bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine Learning Identifies Novel Candidates for Drug Repurposing in Alzheimer’s Disease
Authors: Rodriguez Steve , Hug Clemens , Todorov Petar , Moret Nienke , Boswell Sarah A. , Evans Kyle , Zhou George , Johnson Nathan T. , Hyman Brad , Sorger Peter K. , Albers Mark W. , Sokolov Artem
Published: May 2020

Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. Repurposing can yield a useful therapeutic and also accelerate proof of concept studies that ultimately lead to a new molecular entity. We present a novel machine learning framework, DRIAD (DrugRepurposing InAD), that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD was validated on gene lists known to be associated with AD from other studies and subsequently applied to evaluate lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs were inspected for common trends among their nominal molecular targets and their “off-targets”, revealing a high prevalence of kinases from the Janus (JAK), Unc-51-like (ULK) and NIMA-related (NEK) families. These kinase families are known to modulate pathways related to innate immune signaling, autophagy, and microtubule formation and function, suggesting possible disease-modifying mechanisms of action. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be evaluated in a clinical trial.
Linking Anthocyanin Diversity, Hue, And Genetics In Purple Corn
Authors: Chatham Laura A. , Juvik John A.
Published: May 2020

While maize with anthocyanin-rich pericarp (purple corn) is rising in popularity as a source of natural colorant for foods and beverages, information on color range and stability—factors associated with anthocyanin decorations and compositional profiles—are currently limited. Using the natural anthocyanin diversity present in a purple corn landrace, Apache Red, we generated a population with variable flavonoid profiles—flavonol-anthocyanin condensed forms (0-83%), acylated anthocyanins (2-72%), pelargonidin-derived anthocyanins (5-99%), and C-glycosyl flavone co-pigments up to 1904 µg/g—all of which contributed in part to the absorbance profile, used here as a proxy for hue. This variability offers targets of selection for breeders looking to expand both stability and the available range of colors that can be sourced from purple corn. With genotyping-by-sequencing of this population we mapped these anthocyanin profile traits. Major QTL for anthocyanin type were found near loci previously identified only in aleurone-pigmented maize varieties [Purple aleurone1(Pr1) andAnthocyanin acyltransferase1(Aat1)]. A QTL nearP1(Pericarp color1) was found for both flavone content and flavanol-anthocyanin condensed forms. A significant QTL associated with peonidin-derived anthocyanins near a candidate S-adenosylmethionine-dependent methyltransferase was also identified, warranting further investigation. This population represents the most anthocyanin diverse pericarp-pigmented maize variety characterized to date. Moreover, the candidates identified here will serve as branching points for future research studying the genetic and molecular processes determining anthocyanin profile in pericarp.
A system-view ofB. pertussisbooster vaccine responses in adults primed with whole-cell vs. acellular vaccine in infancy
Authors: da Silva Antunes Ricardo , Pomaznoy Mikhail , Soldevila Ferran , Babor Mariana , Bennett Jason , Tian Yuan , Khalil Natalie , Qian Yu , Mandava Aishwarya , Scheuermann Richard H. , Cortese Mario , Pulendran Bali , Petro Christopher D. , Gilkes Adrienne , Purcell Lisa A. , Sette Alessandro , Peters Bjoern
Published: May 2020

Whole-cell inactivated vaccine againstBordetella pertussis(wP) was substituted in many countries by an acellular subunit vaccine (aP) to reduce side effects. Recent epidemiological studies have shown that aP vaccination in infancy induces less durable immunity than wP vaccination. To determine immunological differences associated with aP vs. wP priming, we performed system-level profiling of the immune response in adults primed with aP vs. wP vaccine in infancy following the Tdap booster vaccination as a surrogate to antigen encounterin vivo. Shared immune responses across cohorts were identified, including an increase of the blood monocyte frequency on day 1, and strong antigen-specific IgG response seven days after boost. Comparing aP and wP primed individuals, we found a subset of aP-primed individuals with higher levels of expression for several genes including CCL3 on day 3 and NFKBIA and ICAM1 on day 7 post immunization. These observations were supported by increased CCL3 concentrations in plasma of aP primed individuals. Contrary to the wP individuals, the CCL3-high aP subset presented boosted PT-specific IgE responses. Furthermore, higher antigen specific IgG4 and IgG3 antibodies against specific vaccine antigens at baseline and post boost of aP individuals was observed, suggesting a long term maintained difference in the IgG subtype response. Overall our findings demonstrate that, while broad immune response patterns to Tdap boost overlap between aP and wP primed individuals, a subset of aP primed individuals present a divergent response. These findings provide candidate targets to study the causes and correlates of waning immunity after aP vaccination.
Habitat loss causes long transients in small trophic chains
Authors: Vidiella Blai , Fontich Ernest , Valverde Sergi , Sardanyés Josep
Published: May 2020

