bluuebunny/crossref_metadata_2025_split huggingface dataset:
High heritability of telomere length, but low evolvability, and no significant heritability of telomere shortening in wild jackdaws
Authors: Bauch Christina , Boonekamp Jelle J. , Korsten Peter , Mulder Ellis , Verhulst Simon 
Published: January 2021

AbstractTelomere length (TL) and shortening rate predict survival in many organisms. Evolutionary dynamics of TL in response to survival selection depend on the presence of genetic variation that selection can act upon. However, the amount of standing genetic variation is poorly known for both TL and TL shortening rate, and has not been studied for both traits in combination in a wild vertebrate. We used experimental (cross-fostering) and statistical (animal models) means to disentangle and estimate genetic and environmental contributions to TL variation in pedigreed free-living jackdaws (Corvus monedula). TL was measured twice early in life (age- and interval-standardized), when shortening is highest, using the high-precision TRF technique, adapted to exclude interstitial telomeric sequences. TL shortened significantly during the nestling phase (10.4 bp/day), was highly repeatable within individuals (R=0.97) and genetically correlated between the two ages (rG>0.99). Additive genetic effects explained the major part of TL variation between individuals, with heritability on average estimated ath2=0.74. Parent- offspring regressions yielded similar estimates for the sexes when accounting for changes in paternal TL over life. Cohort effects explained a small but significant part of TL variation. Heritable variation for telomere shortening was negligible. Despite the high heritability of TL, its evolvability, which scales the additive genetic variance by mean TL, was close to zero. Hence evolutionary change of TL is likely to be slow despite significant selection.
Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial
Authors: Holubovska Olha , Bojkova Denisa , Elli Stefano , Bechtel Marco , Boltz David , Muzzio Miguel , Peng Xinjian , Sala Frederico , Cosentino Cesare , Mironenko Alla , Milde Jens , Lebed Yuriy , Stammer Holger , Goy Andrew , Guerrini Marco , Mueller Lutz , Cinatl Jindrich , Margitich Victor , te Velthuis Aartjan J. W. 
Published: January 2021

AbstractPandemic SARS-CoV-2 causes a mild to severe respiratory disease called Coronavirus Disease 2019 (COVID-19). Control of SARS-CoV-2 spread will depend on vaccine-induced or naturally acquired protective herd immunity. Until then, antiviral strategies are needed to manage COVID-19, but approved antiviral treatments, such as remdesivir, can only be delivered intravenously. Enisamium (laboratory code FAV00A, trade name Amizon®) is an orally active inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. Here we show that enisamium can inhibit SARS-CoV-2 infections in NHBE and Caco-2 cells. In vitro, the previously identified enisamium metabolite VR17-04 directly inhibits the activity of the SARS-CoV-2 RNA polymerase. Docking and molecular dynamics simulations suggest that VR17-04 prevents GTP and UTP incorporation. To confirm enisamium’s antiviral properties, we conducted a double-blind, randomized, placebo-controlled trial in adult, hospitalized COVID-19 patients, which needed medical care either with or without supplementary oxygen. Patients received either enisamium (500 mg per dose) or placebo for 7 days. A pre-planned interim analysis showed in the subgroup of patients needing supplementary oxygen (n = 77) in the enisamium group a mean recovery time of 11.1 days, compared to 13.9 days for the placebo group (log-rank test; p=0.0259). No significant difference was found for all patients (n = 373) or those only needing medical care (n = 296). These results thus suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis and that enisamium treatment shortens the time to recovery for COVID-19 patients needing oxygen.Significance statementSARS-CoV-2 is the causative agent of COVID-19. Although vaccines are now becoming available to prevent SARS-CoV-2 spread, the development of antivirals remains necessary for treating current COVID-19 patients and combating future coronavirus outbreaks. Here, we report that enisamium, which can be administered orally, can prevent SARS-CoV-2 replication and that its metabolite VR17-04 can inhibit the SARS-CoV-2 RNA polymerase in vitro. Moreover, we find that COVID-19 patients requiring supplementary oxygen, recover more quickly than patients treated with a placebo. Enisamium may therefore be an accessible treatment for COVID-19 patients.
Geographical and temporal variation in reduction of malaria infection among children under five years of age throughout Nigeria
Authors: Oyibo Wellington , Ntadom Godwin , Uhomoibhi Perpetua , Oresanya Olusola , Ogbulafor Nnenna , Ajumobi Olufemi , Okoh Festus , Maxwell Kolawole , Ezeiru Sonachi , Nwokolo Ernest , Amajoh Chioma , Ezeigwe Nnenna , Audu Mohammed , Conway David J. 
Published: January 2021

