bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrated Vaccination and Non-Pharmaceutical Interventions based Strategies in Ontario, Canada, as a Case Study: a Mathematical Modeling Study
Authors: Betti Matthew , Bragazzi Nicola Luigi , Heffernan Jane , Kong Jude , Raad Angie 
Published: January 2021

AbstractBackgroundRecently, two “Coronavirus disease 2019” (COVID-19) vaccine products have been authorized in Canada. It is of crucial importance to model an integrated/combined package of non-pharmaceutical (physical/social distancing) and pharmaceutical (immunization) public health control measures.MethodsA modified epidemiological, compartmental SIR model was utilized and fit to the cumulative COVID-19 case data for the province of Ontario, Canada, from September 8, 2020 to December 8, 2020. Different vaccine roll-out strategies were simulated until 75 percent of the population is vaccinated, including a no-vaccination scenario. We compete these vaccination strategies with relaxation of non-pharmaceutical interventions. Non-pharmaceutical interventions were supposed to remain enforced and began to be relaxed on either January 31, March 31, or May 1, 2021.ResultsBased on projections from the data and long-term extrapolation of scenarios, relaxing the public health measures implemented by re-opening too early would cause any benefits of vaccination to be lost by increasing case numbers, increasing the effective reproduction number above 1 and thus increasing the risk of localized outbreaks. If relaxation is, instead, delayed and 75 percent of the Ontarian population gets vaccinated by the end of the year, re-opening can occur with very little risk.InterpretationRelaxing non-pharmaceutical interventions by re-opening and vaccine deployment is a careful balancing act. Our combination of model projections from data and simulation of different strategies and scenarios, can equip local public health decision- and policy-makers with projections concerning the COVID-19 epidemiological trend, helping them in the decision-making process.
Socioeconomic Disparities in the Effects of Pollution on Spread of Covid-19: Evidence from US Counties
Authors: Allen Osvaldo , Brown Ava , Wang Ersong 
Published: January 2021

AbstractThis paper explores disparities in the effect of pollution on confirmed cases of Covid-19 based on counties’ socioeconomic and demographic characteristics. Using data on all US counties on a daily basis over the year 2020 and applying a rich panel data fixed effect model, we document that: 1) there are discernible social and demographic disparities in the spread of Covid-19. Blacks, low educated, and poorer people are at higher risks of being infected by the new disease. 2) The criteria pollutants including Ozone, CO, PM10, and PM2.5 have the potential to accelerate the outbreak of the novel coronavirus. 3) The disadvantaged population is more vulnerable to the effects of pollution on the spread of coronavirus. Specifically, the effects of pollution on confirmed cases become larger for blacks, low educated, and counties with lower average wages in 2019.
An Electronic Health Record Compatible Model to Predict Personalized Treatment Effects from the Diabetes Prevention Program: A Cross-Evidence Synthesis Approach Using Clinical Trial and Real World Data
Authors: Kent David M , Nelson Jason , Pittas Anastassios , Colangelo Francis , Koenig Carolyn , van Klaveren David , Ciemins Elizabeth , Cuddeback John 
Published: January 2021

AbstractBackgroundAn intensive lifestyle modification program or metformin pharmacotherapy reduced the risk of developing diabetes in patients at high risk, but are not widely used in the 88 million American adults with prediabetes.ObjectiveDevelop an electronic health record (EHR)-based risk tool that provides point-of-care estimates of diabetes risk to support targeting interventions to patients most likely to benefit.DesignCross-design synthesis: risk prediction model developed and validated in large observational database, treatment effect estimates from risk-based reanalysis of clinical trial data.SettingOutpatient clinics in US.PatientsRisk model development cohort: 1.1 million patients with prediabetes from the OptumLabs Data Warehouse (OLDW); validation cohort: distinct sample of 1.1 million patients in OLDW. Randomized clinical trial cohort: 3081 people from the Diabetes Prevention Program (DPP) study.InterventionsRandomization in the DPP: 1) an intensive program of lifestyle modification; 2) standard lifestyle recommendations plus 850 mg metformin twice daily; or 3) standard lifestyle recommendations plus placebo twice daily.ResultsEleven variables reliably obtainable from the EHR were used to predict diabetes risk. This model validated well in the OLDW (c-statistic = 0.76; observed 3-year diabetes rate was 1.8% in lowest-risk quarter and 19.6% in highest-risk quarter). In the DPP, the hazard ratio for lifestyle modification was constant across all levels of risk (HR = 0.43, 95% CI 0.35 – 0.53); while the HR for metformin was highly risk-dependent (HR HR = 1.1 [95% CI: 0.61 - 2.0] in the lowest-risk quarter vs. HR=0.45 [95% CI: 0.35 0.59] in the highest risk quarter). Fifty-three percent of the benefits of population-wide dissemination of the DPP lifestyle modification, and 76% of the benefits of population-wide metformin therapy can be obtained targeting the highest risk quarter of patients.LimitationsDifferences in variable definitions and in missingness across observational and trial settings may introduce estimation error in risk-based treatment effects.ConclusionAn EHR-compatible risk model might support targeted diabetes prevention to more efficiently realize the benefits of the DPP interventions.
Blood omega-3 fatty acids and death from COVID-19: A Pilot Study
Authors: Asher Arash , Tintle Nathan L. , Myers Michael , Lockshon Laura , Bacareza Heribert , Harris William S. 
Published: January 2021

