bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Sequence Composition and Patterning on the Structure and Dynamics of Intrinsically Disordered Proteins
Authors: Vovk Andrei , Zilman Anton
Published: June 2020

Unlike the well defined structures of classical natively folded proteins, Intrinsically Disordered Proteins (IDP) and Intrinsically Disordered Regions (IDR) dynamically span large conformational and structural ensembles. This dynamic disorder impedes the study of the relationship between the amino acid sequences of the IDPs and their spatial structures, dynamics, and function. Multiple experimental and theoretical evidence points in many cases to the overall importance of the general properties of the amino acid sequence of the IPDs rather than their precise atomistic details. However, while different experimental techniques can probe aspects of the IDP conformations, often different techniques or conditions offer seemingly contradictory results. Using coarse-grained polymer models informed by experimental observations, we investigate the effects of several key variables on the dimensions and the dynamics of IDPs. The coarse-grained simulations are in a good agreement with the results of atomistic MD. We show that the sequence composition and patterning are well reflected in the global conformational variables such as the radius of gyration and hydrodynamic radius, while the end-to-end distance and dynamics are highly sequence specific. We identify the conditions that allow mapping of highly heterogeneous sequences of IDPs onto averaged minimal polymer models. We discuss the implications of these results for the interpretation of the recent experimental measurements, and for further development of appropriate mesoscopic models of IDPs.
Endogenous Rab29 does not impact basal or nigericin and monensin stimulated LRRK2 pathway activity
Authors: Kalogeropulou Alexia F. , Freemantle Jordana B. , Lis Pawel , Vides Edmundo G. , Polinski Nicole K. , Alessi Dario R.
Published: June 2020

Mutations that enhance LRRK2 protein kinase activity cause inherited Parkinson’s disease. LRRK2 phosphorylates a group of Rab GTPase proteins, including Rab10 and Rab12, within the effector-binding switch-II motif. Previous work has indicated that the PARK16 locus, which harbors the gene encoding for Rab29, is involved in Parkinson’s, and that Rab29 operates in a common pathway with LRRK2. Co-expression of Rab29 and LRRK2 stimulates LRRK2 activity by recruiting LRRK2 to the surface of the trans Golgi network. Here we report that knock-out of Rab29 does not influence endogenous LRRK2 activity, based on assessment of Rab10 and Rab12 phosphorylation, in wildtype LRRK2, LRRK2[R1441C] or VPS35[D620N] knock-in mouse tissues and primary cell lines, including brain extracts and embryonic fibroblasts. We find that in brain extracts, Rab12 phosphorylation is more robustly impacted by LRRK2 inhibitors and pathogenic mutations than Rab10 phosphorylation. Transgenic overexpression of Rab29 in a mouse model was also insufficient to stimulate basal LRRK2 activity. We observed that monovalent cation ionophore antibiotics nigericin and monensin enhance LRRK2-mediated Rab10 and Rab12 phosphorylation 4 to 9-fold, in a manner that is independent from Rab29. Moderate stimulation of Rab10 and Rab12 induced by lysosome stressors chloroquine and LLOMe was also not regulated by Rab29. Our findings indicate that basal, pathogenic, as well as nigericin and monensin stimulated LRRK2 pathway activity is not controlled by Rab29. Further work is required to establish how LRRK2 activity is regulated, and whether other Rab proteins can control LRRK2 by targeting it to diverse membranes.
Reconciling Conformational Heterogeneity and Substrate Recognition in Cytochrome P450
Authors: Dandekar B. , Ahalawat N. , Mondal J.
Published: June 2020

Cytochrome P450, the ubiquitous metalloenzyme involved in detoxification of foreign components, has remained one of the most popular systems for substrate-recognition process. However, despite being known for its high substrate specificity, the mechanistic basis of substrate-binding by archetypal system cytochrome P450cam has remained at odds with the contrasting reports of multiple diverse crystallographic structures of its substrate-free form. Here we address this issue by elucidating the probability of mutual dynamical transition to the other crystallographic pose of cytochrome P450cam and vice versa via unbiased all-atom computer simulation. A robust Markov state model (MSM), constructed using adaptively sampled 84 microsecond-long Molecular dynamics simulation trajectories, maps the broad and heterogenous P450cam conformational landscape into five key sub-states. In particular, the MSM identifies an intermediate-assisted dynamic equilibrium between a pair of conformations of P450cam, in which the substrate-recognition sites remain ‘closed’ and ‘open’ respectively. However, the estimate of a significantly high stationary population of closed conformation, coupled with faster rate of open → closed transition than its reverse process, dictates that the net conformational equilibrium would be swayed in favour of ‘closed’ conformation. Together, the investigation quantitatively infers that while a potential substrate of cytochrome P450cam would in principle explore a diverse array of conformations of substrate-free protein, it would mostly encounter a ‘closed’ or solvent-occluded conformation and hence would follow an induced-fit based recognition process. Overall, the work reconciles multiple precedent crystallographic, spectroscopic investigations and establishes how a statistical elucidation of conformational heterogeneity in protein would provide crucial insights in the mechanism of potential substrate-recognition process.