AbstractBackgroundGlobal progress in reducing malaria has stalled since 2015. Analysis of the situation is particularly needed in Nigeria, the country with by far the largest share of the burden, where approximately a quarter of all cases in the world are estimated to occur.MethodsWe analysed data from three nationwide surveys (Malaria Indicator Surveys in 2010 and 2015, and a National Demographic and Health Survey in 2018), with malaria parasite prevalence in children under five years of age determined by sampling from all 36 states of Nigeria, and blood slide microscopy performed in the same accredited laboratory for all samples. Changes over time were evaluated by calculating prevalence ratio (PR) values with 95% confidence intervals (CI) for each state, together with Mantel-Haenszel adjusted prevalence ratios (PRadj) for each of the six major geopolitical zones of the country.ResultsBetween 2010 and 2018 there were significant reductions in parasite prevalence in 25 states, but not in the remaining 11 states. Prevalence decreased most in southern zones of the country (South West PRadj= 0.53; South East PRadj= 0.59; South South PRadj= 0.51) and the North Central zone (PRadj= 0.36). Changes in the north were less marked, but were significant and indicated overall reductions by more than 20% (North West PRadj= 0.74; North East PRadj= 0.76). Changes in the south occurred mostly between 2010 and 2015, whereas those in the north were more gradual and most continued after 2015. Recent changes were not correlated with survey-reported variation in use of preventive measures.ConclusionReductions in malaria infection in children under five have occurred in most individual states in Nigeria since 2010, but substantial geographical variation in the timing and extent indicate challenges to be overcome to enable global malaria reduction.
Pragmatic, open-label, single-center, randomized, phase II clinical trial to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus in patients with severe pneumonia secondary to COVID-19: the TACROVID trial protocol
Authors: Solanich X , Antolí A , Padullés N , Fanlo-Maresma M , Iriarte A , Mitjavila F , Capdevila O , Molina M , Sabater J , Bas J , Mensa-Vilaró A , Niubó J , Calvo N , Bolivar S , Rigo-Bonnin R , Arregui L , Tebé C , Hereu P , Videla S , Corbella X 
Published: January 2021

ABSTRACTIntroductionSome COVID-19 patients evolve to severe lung injury and systemic hyperinflammatory syndrome triggered by both the coronavirus infection and the subsequent host-immune response. Accordingly, the use of immunomodulatory agents has been suggested but still remains controversial. Our working hypothesis is that methylprednisolone pulses and tacrolimus may be an effective and safety drug combination for treating severe COVID-19 patients.Methods and analysisTACROVID is a randomized, open-label, single-center, phase II trial to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) versus SoC alone, in patients at advanced stage of COVID-19 disease with lung injury and systemic hyperinflammatory response. Patients are randomly assigned (1:1) to one of two arms (42 patients in each group). The primary aim is to assess the time to clinical stability after initiating randomization. Clinical stability is defined as body temperature ≤ 37.5°C, and PaO2/FiO2 > 400 and/or SatO2/FiO2 > 300, and respiratory rate ≤24 rpm; for 48 consecutive hours.DiscussionMethylprednisolone and tacrolimus might be beneficial to treat those COVID-19 patients progressing into severe pulmonary failure and systemic hyperinflammatory syndrome. The rationale for its use is the fast effect of methylprednisolone pulses and the ability of tacrolimus to inhibit both the CoV-2 replication and the secondary cytokine storm. Interestingly, both drugs are low-cost and can be manufactured on a large scale; thus, if effective and safe, a large number of patients could be treated in developed and developing countries.Trial registration numberNCT04341038 / EudraCT: 2020-001445-39
Wastewater Virus Detection Complements Clinical COVID-19 Testing to Limit Spread of Infection at Kenyon College
Authors: Barich Daniel , Slonczewski Joan L. 
Published: January 2021