SUMMARYVery-long chain omega-3 fatty acids (EPA and DHA) have anti-inflammatory properties that may help reduce morbidity and mortality from COVID-19 infection. We conducted a pilot study in 100 patients to test the hypothesis that RBC EPA+DHA levels (the Omega-3 Index, O3I) would be inversely associated with risk for death by analyzing the O3I in banked blood samples drawn at hospital admission. To have adequate power (>80%) in this pilot study, we pre-specified a significance level of 0.10. Fourteen patients died, one of 25 in quartile 4 (Q4) (O3I ≥5.7%) and 13 of 75 in Q1-3. After adjusting for age and sex, the odds ratio for death in patients with an O3I in Q4 vs Q1-3 was 0.25, p=0.07. Thus, we have suggestive evidence that the risk for death from COVID-19 was lower in those with the highest O3I levels. These preliminary findings need to be confirmed in larger studies.
Early Vocal Development in Tuberous Sclerosis Complex
Authors: Gipson Tanjala T. , Ramsay Gordon , Ellison Ellen , Bene Edina , Long Helen L. , Oller D. Kimbrough 
Published: January 2021

AbstractObjectiveTo determine whether entry into the canonical stage, canonical babbling ratios (CBR) and the level of volubility (vocal measures) are delayed in infants with Tuberous Sclerosis Complex (TSC), we completed human coding of their vocalizations at 12 months and compared the results to typically developing infants with no clinical features (TD/NCF).MethodsWe randomly selected videos from 40 infants with TSC from the TACERN database. All 78 videos were coded in real-time in AACT (Action Analysis, Coding and Training).ResultsEntry into thecanonical stagewas delayed in the great majority of the infants with TSC. TheCBRfor the TD/NCF infants was significantly higher than for the infants with TSC (TD/NCF mean = .346, SE = .19; TSC mean = .117, SE = .023).Volubilitylevel in infants with TSC was less than half that of TD/NCF infants (TD/NCF mean = 9.82, SE = 5.78; TSC mean = 3.99, SE = 2.16). CBR and volubility were also lower in TSC infants than in TD/NCF infants recorded all-day at home.ConclusionsEntry into the canonical stage was delayed, while canonical babbling ratios and volubility were low in infants with TSC. Assessing prediction of neurodevelopmental outcome using these vocal measures in combination with non-vocal measures will be the focus of planned studies in this high-risk population.
Characterising SARS-CoV-2 viral clearance kinetics to improve the design of antiviral pharmacometric studies
Authors: Watson James A , Kissler Stephen , Day Nicholas PJ , Grad Yonatan , White Nicholas J 
Published: January 2021

AbstractA consensus methodology for pharmacometric assessment of candidate SARS-CoV-2 antiviral drugs would be useful for comparing trial results and improving trial design. The time to viral clearance, assessed by serial qPCR of nasopharyngeal swab samples, has been the most widely reported measure of virological response in clinical trials, but it has not been compared formally with other metrics, notably model-based estimates of the rate of viral clearance. We analysed prospectively gathered viral clearance profiles from 280 infection episodes in vaccinated and unvaccinated individuals. We fitted different phenomenological pharmacodynamic models (single exponential decay, bi-exponential, penalised splines) and found that the clearance rate, estimated from a mixed effects single exponential decay model, is a robust pharmacodynamic summary of viral clearance. The rate of viral clearance, estimated from viral densities during the first week following peak viral load, provides increased statistical power (reduced type 2 error) compared with time to clearance. We recommend that pharmacometric antiviral assessments should be conducted in early illness with serial qPCR samples taken over one week.
Enhancing cancer targeting of γ9δ2TCR through modified NKG2D co-stimulation
Authors: Hernández-López Patricia , van Diest Eline , Johanna Inez , Heijhuurs Sabine , Straetemans Trudy , Sebestyén Zsolt , Beringer Dennis X. , Kuball Jürgen 
Published: January 2021