STATEMENT OF SIGNIFICANCE

Conformational heterogeneity plays an important role in defining the structural and functional dynamics of the enzymes. While the static three-dimensional crystallographic structures of enzymes solved in different conditions and/or environments are crucial to provide the conformational sub-states of enzymes, these are not sufficient to understand the kinetics and thermodynamics of these sub-states and their role in substrate recognition process. Cytochrome P450cam, the archtypal metalloenzyme, presents such a complex scenario due to prevalent reports of contrasting crystallographic structures of its substrate-free form. This work quantifies the conformational heterogeneity of substrate-free P450cam by exploring the possibility of mutual transition among the crystallographic poses at an atomic resolution and in the process elucidates its possible substrate-recognition mechanism.
Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis
Authors: Sterkel Marcos , Haines Lee R. , Casas-Sánchez Aitor , Adung’a Vincent Owino , Vionette-Amaral Raquel J. , Quek Shannon , Rose Clair , dos Santos Mariana Silva , Escude Natalia Garcia , Ismael Hanafy , Paine Mark I. , Barribeau Seth M. , Wagstaff Simon , MacRae James I. , Masiga Daniel , Yakob Laith , Oliveira Pedro L. , Acosta-Serrano Álvaro
Published: June 2020

Tsetse transmit African trypanosomiasis, which is a disease fatal to both humans and animals. A vaccine to protect against this disease does not exist so transmission control relies on eliminating tsetse populations. Although neurotoxic insecticides are the gold standard for insect control, they negatively impact the environment and reduce insect pollinator species. Here we present a promising, environment-friendly alternative that targets insect tyrosine metabolism pathway. A bloodmeal contains high levels of tyrosine, which is toxic to haematophagous insects if it is not degraded. RNAi silencing of either the first two enzymes in the tyrosine degradation pathway (TAT and HPPD) was lethal to tsetse. Furthermore, nitisinone (NTBC), an FDA-approved tyrosine catabolism inhibitor, killed tsetse regardless if the drug was orally or topically applied. However, it did not affect bumblebee survival. A mathematical model shows that NTBC could reduce the transmission of African trypanosomiasis in sub-Saharan Africa, thus accelerating current elimination programmes.
Towardin vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia
Authors: Wan Hongbin , Selvaggio Gianluca , Pearlstein Robert A.
Published: June 2020

The human ether-a-go-go-related voltage-gated cardiac ion channel (commonly known as hERG) conducts the rapid outward repolarizing potassium current in cardiomyocytes (IKr). Inadvertent blockade of this channel by drug-like molecules represents a key challenge in pharmaceutical R&D due to frequent overlap between the structure-activity relationships of hERG and many primary targets. Building on our previous work, together with recent cryo-EM structures of hERG, we set about to better understand the energetic and structural basis of promiscuous blocker-hERG binding in the context of Biodynamics theory. We propose a two-step blocker binding process consisting of:

Diffusion of a single fully solvated blocker copy into a large cavity lined by the intracellular cyclic nucleotide binding homology domain (the initial capture step). Occupation of this cavity is a necessary but insufficient condition for ion current disruption.

Translocation of the captured blocker along the channel axis (the IKrdisruption step), such that:

The head group, consisting of a quasi-linear moiety, projects into the open pore, accompanied by partial de-solvation of the binding interface.

One tail moiety packs along a kink between the S6 helix and proximal C-linker helix adjacent to the intra-cellular entrance of the pore, likewise accompanied by mutual de-solvation of the binding interface (noting that the association barrier is comprised largely of the total head + tail group de-solvation cost).

Blockers containing a highly planar moiety that projects into a putative constriction zone within theclosedchannel become trapped upon closing, as do blockers terminating prior to this region.

A single captured blocker molecule may associate and dissociate from the pore many times before exiting the CNBHD cavity.

Lastly, we highlight possible flaws in the current hERG safety index (SI) and propose an alternatein vivo-relevantstrategy factoring in:

Benefit/risk.

The predicted arrhythmogenic fractional hERG occupancy (based on action potential simulations of theundiseasedhuman ventricular cardiomyocyte).

Alteration of the safety threshold due to underlying disease.

Risk of exposure escalation toward the predicted arrhythmic limit due to patient-to-patient pharmacokinetic variability, drug-drug interactions, overdose, and use for off-label indications in which the hERG safety parameters may differ from their on-label counterparts.
A consensus-based ensemble approach to improve transcriptome assembly
Authors: Voshall Adam , Behera Sairam , Li Xiangjun , Yu Xiao-Hong , Kapil Kushagra , Deogun Jitender S. , Shanklin John , Cahoon Edgar B. , Moriyama Etsuko N.
Published: June 2020

Background

Systems-level analyses, such as differential gene expression analysis, co-expression analysis, and metabolic pathway reconstruction, depend on the accuracy of the transcriptome. Multiple tools exist to perform transcriptome assembly from RNAseq data. However, assembling high quality transcriptomes is still not a trivial problem. This is especially the case for non-model organisms where adequate reference genomes are often not available. Different methods produce different transcriptome models and there is no easy way to determine which are more accurate. Furthermore, having alternative-splicing events exacerbates such difficult assembly problems. While benchmarking transcriptome assemblies is critical, this is also not trivial due to the general lack of true reference transcriptomes.