ABSTRACTIn-person college instruction during the 2020 pandemic required effective and economical monitoring of COVID-19 prevalence. Kenyon College and the Village of Gambier conducted measurement of SARS-CoV-2 RNA from the village wastewater plant and from an on-campus sewer line. Wastewater RNA detection revealed virus prevalence leading to individual testing and case identification. Wastewater surveillance also showed when case rates had subsided, thus limiting the need for individual clinical testing. Overall, wastewater virus surveillance allows more targeted use of individual testing and increases community confidence in student population management.
Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate
Authors: Prieto-Fernández Endika , Egia-Mendikute Leire , Vila-Vecilla Laura , Bosch Alexandre , Barreira-Manrique Adrián , Lee So Young , García-del Río Ana , Antoñana-Vildosola Asier , Jiménez-Lasheras Borja , Moreno-Cugnon Leire , Jiménez-Barbero Jesús , Berra Edurne , Ereño-Orbea June , Palazon Asis 
Published: January 2021

AbstractA main clinical parameter of COVID-19 pathophysiology is hypoxia. Here we show that hypoxia decreases the attachment of the receptor binding domain (RBD) and the S1 subunit (S1) of the spike protein of SARS-CoV-2 to epithelial cells. In Vero E6 cells, hypoxia reduces the protein levels of ACE2 and neuropilin-1 (NRP1), which might in part explain the observed reduction of the infection rate. In addition, hypoxia inhibits the binding of the spike to NCI-H460 human lung epithelial cells by decreasing the cell surface levels of heparan sulfate (HS), a known attachment receptor of SARS-CoV-2. This interaction is also reduced by lactoferrin, a glycoprotein that blocks HS moieties on the cell surface. The expression of syndecan-1, an HS-containing proteoglycan expressed in lung, is inhibited by hypoxia on a HIF-1α-dependent manner. Hypoxia or deletion of syndecan-1 results in reduced binding of the RBD to host cells. Our study indicates that hypoxia acts to prevent SARS-CoV-2 infection, suggesting that the hypoxia signaling pathway might offer therapeutic opportunities for the treatment of COVID-19.
Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces shedding of SARS-CoV-2 D614G in rhesus macaques
Authors: van Doremalen Neeltje , Purushotham Jyothi N. , Schulz Jonathan E. , Holbrook Myndi G. , Bushmaker Trenton , Carmody Aaron , Port Julia R. , Yinda Claude K. , Okumura Atsushi , Saturday Greg , Amanat Fatima , Krammer Florian , Hanley Patrick W. , Smith Brian J. , Lovaglio Jamie , Anzick Sarah L. , Barbian Kent , Martens Craig , Gilbert Sarah , Lambe Teresa , Munster Vincent J. 
Published: January 2021

AbstractIntramuscular vaccination with ChAdOx1 nCoV-19/AZD1222 protected rhesus macaques against pneumonia but did not reduce shedding of SARS-CoV-2. Here we investigate whether intranasally administered ChAdOx1 nCoV-19 reduces shedding, using a SARS-CoV-2 virus with the D614G mutation in the spike protein. Viral load in swabs obtained from intranasally vaccinated hamsters was significantly decreased compared to controls and no viral RNA or infectious virus was found in lung tissue, both in a direct challenge and a transmission model. Intranasal vaccination of rhesus macaques resulted in reduced shedding and a reduction in viral load in bronchoalveolar lavage and lower respiratory tract tissue. In conclusion, intranasal vaccination reduced shedding in two different SARS-CoV-2 animal models, justifying further investigation as a potential vaccination route for COVID-19 vaccines.
Cerebrospinal fluid in COVID-19 neurological complications: no cytokine storm or neuroinflammation
Authors: Garcia Maria A. , Barreras Paula V. , Lewis Allie , Pinilla Gabriel , Sokoll Lori J. , Kickler Thomas , Mostafa Heba , Caturegli Mario , Moghekar Abhay , Fitzgerald Kathryn C. ,   Hopkins Neuro-COVID-19 Group, Pardo Carlos A. 
Published: January 2021