Transients in ecology are extremely important since they determine how equilibria are approached. The debate on the dynamic stability of ecosystems has been largely focused on equilibrium states. However, since ecosystems are constantly changing due to climate conditions or to perturbations such as the climate crisis or anthropogenic actions (habitat destruction, deforestation, or defaunation), it is important to study how dynamics can proceed till equilibria. In this contribution we investigate dynamics and transient phenomena in small food chains using mathematical models. We are interested in the impact of habitat loss in ecosystems with vegetation undergoing facilitation. We provide a thorough dynamical study of a small food chain system given by three trophic levels: vegetation, herbivores, and predators. The dynamics of the vegetation alone suffers a saddle-node bifurcation, causing extremely long transients. The addition of a herbivore introduces a remarkable number of new phenomena. Specifically, we show that, apart from the saddle node involving the extinction of the full system, a transcritical and a supercritical Hopf-Andronov bifurcation allow for the coexistence of vegetation and herbivores via non-oscillatory and oscillatory dynamics, respectively. Furthermore, a global transition given by a heteroclinic bifurcation is also shown to cause a full extinction. The addition of a predator species to the previous systems introduces further complexity and dynamics, also allowing for the coupling of different transient phenomena such as ghost transients and transient oscillations after the heteroclinic bifurcation. Our study shows how the increase of ecological complexity via addition of new trophic levels and their associated nonlinear interactions may modify dynamics, bifurcations, and transient phenomena.
The scientific basis for currently proposed management options for Hector’s and Maui dolphins: a critique
Authors: Slooten Elisabeth , Dawson Stephen Michael
Published: May 2020

New Zealand’s Ministry for Primary Industries (MPI) developed a risk analysis for Hector’s and Maui dolphins, in order to inform protection options being considered by the Ministers of Fisheries and Conservation. Unfortunately, MPI’s risk analysis combines several estimates that are biased, and the biases consistently act together to underestimate the level of bycatch and overestimate the species’ ability to sustain impacts. In essence, the approach uses abundance estimates that are likely biased high, multiplies them by a reproductive rate that has been arbitrarily raised, multiplied by an assumed figure for calf survival, to reach a number of dolphins that would be added each year if the population were to remain stable. From this number, they subtract their estimates of bycatch, which are almost certainly biased low. The remaining number of dolphins is apportioned a cause of death according to autopsy data from 55 Hector’s and Maui dolphins found dead on beaches. This is then compared to estimates of what level of takes would be sustainable, calculated using a formula that is not well understood and less conservative than the international standard (PBR, developed by the US National Marine Fisheries Service). This is a poor basis for rational management of an endangered, endemic marine mammal. A key problem with the MPI approach is that its definition of “risk” does not relate to the risk of population decline or extinction, and is inconsistent with the modern understanding of the behaviour of meta-populations. The approach defines risk as the likelihood of capture, which is apportioned to different areas according to fishing effort and the habitat model’s outputs for dolphin distribution. The protection options are therefore targeted where high densities of dolphins and high fishing effort coincide. Large populations are allocated the highest level of protection, while small populations remain poorly protected. This approach is likely to increase the risk of local extinctions, contractions of dolphin distribution, population fragmentation, loss of genetic variability and result in increased risk to the species as a whole. Many of these points were made by an International Expert Panel in 2018. MPI have failed to provide a list of recommendations from the Expert Panel Report with their responses (if any) to those recommendations. This standard step in scientific practice, following peer review (e.g. response to reviewers’ comments) has not been followed.
Let it bud: an ultrastructural study ofCryptococcus neoformanssurface during budding events
Authors: Araújo Glauber R. de S. , Alcantara Carolina de L. , Rodrigues Noêmia , de Souza Wanderley , Pontes Bruno , Frases Susana
Published: May 2020

Cryptococcus neoformansis a fungal pathogen that causes life-threatening infections in immunocompromised individuals. It is surrounded by three concentric structures that separate the cell from the extracellular space: the plasma membrane, the cell wall and the polysaccharide capsule. Although several studies have revealed the chemical composition of these structures, little is known about their ultrastructural organization and remodeling duringC. neoformansbudding event. Here, by combining the state-of-the-art in light and electron microscopy techniques we describe the morphological remodeling that occurs synergistically among the capsule, cell wall and plasma membrane during budding inC. neoformans. Our results show that the cell wall deforms to generate a specialized budding region at one of the cell’s poles. This region subsequently begins to break into layers that are slightly separated from each other and with thick tips. We also observe a reduction in density of the capsular polysaccharide around these specialized regions. Daughter cells present a distinct spatial organization, with polysaccharide fibers aligned in the direction of budding. In addition, to control the continuous openings between mother and daughter cells, the latter developed a strategy to shield themselves by forming multilamellar membrane structures in conjunction with their capsules. Together, our findings provide compelling ultrastructural evidence for a dynamicC. neoformanssurface remodeling during budding and may have important implications for future studies exploring these remodeled specialized regions as drug-targets against cryptococcosis.
A Novel Xenonucleic Acid Mediated Molecular Clamping Technology for Early Colorectal Cancer Screening
Authors: Sun Qing , Pastor Larry , Du Jinwei , Powell Michael J. , Zhang Aiguo , Bodmer Walter , Wu Jianzhong , Zheng Shu , Sha Michael Y.
Published: May 2020

Background

Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Early detection is critical to reduce CRC morbidity and mortality. In order to meet this need, we developed a molecular clamping assay called the ColoScape ™ for early colorectal cancer diagnostics.