Results

In this study, we first provide a pipeline to generate a set of the benchmark transcriptome and corresponding RNAseq data. Using the simulated benchmarking datasets, we compared the performance of various transcriptome assembly approaches including bothde novoand genome-guided methods. The results showed that the assembly performance deteriorates significantly when alternative transcripts (isoforms) exist or for genome-guided methods when the reference is not available from the same genome. To improve the transcriptome assembly performance, leveraging the overlapping predictions between different assemblies, we present a new consensus-based ensemble transcriptome assembly approach, ConSemble.

Conclusions

Without using a reference genome, ConSemble using fourde novoassemblers achieved an accuracy up to twice as high as anyde novoassemblers we compared. When a reference genome is available, ConSemble using four genome-guided assemblies removed many incorrectly assembled contigs with minimal impact on correctly assembled contigs, achieving higher precision and accuracy than individual genome-guided methods. Furthermore, ConSemble usingde novoassemblers matched or exceeded the best performing genome-guided assemblers even when the transcriptomes included isoforms. We thus demonstrated that the ConSemble consensus strategy both forde novoand genome-guided assemblers can improve transcriptome assembly. The RNAseq simulation pipeline, the benchmark transcriptome datasets, and the script to perform the ConSemble assembly are all freely available from:http://bioinfolab.unl.edu/emlab/consemble/.
miR-218 in adolescence predicts and mediates vulnerability to stress
Authors: Torres-Berrío Angélica , Morgunova Alice , Giroux Michel , Cuesta Santiago , Nestler Eric J. , Flores Cecilia
Published: June 2020

Adolescence is a period of increased vulnerability to psychiatric disorders including depression. Discovering novel biomarkers to identify individuals who are at high risk is very much needed. Our previous work shows that the microRNA miR-218 mediates susceptibility to stress and depression in adulthood, by targeting the Netrin-1 guidance cue receptor geneDcc(Deleted incolorectalcancer) in the medial prefrontal cortex (mPFC). Here we investigated whether miR-218 regulatesDccexpression in adolescence and could serve as an early predictor of lifetime stress vulnerability. miR-218 expression in the mPFC increases from early adolescence to adulthood and correlates negatively withDcclevels. In blood, postnatal miR-218 expression parallels changes occurring in the mPFC. Notably, circulating miR-218 levels in adolescence associate with vulnerability to social defeat stress in adulthood, with high levels associated with social avoidance severity. Indeed, downregulation of miR-218 in the mPFC in adolescence promotes resilience to stress in adulthood, indicating that adolescent miR-218 expression may serve both as a marker of risk and as a target for early interventions.
Computational modelling unveils how epiblast remodelling and positioning rely on trophectoderm morphogenesis during mouse implantation
Authors: Dokmegang Joel , Yap Moi Hoon , Han Liangxiu , Cavaliere Matteo , Doursat René
Published: June 2020

Understanding the processes by which the mammalian embryo implants in the maternal uterus is a long-standing challenge in embryology. New insights into this morphogenetic event could be of great importance in helping, for example, to reduce human infertility. During implantation the blastocyst, composed of epiblast and trophectoderm, undergoes significant remodelling from an oval ball to an egg cylinder. A main feature of this transformation is symmetry breaking and reshaping of the epiblast into a “cup”. Based on previous studies, we hypothesise that this event is the result of mechanical constraints originating from the trophectoderm, which is also significantly transformed during this process. In order to investigate this hypothesis we propose MG#, an original computational model of biomechanics able to reproduce key cell shape changes and tissue level behavioursin silico. With this model, we simulate epiblast and trophectoderm morphogenesis during implantation. First, our results uphold experimental findings that repulsion at the apical surface of the epiblast is sufficient to drive lumenogenesis. Then, we provide new theoretical evidence that trophectoderm morphogenesis indeed dictates the cup shape of the epiblast and fosters its movement towards the uterine tissue. Together, these results offer mechanical insights into mouse implantation and highlight the usefulness of agent-based modelling methods in the study of embryogenesis.

Author summary

Computational modelling is increasingly used in the context of biological development. Here we propose a novel agent-based model of biological cell and tissue mechanics to investigate important morphological changes during mouse embryo implantation. Our model is able to replicate key biological cell shape changes and tissue-level behaviour. Simulating mouse implantation with this model, we bring theoretical support to previous experimental observations that lumenogenesis in the epiblast is driven by repulsion, and provide theoretical evidence that changes in epiblast shape during implantation are regulated by trophectoderm development.
On the evolution of chaperones and co-chaperones and the expansion of proteomes across the Tree of Life
Authors: Rebeaud Mathieu E. , Mallik Saurav , Goloubinoff Pierre , Tawfik Dan S.
Published: June 2020