AbstractDespite the ability of γδT cells to mediate tumor killing independently of MHC recognition, all the clinical trials that have been carried out using these cells showed low response rate in patients, in part due to its poor proliferation ability. Recently, a new generation of CAR-T cells called αβT cells engineered to express a defined γδTCR (TEG) has been developed. TEGs are αβT cells engineered to express a defined γδTCR. These cells are able to mediate effective antitumor reactivity without showing any reactivity towards healthy tissue, and combine the best qualities of both αβT and γδT cells. In fact, the high affinity γ9δ2TCR clone 5 has recently been selected within the TEG format as a clinical candidate (TEG001). Here we present a strategy to improve the antitumor activity of TEG001 by co-expressing an activating chimeric co-receptor together with γδTCR-Cl5.Therefore, we developed three different co-receptors by fusing the extracellular domain of the activating cell surface receptor NKG2D, that is able to bind stress induced ligands typically expressed on tumor cells, to the cytoplasmic signaling domains of the T cell costimulatory proteins ICOS, CD28 and 4-1BB. We determined that introduction of the chimeric co-receptors NKG2D-CD28wtand NKG2D-4-1BBCD28TMimproved the activity of TEG001 against tumors that were recognized by γδTCR-Cl5 and expressed NKG2D ligands, but did not affect tumors that either were not recognized by γδTCR-Cl5 or did not express NKG2D ligands. This ‘chimeric co-receptors’ approach open a wide range of opportunities that lead to a next generation of TEGs.
Hydraulic diversity stabilizes productivity in a large-scale subtropical tree biodiversity experiment
Authors: Schnabel Florian , Liu Xiaojuan , Kunz Matthias , Barry Kathryn E. , Bongers Franca J. , Bruelheide Helge , Fichtner Andreas , Härdtle Werner , Li Shan , Pfaff Claas-Thido , Schmid Bernhard , Schwarz Julia A. , Tang Zhiyao , Yang Bo , Bauhus Jürgen , von Oheimb Goddert , Ma Keping , Wirth Christian 
Published: January 2021

AbstractExtreme climatic events threaten forests and their climate mitigation potential globally. Understanding the drivers promoting ecosystem stability is therefore considered crucial to mitigate adverse climate change effects on forests. Here, we use structural equation models to explain how tree species richness, asynchronous species dynamics and diversity in hydraulic traits affect the stability of forest productivity along an experimentally manipulated biodiversity gradient ranging from 1 to 24 tree species. Tree species richness improved stability by increasing species asynchrony. That is, at higher species richness, inter-annual variation in productivity among tree species buffered the community against stress-related productivity declines. This effect was mediated by the diversity of species’ hydraulic traits regarding drought tolerance and stomatal control, but not by the community-weighted means of these traits. The identified mechanisms by which tree species richness stabilizes forest productivity emphasize the importance of hydraulically diverse, mixed-species forests to adapt to climate change.
Structural and Functional Analyses Explain Pea KAI2 Receptor Diversity and Reveal Stereoselective Catalysis During Signal Perception
Authors: Guercio Angelica M. , Torabi Salar , Cornu David , Dalmais Marion , Bendahmane Abdelhafid , Signor Christine Le , Pillot Jean-Paul , Bris Philippe Le , Boyer François-Didier , Rameau Catherine , Gutjahr Caroline , de Saint Germain Alexandre , Shabek Nitzan 
Published: January 2021

