bluuebunny/crossref_metadata_2025_split huggingface dataset:
A simple protein-based surrogate neutralization assay for SARS-CoV-2
Authors: Abe Kento T. , Li Zhijie , Samson Reuben , Samavarchi-Tehrani Payman , Valcourt Emelissa J. , Wood Heidi , Budylowski Patrick , Dupuis Alan P. , Girardin Roxie C. , Rathod Bhavisha , Wang Jenny H. , Barrios-Rodiles Miriam , Colwill Karen , McGeer Allison J , Mubareka Samira , Gommerman Jennifer L. , Durocher Yves , Ostrowski Mario , McDonough Kathleen A. , Drebot Michael A. , Drews Steven J. , Rini James M. , Gingras Anne-Claude 
Published: July 2020

AbstractMost of the patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mount a humoral immune response to the virus within a few weeks of infection, but the duration of this response and how it correlates with clinical outcomes has not been completely characterized. Of particular importance is the identification of immune correlates of infection that would support public health decision-making on treatment approaches, vaccination strategies, and convalescent plasma therapy. While ELISA-based assays to detect and quantitate antibodies to SARS-CoV-2 in patient samples have been developed, the detection of neutralizing antibodies typically requires more demanding cell-based viral assays. Here, we present a safe and efficient protein-based assay for the detection of serum and plasma antibodies that block the interaction of the SARS-CoV-2 spike protein receptor binding domain (RBD) with its receptor, angiotensin converting-enzyme 2 (ACE2). The assay serves as a surrogate neutralization assay and is performed on the same platform and in parallel with an enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies against the RBD, enabling a direct comparison. The results obtained with our assay correlate with those of two viral based assays, a plaque reduction neutralization test (PRNT) that uses live SARS-CoV-2 virus, and a spike pseudotyped viral-vector-based assay.
Dual cooperation between HSP70 and the 26S proteasome in co-translational protein quality control
Authors: Tian Guiyou , Hu Cheng , Yun Yun , Yang Wensheng , Dubiel Wolfgang , Cheng Yabin , Wolf Dieter A. 
Published: July 2020

AbstractCo-translational degradation via the ubiquitin-proteasome system mediates quality control of 15 – 25% of nascent proteins, a proportion that is known to increase dramatically as a result of proteotoxic stress. Whereas the ubiquitylation machinery involved has been characterized, mechanisms coordinating the proteasomal destruction of ribosome-attached nascent proteins remain poorly defined. In pursuit of such mechanisms, we discovered dual cooperation of the HSP70 family member HSPA1 with the 26S proteasome: First, in response to proteotoxic stress, HSPA1 promotes proteasome recruitment to translating 80S ribosomes in a manner independent of nascent chain ubiquitylation. Secondly, HSPA1, in association with its cognate nucleotide exchange factor HSPH1, maintains co-translationally ubiquitylated proteins in a soluble state required for efficient proteasomal degradation. Both mechanisms conspire to confer thermotolerance to cells and to promote the growth of esophageal cancer cells in vitro and in animals. Consistent with these observations, HSPH1 knockout impedes tumor growth in vitro and in animals and correlates with favorable prognosis in digestive tract cancers, thus nominating HSPH1 as a cancer drug target.HighlightsProteotoxic stress causes translational arrest, co-translational protein ubiquitylation, and proteasome recruitment to ribosomesCo-translational proteasome recruitment is independent of nascent chain ubiquitylation but is augmented by HSPA1HSPA1-HSPH1 disaggregase confers thermotolerance by maintaining the solubility and proteasomal clearance of ubiquitylated proteinsLow HSPH1 impedes co-translational thermotolerance and tumor growth and correlates with favorable prognosis in various cancers
Functional study of the AMD-associated geneTMEM97in retinal pigmented epithelium using CRISPR interference
Authors: Wang Jiang-Hui , Urrutia-Cabrera Daniel , Mora Santiago Mesa , Nguyen Tu , Hung Sandy , Hewitt Alex W. , Edwards Thomas L. , Wong Raymond C.B. 
Published: July 2020

