bluuebunny/crossref_metadata_2025_split huggingface dataset:
A recombinant SARS-CoV-2 RBD antigen expressed in insect cells elicits immunogenicity and confirms safety in animal models
Authors: Choque-Guevara Ricardo , Poma-Acevedo Astrid , Montesinos-Millán Ricardo , Rios-Matos Dora , Gutiérrez-Manchay Kristel , Montalvan Angela , Quiñones-Garcia Stefany , de Grecia Cauti-Mendoza Maria , Agurto-Arteaga Andres , Ramirez-Ortiz Ingrid , Criollo-Orozco Manuel , Huaccachi-Gonzales Edison , Lázaro Yomara K. Romero , Perez-Martinez Norma , Isasi-Rivas Gisela , Sernaque-Aguilar Yacory , Villanueva-Pérez Doris , Vallejos-Sánchez Katherine , Fernández-Sánchez Manolo , Guevara Luis , Fernández-Díaz Manolo , Zimic Mirko ,   for the COVID-19 Working Group in Perú
Published: November 2021

AbstractCOVID-19 pandemic has accelerated the development of vaccines against its etiologic agent, SARS-CoV-2. However, the emergence of new variants of the virus requires new immunization strategies in addition to the current vaccines approved for human administration. In the present report, the immunological and safety evaluation in mice and hamsters of a subunit vaccine based on the RBD sub-domain with two adjuvants of oil origin is described.The RBD protein was expressed in insect cells and purified by chromatography until >95% purity. The protein was shown to have the appropriate folding as determined by ELISA and flow cytometry binding assays to its receptor, as well as by its detection by hamster immune anti-S1 sera under non-reducing conditions.In immunization assays in mice and hamsters, the purified RBD formulated with adjuvants based on oil-water emulsifications and squalene was able to stimulate specific neutralizing antibodies and confirm the secretion of IFN-γ after stimulating spleen cells with the purified RBD. The vaccine candidate was shown to be safe, as demonstrated by the histopathological analysis in lungs, liver and kidney. These results demonstrate the potential of the purified RBD administered with adjuvants through an intramuscular route, to be evaluated in a challenge against SARS-CoV-2 and determine its ability to confer protection against infection.
Incorporating the mutational landscape of SARS-COV-2 variants and case-dependent vaccination rates into epidemic models
Authors: Chowdhury Mohammad Mihrab , Islam Md Rafiul , Hossain Md Sakhawat , Tabassum Nusrat , Peace Angela 
Published: November 2021

AbstractCoronavirus Disease (COVID-19), which began as a small outbreak in Wuhan, China in December 2019, became a global pandemic within months due to its high transmissibility. In the absence of pharmaceutical treatment, various non-pharmaceutical interventions (NPIs) to contain the spread of COVID-19 brought the entire world to a halt. After almost a year of seemingly returning to normalcy with the world’s quickest vaccine development, the emergence of more infectious and vaccine resistant coronavirus variants is bringing the situation back to where it was a year ago. In the light of this new situation, we conducted a study to portray the possible scenarios based on the three key factors : impact of interventions (pharmaceutical and NPIs), vaccination rate, and vaccine efficacy. In our study, we assessed two of the most crucial factors, transmissibility and vaccination rate, in order to reduce the spreading of COVID-19 in a simple but effective manner. In order to incorporate the time-varying mutational landscape of COVID-19 variants, we estimated a weighted transmissibility composed of the proportion of existing strains that naturally vary over time. Additionally, we consider time varying vaccination rates based on the number of daily new cases. Our method for calculating the vaccination rate from past active cases is an effective approach in forecasting probable future scenarios as it actively tracks people’s attitudes toward immunization as active cases change. Our simulations show that if a large number of individuals cannot be vaccinated by ensuring high efficacy in a short period of time, adopting NPIs is the best approach to manage disease transmission with the emergence of new vaccine breakthrough and more infectious variants.
Neurocognition and its association with adverse childhood experiences and familial risk of mental illness
Authors: Lakkireddy Sai Priya , Balachander Srinivas , Dayal Pavithra , Bhattacharya Mahashweta , Joseph Mino Susan , Kumar Pramod , Kannampuzha Anand Jose , Mallappagari Sreenivasulu , Shruthi Suvarna , Chandy Alen Alexander , Kumaran Muthu , Sheth Sweta , Ramesh Vinutha , Puzhakkal Joan C , Selvaraj S Sowmya , Ithal Dhruva , Sreeraj Vanteemar S , Mahadevan Jayant , Holla Bharath , Venkatasubramanian Ganesan , John John P. , Murthy Pratima , Benegal Vivek , Janardhan Reddy YC , Jain Sanjeev ,   ADBS Consortium, Viswanath Biju 
Published: November 2021

