bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel neutrophil subsets associated with sepsis, vascular dysfunction and metabolic alterations identified using systems immunology
Authors: Parthasarathy U. , Kuang Y. , Thakur G. , Hogan J.D. , Wyche T.P. , Norton J.E. , Killough J.R. , Sana T.R. , Beakes C. , Shyong B. , Zhang N.R. , Gutierrez D.A. , Filbin M. , Christiani D.C. , Therien A. G. , Woelk C.H. , White C.H. , Martinelli R. 
Published: February 2022

AbstractSepsis is a life-threatening condition caused by a dysregulated host response to infection. Despite continued efforts to understand the pathophysiology of sepsis, no effective therapies are currently available. While singular components of the aberrant immune response have been investigated, comprehensive studies linking different data layers are lacking. Using an integrated systems immunology approach, we evaluated neutrophil phenotypes and concomitant changes in cytokines and metabolites in sepsis patients. Our findings identify novel differentially expressed immature neutrophil subsets in sepsis patients. These and other subsets correlate with various proteins, metabolites, and lipids, including pentraxin-3, angiopoietin-2 and lysophosphatidylcholines, in sepsis patients. These results enabled the construction of a predictive model based on weighted multi-omics linear regression analysis for patient classification. These findings could help inform earlier patient stratification and treatment options, as well as facilitate future mechanistic studies targeting the trifecta of surface marker expression, cytokines, and metabolites.
Windborne migration amplifies insect-mediated pollination services
Authors: Jia Huiru , Liu Yongqiang , Li Xiaokang , Li Hui , Pan Yunfei , Hu Chaoxing , Zhou Xianyong , Wyckhuys Kris A.G. , Wu Kongming 
Published: February 2022

AbstractWorldwide, hoverflies (Syrphidae: Diptera) provide crucial ecosystem services (ES) such as pollination and biological pest control. Although many hoverfly species exhibit migratory behavior, the spatiotemporal facets of these movement dynamics and their ES implications are poorly understood. In this study, we use long-term (16 yr) trapping records, trajectory analysis and intrinsic (i.e., isotope, genetic, pollen) markers to describe migration patterns of the hoverflyEpisyrphus balteatusin China. Our work reveals long-range, windborne migration with spring migrants originating in northern China and exhibiting return migration during autumn. Given the substantial night-time dispersal ofE. balteatus, this species possibly adopts a ‘dual’ migration strategy. The extensive genetic mixing and high genetic diversity ofE. balteatuspopulations underscore its adaptive capacity to environmental disturbances e.g., climate change. Pollen markers and molecular gut-analysis further illuminate howE. balteatusvisits min. 1,012 flowering plant species (39 orders) over space and time. By thus delineatingE. balteatustrans-regional movements and pollination networks, we advance our understanding of its migration ecology and facilitate the design of targeted strategies to conserve and enhance its ecosystem services.
High-Resolution Ultrasound and Speckle Tracking: a non-invasive approach to assess in vivo gastrointestinal motility during development
Authors: Sicard Pierre , Falco Amandine , Faure Sandrine , Thireau Jérome , Lindsey Stéphanie E. , Chauvet Norbert , de Santa Barbara Pascal 
Published: February 2022

ABSTRACTGastrointestinal motor activity has been extensively studied in adults, conversely only few studies have investigated fetal motor skills. When the gastrointestinal tract starts to contract during the embryonic period and how this function evolves during development are not known. Here, we adapted a non-invasive high-resolution echography technique combined with speckle tracking analysis to examine the gastrointestinal tract motor activity dynamics during chick embryo development. We provided the first recordings of fetal gastrointestinal motility in living embryos. We found that although gastrointestinal contractions appear very early during development, they become synchronized only at the end of the fetal period. To validate this approach, we used various pharmacological inhibitors and BAPX1 gene overexpression in vivo. We found that the enteric nervous system determinates the onset of the synchronized contractions in the stomach. Moreover, alteration of smooth muscle fiber organization led to an impairment of this functional activity. Altogether, our findings show that non-invasive high-resolution echography and speckle tracking analysis allow visualizing and quantifying gastrointestinal motility during development and highlight the progressive acquisition of functional and coordinated gastrointestinal motility before birth.
Lymphatic-Preserving Treatment Sequencing with Immune Checkpoint Inhibition Unleashes cDC1-Dependent Antitumor Immunity in HNSCC
Authors: Saddawi-Konefka Robert , O’Farrell Aoife , Faraji Farhoud , Clubb Lauren , Allevato Michael M. , Anang Nana-Ama A. S. , Jensen Shawn M. , Wang Zhiyong , Wu Victoria H. , Yung Bryan S. , Msari Riyam Al , Pietryga Ida Franiak , Molinolo Alfredo A. , Mesirov Jill P. , Simon Aaron B. , Fox Bernard A. , Bui Jack D. , Sharabi Andrew , Cohen Ezra E. W. , Califano Joseph A. , Silvio Gutkind J. 
Published: February 2022

