bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational Investigation of Increased Virulence and Pathogenesis of SARS-CoV-2 Lineage B.1.1.7
Authors: Murugan N. Arul , Javali Prashanth S. , Pandian Chitra Jeyaraj , Ali Muhammad Akhtar , Srivastava Vaibhav , Jeyaraman Jeyakanthan 
Published: January 2021

AbstractNew variants of SARS-CoV-2 are being reported worldwide. More specifically, the variants reported in South Africa (501Y.V2) and United Kingdom (B.1.1.7) were found to be more contagious than the wild type. There are also speculations that the variants might evade the host immune responses induced by currently available vaccines and develop resistance to drugs under consideration. The first step of viral infection in COVID-19, occurs through the interaction of receptor binding domain (RBD) of the spike protein with peptidase domain of the human ACE-2 (hACE-2) receptor. So, possibly the mutations in the RBD domain of spike protein in the new variants could modulate the protein-protein interaction with hACE-2 receptor leading to the increased virulence. In this study, we aim to get molecular level understanding into the mechanism behind the increased infection rate due to such mutations in these variants. We have computationally studied the interaction of the spike protein in both wild-type and B.1.1.7 variant with hACE-2 receptor using combined molecular dynamics and binding free energy calculations using molecular mechanics-Generalized Born surface area (MM-GBSA) approach. The binding free energies computed using configurations from minimization run and low temperature simulation show that mutant variant of spike protein has increased binding affinity for hACE-2 receptor (i.e. ΔΔG(N501Y,A570D) is in the range −20.4 to −21.4 kcal/mol)The residue-wise decomposition analysis and intermolecular hydrogen bond analysis evidenced that the N501Y mutation has increased interaction between RBD of spike protein with ACE-2 receptor. We have also carried out calculations using density functional theory and the results evidenced the increased interaction between three pairs of residues (TYR449 (spike)-ASP38 (ACE-2), TYR453-HIE34 and TYR501-LYS353) in the variant that could be attributed to its increased virulence. The free energies of wild-type and mutant variants of the spike protein computed from MM-GBSA approach suggests that latter variant is stable by about −10.4 kcal/mol when compared to wild type suggesting that it will be retained in the evolution due to increased stability. We demonstrate that with the use of the state-of-the art of computational approaches, we can in advance predict the more virulent nature of variants of SARS-CoV-2 and alert the world health-care system.
Fallow time determination in dentistry using aerosol measurement
Authors: Shahdad Shakeel , Hindocha Annika , Patel Tulsi , Cagney Neil , Mueller Jens-Dominik , Kochid Amine , Seoudi Noha , Morgan Claire , Fleming Padhraig , Din Ahmed Riaz 
Published: January 2021

AbstractAimTo calculate fallow time (FT) required following dental aerosol generating procedures (AGPs) in both a dental hospital (mechanically ventilated) and primary care (non-mechanically ventilated). Secondary outcomes were to identify spread and persistence of aerosol in open clinics compared to closed surgeries (mechanically ventilated environment), and identify if extra-oral scavenging (EOS) reduces production of aerosol and FT.MethodsIn vitro simulation of fast handpiece (FHP) cavity preparations using a manikin was conducted in a mechanically and non-mechanically ventilated environment using Optical Particle Sizer™ and NanoScan™ at baseline, during the procedure and fallow period.ResultsAGPs carried out in the non-mechanically, non-ventilated environment failed to achieve baseline particle levels after one hour. In contrast, when windows were opened after AGP, there was an immediate reduction in all particle sizes.In mechanically ventilated environments the baseline levels of particles were very low and particle count returned to baseline within 10 minutes following AGP. There was no detectable difference between particles in mechanically ventilated open bays and closed surgeries.The effect of the EOS was greater in non-mechanically ventilated environment on reducing the particle count; additionally, it also reduced the spikes in particle counts in mechanically ventilated environments.ConclusionHigh-efficiency particulate air filtered mechanical ventilation along with mitigating factors (high-volume suction) resulted in reduction of FT (10 minutes). Non-ventilated rooms failed to reach baseline level even after one hour of FT. There was no difference in particle counts in open bay or closed surgeries in mechanically ventilated settings. The use of an EOS device can reduce the particulate spikes during procedures in both mechanical and non-mechanical environments.This study confirms that AGPs are not recommended in dental surgeries where no ventilation is possible. No difference was demonstrated in FT required in open bays and closed surgeries in mechanically ventilated settings.Clinical significanceAGPs should not be carried out in surgeries where ventilation is not possible. Mechanical ventilation for AGPs should be gold standard; where not available or practical then the use of natural ventilation with EOS helps reduce FT. AGPs can be carried out in open bay environment with a minimum of 6 air changes per hour of mechanical ventilation. Four-handed dentistry with high-volume suction and saliva ejector are essential mitigating factors during AGPs.
Baseline cell proliferation rates and response to UV differ in Lymphoblastoid Cell Lines derived from healthy individuals of extreme constitution types
Authors: Chakraborty Sumita , Singhmar Sunanda , Singh Dayanidhi , Maulik Mahua , Patil Rutuja , Agrawal Satyam Kumar , Mishra Anushree , Ghazi Madeeha , Vats Archana , Natarajan Vivek T , Juvekar Sanjay , Prasher Bhavana , Mukerji Mitali 
Published: January 2021