AbstractBackgroundNeurocognitive deficits are considered an endophenotype for several psychiatric disorders, typically studied in unaffected first-degree relatives (FDRs). Environmental factors such as adverse childhood experiences (ACEs) may also affect neurocognition. This study examines the effect of ACEs on neurocognitive performance in FDRs of patients with severe mental illness in order to determine whether familial risk has a moderating effect on the relationship between ACEs and neurocognition.MethodsThe sample consists of a total of 512 individuals composed of unaffected FDRs from multiplex families with severe mental illnesses (schizophrenia, bipolar disorder, obsessive-compulsive disorder or alcohol use disorder) and healthy controls (with no familial risk). Neurocognitive tests included processing speed (Color Trails), new learning (Auditory Verbal Learning Test), working memory (N-Back), and Theory of Mind (SOCRATIS). ACEs were measured using the WHO ACE-International Questionnaire (ACE-IQ). Regression models adjusted for age, gender and education were done to predict each neurocognitive domain by the effect of familial risk, ACE-IQ Total Score and the interaction (familial risk x ACE-IQ Total score).ResultsWhen all FDRs were examined as a group, the main effect of familial risk predicted poor performance in all domains of neurocognition (p <0.01), and the ACEs x familial risk interaction had a significant negative association with global neurocognition, processing speed & working memory. This interaction effect was driven predominantly by the familial risk of AUD. In FDRs of schizophrenia & bipolar disorder, only the main effects of familial risk were significant (working memory, theory of mind & global neurocognition), with no impact of ACEs or its interaction in both these sub-groups.ConclusionsThe impact of childhood adversity on neurocognition is moderated by familial risk of psychiatric disorders. Genetic or familial vulnerability may play a greater role in disorders such as schizophrenia and bipolar disorder, while the interaction between ACEs and family history may be more relevant in the case of disorders with greater environmental risk, such as substance use.
A microbial mutualist within host individuals increases parasite transmission between host individuals: Evidence from a field mesocosm experiment
Authors: O’Keeffe Kayleigh R. , Wheeler Brandon T. , Mitchell Charles E. 
Published: November 2021

AbstractThe interactions among host-associated microbes and parasites can have clear consequences for disease susceptibility and progression within host individuals. Yet, empirical evidence for how these interactions impact parasite transmission between host individuals remains scarce. We address this scarcity by using a field mesocosm experiment to investigate the interaction between a systemic fungal endophyte,Epichloë coenophiala, and a fungal parasite,Rhizoctonia solani, in leaves of a grass host, tall fescue. Specifically, we investigated how this interaction impacted parasite transmission under field conditions in replicated experimental host populations.Epichloë-inoculated populations tended to have greater disease prevalence over time, though this difference had weak statistical support. More clearly,Epichloë-inoculated populations experienced higher peak parasite prevalences thanEpichloë-free populations.Epichloëconferred a benefit in growth;Epichloë-inoculated populations had greater aboveground biomass thanEpichloë-free populations. Using biomass as a proxy, host density was correlated with peak parasite prevalence, butEpichloëstill increased peak parasite prevalence after controlling for the effect of biomass. Together, these results suggest that within-host microbial interactions can impact disease at the population level. Further, whileEpichloëis clearly a mutualist of tall fescue, it may not be a defensive mutualist in relation toR. solani.
Transient adverse events after REGN-CoV2 administration for mild COVID-19 patients and their potential predictive factors: a single center analysis
Authors: Kano Gen , Taniguchi Kyoko , Oue Yukiko 
Published: November 2021