ABSTRACTBACKGROUNDNeurological complications occur in COVID-19. We aimed to examine cerebrospinal fluid (CSF) of COVID-19 subjects with neurological complications and determine presence of neuroinflammatory changes implicated in pathogenesis.METHODSCross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 subjects with neurological complications categorized by diagnosis (stroke, encephalopathy, headache) and illness severity (critical, severe, moderate, mild). COVID-19 CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders and stroke controls (n=82). Cytokines (IL-6, TNFα, IFNγ, IL-10, IL-12p70, IL-17A), inflammation and coagulation markers (high-sensitivity-C Reactive Protein [hsCRP], ferritin, fibrinogen, D-dimer, Factor VIII) and neurofilament light chain (NF-L), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA.RESULTSCSF from COVID-19 subjects showed a paucity of neuroinflammatory changes, absence of pleocytosis or specific increases in pro-inflammatory markers or cytokines (IL-6, ferritin, or D-dimer). Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. A similar increase of pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 in CSF of COVID-19 and non-COVID-19 stroke subjects was observed compared to controls. CSF-NF-L was elevated in subjects with stroke and critical COVID-19. CSF-hsCRP was present almost exclusively in COVID-19 cases.CONCLUSIONThe paucity of neuroinflammatory changes in CSF of COVID-19 subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation in pathogenesis of neurological complications in COVID-19. Elevated CSF-NF-L indicates neuroaxonal injury in COVID-19 cases. The role of CSF SARS-CoV2 IgG antibodies is still undetermined.FUNDINGThis work was supported by NIH R01-NS110122 and The Bart McLean Fund for Neuroimmunology Research.
High school science fair: Experiences of two groups of undergraduate bioscience students
Authors: Grinnell Frederick , Dalley Simon , Reisch Joan 
Published: January 2021

AbstractScience fairs offer potential opportunities for students to learn first-hand about the practices of science. Over the past six years we have been carrying out voluntary and anonymous surveys with regional and national groups of high school and post high school students to learn about their high school science fair experiences regarding help received, obstacles encountered, and opinions about the value and impact of science fair. Understanding what students think about science fairs will help educators make science fairs more effective learning opportunities. In this paper, we focus on the findings with two national groups of post high school students – undergraduate research fellows (SURF students) who did research at UT Southwestern Medical Center during 2014-2019 and undergraduates biology students attending the 2019 Howard Hughes Medical Institute Science Education Alliance (SEA) summer symposium. About 25% of the students who completed surveys indicated that they had participated in high school science fair, but more than half attended high schools where science fairs were unavailable. Effectively, 6 out of every 10 students participated in science fair if available. Students who could have participated in high school science fair but chose not to do so identifiednot enough timeandcoming up with their project ideaas major reasons why not. About half the SURF students favored requiring non-competitive science fair regardless whether they themselves had participated in science fair. On the other hand, less than 1 in 5 thought that competitive science fair should be required.Introduction to the scientific processandgeneral learningwere mentioned most frequently as the reasons to require non-competitive science fair; these reasons were mentioned rarely in connection with competitive science fair. Unlike the national cohort of high school students we surveyed previously, who mostly did science fair in 9thand 10thgrades, SURF students participated in science fair throughout high school and were twice as likely as high school students to have carried out science fair more than once. In conclusion, our findings suggest that participation of the undergraduate bioscience majors in high school science fairs occurs far more frequently than recognized previously. The findings emphasize further the importance of incentivizing rather than requiring science fair participation, especially in 9thand 10thgrades, and the potential value of developing non-competitive science fairs.
Potent SARS-CoV-2 Neutralizing Antibodies Directed Against Spike N-Terminal Domain Target a Single Supersite
Authors: Cerutti Gabriele , Guo Yicheng , Zhou Tongqing , Gorman Jason , Lee Myungjin , Rapp Micah , Reddem Eswar R. , Yu Jian , Bahna Fabiana , Bimela Jude , Huang Yaoxing , Katsamba Phinikoula S. , Liu Lihong , Nair Manoj S. , Rawi Reda , Olia Adam S. , Wang Pengfei , Chuang Gwo-Yu , Ho David D. , Sheng Zizhang , Kwong Peter D. , Shapiro Lawrence 
Published: January 2021