Methods

Nineteen mutations in four genes APC, KRAS, BRAF and CTNNB1 associated with early events in CRC pathogenesis are targeted in the ColoScape™ assay. Xenonucleic Acid (XNA) mediated qPCR clamping technology was applied to minimize the wild-type background amplification in order to improve assay sensitivity of CRC mutation detection. The assay analytical performance was verified and validated, cfDNA and FFPE CRC patient samples were evaluated, and a ROC cure was applied to evaluate its performance.

Results

The data showed that the assay analytical sensitivity is 0.5% Variant Allele Frequency, corresponding to ~7-8 copies of mutant DNA with 5ng total DNA input per test. This assay is highly reproducible with intra-assay CV <3% and inter-assay <5%. We have investigated 380 clinical samples including plasma cfDNA and FFPE samples from patients with precancerous and different stages of CRC. The preliminary assay clinical specificity and sensitivity for CRC cfDNA were 100% (95% CI, 80.3-97.5%) and 92.2% (95% CI, 94.7-100%) respectively with AUC being about 0.96; and 96% (95% CI, 77.6-99.7%) specificity and 92% (95% CI, 86.1-95.6%) sensitivity with AUC 0.94 for CRC FFPE; and 95% specificity (95% CI, 82.5%-99.1%) and 62.5% sensitivity (95% CI, 35.8%-83.7%) with AUC 0.79 for precancerous lesions cfDNA.

Conclusions

XNA mediated molecular clamping assay is a rapid, precise, and sensitive assay for the detection of precancerous lesions cfDNA and CRC cfDNA or FFPE samples.
Pair-wise Interactions in Gene Expression Determine a Hierarchical Transcription Profile of the Human Brain
Authors: Hua Jiaojiao , Yang Zhengyi , Jiang Tianzi , Yu Shan
Published: May 2020

Orchestrated expressions of tens of thousands of genes give rise to the complexity of the brain. However, it is unclear what is the structure governing these myriads of gene-gene interactions. By analyzing the transcription data obtained from more than 3000 sites in human brains, we found that pair-wise interactions between genes are sufficient to accurately predict both the transcription pattern of the whole genome for individual brain areas and the transcription profile of the entire brain, suggesting a surprisingly simple interaction structure of the transcriptome itself. We further revealed that the strength of gene-gene interaction observed empirically allows the nearly maximal number of transcriptionally similar clusters of areas to form, which may account for the functional and structural richness of the brain.

One Sentence Summary

Pairwise interactions among genes shape the overall structure of human brain transcriptome.
Robust scan synchronized force-fluorescence imaging
Authors: Schmidt Patrick , Lajoie John , Sivasankar Sanjeevi
Published: May 2020

Simultaneous atomic force microscope (AFM) and sample scanning confocal fluorescence microscope measurements are widely used to obtain mechanistic and structural insights into protein dynamics in live cells. However, the absence of a robust technique to synchronously scan both AFM and confocal microscope piezo stages makes it difficult to visualize force-induced changes in fluorescent protein distribution in cells. To address this challenge, we have built an integrated AFM-confocal fluorescence microscope platform that implements a synchronous scanning method which eliminates image artifacts from piezo motion ramping, produces intuitive, accurate pixel binning and enables the collection of a scanned image of a sample while applying force to the sample. As proof of principle, we use this instrument to monitor the redistribution of fluorescent E-cadherin, an essential transmembrane protein, in live cells, upon application of mechanical force.
Accurate prediction of cis-regulatory modules reveals a prevalent regulatory genome of humans
Authors: Ni Pengyu , Su Zhengchang
Published: May 2020

Annotating all cis-regulatory modules (CRMs) and transcription factor (TF) binding sites(TFBSs) in genomes remains challenging. We tackled the task by integrating putative TFBSs motifs found in available 6,092 datasets covering 77.47% of the human genome. This approach enabled us to partition the covered genome regions into a CRM candidate (CRMC) set (56.84%) and a non-CRMC set (43.16%). Intriguingly, like known enhancers, the predicted 1,404,973 CRMCs are under strong evolutionary constraints, suggesting that they might be cis-regulator. In contrast, the non-CRMCs are largely selectively neutral, suggesting that they might not be cis-regulatory. Our method substantially outperforms three state-of-the-art methods (GeneHancers, EnhancerAtlas and ENCODE phase 3) for recalling VISTA enhancers and ClinVar variants, as well as by measurements of evolutionary constraints. We estimated that the human genome might encode about 1.46 million CRMs and 67 million TFBSs, comprising about 55% and 22% of the genome, respectively; for both of which, we predicted 80%. Therefore, the cis-regulatory genome appears to be more prevalent than originally thought.
Guiding and interpreting brain network classification with transcriptional data
Authors: Li Mengbo , Kessler Daniel , Arroyo Jesús , Freytag Saskia , Bahlo Melanie , Levina Elizaveta , Yang Jean
Published: May 2020