Across the Tree of Life (ToL), the complexity of proteomes varies widely. Our systematic analysis depicts that from the simplest archaea to mammals, the total number of proteins per proteome expanded ~200-fold. Individual proteins also became larger, and multi-domain proteins expanded ~50-fold. Apart from duplication and divergence of existing proteins, completely new proteins were born. Along the ToL, the number of different folds expanded ~5-fold and fold-combinations ~20-fold. Proteins prone to misfolding and aggregation, such as repeat and beta-rich proteins, proliferated ~600-fold, and accordingly, proteins predicted as aggregation-prone became 6-fold more frequent in mammalian compared to bacterial proteomes. To control the quality of these expanding proteomes, core-chaperones, ranging from HSP20s that prevent aggregation to HSP60, HSP70, HSP90, and HSP100 acting as ATP-fueled unfolding and refolding machines, also evolved. However, these core-chaperones were already available in prokaryotes, and they comprise ~0.3% of all genes from archaea to mammals. This challenge—roughly the same number of core-chaperones supporting a massive expansion of proteomes, was met by (i) higher cellular abundances of the ancient generalist core-chaperones, and (ii) continuous emergence of new substrate-binding and nucleotide-exchange factor co-chaperones that function cooperatively with core-chaperones, as a network.
A novel epitope tagging system to visualize and monitor antigens in live cells with chromobodies
Authors: Traenkle Bjoern , Segan Sören , Kaiser Philipp D. , Rothbauer Ulrich
Published: June 2020

Epitope tagging is a versatile approach to study different proteins using a well-defined and established methodology. To date, most epitope tags such as myc, HA, V5 and FLAG tags are recognized by antibodies which limits their application to fixed cells, tissues or protein samples. Here we introduce a broadly applicable tagging strategy utilizing a short peptide tag/chromobody (PepTag/PepCB) system. The addition of the small PepTag does not interfere with the examined structures in different cellular compartments and its detection with the fluorescently labeled Pep-chromobody (PepCB) enables optical antigen tracing in real time. By employing the phenomenon of antigen-mediated chromobody stabilization (AMCBS) using a turnover-accelerated PepCB we demonstrated that the system is suitable to visualize and quantify changes in Pep-tagged antigen concentration by quantitative live-cell imaging. We expect that this novel tagging strategy offers new opportunities to study the dynamic regulation of proteins, e.g. during cellular signaling, cell differentiation, or upon drug action.
Cross-subunit Interactions that Stabilize Open States Mediate Gating in NMDA Receptors
Authors: Iacobucci Gary J , Wen Han , Helou Matthew B , Zheng Wenjun , Popescu Gabriela K
Published: June 2020

NMDA receptors are excitatory channels with critical functions in the physiology of central synapses. Their activation reaction proceeds as a series of kinetically distinguishable, reversible steps, whose structural bases are of current interest. Very likely, the earliest steps in the activation reaction include glutamate binding to and compression of the ligand-binding domain. Later, three short linkers transduce this movement to open the gate by mechanical coupling with transmembrane helices. Here, we used double-mutant cycle analyses to demonstrate that a direct chemical interaction between GluN1-I642 (on M3) and GluN2A-L550 (on L1-M1) stabilizes receptors after they have opened, and therefore represents one of the structural changes that occur late in the activation reaction. This native interaction extends the current decay, and its absence predicts deficits in charge transfer by GluN1-I642L, a pathogenic human variant.

SIGNIFICANCE STATEMENT

NMDA receptors are glutamatergic channels whose activations control the strength of excitatory synapses in the central nervous system. Agonist binding initiates a complex activation reaction that consists of a stepwise sequence of reversible isomerizations. In addition to previously identified steps in this series, which include agonist-induced closure of the ligand-binding lobes, and the subsequent mechanical pulling by the ligand-binding domain on the gate-forming transmembrane helix, we identify a new cross-subunit interaction, which stabilizes open receptors and slows the rate of the current decay. Naturally occurring NMDA receptor variants lacking this interaction are pathogenic.
treeclimbR pinpoints the data-dependent resolution of hierarchical hypotheses
Authors: Huang Ruizhu , Soneson Charlotte , Germain Pierre-Luc , Schmidt Thomas S.B. , Von Mering Christian , Robinson Mark D.
Published: June 2020

The arrangement of hypotheses in a hierarchical structure (e.g., phylogenies, cell types) appears in many research fields and indicates different resolutions at which data can be interpreted. A common goal is to find a representative resolution that gives high sensitivity to identify relevant entities (e.g., microbial taxa or cell subpopulations) that are related to a phenotypic outcome (e.g. disease status) while controlling false detections, therefore providing a more compact view of detected entities and summarizing characteristics shared among them. Current methods, either performing hypothesis tests at an arbitrary resolution or testing hypotheses at all possible resolutions leading to nested results, are suboptimal. Moreover, they are not flexible enough to work in situations where each entity has multiple features to consider and different resolutions might be required for different features. For example, in single cell RNA-seq data, an increasing focus is to find differential state genes that change expression within a cell subpopulation in response to an external stimulus. Such differential expression might occur at different resolutions (e.g., all cells or a small set of cells) for different genes. Our new algorithmtreeclimbRis designed to fill this gap by exploiting a hierarchical tree of entities, proposing multiple candidates that capture the latent signal and pinpointing branches or leaves that contain features of interest, in a data-driven way. It outperforms currently available methods on synthetic data, and we highlight the approach on various applications, including microbiome and microRNA surveys as well as single cell cytometry and RNA-seq datasets. With the emergence of various multi-resolution genomic datasets,treeclimbRprovides a thorough inspection on entities across resolutions and gives additional flexibility to uncover biological associations.
Tools for Visualizing and Analyzing Fourier Space Sampling in Cryo-EM
Authors: Baldwin Philip R. , Lyumkis Dmitry
Published: June 2020