AbstractDifferences in human phenotypes and susceptibility to complex diseases are an outcome of genetic and environmental interactions. This is evident in diseases that progress through a common set of intermediate patho-endophenotypes. Precision medicine aims to delineate the molecular players for individualized and early interventions. Functional studies in Lymphoblastoid Cell Line (LCL) model of phenotypically well characterized healthy individuals can help deconvolute and validate these molecular mechanisms. We developed LCLs from eight healthy individuals belonging to three extreme constitution types, deep phenotyped on the basis of Ayurveda. LCLs were characterized by karyotyping and immunophenotyping. Growth characteristics and response to UV was studied in these LCLs. We observed significant differences in cell proliferation rates between the contrasting groups such that one type (Kapha) proliferates significantly slower than the other two (Vata, Pitta). In response to UV, one fast growing group (Vata) shows higher cell death but recovers its numbers due to inherent higher rates of proliferation. The baseline differences in cell proliferation are key to understanding the survival of cells in UV stress. Variability in baseline cellular phenotypes not only explains the cellular basis of different constitutions types but can also help set priors during designing an individualized therapy with DNA damaging agents. This is the first study of its kind that shows variability of intermediate patho-phenotypes amongst healthy individuals that have implications in precision medicine.
L-WNK1 is required for BK channel activation in intercalated cells
Authors: Ray Evan C. , Carrisoza-Gaytan Rolando , Al-Bataineh Mohammad , Marciszyn Allison L. , Nkashama Lubika J. , Chen Jingxin , Winfrey Aaliyah , Flores Daniel , Wu Peng , Wang WenHui , Huang Chou-Long , Subramanya Arohan R. , Kleyman Thomas R. , Satlin Lisa M. 
Published: January 2021

AbstractBK channels expressed in intercalated cells (ICs) in the aldosterone-sensitive distal nephron (ASDN) mediate flow-induced K+secretion. In the ASDN of mice and rabbits, IC BK channel expression and activity increase with a high K+diet. In cell culture, the long isoform of the kinase WNK1 (L-WNK1) increases BK channel expression and activity. Apical L-WNK1 expression is selectively enhanced in ICs in the ASDN of rabbits on a high K+diet, suggesting that L-WNK1 contributes to BK channel regulation by dietary K+. We examined the role of IC L-WNK1 expression in enhancing BK channel activity in response to a high K+diet. Mice with an IC-selective deletion of L-WNK1 (IC-L-WNK1-KO) and littermate control mice were placed on a high K+(5% K+as KCl) diet for at least 10 days. IC-L-WNK1-KO mice exhibited higher blood K+concentrations ([K+]) than controls. BK channel-dependent whole-cell currents in ICs from cortical collecting ducts of high K+fed IC-L-WNK1-KO mice were reduced compared to controls. Six-hour urinary K+excretion in response a saline load was similar in IC-L-WNK1-KO mice and controls. The observations that IC-L-WNK1-KO mice have higher blood [K+] and reduced IC BK channel currents are consistent with impaired urinary K+secretion, and suggest that IC L-WNK1 has a role in the renal adaptation to a high K+diet.
Water and Electrolyte Homeostasis in a Mouse Model with Reduced ENaC Gamma Subunit Expression
Authors: Ray Evan C. , Jordahl Alexa , Marciszyn Allison , Winfrey Aaliyah , Lam Tracey , Barak Yaacov , Sheng Shaohu , Kleyman Thomas R. 
Published: January 2021