The investigation of brain networks has yielded many insights that have helped to characterise many neurological and psychiatric disorders. In particular, network classification of functional magnetic resonance imaging (fMRI) data is an important tool for the identification of prognostic and diagnostic biomarkers of brain connectivity disorders such as schizophrenia and depression. However, existing generic network classification methods provide no direct information on the underlying molecular mechanisms of the selected functional connectivity features when applied to fMRI data. To address this, we propose a novel fMRI network classification method that incor-porates brain transcriptional data using a user-specified gene set collection (GSC) to construct feature groups for use in classification of brain connectivity data. The use of GSCs are an opportunity to incorporate knowledge of potential molecular mechanisms which may be associated with a disease. The inclusion of transcriptional data yields improved prediction accuracy on publicly available schizophrenia fMRI data for several of the GSCs we consider. We also introduce a post-hoc interpretation framework to provide transcriptional-data-guided biological interpretations for discriminative functional connectivity features identified by existing fMRI network classification methods.
Modeling Tempo of COVID-19 Pandemic in India and Significance of Lockdown
Authors: Singh Brijesh P , Singh Gunjan
Published: May 2020

A very special type of pneumonic disease that generated the COVID-19 pandemic was first identified in Wuhan, China in December 2019 and is spreading all over the world. The ongoing outbreak presents a challenge for data scientists to model COVID-19, when the epidemiological characteristics of the COVID-19 are yet to be fully explained. The uncertainty around the COVID-19 with no vaccine and effective medicine available until today create additional pressure on the epidemiologists and policy makers. In such a crucial situation, it is very important to predict infected cases to support prevention of the disease and aid in the preparation of healthcare service. In this paper, we have tried to understand the spreading capability of COVID-19 in India taking into account of the lockdown period. The numbers of confirmed cases are increased in India and states in the past few weeks. A differential equation based simple model has been used to understand the pattern of COVID-19 in India and some states. Our findings suggest that the physical distancing and lockdown strategies implemented in India are successfully reducing the spread and that the tempo of pandemic growth has slowed in recent days.
Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis
Authors: Wilson Jennifer G , Simpson Laura J , Ferreira Anne-Maud , Rustagi Arjun , Roque Jonasel , Asuni Adijat , Ranganath Thanmayi , Grant Philip M , Subramanian Aruna , Rosenberg-Hasson Yael , Maecker Holden T , Holmes Susan P , Levitt Joseph E , Blish Catherine A , Rogers Angela J
Published: May 2020

Rationale: Elevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare to those observed in critically ill patients with ARDS or sepsis due to other causes.
Objectives: To directly compare plasma levels of inflammatory cytokines, with a focus on 6 cytokines associated with cytokine storm (IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFα), between hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients from prior to the COVID-19 pandemic.
Findings: 15 hospitalized COVID-19 patients, 9 of whom were critically ill, were compared to 28 critically ill patients with ARDS or sepsis. There were no statistically significant differences in baseline levels of IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFα between patients with severe COVID-19 and critically ill controls with ARDS or sepsis.
Conclusions: Levels of inflammatory cytokines IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFα were not higher in critically ill COVID-19 patients than in critically ill patients admitted with ARDS or sepsis due to other causes in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 is likely unwarranted.
HB-PLS: An algorithm for identifying biological process or pathway regulators by integrating Huber loss and Berhu penalty with partial least squares regression
Authors: Deng Wenping , Zhang Kui , Wei Zhigang , Wang Lihu , He Cheng , Liu Sanzhen , Wei Hairong
Published: May 2020

Gene expression data features high dimensionality, multicollinearity, and the existence of outlier or non-Gaussian distribution noise, which make the identification of true regulatory genes controlling a biological process or pathway difficult. In this study, we embedded the Huber-Berhu (HB) regression into the partial least squares (PLS) framework and created a new method called HB-PLS for predicting biological process or pathway regulators through construction of regulatory networks. PLS is an alternative to ordinary least squares (OLS) for handling multicollinearity in high dimensional data. The Huber loss is more robust to outliers than square loss, and the Berhu penalty can obtain a better balance between theℓ2penalty and theℓ1penalty. HB-PLS therefore inherits the advantages of the Huber loss, the Berhu penalty, and PLS. To solve the Huber-Berhu regression, a fast proximal gradient descent method was developed; the HB regression runs much faster than CVX, a Matlab-based modeling system for convex optimization. Implementation of HB-PLS to real transcriptomic data fromArabidopsisand maize led to the identification of many pathway regulators that had previously been identified experimentally. In terms of its efficiency in identifying positive biological process or pathway regulators, HB-PLS is comparable to sparse partial least squares (SPLS), a very efficient method developed for variable selection and dimension reduction in handling multicollinearity in high dimensional genomic data. However, HB-PLS is able to identify some distinct regulators, and in one case identify more positive regulators at the top of output list, which can reduce the burden for experimental test of the identified candidate targets. Our study suggests that HB-PLS is instrumental for identifying biological process and pathway genes.
A cell competition-based drug screen identifies a novel compound that induces dual c-Myc depletion and p53 activation
Authors: Tadele Dagim Shiferaw , Robertson Joseph , Crispin Richard , Herrera Maria C. , Chlubnova Marketa , Piechaczyk Laure , Ayuda-Durán Pilar , Singh Sachin Kumar , Gedde-Dahl Tobias , Fløisand Yngvar , Skavland Jørn , Wesche Jørgen , Gjertsen Bjørn-Tore , Enserink Jorrit M.
Published: May 2020