AbstractBackgroundREGN-COV2, a monoclonal antibody cocktail drug against the SARS-COV-2 virus, has proven to be effective in preventing the development of severe COVID-19 and is increasingly being administered in outpatient and home settings. Adverse events such as fever and decreased oxygen saturation may occur after administration of REGN-COV2, and although these symptoms are generally mild and transient, predicting the occurrence of these adverse events is useful in developing a monitoring plan for patients.MethodsWe performed a retrospective analysis of 76 patients who received REGN-CoV2 between August and September 2021. We collected information on fever, decreased oxygen saturation requiring oxygen supplementation, and other adverse events from medical records. Patients were divided into two subgroups: those who presented with fever or oxygen desaturation and those who did not, and underlying medical conditions and laboratory data were compared between each group. The parameters that exhibited significant differences were further tested using Fisher’s exact test to evaluate whether appropriate thresholds could be set to distinguish the incidence group from the non-incidence group.FindingsOf the 76 patients, 47 had fever of 38.5°C or higher within 24 hours after administration, and 27 of these patients had a body temperature of 37.5°C or lower before administration. Oxygen was required in 17 cases, 7 of which required oxygen more than 24 hours after administration of REGN-COV2, and additional treatment such as dexamethasone was given as the disease progressed to moderate. Among the parameters analyzed, lymphocyte count and IFNλ3 showed significant differences between the fever and non-fever groups. This was also the case in the comparison excluding patients who had fever before administration. There was also a significant difference in ferritin and CRP between the oxygen required and non-required groups. In addition to IFNλ3, ferritin, and CRP, there was a significant difference in LDH between the group that required additional treatment and the group that did not. When lymphocytes count <950/µL was used to predict fever, the sensitivity and specificity were 55% and 79%, respectively, with odds ratio 4.746 (95% CI: 1.666 to 14.12, p=0.004) in contingency table analysis. Similarly, when IFNλ3 >5.0 was used as the cutoff, sensitivity 72%, specificity 76%, odds ratio 8.220 (2.857 to 22.22; p<0.0001).InterpretationsTransient fever and decreased oxygen saturation are common adverse events after REGN-CoV2 administration, and their occurrence correlated with the severity factor of COVID-19 itself. Evaluation of these items at the time of administration is useful not only for predicting the severity of COVID-19 but also for the development of adverse events in patients receiving REGN-CoV2.
Mitochondrial DNA copy number, metabolic syndrome, and insulin sensitivity: Insights from the Sugar, Hypertension, and Physical Exercise Studies
Authors: Yang Stephanie Y. , Mirabal Caleb S. , Newcomb Charles E. , Stewart Kerry J. , Arking Dan E. 
Published: November 2021

AbstractMitochondrial DNA copy number (mtDNA-CN) measured in blood has been associated with many aging-related diseases, with higher mtDNA-CN typically associated with lower disease risk. Exercise training is an excellent preventative tool against aging-related disorders and has been shown to increase mitochondrial function in muscle. Using the Sugar, Hypertension, and Physical Exercise cohorts (N = 105), we evaluated the effect of 6-months of exercise intervention on mtDNA-CN measured in blood. Although there was no significant relationship between exercise intervention and mtDNA-CN change (P = 0.29), there was a nominally significant association between mtDNA-CN and metabolic syndrome (P = 0.04), which has been seen in previous literature. We also identified a nominally significant association between higher mtDNA-CN and higher insulin sensitivity (P = 0.02).
Phase Shift Between Age-Specific COVID-19 Incidence Curves Points to a Potential Epidemic Driver Function of Kids and Juveniles in Germany
Authors: Diebner Hans H. 
Published: November 2021

AbstractMutual phase shifts between three German COVID-19 incidence curves corresponding to the age classes of children, juveniles and adults, respectively, are calculated by means of delay-cross-correlations. At the country level, a phase shift of −5 weeks during the first half of the epidemic between the incidence curves corresponding to the juvenile age class and the curve corresponding to the adult class is observed. The children’s incidence curve is shifted by −3 weeks with respect to the adults’ curve. On the regional level of the 411 German districts (Landkreise) the distributions of observed time lags are inclined towards negative values. Regarding the incidence time series of the juvenile sub-population, 20% of the German districts exhibit negative phase shifts and only 3% show positive shifts versus the incidence curves of the adult sub-population. Similarly for the children with 6% positive shifts. Thus, children’s and juveniles’ epidemic activity is ahead of the adults’ activity. The correlation coefficients of shifted curves are large (> 0.9 for juveniles versus adults on the country level) which indicates that aside from the phase shift the sub-populations follow a similar epidemic dynamics. Negative phase shifts of the children’s incidence curves during the first and second epidemic waves are predictors for high incidences during the current fourth wave with respect to the corresponding districts.
An amino residue that guides the correct photoassembly of the water-oxidation complex but is not required for high affinity Mn2+ binding
Authors: Avramov Anton P. , Zhang Minquan , Burnap Robert L. 
Published: November 2021