AbstractThe epithelial Na+channel (ENaC) promotes the absorption of Na+in the aldosterone-sensitive distal nephron, colon, and respiratory epithelia. Deletion of genes encoding ENaC’s subunits results in early post-natal mortality. We present initial characterization of a mouse with dramatically suppressed expression of the γ subunit. We use this hypomorphic (γmt) allele to explore the importance of ENaC’s γ subunit in homeostasis of electrolytes and body fluid volume. At baseline, γ subunit expression in γmt/mtmice is markedly suppressed in kidney and lung, while electrolytes resemble those of littermate controls. Challenge with a high K+diet does not cause significant differences in blood K+, but provokes higher aldosterone in γmt/mtmice than controls. Quantitative magnetic resonance (QMR) measurement of body composition reveals similar baseline body water, lean tissue mass, and fat tissue mass in γmt/mtmice and controls. Surprisingly, euvolemia is sustained without significant changes in aldosterone or atrial natriuretic peptide. γmt/mtmice exhibit a more rapid decline in body water and lean tissue mass in response to a low Na+diet than controls. Replacement of drinking water with 2% saline induces dramatic increases in body fat in both genotypes, and a selective transient increase in body water and lean tissue mass in γmt/mtmice. While ENaC in renal tubules and colon work to prevent extracellular fluid volume depletion, our observations suggest that ENaC in non-epithelial tissues may have a role in preventing extracellular fluid volume overload.
Axial-circular magnetic levitation assisted biofabrication and manipulation of cellular structures
Authors: Anil-Inevi Muge , Delikoyun Kerem , Mese Gulistan , Tekin H. Cumhur , Ozcivici Engin 
Published: January 2021

AbstractDiamagnetic levitation is an emerging technology for remote manipulation of cells in cell and tissue level applications. Low-cost magnetic levitation configurations using permanent magnets are commonly composed of a culture chamber physically sandwiched between two block magnets that limit working volume and applicability. This work describes a single ring magnet-based magnetic levitation system to eliminate physical limitations for biofabrication. Developed configuration utilizes sample culture volume for construct size manipulation and long-term maintenance. Furthermore, our configuration enables convenient transfer of liquid or solid phases during the levitation. Prior to biofabrication, we first calibrated the platform for levitation with polymeric beads, considering the single cell density range of viable cells. By taking advantage of magnetic focusing and cellular self-assembly, millimeter-sized 3D structures were formed and maintained in the system allowing easy and on-site intervention in cell culture with an open operational space. We demonstrated that the levitation protocol could be adapted for levitation of various cell types (i.e., stem cell, adipocyte and cancer cell) representing cells of different densities by modifying the paramagnetic ion concentration that could be also reduced by manipulating the density of the medium. This technique allowed the manipulation and merging of separately formed 3D biological units, as well as the hybrid biofabrication with biopolymers. In conclusion, we believe that this platform will serve as an important tool in broad fields such as bottom-up tissue engineering, drug discovery and developmental biology.
Genetic depletion of BDNF impairs both context-dependent and context-independent extinction learning of a spatial appetitive task
Authors: Méndez-Couz Marta , Manahan-Vaughan Denise 
Published: January 2021

