bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell-to-cell ATP differences can modulate cellular decision-making
Authors: Kerr Ryan , Jabbari Sara , Johnston Iain
Published: July 2020

Cells generate phenotypic diversity both during development and in response to stressful and changing environments, aiding survival. Functionally vital cell fate decisions from a range of phenotypic choices are made by regulatory networks, the dynamics of which rely on gene expression and hence depend on the cellular energy budget (and particularly ATP levels). However, despite pronounced cell-to-cell ATP differences observed across biological systems, the influence of energy availability on regulatory network dynamics is often overlooked as a cellular decision-making modulator, limiting our knowledge of how energy budgets affect cell behaviour. Here, we consider a mathematical model of a highly generalisable, ATP-dependent, decision-making regulatory network, and show that cell-to-cell ATP variability changes the sets of decisions a cell can make. Our model shows that increasing intracellular energy levels can increase the number of supported stable phenotypes, corresponding to increased decision-making capacity. Model cells with sub-threshold intracellular energy are limited to a singular phenotype, forcing the adoption of a specific cell fate. We suggest that energetic differences between cells may be an important consideration to help explain observed variability in cellular decision-making across a broad range of biological systems, including bacteria and the blood stem cell system.
Human embryonic stem cells-derived dopaminergic neurons transplanted in parkinsonian monkeys recover dopamine levels and motor behavior
Authors: López-Ornelas Adolfo , Escobedo-Avila Itzel , Ramírez-García Gabriel , Lara-Rodarte Rolando , Meléndez-Ramírez César , Urrieta-Chávez Beetsi , Barrios-García Tonatiuh , Cáceres-Chávez Verónica A. , Flores-Ponce Xóchitl , Carmona Francia , Reynoso Carlos Alberto , Aguilar Carlos , Kerik Nora E. , Rocha Luisa , Verdugo-Díaz Leticia , Treviño Víctor , Bargas José , Ramos-Mejía Verónica , Fernández-Ruiz Juan , Campos-Romo Aurelio , Velasco Iván
Published: July 2020

Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DAN). Non-human primates (NHPs) injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine develop some alterations observed in Parkinson’s disease (PD) patients. We obtained DAN from hESCs and confirmed that they express dopaminergic markers, generate action potentials, and release dopamine (DA)in vitro. DAN were transplanted bilaterally in the putamen of parkinsonian NHPs. After grafting, animals improved motor behavior, evaluated by the HALLWAY task, and in agreement with this recovery, DA release was detected by microdialysis. Imaging techniques revealed changes in fractional anisotropy and mean diffusivity in magnetic resonance imaging and higher 11C-DTBZ binding in positron-emission tomography scans, associated with grafts.Postmortemanalysis showed that transplanted DAN survived over ten months in the putamen, without developing tumors, in the immunosuppressed NHPs. These results indicate that cell replacement therapy with hESCs-derived DAN causes long-term biochemical, anatomical, and physiological improvements in this model of PD.
Effects of plant community history, soil legacy and plant diversity on soil microbial communities
Authors: Schmid Marc W. , van Moorsel Sofia J. , Hahl Terhi , De Luca Enrica , Deyn Gerlinde B. , Wagg Cameron , Niklaus Pascal A. , Schmid Bernhard
Published: July 2020

Plant and soil microbial diversity are linked through a range of interactions, including the exchange of carbon and nutrients but also herbivory and pathogenic effects. Over time, associations between plant communities and their soil microbiota may strengthen and become more specific, resulting in stronger associations between plant and soil microbial diversity. We tested this hypothesis in a 4-year long field experiment in which we factorially combined plant community history and soil legacy with plant diversity (1, 2, 4, 8, 60 species). Plant community history and soil legacy refer to the presence (“old”) or absence (“new”) of a common history of plants and soils in 52 different plant species compositions during 8 years in a long-term biodiversity experiment in Jena, Germany. After 4 years of growth, we took soil samples in the new field experiment and determined soil bacterial and fungal composition in terms of operational taxonomic units (OTUs) using 16S rRNA gene and ITS DNA sequencing. Plant community history did not affect overall soil community composition but differentially affected bacterial richness and abundances of specific bacteria taxa in association with particular plant species compositions. Soil legacy markedly increased soil bacterial richness and evenness and decreased fungal evenness. Soil fungal richness increased with plant species richness, regardless of plant community history or soil legacy, with the strongest difference between plant monocultures and mixtures. Particular plant species compositions and functional groups were associated with particular bacterial and fungal community compositions. Grasses increased and legumes decreased fungal richness and evenness. Our findings indicate that as experimental ecosystems varying in plant diversity develop over 8 years, plant species associate with specific soil microbial taxa. This can have long-lasting effects on belowground community composition in re-assembled plant communities, as reflected in strong soil legacy signals still visible after 4 years of growing new plant communities. Effects of plant community history on soil communities are subtle and may take longer to fully develop.
Which animals are at risk? Predicting species susceptibility to Covid-19
Authors: Alexander MR , Schoeder CT , Brown JA , Smart CD , Moth C , Wikswo JP , Capra JA , Meiler J , Chen W , Madhur MS
Published: July 2020