AbstractAge-related macular degeneration (AMD) is a blinding disease characterised by dysfunction of the retinal pigmented epithelium (RPE) which culminates in disruption or loss of the neurosensory retina. Genome-wide association studies have identified >65 genetic risk factors for AMD, including theTMEM97locus.TMEM97encodes the Sigma-2 receptor which is involved in apoptosis and cytotoxicity across a range of neurodegenerative diseases. However, the expression pattern ofTMEM97in the human retina and its functional role in retinal cells has remained elusive. Here we utilised CRISPR interference (CRISPRi) to investigate the functional role ofTMEM97in the retina. Transcriptome analysis of all major cell types within the human retina showed thatTMEM97is expressed in the RPE, retinal ganglion cells (RGCs) and amacrine cells. Using CRISPRi, we performed loss-of-function study ofTMEM97in the human RPE cell line, ARPE19. We generated a stable ARPE19 cell line expressing dCas9-KRAB which facilitated knockdown ofTMEM97using specific sgRNAs. Our results show that knockdown ofTMEM97in ARPE19 exerts a protective effect against oxidative stress-induced cell death. This work provides the first functional study ofTMEM97in RPE and supports the role ofTMEM97in AMD pathobiology. Our study highlights the potential for using CRISPRi to study AMD genetics, and the CRISPRi cell line generated here provided an usefulin vitrotool for functional studies of other AMD-associated genes.
Aedes aegyptiSNAP and a calcium transporter ATPase influence dengue virus dissemination
Authors: Marin-Lopez Alejandro , Jiang Junjun , Wang Yuchen , Cao Yongguo , MacNeil Tyler , Hastings Andrew K , Fikrig Erol 
Published: July 2020

AbstractDengue virus (DENV) is a flavivirus that causes marked human morbidity and mortality worldwide, being transmitted to humans byAedes aegyptimosquitoes. Habitat expansion ofAedes, mainly due to climate change and increasing overlap between urban and wild habitats, places nearly half of the world’s population at risk for DENV infection. After a bloodmeal from a DENV-infected host, the virus enters the mosquito midgut. Next, the virus migrates to, and replicates in, other tissues, like salivary glands. Successful viral transmission occurs when the infected mosquito takes another blood meal on a susceptible host and DENV is released from the salivary gland via saliva into the skin. During viral dissemination in the mosquito and transmission to a new mammalian host, DENV interacts with a variety of vector proteins, which are uniquely important during each phase of the viral cycle. Our study focuses on the interaction between DENV particles and protein components in theA. aegyptivector. We performed a mass spectrometry assay where we identified a set ofA aegyptisalivary gland proteins which potentially interact with the DENV virion. Using dsRNA to silence gene expression, we analyzed the role of these proteins in viral infectivity. Two of these candidates, a synaptosomal-associated protein (AeSNAP) and a calcium transporter ATPase (ATPase) appear to play a role in viral replication bothin vitroandin vivo. These findings suggest that AeSNAP plays a protective role during DENV infection of mosquitoes and that ATPase protein is required for DENV during amplification within the vector.ImportanceAedes aegyptimosquitoes are the major vector of different flaviviruses that cause human diseases, including dengue virus. There is a great need for better therapeutics and preventive vaccines against flaviviruses. Flaviviruses create complex virus-host and virus-vector interactions. The interactions between viral particles and protein components in the vector is not completely understood. In this work we characterize how two mosquito proteins, “AeSNAP” and “ATPase”, influence DENV viral dissemination withinA. aegypti, using bothin vitroandin vivomodels. These results elucidate anti-vector measures that may be potentially be used to control dengue virus spread in the mosquito vector.
The Ndr/LATS kinase Cbk1 regulates a specific subset of Ace2 functions and suppresses the hyphae-to-yeast transition inCandida albicans
Authors: Wakade Rohan S. , Ristow Laura C. , Stamnes Mark A. , Kumar Anuj , Krysan Damian J. 
Published: July 2020