BCR-Abl is a driver oncogene that causes chronic myeloid leukemia and a subset of acute lymphoid leukemias. Although tyrosine kinase inhibitors provide an effective treatment for these diseases, they generally do not kill leukemic stem cells. Leukemic stem cells are cancer-initiating cells that compete with normal hematopoietic stem cells for the bone marrow niche. Using BCR-Abl as a model oncogene, we performed a drug screen based on competition between isogenic untransformed cells and BCR-Abl-transformed cells, and identified several compounds that selectively target BCR-Abl-transformed cells. Systems-level analysis of one of these novel compounds, DJ34, revealed that it induced depletion of c-Myc and activation of p53. c-Myc depletion occurred in a wide range of tumor types, including leukemia, lymphoma, lung, glioblastoma and breast cancer. Further analyses revealed that DJ34 interferes with c-Myc synthesis at the level of transcription, and we provide data showing that DJ34 is a DNA intercalator and topoisomerase II inhibitor. Physiologically, DJ34 induced apoptosis, cell cycle arrest and cell differentiation, and primary leukemic stem cells were particularly sensitive to DJ34. Taken together, we have identified a novel compound that dually targets c-Myc and p53 in a wide variety of cancers, and with particularly strong activity against leukemic stem cells.
Plasma metabolomics of presymptomaticPSEN1-H163Y mutation carriers: A pilot study
Authors: Natarajan Karthick , Ullgren Abbe , Khoshnood Behzad , Johansson Charlotte , Laffita-Mesa José Miguel , Pannee Josef , Zetterberg Henrik , Blennow Kaj , Graff Caroline
Published: May 2020

Background and Objective

PSEN1-H163Y carriers, at the presymptomatic stage, have reduced18FDG-PET binding in the cerebrum of the brain [1]. This could imply dysfunctional energy metabolism in the brain. In this study, plasma of presymptomaticPSEN1mutation carriers was analyzed to understand associated metabolic changes.

Methods

We analyzed plasma from non-carriers (NC, n=8) and presymptomaticPSEN1-H163Y mutation carriers (MC, n=6) via untargeted metabolomics using gas and liquid chromatography coupled with mass spectrometry, which identified 1199 metabolites. All the metabolites were compared between MC and NC using univariate analysis, as well as correlated with the ratio of Aβ1-42/Aβ1-40, using Spearman’s correlation. Altered metabolites were subjected to Ingenuity Pathways Analysis (IPA).

Results

When comparing between presymptomatic MC and NC, the levels of 116 different metabolites were altered. Out of 116, only 23 were annotated metabolites, which include amino acids, fatty acyls, bile acids, hexoses, purine nucleosides, carboxylic acids, and glycerophosphatidylcholine species. 1-docosapentaenoyl-GPC, glucose and uric acid were correlated with the ratio of plasma Aβ1-42/Aβ1-40(p < 0.05).

Conclusion

This study finds dysregulated metabolite classes, which are changed before the disease onset. Also, it provides an opportunity to compare with sporadic Alzheimer’s Disease. Observed findings in this study need to be validated in a larger and independent Familial Alzheimer’s Disease (FAD) cohort.

Graphical abstract
Mechanistic modeling of the SARS-CoV-2 and immune system interplay unravels design principles for diverse clinicopathological outcomes
Authors: Sahoo Sarthak , Hari Kishore , Jhunjhunwala Siddharth , Jolly Mohit Kumar
Published: May 2020

The disease caused by SARS-CoV-2 is a global pandemic that threatens to bring long-term changes worldwide. Approximately 80% of infected patients are asymptomatic or have mild symptoms such as fever or cough, while rest of the patients have varying degrees of severity of symptoms, with 3-4% mortality rate. Severe symptoms such as pneumonia and Acute Respiratory Distress Syndrome can be caused by tissue damage mostly due to aggravated and unresolved innate and adaptive immune response, often resulting from a cytokine storm. However, the mechanistic underpinnings of such responses remain elusive, with an incomplete understanding of how an intricate interplay among infected cells and cells of innate and adaptive immune system can lead to such diverse clinicopathological outcomes. Here, we use a dynamical systems approach to dissect the emergent nonlinear intra-host dynamics among virally infected cells, the immune response to it and the consequent immunopathology. By mechanistic analysis of cell-cell interactions, we have identified key parameters affecting the diverse clinical phenotypes associated with COVID-19. This minimalistic yet rigorous model can explain the various phenotypes observed across the clinical spectrum of COVID-19, various co-morbidity risk factors such as age and obesity, and the effect of antiviral drugs on different phenotypes. It also reveals how a fine-tuned balance of infected cell killing and resolution of inflammation can lead to infection clearance, while disruptions can drive different severe phenotypes. These results will help further the case of rational selection of drug combinations that can effectively balance viral clearance and minimize tissue damage simultaneously.