In only a few months, the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, leaving physicians, scientists, and public health officials racing to understand, treat, and contain this zoonotic disease. SARS-CoV-2 has made the leap from animals to humans, but little is known about variations in species susceptibility that could identify potential reservoir species, animal models, and the risk to pets, wildlife, and livestock. While there is evidence that certain species, such as cats, are susceptible, the vast majority of animal species, including those in close contact with humans, have unknown susceptibility. Hence, methods to predict their infection risk are urgently needed. SARS-CoV-2 spike protein binding to angiotensin converting enzyme 2 (ACE2) is critical for viral cell entry and infection. Here we identified key ACE2 residues that distinguish susceptible from resistant species using in-depth sequence and structural analyses of ACE2 and its binding to SARS-CoV-2. Our findings have important implications for identification of ACE2 and SARS-CoV-2 residues for therapeutic targeting and identification of animal species with increased susceptibility for infection on which to focus research and protection measures for environmental and public health.
A novel computational method to design BH3-mimetic peptide inhibitors that can bind specifically to Mcl-1 or Bcl-XL
Authors: Reddy C. Narendra , Manzar Nishat , Ateeq Bushra , Sankararamakrishnan Ramasubbu
Published: July 2020

Interactions between pro- and anti-apoptotic B cell lymphoma 2 (Bcl-2) proteins decide the fate of the cell. BH3 (Bcl-2 homology 3) domain of pro-apoptotic Bcl-2 proteins interacts with the exposed hydrophobic groove of anti-apoptotic counterparts. Design and development of BH3 mimetics that target the hydrophobic groove of specific anti-apoptotic Bcl-2 proteins have the potential to become anti-cancer drugs. We have developed a novel computational method to design sequences with BH3 domain features that can bind specifically to anti-apoptotic Mcl-1 or Bcl-XL. In this method, we retained the four highly conserved hydrophobic and aspartic residues of wild-type BH3 sequences and randomly substituted all other positions to generate a large number of BH3-like sequences. We modeled 20000 complex structures with Mcl-1 or Bcl-XLusing the BH3-like sequences derived from five wild-type pro-apoptotic BH3 peptides. Peptide-protein interaction energies calculated from these models for each set of BH3-like sequences resulted in negatively-skewed extreme value distributions. The selected BH3-like sequences from the extreme negative tail regions have distinctly different distribution of charged residues for Mcl-1 and Bcl-XL. BH3-like sequences with highly favorable interaction energies prefer to have acidic residues for Mcl-1 and are enriched with basic residues when they bind to Bcl-XL. With the charged residues often away from the binding interface, the overall electric field generated by the charged residues result in highly favorable long-range electrostatic interaction energies between the peptide and the protein giving rise to high specificity. Cell viability studies of representative BH3-like peptides further validated the predicted specificity.
Reduced biomechanical models for precision-cut lung-slice stretching experiments
Authors: Pybus Hannah J. , Edgar Lowell T. , O’Dea Reuben D. , Brook Bindi S.
Published: July 2020