AbstractTheRegulation ofAce2 andMorphogenesis (RAM) pathway is an important regulatory network in the human fungal pathogenCandida albicans. The RAM pathway’s two most well-studied components, the NDR/Lats kinase Cbk1 and its putative substrate, the transcription factor Ace2, have a wide range of phenotypes and functions. It is not clear, however, which of these functions are specifically due to the phosphorylation of Ace2 by Cbk1. To address this question, we first compared the transcriptional profiles ofCBK1andACE2deletion mutants. This analysis indicates that, of the large number of genes whose expression is affected by deletion ofCBK1andACE2, only 5.5% of those genes are concordantly regulated. Our data also suggest that Ace2 directly or indirectly represses a large set of genes during hyphal morphogenesis. Second, we generated strains containingACE2alleles with alanine mutations at the Cbk1 phosphorylation sites. Phenotypic and transcriptional analysis of theseace2mutants indicates that, as inSaccharomyces cerevisiae, Cbk1 regulation is important for daughter cell localization of Ace2 and cell separation during yeast phase growth. In contrast, Cbk1 phosphorylation of Ace2 plays a minor role inC. albicansyeast-to-hyphae transition. We have, however, discovered a new function for the Cbk1-Ace2 axis. Specifically, Cbk1 phosphorylation of Ace2 prevents the hyphae-to-yeast transition. To our knowledge, this is one of the first regulators of theC. albicanshyphae-to-yeast transition to be described. Finally, we present an integrated model for the role of Cbk1 in the regulation of hyphal morphogenesis inC. albicans.ImportanceRegulation ofAce2 andMorphogenesis (RAM) pathway is a key regulatory network that plays a role in many aspects ofC. albicanspathobiology. In addition to characterizing the transcriptional effects of this pathway, we discovered that Cbk1 and Ace2, a key RAM pathway regulator-effector pair, mediate a specific set of the overall functions of the RAM pathway. We have also discovered a new function for the Cbk1-Ace2 axis; suppression of the hyphae-to-yeast transition. Very few regulators of this transition have been described and our data indicate that maintenance of hyphal morphogenesis requires suppression of yeast phase growth by Cbk1-regulated Ace2.
Antibody responses to a suite of novel serological markers for malaria surveillance demonstrate strong correlation with clinical and parasitological infection across seasons and transmission settings in The Gambia
Authors: Wu Lindsey , Mwesigwa Julia , Affara Muna , Bah Mamadou , Correa Simon , Hall Tom , Beeson James G. , Tetteh Kevin K.A. , Kleinschmidt Immo , D’Alessandro Umberto , Drakeley Chris 
Published: July 2020

AbstractBackgroundAs malaria transmission declines, sensitive diagnostics are needed to evaluate interventions and monitor transmission. Serological assays measuring malaria antibody responses offer a cost-effective detection method to supplement existing surveillance tools.MethodsA prospective cohort study was conducted from 2013 to 2015 in 12 villages across five administrative regions in The Gambia. Serological analysis included samples from the West Coast Region at the start and end of the season (July and December 2013) and from the Upper River Region in July and December 2013, and April and December 2014. Antigen-specific antibody responses to eight Plasmodium falciparum (P.falciparum) antigens – Etramp5.Ag1, GEXP18, HSP40.Ag1, Rh2.2030, EBA175 RIII-V, PfMSP119, PfAMA1, PfGLURP.R2 - were quantified using a multiplexed bead-based assay. The association between antibody responses and clinical and parasitological endpoints was estimated at the individual, household, and population level.ResultsStrong associations were observed between clinical malaria and concurrent sero-positivity to Etramp5.Ag1 (aOR 4.60 95%CI 2.98 - 7.12), PfMSP119 (aOR 4.09 95%CI 2.60 - 6.44), PfAMA1 (aOR 2.32 95%CI 1.40 - 3.85) and PfGLURP.R2 (aOR 3.12, 95%CI 2.92 – 4.95), while asymptomatic infection was associated with sero-positivity to all antigens. Village-level sero-prevalence amongst children 2-10 years against Etramp5.Ag1, HSP40.Ag1, and PfMSP119 showed the highest correlations with clinical and P.falciparum infection incidence rates. For all antigens, there was increased odds of asymptomatic P.falciparum infection in subjects residing in a compound with greater than 50% sero-prevalence, with a 2- to 3-fold increase in odds of infection associated with Etramp5.Ag1, GEXP18, Rh2.2030, PfMSP119 and PfAMA1. For individuals residing in sero-positive compounds, the odds of clinical malaria were reduced, suggesting a protective effect.ConclusionsAt low transmission, long-lived antibody responses could indicate foci of malaria transmission that have been ongoing for several seasons or years. In settings where sub-patent infections are prevalent and fluctuate below the detection limit of polymerase chain reaction (PCR), the presence of short- lived antibodies may indicate recent infectivity, particularly in the dry season when clinical cases are rare. Serological responses may reflect a persistent reservoir of infection, warranting community- targeted interventions if individuals are not clinically apparent but have the potential to transmit. Therefore, serological surveillance at both the individual and household level may be used to target interventions where there are foci of asymptomatically infected individuals.
Associations of Loneliness and Social Isolation with Healthspan and Lifespan in the US Health and Retirement Study
Authors: Crowe CL , Domingue BW , Hu G , Keyes KM , Kwon Dy , Belsky DW 
Published: July 2020