AbstractBrain derived neurotropic factor (BDNF) supports neuronal survival, growth, and differentiation and is involved in forms of hippocampus-dependent learning, as well as hippocampus-dependent learning. Extinction learning (EL) comprises active inhibition of no-longer relevant learned information, in conjunction with a decreased response of a previously learned behavior. It is highly dependent on context, and evidence exists that it requires hippocampal activation. Concordantly, the participation of BDNF in hippocampus-dependent memory is experience-dependent. BDNF has been associated with synaptic plasticity needed for acquisition and extinction learning of fear conditioning. However, little is known about its influence on the extinction and renewal of spatial appetitive extinction learning (EL). In this study, in BDNF+/−-mice we evaluated to what extent BDNF contributes to spatial appetitive EL in the presence (ABA) or absence (AAA) of a context change. Daily training, to reach acquisition criterion in a T-maze, resulted in a similar outcome in BDNF+/−-mice or their wildtype (wt) littermates. EL was delayed in the AAA, and significantly impaired in the ABA-context compared to EL in wt littermates. When renewal was tested in the ABA paradigm we detected a significant response in wt controls, but not in BDNF+/−-mice. Taken together, these results support an important role for BDNF in EL in AAA and ABA context, as well as renewal of a spatial appetitive task, processes that relate to information updating and retrieval.
Predicting the current and future distribution of four original plants of Gentianae Macrophyllae Radix in China under climate change scenarios
Authors: Cao Houkang , Ma Xiaohui , Liu Li , Xi Shaoyang , Guo Yanxiu , Jin Ling 
Published: January 2021

AbstractThe wild resources of the four original plants (Gentiana crasicaulisDuthie ex Burk,Gentiana dauricaFisch,Gentiana stramineaMaxim, andGentiana macrophyllaPall) of Gentianae Macrophyllae Radix are becoming exhausted. Predicting the distribution under current and future climate scenarios is of significance for the sustainable utilization of resources and ecological protection. In this study, we constructed four species distribution models (SDMs) combining species distribution informations, 19 bioclimatic variables, and the maximum entropy (MaxEnt) model. The results showed that these 4 plants prefer a cool and humid climate. Under the future climate scenarios, the areas of the highly suitable habitats forGentiana crasicaulisDuthie ex Burk andGentiana dauricaFisch were likely to decrease, whileGentiana stramineaMaxim was likely to expand, andGentiana macrophyllaPall was less affected. In addition, the centroids of the highly suitable habitats for the four species shifted north or west. Most notably, most of the highly suitable habitats for the four species remained unchanged, which would be the preferred area for semi-artificial cultivation. The above information in this study would contribute to the development of reasonable strategies to reduce the impact of climate change on the four original plants.
The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome
Authors: Hendriks Ivo A. , Buch-Larsen Sara C. , Prokhorova Evgeniia , Rebak Alexandra K.L.F.S. , Ahel Ivan , Nielsen Michael L. 
Published: January 2021

SUMMARYDespite the involvement of Poly(ADP-ribose) polymerase-1 (PARP1) in many important biological pathways, the target residues of PARP1-mediated ADP-ribosylation remain ambiguous. To explicate the ADP-ribosylation regulome, we analyzed human cells depleted for key regulators of PARP1 activity, histone PARylation factor 1 (HPF1) and ADP-ribosylhydrolase 3 (ARH3). Using quantitative proteomics, we quantified 1,596 ADPr sites, displaying a thousand-fold regulation across investigated knockout cells. We find that HPF1 and ARH3 inversely and homogenously regulate the serine ADP-ribosylome on a proteome-wide scale with consistent adherence to lysine-serine (KS)-motifs suggesting targeting is independent of HPF1 and ARH3. Our data reveal that ADPr globally exists as mono-ADP-ribosylation, and we detail a remarkable degree of histone co-modification with ADPr and other post-translational modifications. Strikingly, no HPF1-dependent target residue switch from serine to glutamate/aspartate was detectable in cells, which challenges current dogma related to PARP1 target residues. Collectively, we elucidate hitherto unappreciated processes related to cellular PARP1 activity.
Population structure limits parallel evolution
Authors: Fang Bohao , Kemppainen Petri , Momigliano Paolo , Merilä Juha 
Published: January 2021