Precision-cut lung-slices (PCLS), in which viable airways embedded within lung parenchyma are stretched or induced to contract, are a widely usedex vivoassay to investigate bronchoconstriction and, more recently, mechanical activation of pro-remodelling cytokines in asthmatic airways. We develop a nonlinear fibre-reinforced biomechanical model accounting for smooth muscle contraction and extracellular matrix strain-stiffening. Through numerical simulation, we describe the stresses and contractile responses of an airway within a PCLS of finite thickness, exposing the importance of smooth muscle contraction on the local stress state within the airway. We then consider two simplifying limits of the model (a membrane representation and an asymptotic reduction in the thin-PCLS-limit), that permit analytical progress. Comparison against numerical solution of the full problem shows that the asymptotic reduction successfully captures the key elements of the full model behaviour. The more tractable reduced model that we develop is suitable to be employed in investigations to elucidate the time-dependent feedback mechanisms linking airway mechanics and cytokine activation in asthma.
AMPA receptor anchoring at CA1 synapses is determined by an interplay of N-terminal domain and TARP γ8 interactions
Authors: Watson Jake F. , Pinggera Alexandra , Ho Hinze , Greger Ingo H.
Published: July 2020

AMPA receptor (AMPAR) abundance and positioning at excitatory synapses regulates the strength of transmission. Changes in AMPAR localisation can enact synaptic plasticity, allowing long-term information storage, and is therefore tightly controlled. Multiple mechanisms regulating AMPAR synaptic anchoring have been described, but with limited coherence or comparison between reports, our understanding of this process is unclear. Here, combining synaptic recordings and super-resolution imaging, we compare the contributions of three AMPAR interaction domains controlling transmission at hippocampal CA1 synapses. We show that the AMPAR C-termini play only a modulatory role, whereas the extracellular N-terminal domain (NTD) and PDZ interactions of the auxiliary subunit TARP γ8 are both crucial, and each is sufficient to maintain transmission. Our data support a model in which γ8 accumulates AMPARs at the postsynaptic density, where the NTD further tunes their positioning. This interplay between cytosolic (γ8) and synaptic cleft (NTD) interactions provides versatility to regulate synaptic transmission and plasticity.
Activity Mapping the Acyl Carrier Protein - Elongating Ketosynthase Interaction in Fatty Acid Biosynthesis
Authors: Mindrebo Jeffrey T. , Misson Laetitia E. , Johnson Caitlin , Noel Joseph P. , Burkart Michael D.
Published: July 2020

Elongating ketosynthases (KSs) catalyze carbon-carbon bond forming reactions during the committed step for each round of chain extension in both fatty acid synthases (FASs) and polyketide synthases (PKSs). A small α-helical acyl carrier protein (ACP) shuttles fatty acyl intermediates between enzyme active sites. To accomplish this task, ACP relies on a series of dynamic interactions with multiple partner enzymes of FAS and associated FAS-dependent pathways. Recent structures of theEscherichia coliFAS ACP, AcpP, in covalent complexes with its two cognate elongating KSs, FabF and FabB, provide high-resolution detail of these interfaces, but a systematic analysis of specific interfacial interactions responsible for stabilizing these complexes has not yet been undertaken. Here, we use site-directed mutagenesis with bothin vitroandin vivoactivity analyses to quantitatively evaluate these contacting surfaces between AcpP and FabF. We delineate the FabF interface into three interacting regions and demonstrate the effects of point mutants, double mutants, and region delete variants. Results from these analyses reveal a robust and modular FabF interface capable of tolerating seemingly critical interface mutations with only the deletion of entire regions significantly compromising activity. Structure and sequence analysis of FabF orthologs from related type II FAS pathways indicate significant conservation of type II FAS KS interface residues and, overall, support its delineation into interaction regions. These findings strengthen our mechanistic understanding of molecular recognition events between ACPs and FAS enzymes and provide a blueprint for engineering ACP-dependent biosynthetic pathways.
Prognostic Value of Long Noncoding RNA NORAD in Various cancers: a meta-analysis
Authors: Yang Qin , Zhang Zheng , Gong Yuan-Yuan , Li Zhi-Ran , Zhang Hua-Zhu , He Gong-Hao
Published: July 2020

Objective

Accumulating studies reported that noncoding RNA activated by DNA damage (NORAD) was correlated with poor survival outcomes for patients in different cancers. However, the effects of NORAD on cancer prognosis were controversial. Therefore, a meta-analysis was carried out to elucidate this issue.

Methods

Literature search was performed to collect eligible relevant publications until June 2020. The pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association of NORAD with prognosis and clinical features in diverse cancers. In addition, bioinformatics analysis was also utilized to validate the results of the meta-analysis.