SummaryNumerous antibodies that neutralize SARS-CoV-2 have been identified, and these generally target either the receptor-binding domain (RBD) or the N-terminal domain (NTD) of the viral spike. While RBD-directed antibodies have been extensively studied, far less is known about NTD-directed antibodies. Here we report cryo-EM and crystal structures for seven potent NTD-directed neutralizing antibodies in complex with spike or isolated NTD. These structures defined several antibody classes, with at least one observed in multiple convalescent donors. The structures revealed all seven antibodies to target a common surface, bordered by glycansN17,N74,N122, andN149. This site – formed primarily by a mobile β-hairpin and several flexible loops – was highly electropositive, located at the periphery of the spike, and the largest glycan-free surface of NTD facing away from the viral membrane. Thus, in contrast to neutralizing RBD-directed antibodies that recognize multiple non-overlapping epitopes, potent NTD-directed neutralizing antibodies target a single supersite.
Mechanisms shaping the synergism of zeaxanthin and PsbS in photoprotective energy dissipation in the photosynthetic apparatus of plants
Authors: Welc Renata , Luchowski Rafal , Kluczyk Dariusz , Zubik Monika , Grudzinski Wojciech , Maksim Magdalena , Reszczynska Emilia , Sowinski Karol , Mazur Radosław , Nosalewicz Artur , Gruszecki Wieslaw I. 
Published: January 2021

AbstractSafe operation of photosynthesis is vital to plants and is ensured by the activity of numerous processes protecting chloroplasts against photo-damage. The harmless dissipation of excess excitation energy is believed to be the main photoprotective mechanism and is most effective with the simultaneous presence of PsbS protein and zeaxanthin, a xanthophyll accumulated in strong light as a result of the xanthophyll cycle activity. Here we address the problem of specific molecular mechanisms underlying the synergistic effect of zeaxanthin and PsbS. The experiments were conducted withArabidopsis thaliana, the wild-type and the mutants lacking PsbS (npq4) and affected in the xanthophyll cycle (npq1), with the application of multiple molecular spectroscopy and imaging techniques. Research results lead to the conclusion that PsbS interferes with the formation of tightly packed aggregates of thylakoid membrane proteins, thus enabling the incorporation of xanthophyll cycle pigments into such structures. It was found that xanthophylls trapped within supramolecular structures, most likely in the interfacial protein region, determine their photophysical properties. The structures formed in the presence of violaxanthin are characterized by minimized dissipation of excitation energy. In contrast, the structures formed in the presence of zeaxanthin show enhanced excitation quenching, thus protecting the system against photo-damage.
Impact of South African 501.V2 Variant on SARS-CoV-2 Spike Infectivity and Neutralization: A Structure-based Computational Assessment
Authors: Cheng Mary Hongying , Krieger James M , Kaynak Burak , Arditi Moshe , Bahar Ivet 
Published: January 2021

AbstractMotivationThe SARS-CoV-2 variants emerging from South Africa (501.V2) and the UK (B.1.1.7) necessitate rapid assessment of the effects of the corresponding amino acid substitutions in the spike (S) receptor-binding domain (RBD) of the variants on the interactions with the human ACE2 receptor and monoclonal antibodies (mAbs) reported earlier to neutralize the spike.ResultsMolecular modeling and simulations reveal that N501Y, shared by both variants, increases ACE2 binding affinity, and may impact the collective dynamics of the ACE2-RBD complex, occupying a central hinge site that modulates the overall dynamics of the complex. In contrast, the substitutions K417N and E484K in the South African variant 501.V2 would reduce the ACE2-binding affinity by abolishing two interfacial salt bridges that facilitate RBD binding to ACE2, K417(S)-D30(ACE2) and E484 (S)-K31(ACE2). These two mutations may thus be more than compensating the attractive effect induced by N501Y, overall resulting in an ACE2-binding affinity comparable to that of the wildtype RBD. Further analysis of the impact of these mutations on the interactions with mAbs targeting the spike indicate that the substitutions K417N and E484K may also abolish the salt bridges between the spike and selected mAbs, such as REGN10933, BD23, H11_H4, and C105, thus reducing the binding affinity and effectiveness of these mAbs.Contactbahar@pitt.eduSupplementary informationSupplementary data are available atBioinformaticsonline.