bluuebunny/crossref_metadata_2025_split huggingface dataset:
Olfactory detection of viruses shapes brain immunity and behavior in zebrafish
Authors: Kraus Aurora , Garcia Benjamin , Ma Jie , Herrera Kristian J. , Zwaka Hanna , Harpaz Roy , Wong Ryan Y. , Engert Florian , Salinas Irene 
Published: March 2023

AbstractOlfactory sensory neurons (OSNs) are constantly exposed to pathogens, including viruses. However, serious brain infection via the olfactory route rarely occurs. When OSNs detect a virus, they coordinate local antiviral immune responses to stop virus progression to the brain. Despite effective immune control in the olfactory periphery, pathogen-triggered neuronal signals reach the CNS via the olfactory bulb (OB). We hypothesized that neuronal detection of a virus by OSNs initiates neuroimmune responses in the OB that prevent pathogen invasion. Using zebrafish (Danio rerio) as a model, we demonstrate viral-specific neuronal activation of OSNs projecting into the OB, indicating that OSNs are electrically activated by viruses. Further, behavioral changes are seen in both adult and larval zebrafish after viral exposure. By profiling the transcription of single cells in the OB after OSNs are exposed to virus, we found that both microglia and neurons enter a protective state. Microglia and macrophage populations in the OB respond within minutes of nasal viral delivery followed decreased expression of neuronal differentiation factors and enrichment of genes in the neuropeptide signaling pathway in neuronal clusters. Pituitary adenylate-cyclase-activating polypeptide (pacap), a known antimicrobial, was especially enriched in a neuronal cluster. We confirm that PACAP is antiviralin vitroand that PACAP expression increases in the OB 1 day post-viral treatment. Our work reveals how encounters with viruses in the olfactory periphery shape the vertebrate brain by inducing antimicrobial programs in neurons and by altering host behavior.
Evidence of depression affecting multimorbidity in survey data from the Brazilian population
Authors: Silva Castro-de-Araujo Luis Fernando , de Araujo Jacyra Azevedo Paiva , Rodrigues Elisângela da Silva , Rodrigues Rodrigo Lins , Kanaan Richard A 
Published: March 2023

AbstractObjectivesDepression is associated with multimorbidity, the occurrence of two or more chronic diseases. Although the effect of multimorbidity on depression is relatively well known, the opposite effect is less well studied. We aimed to examine the effect of depression on multimorbidity using data from a nationally representative Brazilian survey.MethodsWe used information from all respondents above 15 years of age of the Brazilian National Survey on Access, Use, and Promotion of the Rational Use of Medicines (PNAUM) from 2014. A structural equation model was fit to the data with a specification that included the relationship between depressive syndrome and multimorbidity, controlled by age and body mass index.ResultsThe data set comprised 28,382 subjects. The model presented fit the data well, and revealed a statistically significant, positive, moderate-size effect (0.355) of depression on multimorbidity.ConclusionDepression appears to make a moderate contribution to the development of multimorbidity.
A central serotonin regulating gene polymorphism (TPH2) determines vulnerability to acute tryptophan depletion-induced anxiety and ventromedial prefrontal threat reactivity
Authors: Liu Congcong , Li Keshuang , Fu Meina , Zhang YingYing , Sindermann Cornelia , Montag Christian , Zheng Xiaoxiao , Zhang Hongxing , Shuxia Yao , Wang Zheng , Zhou Bo , Kendrick Keith M. , Becker Benjamin 
Published: March 2023