Results

Fourteen relevant articles involving 867 patients were enrolled in the present study. The pooled results showed that elevated expression of NORAD was a risk factor for overall survival (HR = 1.46, 95% CI: 1.06-2.01, P = 0.020), disease-free survival (HR = 1.74, 95% CI: 1.18-2.57, P = 0.005) and recurrence-free survival. Besides, overexpression of NORAD significantly correlated with lymph node metastasis and T stage. Additionally, bioinformatics analysis further strengthened and complemented the results of the present study.

Conclusion

Our results showed that NORAD was a risk factor for survival outcomes and clinicopathological parameters in cancer patients. These findings indicated that NORAD may be a promising candidate for prognosis prediction and potential therapeutic target in diverse cancers.
Estimating the time-varying reproduction number of COVID-19 with a state-space method
Authors: Koyama Shinsuke , Horie Taiki , Shinomoto Shigeru
Published: July 2020

After slowing down the spread of the novel coronavirus COVID-19, many countries have started to relax their confinement measures in the face of critical damage to socioeconomic structures. At this stage, it is desirable to monitor the degree to which political measures or social affairs have exerted influence on the spread of disease. Though it is difficult to trace back individual transmission of infections whose incubation periods are long and highly variable, estimating the average spreading rate is possible if a proper mathematical model can be devised to analyze daily event-occurrences. To render an accurate assessment, we have devised a state-space method for fitting the Hawkes process to a given dataset of daily confirmed cases. The proposed method detects changes occurring in each country and assesses the impact of social events in terms of the temporally varying reproduction number, which corresponds to the average number of cases directly caused by a single infected case. Moreover, the proposed method can be used to predict the possible consequences of alternative political measures. This information can serve as a reference for behavioral guidelines that should be adopted according to the varying risk of infection.
Somatic transposition in theDrosophilaintestine occurs in active chromatin and is associated with tumor suppressor gene inactivation
Authors: Siudeja Katarzyna , van den Beek Marius , Riddiford Nick , Boumard Benjamin , Wurmser Annabelle , Stefanutti Marine , Lameiras Sonia , Bardin Allison J.
Published: July 2020

Transposable elements (TEs) play a significant role in evolution by contributing to genetic variation through germline insertional activity. However, how TEs act in somatic cells and tissues is not well understood. Here, we address the prevalence of transposition in a somatic tissue, exploiting theDrosophilamidgut as a model system. Using whole-genome sequencing ofin vivoclonally expanded gut tissue, we map hundreds of high-confidence somatic TE integration sites genome-wide. We show that somatic retrotransposon insertions are associated with inactivation of the tumor suppressorNotch, likely contributing to neoplasia formation. Moreover, by applying Oxford Nanopore long-read sequencing technology, as well as by mapping germline TE activity, we provide evidence suggesting tissue-specific differences in retrotransposition. By comparing somatic TE insertional activity with transcriptomic and small RNA sequencing data, we demonstrate that transposon mobility cannot be simply predicted by whole tissue TE expression levels or by small RNA pathway activity. Finally, we reveal that somatic TE insertions in the adult fly intestine are found preferentially in genic regions and open, transcriptionally active chromatin. Together, our findings provide clear evidence of ongoing somatic transposition inDrosophilaand delineate previously unknown underlying features of somatic TE mobilityin vivo.
treeheatr: an R package for interpretable decision tree visualizations
Authors: Le Trang T. , Moore Jason H.
Published: July 2020

treeheatris an R package for creating interpretable decision tree visualizations with the data represented as a heatmap at the tree’s leaf nodes. The integrated presentation of the tree structure along with an overview of the data efficiently illustrates how the tree nodes split up the feature space and how well the tree model performs. This visualization can also be examined in depth to uncover the correlation structure in the data and importance of each feature in predicting the outcome. Implemented in an easily installed package with a detailed vignette,treeheatrcan be a useful teaching tool to enhance students’ understanding of a simple decision tree model before diving into more complex tree-based machine learning methods.

Availability

Thetreeheatrpackage is freely available under the permissive MIT license athttps://trang1618.github.io/treeheatrandhttps://cran.r-project.org/package=treeheatr. It comes with a detailed vignette that is automatically built with GitHub Actions continuous integration.