A complete understanding of how an orientation distribution contributes to a cryo-EM reconstruction remains lacking. It is necessary to begin critically assessing the set of views to gain an understanding of its effect on experimental reconstructions. Toward that end, we recently suggested that the type of orientation distribution may alter resolution measures in a systematic manner. We introduced the sampling compensation factor (SCF), which incorporates how the collection geometry might change the spectral signal-to-noise ratio (SSNR), irrespective of the other experimental aspects. We show here that knowledge of the sampling restricted to spherical surfaces of sufficiently large radii in Fourier space is equivalent to knowledge of the set of projection views. Moreover, the SCF geometrical factor may be calculated from one such surface. To aid cryo-EM researchers, we developed a graphical user interface (GUI) tool that evaluates experimental orientation distributions. The GUI returns plots of projection directions, sampling constrained to the surface of a sphere, the SCF value, the fraction of the empty region of Fourier space, and a histogram of the sampling values over the points on a sphere. Finally, a fixed tilt angle may be incorporated to determine how tilting the grid during collection may improve the distribution of views and Fourier space sampling. We advocate this simple conception of sampling and the use of such tools as a complement to the distribution of views to capture the different aspects of the effect of projection directions on cryo-EM reconstructions.
Combinatorial Library Designing and Virtual Screening of Cryptolepine Derivatives against Topoisomerase II by Molecular Docking
Authors: Maria  , Khan Zahid
Published: June 2020

Computational approaches have emerging role for designing potential inhibitors against topoisomerase 2 for treatment of cancer. TOP2A plays a key role in DNA replication before cell division and thus facilitates the growth of cells. This function of TOP2A can be suppressed by targeting with potential inhibitors in cancer cells to stop the uncontrolled cell division. Among potential inhibitors cryptolepine is more selective and has the ability to intercalate into DNA, effectively block TOP2A and cease cell division in cancer cells. However, cryptolepine is non-specific and have low affinity, therefore, a combinatorial library was designed and virtually screened for identification of its derivatives with greater TOP2A binding affinities.

A combinatorial library of 31114 derivatives of cryptolepine was formed and the library was virtually screened by molecular docking to predict the molecular interactions between cryptolepine derivatives and TOP2A taking cryptolepine as standard. The overall screening and docking approach explored all the binding poses of cryptolepine for TOP2A to calculate binding energy. The compounds are given database number 8618, 907, 147, 16755, and 8186 scored lowest binding energies of −9.88kcal/mol, −9.76kcal/mol, −9.75kcal/mol, −9.73kcal/mol, and −9.72kcal/mol respectively and highest binding affinity while cryptolepine binding energy is −6.09kcal/mol. The good binding interactions of the derivatives showed that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of derivatives with different amino acid residues were also observed. A comprehensive understanding of the interactions of proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This Computational study suggests useful references to understand inhibition mechanisms that will help in the modification of TOP2A inhibitors.
Attention differentially affects acoustic and phonetic feature encoding in a multispeaker environment
Authors: Teoh Emily S. , Lalor Edmund C.
Published: June 2020

Humans have the remarkable ability to selectively focus on a single talker in the midst of other competing talkers. The neural mechanisms that underlie this phenomenon remain incompletely understood. In particular, there has been longstanding debate over whether attention operates at an early or late stage in the speech processing hierarchy. One way to better understand this is to examine how attention might differentially affect neurophysiological indices of hierarchical acoustic and linguistic speech representations. In this study, we do this by using encoding models to identify neural correlates of speech processing at various levels of representation. Specifically, using EEG recorded during a “cocktail party” attention experiment, we show that phonetic feature processing is evident for attended, but not unattended speech. Furthermore, we show that attention specifically enhances isolated indices of phonetic feature processing, but that such attention effects are not apparent for isolated measures of acoustic processing. These results provide new insights into the effects of attention on different pre-lexical representations of speech, insights that complement recent anatomical accounts of the hierarchical encoding of attended speech. Furthermore, our findings support the notion that – for attended speech – phonetic features are processed as a distinct stage, separate from the processing of the speech acoustics.
Influenza-induced activation of recruited alveolar macrophages during the early inflammatory phase drives lung injury and lethality
Authors: Koch Clarissa M , Anekalla Kishore R , Hu Yuan-Shih , Davis Jennifer M. , Ciesielski Mark , Gadhvi Gaurav , Chen Shang-Yang , Turner Margaret , Cheng Yuan , Coates Bria M , Abdala-Valencia Hiam , Reyfman Paul A , Misharin Alexander V , Budinger GR Scott , Winter Deborah R , Ridge Karen M
Published: June 2020