AbstractImmune checkpoint inhibition (ICI) with anti-CTLA-4 and anti-PD-1 has revolutionized oncology; however, response rates remain limited in most cancer types, highlighting the need for more effective immune oncology (IO) treatment strategies. Paradoxically, head and neck squamous cell carcinoma (HNSCC), which bears a mutational burden and immune infiltrate commensurate with cancers that respond robustly to ICI, has demonstrated no response to anti- CTLA-4 in any setting or to anti-PD-1 for locally-advanced disease. Scrutiny of the landmark clinical trials defining current IO treatments in HNSCC reveals that recruited patients necessarily received regional ablative therapies per standard of care, prompting us to hypothesize that standard therapies, which by design ablate locoregional lymphatics, may compromise host immunity and the tumor response to ICI. To address this, we employed tobacco-signature HNSCC murine models in which we mapped tumor-draining lymphatics and developed models for regional lymphablation with surgery or radiation. Remarkably, we found that lymphablation eliminates the tumor ICI response, significantly worsening overall survival and repolarizing the tumor- and peripheral-immune compartments. Mechanistically, within tumor-draining lymphatics, we observed an upregulation of cDC1 cells and IFN-I signaling, showed that both are necessary for the ICI response and lost with lymphablation. Ultimately, we defined rational IO sequences that mobilize peripheral immunity, achieve optimal tumor responses, confer durable immunity and control regional lymphatic metastasis. In sum, we provide a mechanistic understanding of how standard regional, lymphablative therapies impact the response to ICI, which affords insights that can be applied to define rational, lymphatic-preserving IO treatment sequences for cancer.One Sentence SummaryDespite the promise of immune checkpoint inhibition, therapeutic responses remain limited, raising the possibility that standard of care treatments delivered in concert may compromise the tumor response; here, we provide a mechanistic understanding of how standard oncologic therapies targeting regional lymphatics impact the tumor response to immune-oncology therapy in order to define rational treatment sequences that mobilize systemic antitumor immunity, achieve optimal tumor responses, confer durable antitumor immunity, and control regional metastatic disease.Graphical Abstract
Augmented efficacy of uttroside B over sorafenib in a murine model of human hepatocellular carcinoma
Authors: Swetha Mundanattu , Keerthana C.K. , Rayginia Tennyson P , Nath Lekshmi R , Haritha Nair Hariprasad , Kalimuthu Kalishwaralal , Janet Somaraj , Pillai Sreekumar , Harikumar Kuzhuvelil B , Sundaram Sankar , Anto Nikhil Ponnoor , Wu Dee H , Lankalapalli Ravi Shankar , Towner Rheal , Isakov Noah , Sathyaseelan Deepa , Anto Ruby John 
Published: February 2022

BackgroundWe previously reported the potency ofS. nigrum-derived uttroside B (Utt-B). Recently Utt-B is flagged as an ‘orphan drug’ against hepatocellular carcinoma (HCC) by the US FDA. The current study aims to validate the enhancedin vivoefficacy of Utt-B over sorafenib, the first-line treatment option against HCC.MethodsHuman liver cancer cell line, HepG2 was employed as an HCC model and the comparison between Utt-Bvssorafenib therapeutic efficacies against HCCin vivowere evaluated in NOD.CB17-Prkdcscid/J mice that bear HepG2-induced HCC xenografts.ResultsOur data indicate that Utt-B is a more potent anti-HCC drug than sorafenib,in vivo. Apart from the superior therapeutic benefit over sorafenib, Utt-B is pharmacologically saferin vivo, and owing to this virtue, the drug-induced side effects are largely alleviated in the context of HCC chemotherapy.ConclusionsOur data demonstrate the superior therapeutic index of Utt-B over sorafenib against HCC. Clinical studies in HCC patients utilizing Utt-B, which now holds the US FDA approval as an ‘orphan drug’, is an essential step to promote this drug from bench to bedside.
SARS-CoV-2 Omicron variant, lineage BA.1, is associated with lower viral load in nasopharyngeal samples compared to Delta variant
Authors: Sentis Célia , Billaud Geneviève , Bal Antonin , Frobert Emilie , Bouscambert Maude , Destras Gregory , Josset Laurence , Lina Bruno , Morfin Florence , Gaymard Alexandre ,   the COVID-Diagnosis HCL Study Group
Published: February 2022