AbstractKAI2 are plant α/β hydrolase receptors, which perceive smoke-derived butenolide signals (karrikins) and putative endogenous, yet unidentified phytohormones (KAI2-ligands, KLs). The number of functional KAI2 receptors varies among plant species. It has been suggested thatKAI2gene duplication and sub-functionalization plays an adaptative role for diverse environments or ligand diversification by altering the receptor responsiveness to specific KLs. Legumes represent one of the largest families of flowering plants and contain many essential agronomic crops. Prior to legume diversification,KAI2underwent duplication, resulting inKAI2AandKAI2B. Integrating plant genetics, ligand perception and enzymatic assays, and protein crystallography, we demonstrate thatPisum sativumKAI2A and KAI2B act as receptors and enzymes with divergent ligand stereoselectivity. KAI2B has a stronger affinity than KAI2A towards the KAI2-ligand (-)-GR24 and remarkably hydrolyses a broader range of substrates including the strigolactone-like isomer (+)-GR24. We determine the crystal structures of PsKAI2B in apo and butenolide-bound states. The biochemical and structural analyses as well as recorded mass spectra of KAI2s reveal a transient intermediate on the catalytic serine and a stable adduct on the catalytic histidine, further illuminating the role of KAI2 not only as receptors but also asbona fideenzymes. Our work uncovers the stereoselectivity of ligand perception and catalysis by evolutionarily diverged KAI2 receptors in KAR/KL signaling pathways and proposes adaptive sensitivity to KAR/KL and strigolactone phytohormones by KAI2B.
Loss of cGMP-dependent protein kinase II alters ultrasonic vocalizations in mice, a model for speech impairment in human microdeletion 4q21 syndrome
Authors: Tran Tiffany M. , Sherwood Jessica K. , Sathler Matheus F. , Hofmann Franz , Stone-Roy Leslie M. , Kim Seonil 
Published: January 2021

AbstractChromosome 4q21 microdeletion leads to a human syndrome that exhibits restricted growth, facial dysmorphisms, mental retardation, and absent or delayed speech. One of the key genes in the affected region of the chromosome isPRKG2, which encodes cGMP-dependent protein kinase II (cGKII). Mice lacking cGKII exhibit restricted growth and deficits in learning and memory, as seen in the human syndrome. However, speech/vocalization impairments in these mice have not been determined. Moreover, the molecular pathway underlying speech impairment in humans is not fully understood. Here, we employed cGKII knockout (KO) mice as a model for the human microdeletion syndrome to test whether vocalizations are affected by loss of thePRKG2gene. Mice emit ultrasonic vocalizations (USVs) to communicate in social situations, stress, and isolation. We thus recorded ultrasonic vocalizations as a model for speech in humans. We isolated postnatal day 5-7 pups from the nest to record and analyze USVs and found significant differences in vocalizations of KO mice relative to wild-type and heterozygous mutant mice. KO mice produced fewer calls that were shorter duration, higher frequency, and lower intensity. Because neuronal activity in the hypothalamus is important for the production of animal USVs following isolation from the nest, we assessed hypothalamic activity in KO pups following isolation. Indeed, we found abnormal hyperactivation of hypothalamic neurons in cGKII KO pups after isolation. Taken together, our studies indicate that cGKII is important for neuronal activation in the hypothalamus, which is required for the production of USVs in neonatal mice. We further suggest cGKII KO mice can be a valuable animal model for human microdeletion 4q21 syndrome.HighlightsChromosome 4q21 microdeletion leads to a human syndrome that exhibits restricted growth, mental retardation, and absent or delayed speech.ThecGMP-dependent protein kinase II (cGKII)gene is one of the genes located in the affected region of the chromosome.cGKII knockout mice show restricted growth and deficits in learning and memory.Altered ultrasonic vocalizations and abnormal activation in hypothalamic neurons are found when infant cGKII knockout pups are isolated from the nest.cGKII knockout mice can be a valuable animal model for human microdeletion 4q21 syndrome.
Guanosine tetraphosphate (ppGpp) accumulation inhibits chloroplast gene expression and promotes super grana formation in the mossPhyscomitrium(Physcomitrella)patens
Authors: Harchouni Seddik , England Samantha , Vieu Julien , Aouane Aicha , Citerne Sylvie , Legeret Bertrand , Li-Beisson Yonghua , Menand Benoît , Field Ben 
Published: January 2021