Severe respiratory virus infections initiate a robust host immune response that contributes to disease severity. Immunomodulatory strategies that limit virus-initiated inflammation are of critical importance. In this study, we compared the host response to influenza A virus (IAV) infection in susceptible animals (wild-type, WT) to resilient mice (Vimentin-/-mice). We identified distinct gene expression patterns in recruited monocyte-derived alveolar macrophages (MoAMs) associated with three phases (Infiltrating, Early Inflammatory, Late Inflammatory) that evolve in sequence over the course of IAV infection. We report a core set of pro-inflammatory genes involved in the WT MoAM Early Inflammatory response that is suppressed inVim-/-MoAMs. Moreover, we identify CEBPB, Jun-AP1, and IRF transcriptions factors as regulators of this attenuated inflammatory response. We performed causal experiments using bone-marrow chimeras to credential thatVim-/-MoAMs with suppressed pro-inflammatory genes confer protection from influenza-induced mortality in WT susceptible mice. Taken together, these data support the notion that vimentin plays a causal role in determining the pro-inflammatory function of recruited MoAMs and drives IAV-induced lung injury.
Effect of organic zinc supplementation in hens on fertility from cryopreserved semen
Authors: Murugesan Shanmugam , Kannan Alagarsamy , Mahapatra Ramkrishna
Published: June 2020

Organic zinc supplementation in hen has been reported to improve fertility. The current study evaluated the effect of organic zinc supplementation in hens on fertility after insemination with cryopreserved semen. White Leghorn rooster semen was cryopreserved using 4% dimethylsulfoxide (DMSO) in 0.5ml French straws. Different semen parameters and fertility were assessed in post-thaw samples. White Leghorn hens were divided into 5 groups with 30 birds in each group. Each group was further divided into six replicates of five birds each. The control group was fed basal diet, other groups were fed with basal diet supplemented with 40, 60, 120 and 160 mg/kg organic zinc (zinc proteinate). After two weeks of feeding insemination was done in hens per vagina using thawed semen (200 million sperm/0.1 ml). Basal group hens were inseminated with fresh or cryopreserved semen and served as control groups. Sperm motility, live sperm, and acrosome intact sperm parameters were significantly (p< 0.05) lower in post-thaw semen samples. Fertility from cryopreserved semen was significantly (p< 0.05) lower and organic zinc supplemented hens had fertility similar to that of cryopreserved semen inseminated into basal diet group hens. In conclusion, organic zinc supplementation in hens does not improve fertility after insemination with 4% DMSO cryopreserved semen.
Serological Assays Estimate Highly Variable SARS-CoV-2 Neutralizing Antibody Activity in Recovered COVID19 Patients
Authors: Luchsinger Larry L. , Ransegnola Brett , Jin Daniel , Muecksch Frauke , Weisblum Yiska , Bao Weili , George Parakkal Jovvian , Rodriguez Marilis , Tricoche Nancy , Schmidt Fabian , Gao Chengjie , Jawahar Shabnam , Pal Mouli , Schnall Emily , Zhang Huan , Strauss Donna , Yazdanbakhsh Karina , Hillyer Christopher D. , Bieniasz Paul D. , Hatziioannou Theodora
Published: June 2020

The development of neutralizing antibodies (nAb) against SARS-CoV-2, following infection or vaccination, is likely to be critical for the development of sufficient population immunity to drive cessation of the COVID19 pandemic. A large number of serologic tests, platforms and methodologies are being employed to determine seroprevalence in populations to select convalescent plasmas for therapeutic trials, and to guide policies about reopening. However, tests have substantial variability in sensitivity and specificity, and their ability to quantitatively predict levels of nAb is unknown. We collected 370 unique donors enrolled in the New York Blood Center Convalescent Plasma Program between April and May of 2020. We measured levels of antibodies in convalescent plasma using commercially available SARS-CoV-2 detection tests and in-house ELISA assays and correlated serological measurements with nAb activity measured using pseudotyped virus particles, which offer the most informative assessment of antiviral activity of patient sera against viral infection. Our data show that a large proportion of convalescent plasma samples have modest antibody levels and that commercially available tests have varying degrees of accuracy in predicting nAb activity. We found the Ortho Anti-SARS-CoV-2 Total Ig and IgG high throughput serological assays (HTSAs), as well as the Abbott SARS-CoV-2 IgG assay, quantify levels of antibodies that strongly correlate with nAb assays and are consistent with gold-standard ELISA assay results. These findings provide immediate clinical relevance to serology results that can be equated to nAb activity and could serve as a valuable ‘roadmap’ to guide the choice and interpretation of serological tests for SARS-CoV-2.
A consensus Covid-19 immune signature combines immuno-protection with discrete sepsis-like traits associated with poor prognosis
Authors: Laing Adam G. , Lorenc Anna , Del Molino Del Barrio Irene , Das Abhishek , Fish Matthew , Monin Leticia , Muñoz-Ruiz Miguel , McKenzie Duncan R. , Hayday Thomas S. , Francos-Quijorna Isaac , Kamdar Shraddha , Joseph Magdalene , Davies Daniel , Davis Richard , Jennings Aislinn , Zlatareva Iva , Vantourout Pierre , Wu Yin , Sofra Vasiliki , Cano Florencia , Greco Maria , Theodoridis Efstathios , Freedman Joshua , Gee Sarah , En Chan Julie Nuo , Ryan Sarah , Bugallo-Blanco Eva , Peterson Pärt , Kisand Kai , Haljasmägi Liis , Martinez Lauren , Merrick Blair , Bisnauthsing Karen , Brooks Kate , Ibrahim Mohammad , Mason Jeremy , Gomez Federico Lopez , Babalola Kola , Abdul- Jawad Sultan , Cason John , Mant Christine , Doores Katie J , Seow Jeffrey , Graham Carl , Rosa Francesca Di , Edgeworth Jonathan , Shankar-Hari Manu , Hayday Adrian C.
Published: June 2020