AbstractHigh viral load in upper respiratory tract specimens observed for Delta cases may contributed to its increased infectivity compared to the Alpha variant. Herein, we showed that the RT-PCR Ct values in Health Care Workers sampled within five days after symptom onset were significantly higher for Omicron cases than Delta cases (+2.84 Ct, p=0.008). This result comfort the studies showing that the increased transmissibility of Omicron is related to other mechanisms than higher virus excretion.
Impact of SARS-CoV-2 variants on inpatient clinical outcome
Authors: Robinson Matthew L. , Morris C. Paul , Betz Josh , Zhang Yifan , Bollinger Robert , Wang Natalie , Thiemann David R , Fall Amary , Eldesouki Raghda E. , Norton Julie M. , Gaston David C. , Forman Michael , Luo Chun Huai , Zeger Scott L. , Gupta Amita , Garibaldi Brian T. , Mostafa Heba H. 
Published: February 2022

ABSTRACTBackgroundPrior observation has shown differences in COVID-19 hospitalization rates between SARS-CoV-2 variants, but limited information describes differences in hospitalization outcomes.MethodsPatients admitted to 5 hospitals with COVID-19 were included if they had hypoxia, tachypnea, tachycardia, or fever, and data to describe SARS-CoV-2 variant, either from whole genome sequencing, or inference when local surveillance showed ≥95% dominance of a single variant. The average effect of SARS-CoV-2 variant on 14-day risk of severe disease, defined by need for advanced respiratory support, or death was evaluated using models weighted on propensity scores derived from baseline clinical features.ResultsSevere disease or death within 14 days occurred for 950 of 3,365 (28%) unvaccinated patients and 178 of 808 (22%) patients with history of vaccination or prior COVID-19. Among unvaccinated patients, the relative risk of 14-day severe disease or death for Delta variant compared to ancestral lineages was 1.34 (95% confidence interval [CI] 1.13-1.55). Compared to Delta variant, this risk for Omicron patients was 0.78 (95% CI 0.62-0.97) and compared to ancestral lineages was 1.04 (95% CI 0.84-1.24). Among Omicron and Delta infections, patients with history of vaccination or prior COVID-19 had one-half the 14-day risk of severe disease or death (adjusted hazard ratio 0.46, IQR 0.34-0.62) but no significant outcome difference between Delta and Omicron infections.ConclusionsAlthough the risk of severe disease or death for unvaccinated patients with Omicron was lower than Delta, it was similar to ancestral lineages. Severe outcomes were less common in vaccinated patients, but there was no difference between Delta and Omicron infections.
Monitoring rapid evolution of plant populations at scale with Pool-Sequencing
Authors: Czech Lucas , Peng Yunru , Spence Jeffrey P. , Lang Patricia L.M. , Bellagio Tatiana , Hildebrandt Julia , Fritschi Katrin , Schwab Rebecca , Rowan Beth A. ,   GrENE-net consortium, Weigel Detlef , Scheepens J.F. , Vasseur François , Exposito-Alonso Moises 
Published: February 2022