SummaryThe nucleotides guanosine tetraphosphate and pentaphosphate (or ppGpp) are implicated in the regulation of chloroplast function in plants. ppGpp signalling is best understood in the model vascular plantArabidopsis thalianawhere it acts to regulate plastid gene expression to influence photosynthesis, plant development and immunity. However, little is known about the conservation or diversity of ppGpp signaling in other land plants. Here, we studied the function of ppGpp in the mossPhyscomitrium(previouslyPhyscomitrella)patensusing an inducible system for triggering ppGpp accumulation. We used this approach to investigate the effects of ppGpp on chloroplast function, photosynthesis and growth. We demonstrate that ppGpp accumulation causes a dramatic drop in photosynthetic capacity by inhibiting chloroplast gene expression. This was accompanied by the unexpected reorganisation of the thylakoid system into super grana. Surprisingly, these changes did not affect gametophore growth, suggesting that bryophytes and vascular plants may have different tolerances to defects in photosynthesis. Our findings point to the existence of both highly conserved and more specific targets of ppGpp signalling in the land plants that may reflect different growth strategies.
INPP5E regulates CD3ζ enrichment at the immune synapse by phosphoinositide distribution control
Authors: Chiu Tzu-Yuan , Yang Fu-Hua , Chong Weng Man , Tsai Hsing-Chen , Wang Won-Jing , Liao Jung-Chi 
Published: January 2021

AbstractThe immune synapse, a specialized interface formed between T lymphocytes and antigen-presenting cells (APCs) after antigen recognition, is essential for T cell activation and the adaptive immune response. It has been shown that this interface shares similarities with the primary cilium, a sensory organelle in eukaryotic cells, although roles of ciliary proteins on the immune synapse remain elusive. In this study, we find that inositol polyphosphate-5-phosphatase E (INPP5E), a cilium-enriched protein responsible for regulating phosphoinositide localization, accumulated at the immune synapse during antigen-specific conjugation or antibody capping, and formed a complex with CD3ζ, ZAP-70, and Lck. Silencing INPP5E in T-cells impaired polarized distribution of CD3ζ at the immune synapse, and correlated with a failure of PI(4,5)P2clearance at the center of the synapse. Moreover, INPP5E silencing decreased proximal TCR signaling, including phosphorylation of CD3ζ and ZAP-70, and finally, attenuated IL-2 secretion. Our results suggest that INPP5E is a new player in phosphoinositide manipulation at the synapse, controlling the TCR signaling cascade.
Altered A-type potassium channel function impairs dendritic spike initiation and temporammonic long-term potentiation in Fragile X syndrome
Authors: Ordemann Gregory J. , Apgar Christopher J. , Chitwood Raymond A. , Brager Darrin H. 
Published: January 2021

AbstractFragile X syndrome (FXS) is the leading monogenetic cause of cognitive impairment and autism spectrum disorder. Area CA1 of the hippocampus receives current information about the external world from the entorhinal cortex via the temporoammonic (TA) pathway. Given its role in learning and memory, it is surprising that little is known about TA long-term potentiation (TA-LTP) in FXS. We found that TA-LTP was impaired infmr1KO mice. Furthermore, dendritic Ca2+influx was smaller and dendritic spike threshold was depolarized infmr1KO mice. Dendritic spike threshold and TA-LTP were restored by block of A-type K+channels. The impairment of TA-LTP coupled with enhanced Schaffer collateral LTP may contribute to spatial memory alterations in FXS. Furthermore, as both of these LTP phenotypes are attributed to changes in A-type K+channels in FXS, our findings provide a potential therapeutic target to treat cognitive impairments in FXS.
Consistent Force Field Captures Homolog Resolved HP1 Phase Separation
Authors: Latham Andrew P. , Zhang Bin 
Published: January 2021

AbstractMany proteins have been shown to function via liquid-liquid phase separation. Computational modeling could offer much needed structural details of protein condensates and reveal the set of molecular interactions that dictate their stability. However, the presence of both ordered and disordered domains in these proteins places a high demand on the model accuracy. Here, we present an algorithm to derive a coarse-grained force field, MOFF, that can model both ordered and disordered proteins with consistent accuracy. It combines maximum entropy biasing, least-squares fitting, and basic principles of energy landscape theory to ensure that MOFF recreates experimental radii of gyration while predicting the folded structures for globular proteins with lower energy. The theta temperature determined from MOFF separates ordered and disordered proteins at 300 K and exhibits a strikingly linear relationship with amino acid sequence composition. We further applied MOFF to study the phase behavior of HP1, an essential protein for posttranslational modification and spatial organization of chromatin. The force field successfully resolved the structural difference of two HP1 homologs, despite their high sequence similarity. We carried out large scale simulations with hundreds of proteins to determine the critical temperature of phase separation and uncover multivalent interactions that stabilize higher-order assemblies. In all, our work makes significant methodological strides to connect theories of ordered and disordered proteins and provides a powerful tool for studying liquid-liquid phase separation with near-atomistic details.