Person-to-person transmission of SARS-CoV-2 virus has triggered a global emergency because of its potential to cause life-threatening Covid-19 disease. By comparison to paucisymptomatic virus clearance by most individuals, Covid-19 has been proposed to reflect insufficient and/or pathologically exaggerated immune responses. Here we identify a consensus peripheral blood immune signature across 63 hospital-treated Covid-19 patients who were otherwise highly heterogeneous. The core signature conspicuously blended adaptive B cell responses typical of virus infection or vaccination with discrete traits hitherto associated with sepsis, including monocyte and dendritic cell dampening, and hyperactivation and depletion of discrete T cell subsets. This blending of immuno-protective and immuno-pathogenic potentials was exemplified by near-universal CXCL10/IP10 upregulation, as occurred in SARS1 and MERS. Moreover, specific parameters including CXCL10/IP10 over-expression, T cell proliferation, and basophil and plasmacytoid dendritic cell depletion correlated, often prognostically, with Covid-19 progression, collectively composing a resource to inform SARS-CoV-2 pathobiology and risk-based patient stratification.
Households at Higher Risk of Losing at Least One Individual in India: if COVID-19 is a new normal
Authors: Singh Rajeev Ranjan , Sharma Palak , Maurya Priya
Published: June 2020

After the outbreak of COVID-19 and the passing of a few months with this pandemic; the world has started to adopt strategies to live with the virus. The WHO has also accepted that the pandemic caused by the novel coronavirus is going to last longer, and suggested that one needs to learn to live with this virus. Accepting this bitter truth that this pandemic is going to be a new normal and people of all ages can be infected by the new coronavirus; however, older people and those with chronic diseases are more vulnerable to the virus. The study tries to access the household with at least one patient with few selected chronic diseases in India, which are presumed to be at a higher risk of losing at least one individual if this pandemic scenario is going to last long and spread is wider. The study used nationally representative data (NSSO) for information on morbidity and other health-related issues. Data from the official website of the Ministry of Health and Family Welfare dedicated to COVID-19 reports have been used to look into the recent happenings caused by COVID-19 pandemic in India. Bivariate analysis has been used to calculate household at risk, and binary logistic regression has been used for the likelihood of household at risk. The case-fatality ratio is calculated using the number of confirmed cases and the number deceased due to the same. The study found that about 9.4% of Indian households are at a higher risk of losing at least one individual. Older people (60+), males and households with better economic status are at a higher risk. The chronic condition varies by states and social-economic and demographic status. The share of households at higher risk was highest in Kerala (33.19%), followed by Andhra Pradesh (19.85%) and Chandigarh (19.05%).
Controlling the Spread of COVID-19: Optimal Control Analysis
Authors: Madubueze Chinwendu E. , Dachollom Sambo , Onwubuya Isaac Obiajulu
Published: June 2020

Coronavirus disease 2019 (COVID-19) is a disease caused by Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2). It was declared on March 11, 2020, by the World Health Organization as pandemic disease. The disease has neither approved medicine nor vaccine and has made government and scholars search for drastic measures in combating the pandemic. Regrettably, the spread of the virus and mortality due to COVID-19 has continued to increase daily. Hence, it is imperative to control the spread of the disease particularly using non-pharmacological strategies such as quarantine, isolation and public health education. This work studied the effect of these different control strategies as time-dependent interventions using mathematical modeling and optimal control approach to ascertain their contributions in the dynamic transmission of COVID-19. The model was proven to have an invariant region and was well-posed. The basic reproduction number was computed with and without interventions and was used to carry out the sensitivity analysis that identified the critical parameters contributing to the spread of COVID-19. The optimal control analysis was carried out using the Pontryagin’s maximum principle to figure out the optimal strategy necessary to curtail the disease. The findings of the optimal control analysis and numerical simulations revealed that time-dependent interventions reduced the number of exposed and infected individuals compared to time-independent interventions. These interventions were time-bound and best implemented within the first 100 days of the outbreak. Again, the combined implementation of only two of these interventions produced a good result in reducing infection in the population, while the combined implementation of all three interventions performed better, even though zero infection was not achieved in the population. This implied that multiple interventions need to be deployed early in order to the virus to the barest minimum.
Indian Publications on SARS-CoV-2: A Bibliometric Study of WHO COVID-19 Database
Authors: Vasantha Raju N. , Patil S.B.
Published: June 2020