AbstractThe change in allele frequencies within a population over time represents a fundamental process of evolution. By monitoring allele frequencies, we can analyze the effects of natural selection and genetic drift on populations. To efficiently track time-resolved genetic change, large experimental or wild populations can be sequenced as pools of individuals sampled over time using high-throughput genome sequencing (called the Evolve & Resequence approach, E&R). Here, we present a set of experiments using hundreds of natural genotypes of the model plantArabidopsis thalianato showcase the power of this approach to study rapid evolution at large scale. First, we validate that sequencing DNA directly extracted from pools of flowers from multiple plants -- organs that are relatively consistent in size and easy to sample -- produces comparable results to other, more expensive state-of-the-art approaches such as sampling and sequencing of individual leaves. Sequencing pools of flowers from 25-50 individuals at ∼40X coverage recovers genome-wide frequencies in diverse populations with accuracyr> 0.95. Secondly, to enable analyses of evolutionary adaptation using E&R approaches of plants in highly replicated environments, we provide open source tools that streamline sequencing data curation and calculate various population genetic statistics two orders of magnitude faster than current software. To directly demonstrate the usefulness of our method, we conducted a two-year outdoor evolution experiment withA. thalianato show signals of rapid evolution in multiple genomic regions. We demonstrate how these laboratory and computational Pool-seq-based methods can be scaled to study hundreds of populations across many climates.
Neural mechanism of acute stress management by trace aminergic signalling in the lateral habenula
Authors: Yang Soo Hyun , Yang Esther , Lee Jaekwang , Kim Jin Yong , Yoo Hyeijung , Park Hyung Sun , Jung Jin Taek , Lee Dongmin , Chun Sungkun , Lee Hyun Woo , Kim Hyun 
Published: February 2022

AbstractStress management is a prerequisite for the survival of vertebrates because chronic stress may cause depression and is known to negatively modulate the dopaminergic reward system1. Enhanced excitability of neurons in the lateral habenula (LHb) induced by chronic stress is essential for silencing dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neurons in the rostromedial tegmental nucleus (RMTg)2–10. However, the effect of acute stress on the LHb-RMTg-VTA pathway is unknown11–14. Here, we show that both aromatic L-amino acid decarboxylase (AADC)-expressing neurons (D-neurons)15 in the LHb and dopaminergic neurons in the VTA are activated by acute stress, whereas GABAergic neurons in the RMTg are not. Selective stimulation of LHb D-neurons and AADC knockdown of these neurons reverse-regulate the RMTg-VTA pathway. Circuit tracing and electrophysiology data demonstrate that trace aminergic signalling by LHb D-neurons directly suppresses RMTg GABAergic neurons. Furthermore, local activation of trace amine-associated receptor 1 (TAAR1; a trace amine receptor) in the RMTg is sufficient to rescue the despair-like behaviour produced by the loss of AADC expression. Our results identify a novel efferent pathway from the LHb to the RMTg whereby trace aminergic signalling allows the brain to manage acute stress by preventing VTA dopaminergic neuron hypoactivity. The TAAR1-mediated trace aminergic signalling in the LHb-RMTg pathway may hold promise as a therapeutic target for stress-mediated psychological diseases.
Development and optimisation of a high-throughput screening assay for in vitro anti–SARS-CoV-2 activity: evaluation of 5676 phase 1 passed structures
Authors: Chiu Winston , Verschueren Lore , Van den Eynde Christel , Buyck Christophe , De Meyer Sandra , Jochmans Dirk , Bojkova Denisa , Ciesek Sandra , Cinatl Jindrich , De Jonghe Steven , Leyssen Pieter , Neyts Johan , Van Loock Marnix , Van Damme Ellen 
Published: February 2022

ABSTRACTAlthough vaccines are currently used to control the coronavirus disease 2019 (COVID-19) pandemic, treatment options are urgently needed for those who cannot be vaccinated and for future outbreaks involving new severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) strains or coronaviruses not covered by current vaccines. Thus far, few existing antivirals are known to be effective against SARS-CoV-2 and clinically successful against COVID-19.As part of an immediate response to the COVID-19 pandemic, a high-throughput, high content imaging–based SARS-CoV-2 infection assay was developed in VeroE6-eGFP cells and was used to screen a library of 5676 compounds that passed phase 1 clinical trials. Eight candidates (nelfinavir, RG-12915, itraconazole, chloroquine, hydroxychloroquine, sematilide, remdesivir, and doxorubicin) with in vitro anti–SARS-CoV-2 activity in VeroE6-eGFP and/or Caco-2 cell lines were identified. However, apart from remdesivir, toxicity and pharmacokinetic data did not support further clinical development of these compounds for COVID-19 treatment.
COVID-19 infection enhances susceptibility to oxidative-stress induced parkinsonism
Authors: Smeyne Richard J , Eells Jeffrey , Chatterjee Debotri , Byrne Matthew , Akula Shaw M. , Sriramula Srinivas , O’Rourke Dorcas P. , Schmidt Peter 
Published: February 2022