AbstractSerotonin (5-HT) has long been implicated in adaptive emotion regulation as well as the development and treatment of emotional dysregulations in mental disorders. Accumulating evidence suggests that a genetic vulnerability may render some individuals at a greater risk for the detrimental effects of transient variations in 5-HT signaling. The present study aimed to investigate whether individual variations in the Tryptophan hydroxylase 2 (TPH2) genetics influence susceptibility for behavioral and neural threat reactivity dysregulations during transiently decreased 5-HT signaling. To this end, interactive effects between TPH2 (rs4570625) genotype and acute tryptophan depletion (ATD) on reactivity towards angry, neutral and happy faces were examined in a within-subject placebo-controlled pharmacological fMRI trial (n = 51). An a priori genotype stratification approach of extreme groups (GG vs. TT) allowed balanced sampling. While no main effects of ATD on neural reactivity to threat-related stimuli and mood state were observed in the entire sample, accounting for TPH2 genotype revealed an ATD-induced increase in subjective anxious arousal in the GG but not the TT carriers. The effects were mirrored on the neural level, such that ATD specifically reduced ventromedial prefrontal cortex (vmPFC) reactivity towards threat-related stimuli in the GG carriers. Furthermore, the ATD-induced increase in subjective anxiety positively associated with the extent of ATD-induced changes in vmPFC activity in response to threat-related stimuli in GG carriers. Together the present findings suggest for the first time that individual variations in TPH2 genetics render individuals susceptible to the anxiogenic and neural effects of a transient decrease in 5-HT signaling.
Mouse Adapted SARS-CoV-2 Model Induces “Long-COVID” Neuropathology in BALB/c Mice
Authors: Gressett Timothy E. , Leist Sarah R. , Ismael Saifudeen , Talkington Grant , Dinnon Kenneth H. , Baric Ralph S. , Bix Gregory 
Published: March 2023

AbstractThe novel coronavirus SARS-CoV-2 has caused significant global morbidity and mortality and continues to burden patients with persisting neurological dysfunction. COVID-19 survivors develop debilitating symptoms to include neuro-psychological dysfunction, termed “Long COVID”, which can cause significant reduction of quality of life. Despite vigorous model development, the possible cause of these symptoms and the underlying pathophysiology of this devastating disease remains elusive. Mouse adapted (MA10) SARS-CoV-2 is a novel mouse-based model of COVID-19 which simulates the clinical symptoms of respiratory distress associated with SARS-CoV-2 infection in mice. In this study, we evaluated the long-term effects of MA10 infection on brain pathology and neuroinflammation. 10-week and 1-year old female BALB/cAnNHsd mice were infected intranasally with 104plaque-forming units (PFU) and 103PFU of SARS-CoV-2 MA10, respectively, and the brain was examined 60 days post-infection (dpi). Immunohistochemical analysis showed a decrease in the neuronal nuclear protein NeuN and an increase in Iba-1 positive amoeboid microglia in the hippocampus after MA10 infection, indicating long-term neurological changes in a brain area which is critical for long-term memory consolidation and processing. Importantly, these changes were seen in 40-50% of infected mice, which correlates to prevalence of LC seen clinically. Our data shows for the first time that MA10 infection induces neuropathological outcomes several weeks after infection at similar rates of observed clinical prevalence of “Long COVID”. These observations strengthen the MA10 model as a viable model for study of the long-term effects of SARS-CoV-2 in humans. Establishing the viability of this model is a key step towards the rapid development of novel therapeutic strategies to ameliorate neuroinflammation and restore brain function in those suffering from the persistent cognitive dysfunction of “Long-COVID”.
ATG5 suppresses type I IFN-dependent neutrophil swarming and NETosis
Authors: Kinsella Rachel L. , Chowdhury Chanchal Sur , Smirnov Asya , Mreyoud Yassin , Kimmey Jacqueline M. , Esaulova Ekaterina , Kreamalmeyer Darren , Artyomov Maxim N. , Stallings Christina L. 
Published: March 2023

SUMMARYInflammation is critical for controlling infections, but when left unchecked can cause tissue damage and disease. For tuberculosis, the leading cause of death due to infection1, host inflammation is responsible for the clinical symptoms2, morbidity2, and mortality3,4. Specifically, neutrophil-dominated inflammation is associated with tuberculosis disease progression3,5,6. Therefore, understanding how neutrophil functions are regulated during infection is important for developing ways to prevent disease.Atg5was the first gene shown to specifically function within neutrophils to promote control ofMycobacterium tuberculosis7, the causative agent of tuberculosis. ATG5 is best studied for its role in autophagy8–11, however, the protective activity of ATG5 in neutrophils was unexpectedly independent of other autophagy proteins and remained elusive7. We report here that ATG5, but not other autophagy proteins, is required in neutrophils to suppress neutrophil NETosis and swarming that occur due to elevated type I interferon levels duringM. tuberculosisinfection. The elevated level of NETosis that results from loss of ATG5 expression contributes to the early susceptibility ofAtg5fl/fl-LysM-Cremice duringM. tuberculosisinfection. NETosis is associated with poor disease outcomes in tuberculosis12,13and COVID-19 patients14,15, as well as during other inflammatory diseases in humans16,17. Our studies identify an essential regulator of NETosis and elucidate previously unappreciated roles for ATG5 during infection, which may inform the design of host-directed therapeutics modulating these pathways.
Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice
Authors: Brown Ariane J. , Won John J. , Wolfisberg Raphael , Fahnøe Ulrik , Catanzaro Nicholas , West Ande , Moreira Fernando R. , Batista Mariana Nogueira , Ferris Martin T. , Linnertz Colton L. , Leist Sarah R. , Nguyen Cameron , De la Cruz Gabriela , Midkiff Bentley R. , Xia Yongjuan , Montgomery Stephanie A. , Billerbeck Eva , Bukh Jens , Scheel Troels K.H. , Rice Charles M. , Sheahan Timothy P. 
Published: March 2023