Significance Statement

The SARS-CoV-2 pandemic has already infected millions of people, and thousands of lives have been lost to it. The pandemic has already tested the limits of our public healthcare systems with a wide spectrum of clinicopathological symptoms and outcomes. The mechanistic underpinnings of the resultant immunopathology caused by the viral infection still remains to be elucidated. Here we propose a minimalistic but rigorous description of the interactions of the virus infected cells and the core components of the immune system that can potentially explain such diversity in the observed clinical outcomes. Our proposed framework could enable a platform to determine the efficacy of various treatment combinations and can contributes a conceptual understanding of dynamics of disease pathogenesis in SARS-CoV-2 infections.
Genome-wide identification and characterization ofSolanum tuberosum BiPgenes reveals the role of the promoter architecture in BiP gene diversity
Authors: Herath Venura , Gayral Mathieu , Adhikari Nirakar , Miller Rita , Verchot Jeanmarie
Published: May 2020

The endoplasmic reticulum (ER) immunoglobulin binding proteins (BiPs) are molecular chaperones involved in normal protein maturation and refolding malformed proteins through the unfolded protein response (UPR). Plants BiPs belong to a multi-gene family contributing to development, immunity, and responses to environmental stresses. This study identified threeBiPhomologues in theSolanum tuberosum(potato) genome using phylogenetic, amino acid sequence, 3-D protein modeling and gene structure analysis. These analyses revealed thatStBiP1andStBiP2grouped withAtBiP2, whereasStBiP3grouped withAtBiP3. While the protein sequences and folding structures are highly similar, theseStBiPsare distinguishable by their expression patterns in different tissues and in response to environmental stressors such as treatment with heat, chemicals, or virus elicitors of UPR.Ab initiopromoter analysis revealed that potato and ArabidopsisBiP1andBiP2promoters were highly enriched with cis regulatory elements (CREs) linked to developmental processes, whereasBiP3promoters were enriched with stress-related CREs. The frequency and linear distribution of these CREs produced two phylogenetic branches that further resolve the groups identified through gene phylogeny and exon/intron phase analysis. These data reveal that the CRE architecture ofBiPpromoters potentially define their spatio -temporal expression patterns under developmental and stress related cues.
Label-free optical detection of bioelectric potentials using electrochromic thin films
Authors: Alfonso Felix S. , Zhou Yuecheng , Liu Erica , McGuire Allister F. , Yang Yang , Kantarci Husniye , Li Dong , Copenhaver Eric , Zuchero J. Bradley , Müller Holger , Cui Bianxiao
Published: May 2020

Understanding how a network of interconnected neurons receives, stores, and processes information in the human brain is one of the outstanding scientific challenges of our time. The ability to reliably detect neuroelectric activities is essential to addressing this challenge. Optical recording using voltage-sensitive fluorescent probes has provided unprecedented flexibility for choosing regions of interest in recording neuronal activities. However, when recording at a high frame rate such as 500-1000 Hz, fluorescence-based voltage sensors often suffer from photobleaching and phototoxicity, which limit the recording duration. Here, we report a new approach, Electro-Chromic Optical REcording (ECORE), that achieves label-free optical recording of spontaneous neuroelectrical activities. ECORE utilizes the electrochromism of PEDOT:PSS thin films, whose optical absorption can be modulated by an applied voltage. Being based on optical reflection instead of fluorescence, ECORE offers the flexibility of an optical probe without suffering from photobleaching or phototoxicity. Using ECORE, we optically recorded spontaneous action potentials in cardiomyocytes, cultured hippocampal and dorsal root ganglion neurons, and brain slices. With minimal perturbation to cells, ECORE allows long-term optical recording over multiple days.
Non-thalamic origin of zebrafish sensory relay nucleus: convergent evolution of visual pathways in amniotes and teleosts
Authors: Bloch Solal , Hagio Hanako , Thomas Manon , Heuzé Aurélie , Hermel Jean-Michel , Lasserre Elodie , Colin Ingrid , Saka Kimiko , Affaticati Pierre , Jenett Arnim , Kawakami Koichi , Yamamoto Naoyuki , Yamamoto Kei
Published: May 2020

Ascending visual projections similar to the mammalian thalamocortical pathway are found in a wide range of vertebrate species, but their homologous relationship is debated. To get better insights into their evolutionary origin, we examined the developmental origin of a visual relay nucleus in zebrafish (a teleost fish). Similarly to the tectofugal visual thalamic nuclei in amniotes, the lateral part of the preglomerular complex (PG) in teleosts receives tectal information and projects to the pallium. However, our cell lineage study reveals that the majority of PG cells are derived from the midbrain, not from the forebrain. We also demonstrate that the PG projection neurons develop gradually until juvenile stage, unlike the thalamic projection neurons. Our data suggest that teleost PG is not homologous to the amniote thalamus and that thalamocortical-like projections can evolve from a non-forebrain cell population. Thus, sensory pathways in vertebrate brains exhibit a surprising degree of variation.
Unraveling molecular interactions in a phase-separating protein by atomistic simulations
Authors: Paloni Matteo , Bailly Rémy , Ciandrini Luca , Barducci Alessandro
Published: May 2020