AbstractBackgroundViral induction of neurological syndromes has been a concern since parkinsonian-like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses following SARS-CoV-2 infection with those observed after pandemic influenza, there is a question if a similar syndrome of post-encephalic parkinsonism could follow COVID-19 infection.ObjectivesTo determine if prior infection with SARS-CoV-2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism.MethodshACE2 mice were infected with SARS-CoV-2 to induce mild to moderate disease. After 31 days recovery, mice were administered a non-lesion inducing dose of the parkinsonian toxin MPTP. Subsequent neuroinflammation and SNpc dopaminergic neuron loss was determined and compared to SARS-CoV-2 or MPTP alone.ResultshACE2 mice infected with SARS-CoV-2 or MPTP showed no SNpc DA neuron loss following MPTP. In mice infected and recovered from SARS-CoV-2 infection, MPTP induced a 23% or 19% greater loss of SNpc dopaminergic neurons than SARS-CoV-2 or MPTP, respectively (p□<□0.05).Examination of microglial activation showed a significant increase in the number of activated microglia in the SARS-CoV-2 + MPTP group compared to SARS-CoV-2 or MPTP alone.ConclusionsOur observations have important implications for long-term public health, given the number of people that have survived SARS-CoV-2 infection as well as for future public policy regarding infection mitigation. However, it will be critical to determine if other agents known to increase risk of PD also have synergistic effects with SARS-CoV-2 and if are abrogated by vaccination.FundingThis work was supported by grant from the State of North Carolina (PS, JE, DOR, RJS) and R21 NS122280 (RJS).
PRMT5 regulates ATF4 transcript splicing and oxidative stress response
Authors: Szewczyk Magdalena M. , Luciani Genna M. , Vu Victoria , Murison Alex , Dilworth David , Lupien Mathieu , Arrowsmith Cheryl H , Minden Mark D. , Barsyte-Lovejoy Dalia 
Published: February 2022

AbstractProtein methyltransferase 5 (PRMT5) symmetrically dimethylates arginine residues leading to regulation of transcription and splicing programs. Although PRMT5 has emerged as an attractive oncology target, the molecular determinants of PRMT5 dependency in cancer remain incompletely understood. Our transcriptomic analysis identified PRMT5 regulation of the activating transcription factor 4 (ATF4) pathway in acute myelogenous leukemia (AML). PRMT5 inhibition resulted in the expression of unstable, intron-retaining ATF4 mRNA that is detained in the nucleus. Concurrently, the decrease in the spliced cytoplasmic transcript of ATF4 led to lower levels of ATF4 protein and downregulation of ATF4 target genes. Upon loss of functional PRMT5, cells with low ATF4 displayed increased oxidative stress, growth arrest, and cellular senescence. Interestingly, leukemia cells with EVI1 oncogene overexpression demonstrated dependence on PRMT5 function. EVI1 and ATF4 regulated gene signatures were inversely correlated. We show that EVI1-high AML cells have reduced ATF4 levels, elevated baseline reactive oxygen species and increased sensitivity to PRMT5 inhibition. Thus, EVI1-high cells demonstrate dependence on PRMT5 function and regulation of oxidative stress response. Overall, our findings identify the PRMT5-ATF4 axis to be safeguarding the cellular redox balance that is especially important in high oxidative stress states, such as those that occur with EVI1 overexpression.
Apolipoprotein E4 has extensive conformational heterogeneity in lipid free and bound forms
Authors: Stuchell-Brereton Melissa D. , Zimmerman Maxwell I. , Miller Justin J. , Mallimadugula Upasana L. , Incicco J. Jeremias , Roy Debjit , Smith Louis G. , Baban Berevan , DeKoster Gregory T. , Frieden Carl , Bowman Gregory R. , Soranno Andrea 
Published: February 2022

AbstractThe ε4-allele variant of Apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer’s disease, though it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. We apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct an atomically-detailed model of monomeric ApoE4 and probe the effect of lipid association. Our data reveal that ApoE4 is far more disordered than previously thought and retains significant conformational heterogeneity after binding lipids. In particular, the behavior of the hinge region and C-terminal domain of ApoE4 differs substantially from that proposed in previous models and provides a crucial foundation for understanding how ApoE4 differs from non-pathogenic and protective variants of the protein.