ABSTRACTBackgroundLoneliness and social isolation are emerging public health challenges for aging populations.MethodsWe followed N=11,302 US Health and Retirement Study (HRS) participants aged 50-95 from 2006-2014 to measure persistence of experiences of loneliness and exposure to social isolation. We tested associations of longitudinal loneliness and social isolation phenotypes with disability, morbidity, mortality, and biological aging through 2018.ResultsDuring follow-up, 18% of older adults met criteria for loneliness, with 6% meeting criteria at two or more follow-up assessments. For social isolation, these fractions were 21% and 8%. HRS participants who experienced loneliness and were exposed to social isolation were at increased risk for disease, disability, and mortality. Those experiencing persistent loneliness were at a 57% increased hazard of mortality compared to those who never experienced loneliness. For social isolation, the increase was 28%. Effect-sizes were somewhat larger for counts of prevalent activity limitations and somewhat smaller for counts of prevalent chronic diseases. Covariate adjustment for socioeconomic and psychological risks attenuated but did not fully explain associations. Older adults who experienced loneliness and were exposed to social isolation also exhibited physiological indications of advanced biological aging (Cohen’s-d for persistent loneliness and social isolation=0.26 and 0.21, respectively). For loneliness, but not social isolation, persistence was associated with increased risk.ConclusionDeficits in social connectedness prevalent in a national sample of US older adults were associated with morbidity, disability, and mortality and with more advanced biological aging. Bolstering social connectedness to interrupt experiences of loneliness may promote healthy aging.
COVID-19 severity is predicted by earlier evidence of accelerated aging
Authors: Kuo Chia-Ling , Pilling Luke C. , Atkins Janice L , Masoli Jane AH , Delgado João , Tignanelli Christopher , Kuchel George A , Melzer David , Beckman Kenneth B , Levine Morgan E. 
Published: July 2020

AbstractWith no known treatments or vaccine, COVID-19 presents a major threat, particularly to older adults, who account for the majority of severe illness and deaths. The age-related susceptibility is partly explained by increased comorbidities including dementia and type II diabetes [1]. While it is unclear why these diseases predispose risk, we hypothesize that increased biological age, rather than chronological age, may be driving disease-related trends in COVID-19 severity with age. To test this hypothesis, we applied our previously validated biological age measure (PhenoAge) [2] composed of chronological age and nine clinical chemistry biomarkers to data of 347,751 participants from a large community cohort in the United Kingdom (UK Biobank), recruited between 2006 and 2010. Other data included disease diagnoses (to 2017), mortality data (to 2020), and the UK national COVID-19 test results (to May 31, 2020) [3]. Accelerated aging 10-14 years prior to the start of the COVID-19 pandemic was associated with test positivity (OR=1.15 per 5-year acceleration, 95% CI: 1.08 to 1.21, p=3.2×10−6) and all-cause mortality with test-confirmed COVID-19 (OR=1.25, per 5-year acceleration, 95% CI: 1.09 to 1.44, p=0.002) after adjustment for demographics including current chronological age and pre-existing diseases or conditions. The corresponding areas under the curves were 0.669 and 0.803, respectively. Biological aging, as captured by PhenoAge, is a better predictor of COVID-19 severity than chronological age, and may inform risk stratification initiatives, while also elucidating possible underlying mechanisms, particularly those related to inflammaging.
The emergence of COVID-19 in Indonesia: analysis of predictors of infection and mortality using independent and clustered data approaches
Authors: Burhan Erlina , Syam Ari Fahrial , Rahyussalim Ahmad Jabir , Prasenohadi  , Wulung Navy G Lolong , Susanto Agus Dwi , Ketut Sajinadiyasa I Gede , Puspitorini Dewi , Lestari Dewi , Widyahening Indah Suci , Setiawaty Vivi , Ocviyanti Dwiana , Putri Kartika Qonita , Guntara Aswin , Rianda Davrina , Shankar Anuraj H , Agustina Rina 
Published: July 2020