Membraneless organelles are dynamical cellular condensates formed by the liquid-liquid phase separation of proteins and RNA molecules. Multiple evidence suggests that disordered proteins are structural scaffolds that drive the condensation by forming a dynamic network of inter- and intra-molecular contacts. Despite the blooming research activity in this field, the structural characterization of these condensates is very limited and we still do not understand how the phase behaviour is encoded in the amino-acid sequences of the scaffolding proteins. Here we exploited explicit-solvent atomistic simulations to disentangle the molecular interactions governing the phase behaviour of the N-terminal disordered region of DEAD-box helicase 4 (NDDX4), which is a well-established model for phase separationin vitroandin vivo. Single-molecule simulations clarified the interplay between the intramolecular interactions that shape NDDX4 conformational ensemble and the known determinants of its phase behaviour, such as the attraction between oppositely-charged regions and the presence of arginine and phenylalanine. We then investigated intermolecular interactions associated with phase separation via a divide-and-conquer strategy based on the simulations of various NDDX4 fragments at high concentration. Our approach allowed us to probe conditions mimicking real condensates and revealed, in agreement with mutagenesis results, how these interactions arise from the complex interplay of diverse molecular mechanisms. Particularly, we characterized the transient formation of clusters of arginine and aromatic residues, which may stabilize the assembly of several MLOs. Overall, our results reveal the potential of atomistic simulations in the investigation of biomolecular phase separation paving the way for future studies.
Probabilistic Optically-Selective Single-molecule Imaging Based Localization Encoded (POSSIBLE) Microscopy for Ultra-superresolution Imaging of Dendra2-HA transfected NIH3T3 cells
Authors: Mondal Partha Pratim
Published: May 2020

To be able to resolve molecular-clusters it is crucial to access vital informations (such as, molecule density and cluster-size) that are key to understand disease progression and the underlying mechanism. Traditional single-molecule localization microscopy (SMLM) techniques use molecules of variable sizes (as determined by its localization precisions (LPs)) to reconstruct super-resolution map. This results in an image with overlapping and superimposing PSFs (due to a wide size-spectrum of single molecules) that degrade image resolution. Ideally it should be possible to identify the brightest molecules (also termed as, thefortunate molecules) to reconstruct ultra-superresolution map, provided sufficient statistics is available from the recorded data. POSSIBLE microscopy explores this possibility by introducing narrow probability size-distribution of single molecules (narrow size-spectrum about a predefined mean-size). The reconstruction begins by presetting the mean and variance of the narrow distribution function (Gaussian function). Subsequently, the dataset is processed and single molecule filtering is carried out by the Gaussian distribution function to filter out unfortunate molecules. The fortunate molecules thus retained are then mapped to reconstruct ultra-superresolution map. In-principle, the POSSIBLE microscopy technique is capable of infinite resolution (resolution of the order of actual single molecule size) provided enough fortunate molecules are experimentally detected. In short, bright molecules (with large emissivity) holds the key. Here, we demonstrate the POSSIBLE microscopy technique and reconstruct single molecule images with an average PSF sizes ofσ± Δσ= 15 ± 10nm, 30 ± 2nm& 50 ± 2nm. Results show better-resolved Dendra2-HA clusters with large cluster-density in transfected NIH3T3 fibroblast cells as compared to the traditional SMLM techniques.
The effect of boundaries on grid cell patterns
Authors: Monsalve-Mercado Mauro M. , Leibold Christian
Published: May 2020

Mammalian grid cells represent spatial locations in the brain via triangular firing patterns that tessellate the environment. They are regarded as the biological substrate for path integration thereby generating an efficient code for space. However, grid cell patterns are strongly influenced by environmental manipulations, in particular exhibiting local geometrical deformations and defects tied to the shape of the recording enclosure, challenging the view that grid cells constitute a universal code for space. We show that the observed responses to environmental manipulations arise as a natural result under the general framework of feedforward models with spatially unstructured feedback inhibition, which puts the development of triangular patterns in the context of a Turing pattern formation process over physical space. The model produces coherent neuronal populations with equal grid spacing, field size, and orientation.

PACS numbers

87.19.lv,87.10.Ed,02.30.Jr
A comprehensive germline variant and expression analyses ofACE2,TMPRSS2and SARS-CoV-2 activatorFURINgenes from the Middle East: Combating SARS-CoV-2 with precision medicine
Authors: Al-Mulla Fahd , Mohammad Anwar , Al Madhoun Ashraf , Haddad Dania , Ali Hamad , Eaaswarkhanth Muthukrishnan , John Sumi Elsa , Nizam Rasheeba , Channanath Arshad , Abu-Farha Mohamed , Ahmad Rasheed , Abubaker Jehad , Thanaraj Thangavel Alphonse
Published: May 2020