AbstractThe assembly of the Mn4O5Ca cluster of the photosystem II (PSII) starts from the initial binding and photooxidation of the first Mn2+ at a high affinity site (HAS). Recent cryo-EM apo-PSII structures reveal an altered geometry of amino ligands in this region and suggest the involvement of D1-Glu189 ligand in the formation of the HAS. We now find that Gln and Lys substitution mutants photoactivate with reduced quantum efficiency compared to the wild-type. However, the affinity of Mn2+ at the HAS in D1-E189K was very similar to the wild-type (~2.2 μM). Thus, we conclude that D1-E189 does not form the HAS (~2.9 μM) and that the reduced quantum efficiency of photoactivation in D1-E189K cannot be ascribed to the initial photooxidation of Mn2+ at the HAS. Besides reduced quantum efficiency, the D1-E189K mutant exhibits a large fraction of centers that fail to recover activity during photoactivation starting early in the assembly phase, becoming recalcitrant to further assembly. Fluorescence relaxation kinetics indicate on the presence of an alternative route for the charge recombination in Mn-depleted samples in all studied mutants and exclude damage to the photochemical reaction center as the cause for the recalcitrant centers failing to assemble and show that dark incubation of cells reverses some of the inactivation. This reversibility would explain the ability of these mutants to accumulate a significant fraction of active PSII during extended periods of cell growth. The failed recovery in the fraction of inactive centers appears to a reversible mis-assembly involving the accumulation of photooxidized, but non-catalytic high valence Mn at the donor side of photosystem II, and that a reductive mechanism exists for restoration of assembly capacity at sites incurring mis-assembly. Given the established role of Ca2+ in preventing misassembled Mn, we conclude that D1-E189K mutant impairs the ligation of Ca2+ at its effector site in all PSII centers that consequently leads to the mis-assembly resulting in accumulation of non-catalytic Mn at the donor side of PSII. Our data indicate that D1-E189 is not functionally involved in Mn2+ oxidation\binding at the HAS but rather involved in Ca2+ ligation and steps following the initial Mn2+ photooxidation.
Orthoformimycin inhibits translation elongation by displacing the A-site tRNA and preventing peptide bond formation
Authors: Schedlbauer Andreas , Kaminishi Tatsuya , Fabbretti Attilio , Milón Pohl , Han Xu , Ochoa-Lizarralde Borja , Çapuni Retina , Gualerzi Claudio O. , Connell Sean R. , Fucini Paola 
Published: November 2021

ABSTRACTThe ribosome is a major target for antibiotics owing to its essential cellular role in protein synthesis. Structural analysis of ribosome-antibiotic complexes provides insight into the molecular basis for their inhibitory action and highlights possible avenues to improve their potential or overcome existing resistance mechanisms. Here we use X-ray crystallography and pre-steady state kinetics to detail the inhibitory mechanism of the antimicrobial on the large ribosomal subunit.
A Conformational Transition of Von Willebrand Factor’s D’D3 Domain Primes It For Multimerization
Authors: Gruber Sophia , Löf Achim , Hausch Adina , Jöhr Res , Obser Tobias , König Gesa , Schneppenheim Reinhard , Brehm Maria A. , Benoit Martin , Lipfert Jan 
Published: November 2021

AbstractVon Willebrand factor (VWF) is a multimeric plasma glycoprotein that is critically involved in hemostasis. Biosynthesis of long VWF concatemers in the endoplasmic reticulum and the (trans-)Golgi is still not fully understood. We use the single-molecule force spectroscopy technique magnetic tweezers to analyze a previously hypothesized conformational change in the D’D3 domain crucial for VWF multimerization. We find that the interface formed by submodules C8-3, TIL3, and E3 wrapping around VWD3 can open and expose two previously buried cysteines that are known to be vital for multimerization. By characterizing the conformational change at varying levels of force, we are able to quantify the kinetics of the transition and the stability of the interface. We find a pronounced destabilization of the interface upon lowering the pH from 7.4 to 6.2 and 5.5. This is consistent with initiation of the conformational change that enables VWF multimerization at the D’D3 domain by a decrease in pH in the trans-Golgi network and Weibel-Palade bodies. Furthermore, we find a stabilization of the interface in the presence of coagulation factor VIII (FVIII), providing evidence for a previously hypothesized binding site in submodule C8-3. Our findings highlight the critical role of the D’D3 domain in VWF biosynthesis and function and we anticipate our methodology to be applicable to study other, similar conformational changes in VWF and beyond.
A positive feedback loop mediates crosstalk between calcium, cyclic nucleotide and lipid signalling in Toxoplasma gondii
Authors: Dominicus Caia , Nofal Stephanie D. , Broncel Malgorzata , Katris Nicholas J. , Flynn Helen R. , Arrizabalaga Gustavo , Botté Cyrille Y. , Invergo Brandon M. , Treeck Moritz 
Published: November 2021

