metabolic switch from growth on small organic acids to catabolism of more complex carbon substrates. EvolvedAlteromonaswere also poorer “helpers” forProchlorococcus, supporting the assertion that the interaction betweenProchlorococcusand heterotrophic bacteria is not a true mutualism but rather a competitive interaction stabilized by Black Queen processes. This work provides new insights on how phytoplankton will respond to anthropogenic change and on the evolutionary mechanisms governing the structure and function of marine microbial communities.
Global genomic epidemiology ofblaGES-5carbapenemase-associated integrons
Authors: Matlock William , Shaw Liam P. , Stoesser Nicole
Published: February 2024

Antimicrobial resistance (AMR) gene cassettes comprise an AMR gene flanked by short recombination sites (attI×attCorattC×attC). Integrons are genetic elements able to capture, excise, and shuffle these cassettes, providing ‘adaptation on demand’, and can be found on both chromosomes and plasmids. Understanding the patterns of integron diversity may help to understand the epidemiology of AMR genes. As a case study, we examined the clinical resistance geneblaGES-5, an integron-associated class A carbapenemase first reported in Greece in 2004 and since observed worldwide, which to our knowledge has not been the subject of a previous global analysis. Using a dataset comprising all NCBI contigs containingblaGES-5(n= 431), we developed a pangenome graph-based workflow to characterise and cluster the diversity ofblaGES-5-associated integrons. We demonstrate thatblaGES-5-associated integrons on plasmids are different to those on chromosomes. Chromosomal integrons were almost all identified inP. aeruginosaST235, with a consistent gene cassette content and order. We observed instances where insertion sequence IS110disruptedattCsites, which might immobilise the gene cassettes and explain the conserved integron structure despite the presence ofintI1integrase promoters, which would typically facilitate capture or excision and rearrangement. The plasmid-associated integrons were more diverse in their gene cassette content and order, which could be an indication of greater integrase activity and ‘shuffling’ of integrons on plasmids.
Parvalbumin Interneuron Impairment Leads to Synaptic Transmission Deficits and Seizures inSCN8AEpileptic Encephalopathy
Authors: Miralles Raquel M. , Boscia Alexis R. , Kittur Shrinidhi , Vundela Shreya R. , Wengert Eric R. , Patel Manoj K.
Published: February 2024

SCN8Aepileptic encephalopathy (EE) is a severe epilepsy syndrome resulting fromde novomutations in the voltage-gated sodium channel Nav1.6, encoded by the geneSCN8A. Nav1.6 is expressed in both excitatory and inhibitory neurons, yet previous studies have primarily focused on the impactSCN8Amutations have on excitatory neuron function, with limited studies on the importance of inhibitory interneurons to seizure onset and progression. Inhibitory interneurons are critical in balancing network excitability and are known to contribute to the pathophysiology of other epilepsies. Parvalbumin (PV) interneurons are the most prominent inhibitory neuron subtype in the brain, making up about 40% of inhibitory interneurons. Notably, PV interneurons express high levels of Nav1.6. To assess the role of PV interneurons withinSCN8AEE, we used two mouse models harboring patient-derivedSCN8Again-of-function mutations,Scn8aD/+, where theSCN8Amutation N1768D is expressed globally, andScn8aW/+-PV, where theSCN8Amutation R1872W is selectively expressed in PV interneurons. Expression of the R1872WSCN8Amutation selectively in PV interneurons led to the development of spontaneous seizures inScn8aW/+-PV mice and seizure-induced death, decreasing survival compared to wild-type. Electrophysiology studies showed that PV interneurons inScn8aD/+andScn8aW/+-PV mice were susceptible to depolarization block, a state of action potential failure.Scn8aD/+andScn8aW/+-PV interneurons also exhibited increased persistent sodium current, a hallmark ofSCN8Again-of-function mutations that contributes to depolarization block. Evaluation of synaptic connections between PV interneurons and pyramidal cells showed an increase in synaptic transmission failure at high frequencies (80-120Hz) as well as an increase in synaptic latency inScn8aD/+andScn8aW/+-PV interneurons. These data indicate a distinct impairment of synaptic transmission inSCN8AEE, potentially decreasing overall cortical network inhibition. Together, our novel findings indicate that failure of PV interneuron spiking via depolarization block along with frequency-dependent inhibitory synaptic impairment likely elicits an overall reduction in the inhibitory drive inSCN8AEE, leading to unchecked excitation and ultimately resulting in seizures and seizure-induced death.
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

Pluripotent 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

The 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

The 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

Basal 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

Angelman 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.

Teaser

Human 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

Inflammatory 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

Resolving 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

In 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

Developmental 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

Protein 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

Background

Mutations 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).

>Objective

We 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.

Methods

Using 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.

Results

The 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.

Conclusion

Within 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

Background

The 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.

Methods

To 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.

Results

Immunization 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.

Conclusions

The 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.
Using high-resolution functional MRI to differentiate impacts of strabismic and anisometropic amblyopia on evoked ocular dominance activity in humans
Authors: Nasr Shahin , Skerswetat Jan , Gaier Eric D. , Malladi Sarala N. , Kennedy Bryan , Tootell Roger B.H. , Bex Peter , Hunter David G.
Published: February 2024

We employed high-resolution functional MRI (fMRI) to distinguish the impacts of anisometropia and strabismus (the two most frequent causes of amblyopia) on the evoked ocular dominance (OD) response. Sixteen amblyopic participants (8 females), comprising 8 individuals with strabismus, 7 with anisometropia, 1 with deprivational amblyopia, along with 8 individuals with normal visual acuity (1 female), participated in this study for whom, we measured the difference between the response to stimulation of the two eyes, across early visual areas (V1-V4).

In controls, as expected from the organization of OD columns, the evoked OD response formed a striped pattern that was mostly confined to V1. Compared to controls, the OD response in amblyopic participants formed larger fused patches that extended into downstream visual areas. Moreover, both anisometropic and strabismic participants showed stronger OD responses in V1, as well as in downstream visual areas V2-V4. Although this increase was most pronounced in V1, the correlation between the OD response level and the interocular visual acuity difference (measured behaviorally) was stronger in higher-level visual areas (V2–V4).

Beyond these common effects, and despite similar densities of amblyopia between the anisometropic and strabismic participants, we found a greater increase in the size of V1 portion that responded preferentially to fellow eye stimulation in anisometropic compared to strabismic individuals. We also found a greater difference between the amplitudes of the response to binocular stimulation, in those regions that responded preferentially to the fellow vs. amblyopic eye, in anisometropic compared to strabismic subjects. In contrast, strabismic subjects demonstrated increased correlation between the OD responses evoked within V1 superficial and deep cortical depths, whereas anisometropic subjects did not.

These results provide some of the first direct functional evidence for distinct impacts of strabismus and anisometropia on the mesoscale functional organization of the human visual system, thus extending what was inferred previously about amblyopia from animal models.