Nowadays, the whole World is under threat of Coronavirus disease (COVID-19). The ongoing COVID-19 pandemic has resulted in many fatalities and forced scientific communities to foster their Research and Development (R & D) activities. As a result, there is an enormous growth of scholarly literature on the subject. In order to combat this novel coronavirus, the open access to scientific literature is essential. On this line, many reputed academic institutions and publication firms have made their literature on COVID-19 accessible to all. By maintaining the database of updated information on global literature on Coronavirus disease, the World Health Organization (WHO) is playing a pivotal role. The present study analyzed 89 Indian publications on SARS-CoV-2 accessible through WHO COVID-19 database. The research data was restricted for the period of 2/3/2020 to 12/5/2020. The analysis was carried out in light of the objectives of the study. The study found the considerable and constant growth of Indian publications on COVID-19 from mid-April. It is interesting to note that the prolific authors belong to either AIIMS or ICMR institutes. Majority of the COVID-19 articles were found to be collaborative publications. The study noticed that no research publications on COVID-19 have appeared from North Eastern region. Regarding the research output on COVID-19, the performance of largest states like Uttar Pradesh, Madhya Pradesh and Bihar was found to be poor. Delhi state contributed highest publications on COVID-19. The All India Institute of Medical Sciences (AIIMS), New Delhi was the most productive institution in terms of publications. It is also important to note that the central government undertakings like AIIMS and ICMR, New Delhi and its affiliated institutions shared largest proportion of publications on COVID-19. The Indian Journal of Medical Research has emerged as the productive journal contributing highest number of the publications. The highest contribution in COVID-19 research takes the form of journal articles. In terms of research area, the majority of the publications were related to Epidemiology. The study reported covid, coronavirus, India, pandemic, sars etc. as the frequently occurred keywords in the COVID-19 publications. The highly cited publications were of evidenced based studies. It is observed that the studies pertaining to virology, diagnosis and treatment, clinical features etc. have received highest citations than general studies on epidemiology or pandemic.
Operationalizing genomic epidemiology during the Nord-Kivu Ebola outbreak, Democratic Republic of the Congo
Authors: Kinganda-Lusamaki Eddy , Black Allison , Mukadi Daniel , Hadfield James , Mbala-Kingebeni Placide , Pratt Catherine B , Aziza Amuri , Diagne Moussa M , White Bailey , Bisento Nella , Nsunda Bibiche , Akonga Marceline , Faye Martin , Faye Ousmane , Edidi-Atani Francois , Matondo Meris , Mambu Fabrice , Bulabula Junior , Paola Nicholas Di , Palacios Gustavo , Delaporte Eric , Sall Amadou Alpha , Peeters Martine , Wiley Michael R. , Ahuka-Mundeke Steve , Bedford Trevor , Muyembe Tamfum Jean-Jacques
Published: June 2020

The Democratic Republic of the Congo declared its tenth Ebola virus disease outbreak in July 2018, which has circulated primarily in the Nord Kivu province. In addition to standard epidemiologic surveillance and response efforts, the Institut National de Recherche Biomédicale implemented an end-to-end genomic surveillance system, including sequencing, bioinformatic analysis, and dissemination of genomic epidemiologic results to frontline public health workers. Here we report 538 new genomes from this outbreak; together with previously available sequence data (n = 48 genomes), this represents an unprecedented 17% of all laboratory-confirmed infections. To support outbreak response efforts, we reconstructed spatiotemporal transmission dynamics at broad and at fine scales as new data were available and disseminated the results via an interactive narrative-based platform. Our innovative system enables actionable information sharing between scientists and epidemiologists coordinating the day-to-day response on the time scales necessary to guide response efforts. The development of this genomic surveillance pipeline, within a resource-limited setting, represents significant technological and scientific progress in genomic epidemiology. Here we present a phylodynamic analysis of the outbreak as of February 2020, and describe the types of epidemiologic dynamics that we monitor the genomic data for, including resolution of co-circulating transmission chains, detection of superspreading events, inference of regions that act as transmission sources and sinks, and differentiation of closely linked cases versus propagated transmission. These findings have ameliorated the current outbreak response and are directly applicable to future outbreaks.
An optimal lockdown relaxation strategy for minimizing the economic effects of covid–19 outbreak
Authors: Mahasinghe A.C. , Erandi K.K.W.H. , Perera S.S.N.
Published: June 2020

In order to recover the damage to the economy by the ongoing covid–19 pandemic, many countries consider the transition from strict lockdowns to partial lockdowns through relaxation of preventive measures. In this work, we propose an optimal lockdown relaxation strategy, which is aimed at minimizing the damage to the economy, while confining the covid–19 incidence to a level endurable by the available healthcare facilities in the country. In order to capture the transmission dynamics, we adopt the compartment models and develop the relevant optimization model, which turns out to be non–linear. We generate approximate solutions to the problem, whereas our experimentation is based on the data on the covid–19 outbreak in Sri Lanka.
A web survey to assess the use efficacy of personnel protective materials among allied health care workers during COVID-19 pandemic at North-East India
Authors: Kotian Rahul P , Debnath Manna , Zosangliani  , D’souza Brayal , Faujdar Disha
Published: June 2020

The rising pandemic is resulting in increased usage of personnel protective equipment in the hospital and community. The efficient and effective use of appropriate personal protective equipment will help assure its availability and healthcare provider safety. The purpose of this study was to assess the use efficacy of PPE among health care workers through a web based survey during the pandemic. the response rate of the survey was 66.75%. 35.2% gave a full rating on a point of 5 regarding the control measures taken by the hospital, 39% of respondents did not use the PPE, 90.6% used a surgical mask while 65.9% wore the disposable gloves and only 47.6% wore the goggles/face shield More than half the respondents did not wear the shoe-cover. 97.4% used the hand sanitizer and around 97% maintained hand hygiene practice.