Contact

ttle@pennmedicine.upenn.edu
A coarse-grained methodology identifies intrinsic mechanisms that dissociate interacting protein pairs
Authors: Abdizadeh Haleh , Jalalypour Farzaneh , Atilgan Ali Rana , Atilgan Canan
Published: July 2020

We address the problem of triggering dissociation events between proteins that have formed a complex. We have collected a set of 25 non-redundant, functionally diverse protein complexes having high-resolution three-dimensional structures in both the unbound and bound forms. We unify elastic network models with perturbation response scanning (PRS) methodology as an efficient approach for predicting residues that have the propensity to trigger dissociation of an interacting protein pair, using the three-dimensional structures of the bound and unbound proteins as input. PRS reveals that while for a group of protein pairs, residues involved in the conformational shifts are confined to regions with large motions, there are others where they originate from parts of the protein unaffected structurally by binding. Strikingly, only a few of the complexes have interface residues responsible for dissociation. We find two main modes of response: In one mode, remote control of disassociation in which disruption of the electrostatic potential distribution along protein surfaces play the major role; in the alternative mode, mechanical control of dissociation by remote residues prevail. In the former, dissociation is triggered by changes in the local environment of the protein e.g. pH or ionic strength, while in the latter, specific perturbations arriving at the controlling residues, e.g. via binding to a third interacting partner is required for decomplexation. We resolve the observations by relying on an electromechanical coupling model which reduces to the usual elastic network result in the limit of the lack of coupling. We validate the approach by illustrating the biological significance of top residues selected by PRS on select cases where we show that the residues whose perturbation leads to the observed conformational changes correspond to either functionally important or highly conserved residues in the complex.
scMET: Bayesian modelling of DNA methylation heterogeneity at single-cell resolution
Authors: Kapourani Chantriolnt-Andreas , Argelaguet Ricard , Sanguinetti Guido , Vallejos Catalina A.
Published: July 2020

High throughput measurements of DNA methylomes at single-cell resolution are a promising resource to quantify the heterogeneity of DNA methylation and uncover its role in gene regulation. However, limitations of the technology result in sparse CpG coverage, effectively posing challenges to robustly quantify genuine DNA methylation heterogeneity. Here we tackle these issues by introducing scMET, a hierarchical Bayesian model which overcomes data sparsity by sharing information across cells and genomic features, resulting in a robust and biologically interpretable quantification of variability. scMET can be used to both identify highly variable features that drive epigenetic heterogeneity and perform differential methylation and differential variability analysis between pre-specified groups of cells. We demonstrate scMET’s effectiveness on some recent large scale single cell methylation datasets, showing that the scMET feature selection approach facilitates the characterisation of epigenetically distinct cell populations. Moreover, we illustrate how scMET variability estimates enable the formulation of novel biological hypotheses on the epigenetic regulation of gene expression in early development. An R package implementation of scMET is publicly available athttps://github.com/andreaskapou/scMET.
Intrinsic growth heterogeneity of mouse leukemia cells underlies differential susceptibility to a growth-inhibiting anticancer drug
Authors: Seita Akihisa , Nakaoka Hidenori , Okura Reiko , Wakamoto Yuichi
Published: July 2020

Cancer cell populations consist of phenotypically heterogeneous cells. Growing evidence suggests that pre-existing phenotypic differences among cancer cells correlate with differential susceptibility to anticancer drugs and eventually lead to a relapse. Such phenotypic differences can arise not only externally driven by the environmental heterogeneity around individual cells but also internally by the intrinsic fluctuation of cells. However, the quantitative characteristics of intrinsic phenotypic heterogeneity emerging even under constant environments and their relevance to drug susceptibility remain elusive. Here we employed a microfluidic device, mammalian mother machine, for studying the intrinsic heterogeneity of growth dynamics of mouse lymphocytic leukemia cells (L1210) across tens of generations. The generation time of this cancer cell line had a distribution with a long tail and a heritability across generations. We determined that a minority of cell lineages exist in a slow-cycling state for multiple generations. These slow-cycling cell lineages had a higher chance of survival than the fast-cycling lineages under continuous exposure to the anticancer drug Mitomycin C. This result suggests that heritable heterogeneity in cancer cells’ growth in a population influences their susceptibility to anticancer drugs.
Temperature triggers provide quantitative predictions of multi-species fish spawning peaks
Authors: Choi Emma S. , Saberski Erik T. , Lorimer Tom , Smith Cameron , Kandage-don Unduwap , Burton Ronald S. , Sugihara George
Published: July 2020