AbstractBackground & AimsHuman genetic variation is thought to guide the outcome of hepatitis C virus (HCV) infection but model systems within which to dissect these host genetic mechanisms are limited. Norway rat hepacivirus (NrHV), closely related to HCV, causes chronic liver infection in rats but causes acute self-limiting hepatitis in typical strains of laboratory mice, which resolves in two weeks. The Collaborative Cross (CC) is a robust mouse genetics resource comprised of a panel of recombinant inbred strains, which model the complexity of the human genome and provide a system within which to understand diseases driven by complex allelic variation.Approach & ResultsWe infected a panel of CC strains with NrHV and identified several that failed to clear virus after 4 weeks. Strains displayed an array of virologic phenotypes ranging from delayed clearance (CC046) to chronicity (CC071, CC080) with viremia for at least 10 months. Body weight loss, hepatocyte infection frequency, viral evolution, T-cell recruitment to the liver, liver inflammation and the capacity to develop liver fibrosis varied among infected CC strains.ConclusionsThese models recapitulate many aspects of HCV infection in humans and demonstrate that host genetic variation affects a multitude of virus and host phenotypes. These models can be used to better understand the molecular mechanisms that drive hepacivirus clearance and chronicity, the virus and host interactions that promote chronic disease manifestations like liver fibrosis, therapeutic and vaccine performance, and how these factors are affected by host genetic variation.
SARS-CoV-2 NSP12 associates with the TRiC complex and the P323L substitution is a host adaption
Authors: Alruwaili Muhannad , Armstrong Stuart , Prince Tessa , Erdmann Maximilian , Matthews David A. , Davidson Andrew , Aljabr Waleed , Hiscox Julian A. 
Published: March 2023

SummarySARS-CoV-2 emerged into the human population in late 2019 and human to human transmission has dominated the evolutionary landscape and driven the selection of different lineages. The first major change that resulted in increased transmission was the D614G substitution in the spike protein. This was accompanied by the P323L substitution in the viral RNA dependent RNA polymerase (RdRp) (NSP12). Together, with D614G these changes are the root of the predominant global SARS-CoV-2 landscape. Here, we found that NSP12 formed an interactome with cellular proteins. The functioning of NSP12 was dependent on the T-complex protein Ring Complex, a molecular chaperone. In contrast, there was differential association between NSP12 variants and components of a phosphatase complex (PP2/PP2A and STRN3). Virus expressing NSP12L323was less sensitive to perturbations in PP2A and supports the paradigm that ongoing genotype to phenotype adaptation of SARS- CoV-2 in humans is not exclusively restricted to the spike protein.
Data-driven control of airborne infection risk and energy use in buildings
Authors: Risbeck Michael J. , Cohen Alexander E. , Douglas Jonathan D. , Jiang Zhanhong , Fanone Carlo , Bowes Karen , Doughty Jim , Turnbull Martin , DiBerardinis Louis , Lee Young M. , Bazant Martin Z. 
Published: March 2023