AbstractPopulation genetic theory predicts that small effective population sizes (Ne) and restricted gene flow limit the potential for local adaptation. In particular, the probability of evolving similar phenotypes based on shared genetic mechanisms (i.e. parallel evolution), is expected to be reduced. We tested these predictions in a comparative genomic study of two ecologically similar and geographically co-distributed stickleback species(viz. Gasterosteus aculeatusandPungitius pungitius). We found thatP. pungitiusharbours less genetic diversity and exhibits higher levels of genetic differentiation and isolation-by-distance thanG. aculeatus.Conversely,G. aculeatusexhibits a stronger degree of genetic parallelism across freshwater populations thanP. pungitius:2996vs.379 SNPs located within 26vsnine genomic regions show evidence of selection in multiple freshwater populations ofG. aculeatusandP. pungitius, respectively. Most regions involved in parallel evolution inG. aculeatusshowed increased levels of divergence, suggestive of selection on ancient haplotypes. In contrast, regions involved in freshwater adaptation inP. pungitiuswere younger, and often associated with reduced diversity. In accordance with theory, the results suggest that connectivity and genetic drift play crucial roles in determining the levels and geographic distribution of standing genetic variation, providing evidence that population subdivision limits local adaptation and therefore also the likelihood of parallel evolution.
Identification of TIA1 mRNA targets during human neuronal development
Authors: Byres Loryn P. , Mufteev Marat , Yuki Kyoko E. , Wei Wei , Piekna Alina , Wilson Michael D. , Rodrigues Deivid C. , Ellis James 
Published: January 2021

AbstractBackgroundNeuronal development is a tightly controlled process involving multi-layered regulatory mechanisms. While transcriptional pathways regulating neurodevelopment are well characterized, post-transcriptional programs are still poorly understood. TIA1 is an RNA-binding protein that can regulate splicing, stability, or translation of target mRNAs, and has been shown to play critical roles in neurodevelopment. However, the identity of mRNAs regulated by TIA1 during neurodevelopment is still unknown.Methods and ResultsTo identify the mRNAs targeted by TIA1 during the first stages of human neurodevelopment, we performed RNA immunoprecipitation-sequencing (RIP-seq) on human embryonic stem cells (hESCs) and derived neural progenitor cells (NPCs), and cortical neurons. While there was no change in TIA1 protein levels, the number of TIA1 targeted mRNAs decreased from pluripotent cells to neurons. We identified 2400, 845, and 330 TIA1 mRNA targets in hESCs, NPC, and neurons, respectively. The vast majority of mRNA targets in hESC were genes associated with neurodevelopment and included autism spectrum disorder-risk genes that were not bound in neurons. Additionally, we found that most TIA1 mRNA targets have reduced ribosomal engagement levels.ConclusionOur results reveal TIA1 mRNA targets in hESCs and during human neurodevelopment, indicate that translation repression is a key process targeted by TIA1 binding and implicate TIA1 function in neuronal differentiation.
Emergent signal execution modes in biochemical reaction networks calibrated to experimental data
Authors: Ortega Oscar O. , Ozen Mustafa , Wilson Blake A. , Pino James C. , Irvin Michael W. , Ildefonso Geena V. , Garbett Shawn P. , Lopez Carlos F. 
Published: January 2021

AbstractMathematical models of biomolecular networks are commonly used to study cellular processes; however, their usefulness to explain and predict dynamic behaviors is often questioned due to the unclear relationship between parameter uncertainty and network dynamics. In this work, we introduce PyDyNo (Python Dynamic analysis of biochemical NetwOrks), a non-equilibrium reaction-flux based analysis to identify dominant reaction paths within a biochemical reaction network calibrated to experimental data. We first show, in a simplified apoptosis execution model, that Bayesian parameter optimization can yield thousands of parameter vectors with equally good fits to experimental data. Our analysis however enables us to identify the dynamic differences between these parameter sets and identify three dominant execution modes. We further demonstrate that parameter vectors from each execution mode exhibit varying sensitivity to perturbations. We then apply our methodology to JAK2/STAT5 network in colony-forming unit-erythroid (CFU-E) cells to identify its signal execution modes. Our analysis identifies a previously unrecognized mechanistic explanation for the survival responses of the CFU-E cell population that would have been impossible to deduce with traditional protein-concentration based analyses.Impact StatementGiven the mechanistic models of network-driven cellular processes and the associated parameter uncertainty, we present a framework that can identify dominant reaction paths that could in turn lead to unique signal execution modes (i.e., dominant paths of flux propagation), providing a novel statistical and mechanistic insights to explain and predict signal processing and execution.