We find a startling correlation (Pearson ρ > 0.97) between a single event in daily sea surface temperatures each spring, and peak fish egg abundance measurements the following summer, in 7 years of approximately weekly fish egg abundance data collected at Scripps Pier in La Jolla California. Even more surprising is that this event-based result persists despite the large and variable number of fish species involved (up to 46), and the large and variable time interval between trigger and response (up to ~3 months). To mitigate against potential over-fitting, we make a true out-of-sample prediction for the peak summer egg abundance that will be observed at Scripps Pier this year.
Comprehensive in-vivo secondary structure of the SARS-CoV-2 genome reveals novel regulatory motifs and mechanisms
Authors: Huston Nicholas C. , Wan Han , Araujo Tavares Rafael de Cesaris , Wilen Craig , Pyle Anna Marie
Published: July 2020

SARS-CoV-2 is the positive-sense RNA virus that causes COVID-19, a disease that has triggered a major human health and economic crisis. The genome of SARS-CoV-2 is unique among viral RNAs in its vast potential to form stable RNA structures and yet, as much as 97% of its 30 kilobases have not been structurally explored in the context of a viral infection. Our limited knowledge of SARS-CoV-2 genomic architecture is a fundamental limitation to both our mechanistic understanding of coronavirus life cycle and the development of COVID-19 RNA-based therapeutics. Here, we apply a novel long amplicon strategy to determine for the first time the secondary structure of the SARS-CoV-2 RNA genome probed in infected cells. In addition to the conserved structural motifs at the viral termini, we report new structural features like a conformationally flexible programmed ribosomal frameshifting pseudoknot, and a host of novel RNA structures, each of which highlights the importance of studying viral structures in their native genomic context. Our in-depth structural analysis reveals extensive networks of well-folded RNA structures throughout Orf1ab and reveals new aspects of SARS-CoV-2 genome architecture that distinguish it from other single-stranded, positive-sense RNA viruses. Evolutionary analysis of RNA structures in SARS-CoV-2 shows that several features of its genomic structure are conserved across beta coronaviruses and we pinpoint individual regions of well-folded RNA structure that merit downstream functional analysis. The native, complete secondary structure of SAR-CoV-2 presented here is a roadmap that will facilitate focused studies on mechanisms of replication, translation and packaging, and guide the identification of new RNA drug targets against COVID-19.
Quantum aspects of evolution: a contribution toward evolutionary explorations of genotype networks via quantum walks
Authors: Santiago-Alarcon Diego , Tapia-McClung Horacio , Lerma-Hernández Sergio , Venegas-Andraca Salvador E.
Published: July 2020

Quantum biology seeks to explain biological phenomena via quantum mechanisms, such as enzyme reaction rates via tunneling and photosynthesis energy efficiency via coherent superposition of states. However, less effort has been devoted to study the role of quantum mechanisms in biological evolution. In this paper, we used transcription factor networks with two and four different phenotypes, and used classical random walks (CRW) and quantum walks (QW) to compare network search behavior and efficiency at finding novel phenotypes between CRW and QW. In the network with two phenotypes, at temporal scales comparable to decoherence time TD, QW are as efficient as CRW at finding new phenotypes. In the case of the network with four phenotypes, the QW had a higher probability of mutating to a novel phenotype than the CRW, regardless of the number of mutational steps (i.e., 1, 2 or 3) away from the new phenotype. Before quantum decoherence, the QW probabilities become higher turning the QW effectively more efficient than CRW at finding novel phenotypes under different starting conditions. Thus, our results warrant further exploration of the QW under more realistic network scenarios (i.e., larger genotype networks) in both closed and open systems (e.g., by considering Lindblad terms).
Early Repolarization Pattern and Suicidal Risks: A Single Center Case-Control Study
Authors: Kameyama Hiroshi , Sugimoto Kenichi , Itoh Kyoko , Nukariya Kazutaka , Kato Tomohiro , Shigeta Masahiro
Published: July 2020

Background

Early repolarization pattern was reported to be associated with mental illness. However, its role in patients with the suicidal risks remains unclear.

Objective

The aim of this study is to examine the frequency of Early repolarization pattern in patients with the suicidal risks compared with the age matched medical checkups.