AbstractThe global devastation of the COVID-19 pandemic has led to calls for a revolution in heating, ventilation, and air conditioning (HVAC) systems to improve indoor air quality (IAQ), due to the dominant role of airborne transmission in disease spread. While simple guidelines have recently been suggested to improve IAQ mainly by increasing ventilation and filtration, this goal must be achieved in an energy-efficient and economical manner and include all air cleaning mechanisms. Here, we develop a simple protocol to directly, quantitatively, and optimally control transmission risk while minimizing energy cost. We collect a large dataset of HVAC and IAQ measurements in buildings and show how models of infectious aerosol dynamics and HVAC operation can be combined with sensor data to predict transmission risk and energy consumption. Using this data, we also verify that a simple safety guideline is able to limit transmission risk in full data-driven simulations and thus may be used to guide public health policy. Our results provide a comprehensive framework for quantitative control of transmission risk using all available air cleaning mechanisms in an indoor space while minimizing energy costs to aid in the design and automated operation of healthy, energy-efficient buildings.
Mutant forms of DDX3X with diminished catalysis form hollow condensates that exhibit sex-specific regulation
Authors: Owens Michael C. , Shen Hui , Yanas Amber , Mendoza-Figueroa Maria Saraí , Lavorando Ellen , Wei Xiaoyu , Shweta Him , Tang Hsin-Yao , Goldman Yale E. , Liu Kathy Fange 
Published: March 2023

AbstractMutations in the RNA helicase DDX3X, implicated in various cancers and neurodevelopmental disorders, often impair RNA unwinding and translation. However, the mechanisms underlying this impairment and the differential interactions of DDX3X mutants with wild-type (WT) X-linked DDX3X and Y-linked homolog DDX3Y remain elusive. This study reveals that specific DDX3X mutants more frequently found in disease form distinct hollow condensates in cells. Using a combined structural, biochemical, and single-molecule microscopy study, we show that reduced ATPase and RNA release activities contribute to condensate formation and the catalytic deficits result from inhibiting the catalytic cycle at multiple steps. Proteomic investigations further demonstrate that these hollow condensates sequester WT DDX3X/DDX3Y and other proteins crucial for diverse signaling pathways. WT DDX3X enhances the dynamics of heterogeneous mutant/WT hollow condensates more effectively than DDX3Y. These findings offer valuable insights into the catalytic defects of specific DDX3X mutants and their differential interactions with wild-type DDX3X and DDX3Y, potentially explaining sex biases in disease.
Design and Preparation Of A Novel Hydrogel Based An Maleimide–Thiol Conjugation
Authors: Jiang Song , Mohanty Monalisa 
Published: March 2023

AbstractThis article synthesized and characterized a novel hydrogel, which is formed using maleimide–thiol conjugation. Two precursors chitosan functionalized thiol groups and dextran functionalized maleimide groups prepared and characterized by NMR. The hydrogel studied by gelation time, swelling studies, viscoelastic properties, degradation rate. From gelation time result, we found that formed hydrogel gelation time could be changed with diffident weight percentage of precursors. Based on references, we found the best formular for the gelation and it was also determined for other studies. The swelling study indicated hydrogel has good flexibility and the degradation test indicated hydrogel is biodegradable. The viscoelastic test indicated hydrogel is elastic solid. From these studies, this a novel hydrogel could be potential for biomedical applications.
Hepatitis B Virus (HBV) prevalence and characteristics in HIV-transmitting mothers and their infants in KwaZulu-Natal, South Africa
Authors: Millar Jane , Cromhout Gabriela Z.L. , Mchunu Noxolo , Bengu Nomonde , Ndung’u Thumbi , Goulder Philip J , Matthews Philippa C , McNaughton Anna L 
Published: March 2023