The severity of the new COVID-19 pandemic caused by the SARS-CoV-2 virus is strikingly variable in different global populations. SARS-CoV-2 usesACE2as a cell receptor,TMPRSS2protease, andFURINpeptidase to invade human cells. Here, we investigated 1,378 whole-exome sequences of individuals from the Middle Eastern populations (Kuwait, Qatar, and Iran) to explore natural variations in theACE2,TMPRSS2,andFURINgenes. We identified two activating variants (K26R and N720D) in theACE2gene that are more common in Europeans than in the Middle Eastern, East Asian, and African populations. We postulate that K26R can activateACE2and facilitate binding to S-protein RBD while N720D enhancesTMPRSS2cutting and, ultimately, viral entry. We also detected deleterious variants inFURINthat are frequent in the Middle Eastern but not in the European populations. This study highlights specific genetic variations in theACE2andFURINgenes that may explain SARS-CoV-2 clinical disparity. We showed structural evidence of the functionality of these activating variants that increase the SARS-CoV-2 aggressiveness. Finally, our data illustrate a significant correlation betweenACE2variants identified in people from Middle Eastern origins that can be further explored to explain the variation in COVID-19 infection and mortality rates globally.
The Mystery of a Marine Monster: Morphological and Performance Modifications in the World’s only Marine Lizard, the Galápagos Marine Iguana
Authors: Berry Kate A. , Muñoz-Pérez Juan Pablo , Vintimilla-Palacios Cristina P. , Clemente Christofer J.
Published: May 2020

Reptiles have repeatedly invaded and thrived in aquatic environments throughout history, however fewer than 8% of the 6000 extant species are primarily aquatic. The Galápagos Marine Iguana (Amblyrhynchus cristatus), the world’s only marine lizard, may have had one of the most unique and challenging transitions to aquatic life. Curiously, previous studies have identified relatively few physiological adaptations in Marine Iguanas, however, little is known about the extent of morphological specialisation and performance trade-offs associated with the marine environment. By examining the morphology and locomotory performance of the Marine Iguana in comparison to their closely related mainland ancestors, the Black Spiny-tailed iguana (Ctenosaura similis) and Green Iguana (Iguana iguana), we found variation reflected specialisation to ecological niches. However, variation was more pronounced among subspecies of Marine Iguana, suggesting that little morphological or performance modification is required for iguanids to successfully invade aquatic environments, thus raising the question why there are so few extant aquatic reptilian lineages. We found that specialisation for the marine environment resulted in a trade-off in sprint speed in a terrestrial environment, similar to that seen in extant crocodilians. Reduced performance in a terrestrial environment likely poses little risk to large-bodied apex predators, whereas in iguanids, a performance trade-off would likely incur increased predation. As such, we suggest that this may explain why iguanids and other ancestral lineages have not undergone transitions to aquatic life. Additionally, we found that the magnitude of morphological and performance variation was more pronounced between subspecies of Marine Iguana than between iguanid species.

Summary Statement

The Marine Iguana has undergone a unique evolutionary transition to aquatic behaviour, we explore the extent of morphological and performance specialisation required and why there are so few extant marine reptiles.
MutantHuntWGS: A Pipeline for IdentifyingSaccharomyces cerevisiaeMutations
Authors: Ellison Mitchell A. , Walker Jennifer L. , Ropp Patrick J. , Durrant Jacob D. , Arndt Karen M.
Published: May 2020

MutantHuntWGS is a user-friendly pipeline for analyzingSaccharomyces cerevisiaewhole-genome sequencing data. It uses available open-source programs to: (1) perform sequence alignments for paired and single-end reads, (2) call variants, and (3) predict variant effect and severity. MutantHuntWGS outputs a shortlist of variants while also enabling access to all intermediate files. To demonstrate its utility, we use MutantHuntWGS to assess multiple published datasets; in all cases, it detects the same causal variants reported in the literature. To encourage broad adoption and promote reproducibility, we distribute a containerized version of the MutantHuntWGS pipeline that allows users to install and analyze data with only two commands. The MutantHuntWGS software and documentation can be downloaded free of charge fromhttps://github.com/mae92/MutantHuntWGS.
Chromatin folding variability across single-cells results from state degeneracy in phase-separation
Authors: Conte Mattia , Fiorillo Luca , Bianco Simona , Chiariello Andrea M. , Esposito Andrea , Nicodemi Mario
Published: May 2020

Chromosome spatial organization controls functional interactions between genes and regulators, yet the molecular and physical mechanisms underlying folding at the single DNA molecule level remain to be understood. Here we employ models of polymer physics to investigate the conformations of two 2Mb-wide DNA loci in human HCT116 and IMR90 wild-type and cohesin depleted cells. Model predictions on the 3D structure of single-molecules are consistently validated against super-resolution single-cell imaging data, providing evidence that the architecture of the studied loci is controlled by a thermodynamics mechanism ofpolymer phase separationwhereby chromatin self-assembles in segregated globules. The process is driven by interactions between distinct types of cognate binding sites, correlating each with a different combination of chromatin factors, including CTCF, cohesin and histone marks. The intrinsic thermodynamics degeneracy of conformations results in a broad structural and time variability of single-molecules, reflected in their varying TAD-like contact patterns. Globules breathe in time, inducing stochastic unspecific interactions, yet they produce stable, compact environments where specific contacts become highly favored between regions enriched for cognate binding sites, albeit characterized by weak biochemical affinities. Cohesin depletion tends to reverse globule phase separation into a coil, randomly folded state, resulting in much more variable contacts across single-molecules, hence erasing population-averaged patterns. Overall, globule phase separation appears to be a robust, reversible mechanism of chromatin organization, where stochasticity and specificity coexist.