Method

A retrospective analysis of 27 patients with a history of suicide risks, including suicide attempt and nonsuicidal self-injury, and a family history of suicide. The presence of early repolarization pattern was compared in patients with suicidal risks and controls. Social and psychological factors were also compared among the patients with suicidal risks with or without Early repolarization pattern.

Result

Comparing the controls, Early repolarization pattern was significantly observed in the patients (14 patients: 52%, 7 controls: 9%, P<0.001). After logistic regression including the other clinical findings among the patients and controls, the presence of Early repolarization pattern was associated with the patients with the suicidal risks (p < 0.001). In the patients with suicide, there were no difference between the clinical factors compared with or without Early repolarization pattern.

Conclusion

There could be association between Early repolarization pattern and the patients with the suicidal risks. Further studies are needed to confirm the association between suicidal risks and Early repolarization pattern.
ICU admissions and in-hospital deaths linked to covid-19 in the Paris region are correlated with previously observed ambient temperature
Authors: Mejdoubi Mehdi , Kyndt Xavier , Djennaoui Mehdi
Published: July 2020

OBJECTIVE

To study the effect of weather on severity indicators of coronavirus disease 2019 (covid-19).

DESIGN

Ecological study.

SETTING

Paris region.

POPULATION

Severely ill patients with covid-19.

MAIN OUTCOME MEASURES

Daily covid-19-related intensive care unit (ICU) admission and in-hospital deaths in the Paris region, and the daily weather characteristics of Paris midtown.

RESULTS

Daily ICU admissions and in-hospital deaths were strongly and negatively correlated to ambient temperatures, with a time lag. The highest Pearson correlation coefficients and statistically significant P values were found 8 days before occurrence of ICU admissions and 15 days before deaths.

CONCLUSIONS

The study findings show a strong effect of previously observed ambient temperature that has an effect on severity indicators of covid-19.

Strengths and limitations of this study

We assessed the link between weather characteristics with a time lag and covid-19-related hospital severity indicators.

This is the first study, with reliable data, to find a strong negative correlation between previously observed ambient temperature with covid-19-related iCU admissions and in-hospital deaths.

It is compatible with the natural history (including hospitalisation) of covid-19 outbreak in a highly developed country.

We also report the duration after which iCU admissions and in-Hospital deaths occurs following temperature variation (respectively median of 8 and 15 days).

Our analyses are mainly valid for temperate climate countries.
Eurofins Covid-19 Sentinel™ Wastewater Test Provide Early Warning of a potential COVID-19 outbreak
Authors: Jørgensen Alissa Carina Udi , Gamst Jesper , Hansen Line Visby , Knudsen Ida Ingeborg Høgh , Jensen Søren Krohn Skovgaard
Published: July 2020

The Eurofins Covid-19 Sentinel™ program was developed to monitor the evolution of the pandemic and for early detection of outbreaks. The study objective was to develop a wastewater testing method to analyze SARS-CoV-2 as an indicator of community infection rate as of resurgence of COVID-19 in well-defined sites such as production facilities, hospitals or nursing homes. Eurofins performed >700 tests on 78 unique samples from 18 sites in Denmark, France and Belgium. Ten variant test protocols were trialed. Protocol variations trialed included centrifugation, precipitation of the SARS-CoV-2 RNA, agitation prior to precipitation, cooling, and pasteurization of the samples. A method was succesfully developed and reliability was supported by stability, reproducibility, and dilution & linearity studies. Results obtained showed a direct link to number of RNA copies in the sample using a calibration curve with synthetic SARS-CoV-2. Analysis was performed on both the liquid phase and solid phase of wastewater samples, with virus RNA detected in both phases but more frequently in the liquid phase. The virus was present in a sample from a Danish community wastewater treatment plant collected on February 24, 3 days before the first COVID-19 case was officially reported in the country. The greatest concentration of virus detected corresponded to when the COVID-19 crisis was at its peak in Denmark. Based on studies carried out in a Danish hospital, the wastewater testing method is expected to be able to detect a community COVID-19 prevalence rate as low as a 0,02%-0,1% (i.e. between 2 virus shedders per 10000 persons and 1 virus shedder per 1000). The wastewater testing method was used to monitor a Danish Community after a COVID-19 outbreak and it was shown that the method can be used as a semi-quantitative method to monitor the development of an outbreak.
Genomic Evidences Support an Independent History of Grapevine Domestication in the Levant
Authors: Sivan Aviad , Rahimi Oshrit , Salmon-Divon Mail , Weiss Ehud , Drori Elyashiv , Hübner Sariel
Published: July 2020