AbstractFundamental processes of obligate intracellular parasites, such as Toxoplasma gondii and Plasmodium falciparum, are controlled by a set of plant-like calcium dependent kinases (CDPKs), the conserved cAMP- and cGMP-dependent protein kinases (PKA and PKG), secondary messengers and lipid signalling. While some major components of the signalling networks have been identified, how these are connected remains largely unknown. Here, we compare the phospho-signalling networks during Toxoplasma egress from its host cell by artificially raising cGMP or calcium levels to activate PKG or CDPKs, respectively. We show that both these inducers trigger near identical signalling pathways and provide evidence for a positive feedback loop involving CDPK3. We measure phospho- and lipid signalling in parasites treated with the Ca2+ ionophore A23187 in a sub-minute timecourse and show CDPK3-dependent regulation of diacylglycerol levels and increased phosphorylation of four phosphodiesterases (PDEs), suggesting their function in the feedback loop. Disruption of CDPK3 leads to elevated cAMP levels and inhibition of PKA signalling rescues the egress defect of ΔCDPK3 parasites treated with A23187. Biochemical analysis of the four PDEs identifies PDE2 as the only cAMP-specific PDE among these candidates, while the other PDEs are cGMP specific, two of which are inhibited by the predicted PDE inhibitor BIPPO. Conditional deletion of the four PDEs supports an important, but non-essential role for PDE1 and PDE2 in growth, with PDE2 controlling A23187-mediated egress. In summary we uncover a positive feedback loop that enhances signalling during egress and links several signalling pathways together.
Effect of gastrointestinal alterations mimicking elderly conditions on in vitro digestion of meat and soy proteins
Authors: Wang Chong , Zhao Fan , Bai Yun , Li Chunbao , Xu Xinglian , Kristiansen Karsten , Zhou Guanghong 
Published: November 2021

AbstractWe evaluated the digestion of meat (chicken, beef, and pork) and soy proteins under in vitro conditions mimicking gastrointestinal (GI) conditions of adults (control, C) and elderly with achlorhydria (EA). The changes in degree of hydrolysis (DH), SDS-PAGE profiles, peptide concentration, and proteomics profiles during the digestion process were investigated. Digestion under the EA condition markedly decreased the DH of all protein sources, especially for soy protein. SDS-PAGE profiling and proteomics showed that myofibrillar/sarcoplasmic protein from meat and glycinin/beta-conglycinin from soy were the proteins most affected by the different digestive conditions. Our results indicated that the difference in the digestibility of meat protein between EA and control conditions gradually narrowed from the gastric to the intestinal phase, while a pronounced difference between control and EA conditions was maintained also in the intestinal phase. This work provides new insights of value for future dietary recommendations for elderly individuals.
Non-random interactions within and across guilds shape the potential to coexist in multi-trophic ecological communities
Authors: García-Callejas David , Godoy Oscar , Buche Lisa , Hurtado María , Lanuza Jose B. , Allen-Perkins Alfonso , Bartomeus Ignasi 
Published: November 2021

AbstractTheory posits that the persistence of species in ecological communities is shaped by their interactions within and across trophic guilds. However, we lack empirical evaluations of how the structure, strength, and sign of biotic interactions drive the potential to coexist in diverse multi-trophic communities. Here we model community feasibility domains, a theoretically-informed measure of multi-species coexistence probability, from grassland communities comprising more than 45 species on average from three trophic guilds (plants, pollinators, and herbivores). Contrary to our hypothesis, increasing community complexity, measured either as the number of guilds or community richness, did not decrease community feasibility. Rather, we observed that high degrees of species self-regulation and niche partitioning allow maintaining larger levels of community feasibility and higher species persistence in more diverse communities. Our results show that biotic interactions within and across guilds are not random in nature and both structures significantly contribute to maintaining multi-trophic diversity.