AbstractBackgroundAnalyses of correlates of SARS-CoV-2 infection or mortality have usually assessed individual predictors. This study aimed to determine if patterns of combined predictors may better identify risk of infection and mortalityMethodsFor the period of March 2ndto 10th2020, the first 9 days of the COVID-19 pandemic in Indonesia, we selected all 18 confirmed cases, of which 6 died, and all 60 suspected cases, of which 1 died; and 28 putatively negative patients with pneumonia and no travel history. We recorded data for travel, contact history, symptoms, haematology, comorbidities, and chest x-ray. Hierarchical cluster analyses (HCA) and principal component analyses (PCA) identified cluster and covariance patterns for symptoms or haematology which were analysed with other predictors of infection or mortality using logistic regression.ResultsFor univariate analyses, no significant association with infection was seen for fever, cough, dyspnoea, headache, runny nose, sore throat, gastrointestinal complaints (GIC), or haematology. A PCA symptom component for fever, cough, and GIC tended to increase risk of infection (OR 3.41; 95% CI 1.06-14; p=0.06), and a haematology component with elevated monocytes decreased risk (OR 0.26; 0.07-0.79; 0.027). Multivariate analysis revealed that an HCA cluster of 3-5 symptoms, typically fever, cough, headache, runny nose, sore throat but little dyspnoea and no GIC tended to reduce risk (aOR 0.048; <0.001–0.52; 0.056). In univariate analyses for death, an HCA cluster of cough, fever and dyspnoea had increased risk (OR 5.75; 1.06 − 31.3, 0.043), but no other individual predictor, cluster or component was associated. Other significant predictors of infection were age ≥ 45, international travel, contact with COVID-19 patient, and pneumonia. Diabetes and history of contact were associated with higher mortality.ConclusionsCluster groups and co-variance patterns may be stronger correlates of SARS-CoV-2 infection than individual predictors. Comorbidities may warrant careful attention as would COVID-19 exposure levels.
Inhibitory KIR-Ligand Interactions and Relapse Protection Following HLA Matched Allogeneic HCT for AML
Authors: Krieger Elizabeth , Qayyum Rehan , Toor Amir 
Published: July 2020

AbstractKiller immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell mediated graft versus leukemia effect (GVL) after hematopoietic stem cell transplant (HCT) for AML. Mathematically accounting for KIR-KIRL interactions may identify donors with optimal NK cell mediated alloreactivity and GVL. In this retrospective study of 2359 donor recipient pairs (DRP) who underwent unrelated donor (URD) HCT for AML, KIR-KIRL interaction scores were determined. Relapse risk was significantly reduced in donor-recipient pairs (DRP) with higher inhibitory KIR-KIRL interaction and missing KIRL (mKIR) scores, with HR=0.86 (P=0.01) & HR=0.84 (P=0.02) respectively. This effect was not observed with activating KIR-KIRL interactions. The inhibitory KIR-KIRL (iKIR) interaction score components were summed to give an inhibitory-missing ligand (IM-KIR) score, which if it was 5 as opposed to <5, was also associated with a lower relapse risk, SHR 0.8 (P=0.004). Acute and chronic graft vs. host disease (GVHD), survival, GRFS and relapse free survival were not significantly different. However, TRM was increased among those with IM-KIR=5, HR, 1.32 (P=0.01). Among those with HLA matched DRP, anti-thymocyte globulin recipients with IM-KIR=5, had a lower relapse rate HR, 0.61 (p=0.001), however TRM was increased in these patients with a HR, 1.49 (p=0.034). This study demonstrates that unrelated DRPs with high inhibitory KIR content scores confer relapse protection, albeit with increased TRM. Clinical trials utilizing donors with a higher iKIR content in conjunction with novel strategies to reduce TRM should be considered for URD HCT recipients with AML to optimize clinical outcomes.HighlightsInhibitory and missing KIR-KIRL interactions, both individually and collectively are predictive of relapse following URD HCT for AML.Amongst 8/8 HLA matched donor recipient pair relapse reduction was observed in those undergoing in vivo T cell depletion with ATG.TRM is increased in patients with greater magnitude of inhibitory and missing KIR-KIRL interactions.
Clinical importance of reporting SARS-CoV-2 viral loads across the different stages of the COVID-19 pandemic
Authors: Moraz M. , Jacot D. , Papadimitriou-Olivgeris M. , Senn L. , Greub G. , Jaton K. , Opota O. 
Published: July 2020

AbstractOn April 25th, corresponding to the first deconfinement phase after the end of the lockdown in Switzerland, a universal admission screening strategy for COVID-19 was introduced in our hospital. All patients, including asymptomatic patients were tested for SARS-CoV-2 by quantitative reverse transcription polymerase chain reaction (RT-PCR). In addition to a qualitative answer, providing viral load values to the RT-PCR results not only helped the clinician to evaluate the stage of the infection but addressed patient contagiousness and guided infection control decisions. Here, we discuss the importance of reporting viral load values when a shift from a symptomatic to a universal screening strategy was performed.