AbstractBackgroundHIV and hepatitis B virus (HBV) prevalence are high in KwaZulu-Natal (KZN), South Africa. HIV co-infection negatively impacts HBV prognosis, and can increase likelihood of HBV mother-to-child-transmission (MTCT). In an established early treatment intervention cohort of HIV-transmitting mother-child pairs in KZN, we characterised HBV serological makers in mothers, and screened at-risk infants for HBV.MethodsMaternal samples (n=175) were screened for HBV infection (HBsAg), exposure to HBV (anti-HBc) and vaccination responses (anti-HBs-positive without other HBV markers). Infants of HBV-positive mothers were screened for HBsAg at 1 and 12 months.ResultsHBV infection was present in 8.6% (15/175) of mothers. Biomarkers for HBV exposure were present in 31.4% (55/175), but absent in 53.3% (8/15) maternal HBV-positive cases. Maternal HBV vaccination appeared rare (8.0%; 14/175). Despite prescription of antiretroviral therapy (ART) active against HBV, HBV DNA was detectable in 46.7% (7/15) HBsAg-positive mothers, with (5/7) also viraemic for HIV. Three mothers had HBV viral loads >5.3log10IU/ml, making them high-risk for HBV MTCT. Screening of available infant samples at one month of age (n=14) found no cases of HBV MTCT, and at 12 months (n=13) identified one HBV infection. Serological vaccination evidence was present in 53.8% (7/13) infants tested.DiscussionThis vulnerable cohort of HIV-transmitting mothers had a high undiagnosed HBV prevalence. Early infant ART may have reduced risk of MTCT in high-risk cases. Current HBV guidelines recommend antenatal antiviral prophylaxis but these data underline a potential role for infant post-exposure prophylaxis in high-risk MTCT pairs, warranting further investigation.
Diagnosing and staging epithelial ovarian cancer by serum glycoproteomic profiling
Authors: Dhar Chirag , Ramachandran Prasanna , Xu Gege , Pickering Chad , Čaval Tomislav , Rice Rachel , Zhou Bo , Srinivasan Apoorva , Hundal Itati , Cheng Robert , Aiyetan Paul , Chu Chih-Wei , Herzog Thomas J. , Olawaiye Alexander Babatunde , Czerwieniec Gregg , Jacob Francis , Serie Daniel , Lindpaintner Klaus , Schwarz Flavio 
Published: March 2023

AbstractMinimally invasive technologies for early diagnosis of epithelial ovarian cancer (EOC) remain an unmet clinical need. CA-125, a tumor marker secreted into the circulation, is utilized to monitor treatment response and disease relapse in EOC, but has limited utility in accurately triaging patients with pelvic masses of unknown histology. To address this unmet need, we applied a novel blood-based glycoproteomic platform that relies on mass spectrometry coupled to machine learning tools, and identified glycopeptide biomarkers that differentiate between patients with benign pelvic masses and malignant EOC. We then used a subset of these markers to generate a classifier that discriminated between benign pelvic tumors and EOC with sensitivity and specificity of 83.5% and 90.1% in the training set and 86.7 and 86.7% in the testing set, respectively. On subgroup analyses, we noticed that patients with malignant EOC had higher levels of fucosylated markers, primarily of hepatic origin. Furthermore, patients with late-stage EOC (FIGO stage III and IV) had markedly higher levels of tri- and tetra-antennary glycopeptide markers containing fucose. We used these markers to build an independent algorithm that can differentiate between early- and late-stage EOC. Lastly, we detected a similar upregulation of fucosylated glycans and gene expression signatures suggestive of multi-antennary glycans in late-stage EOC tissues. We posit that common mechanisms - possibly driven by cytokines - affect both the tumor glycocalyx and liver-derived glycoproteins. In summary, we generated blood glycoproteomic profiles resemblant of distinct tumor states and identified biomarkers that differentiate between benign and malignant pelvic masses, and/or between early- and late-stage EOC. We also provide mechanistic insights suggesting a direct link between the tumor site and the circulating glycoproteome. These data may inform the development of robust clinical tests to diagnose and stage patients with EOC.
Over one year of survival difference between distinct cohorts of glioblastoma patients
Authors: Poon Michael TC , Woo Peter YM , Helali Aya El , Brennan Paul M 
Published: March 2023

AbstractUnderstanding the differences in outcomes based on study and patient characteristics can inform better research designs and improve the interpretation of translational glioblastoma studies. This study compared the clinical features and median overall survival (mOS) of 2,203 patients from two genomic cohorts (The Cancer Genome Atlas [TCGA] and the Chinese Glioma Genome Atlas [CGGA]) and two consecutive regional cohorts (Hong Kong [HK] and Southeast [SE] Scotland) with histologically confirmed glioblastoma. Differences in clinical characteristics reflected the distinct patient selection criteria for surgery. While the mOS were similar, the mOS of those who completed temozolomide chemoradiotherapy were 35.2 months in SE Scotland, 22.2 in HK, and 14.1 in the TCGA cohort. Survival functions were comparable in the multivariable survival analysis. Our findings highlight how a lack of clinical data impedes the translational value of research. Therefore, there is a need to develop common data elements to derive meaningful conclusions.