The ancient grapevines of the Levant have inspired beliefs and rituals in human societies which are still practiced today in religious and traditional ceremonies around the world. Despite their importance, the original Levantine wine-grapes varieties were lost due to cultural turnovers commencing in the 7thcentury CE, which lead to the collapse of a flourishing winemaking industry in this region. Recently, a comprehensive survey of feral grapevines was conducted in Israel in an attempt to identify local varieties, yet the origin of these domesticated accessions is unclear. Here we study the origin of Levantine grapevines using whole-genome sequence data generated for a diversity panel of wild and cultivated accessions. Comparison between Levantine and Eurasian grapevines indicated that the Levantine varieties represent a distinct lineage from the Eurasian varieties. Demographic models further supported this observation designating that domestication in the Caucasus region predated the emergence of the Levantine samples in circa 5000 years and that authentic descendants of ancient varieties are represented among the Levantine samples. We further explore the pedigree relationship among cultivated grapevines, identify footprints of selective sweeps, and estimate the extent of genetic load in each group. We conclude that the Levantine varieties are distinct from the Eurasian varieties and that resistance to disease and abiotic stress are key traits in the development of both Eurasian and Levantine varieties.
Task-induced modulations of neuronal activity along the auditory pathway
Authors: De Franceschi Gioia , Barkat Tania Rinaldi
Published: July 2020

Sensory processing varies depending on behavioral context. Here, we asked how task-engagement modulates neurons in the auditory system. We trained mice in a simple tone-detection task, and compared their neuronal activity during passive hearing and active listening. Electrophysiological extracellular recordings in the inferior colliculus, medial geniculate body, primary auditory cortex and anterior auditory field revealed widespread modulations across all regions and cortical layers, and in both putative regular and fast-spiking cortical neurons. Clustering analysis unveiled ten distinct modulation patterns that could either enhance or suppress neuronal activity. Task-engagement changed the tone-onset response in most neurons. Such modulations first emerged in subcortical areas, ruling out cortical feedback from primary auditory areas as the only mechanism underlying subcortical modulations. Half the neurons additionally displayed late modulations associated with licking, arousal or reward. Our results reveal the presence of functionally distinct subclasses of neurons, differentially sensitive to specific task-related variables but anatomically distributed along the auditory pathway.
Pairwise Interactions in Adjuvant Combinations Dictate Immune Responses and Inform Cancer Immunotherapy Design
Authors: Pandey Surya , Gruenbaum Adam , Kanashova Tamara , Mertins Philipp , Cluzel Philippe , Chevrier Nicolas
Published: July 2020

The immune system makes decisions in response to complex combinations of microbial inputs. We do not understand the combinatorial logic that governs how the interplay between higher-order combinations of microbial or adjuvant signals shape immune responses, which hampers the rational design of vaccines and immunotherapies. Here, usingin vitrococulture experiments and statistical analyses, we discover a general property for the combinatorial sensing of microbial signals, whereby the effects of triplet combinations of adjuvants on immune responses can be explained by the effects of single and pairwise stimulations. Mechanistically, we find that adjuvant singles and pairs dictate the information signaled by triplets in mouse and human DCs at the levels of transcription, chromatin and protein secretion. Furthermore, we exploit this simplifying property to develop and characterize cell-based immunotherapies using adjuvant combinations with anti-tumor properties in mouse models. We conclude that the processing of complex mixtures of microbial or adjuvant inputs by immune cells is governed by pairwise effects, which will inform the rationale combination of immunomodulatory agents such as adjuvants to manipulate immunity.
Deconvolution of ears’ activity (DEA): A new experimental paradigm to investigate central auditory processing
Authors: Bardy Fabrice
Published: July 2020

A novel experimental paradigm, “deconvolution of ears’ activity” (DEA), is presented which allows to disentangle overlapping neural activity from both auditory cortices when two auditory stimuli are presented closely together in time in each ear.

Pairs of multi-tone complexes were presented either binaurally, or sequentially by alternating presentation order in each ear (i.e., first tone complex of the pair presented to one ear and second tone complex to the other ear), using stimulus onset asynchronies (SOAs) shorter than the neural response length. This timing strategy creates overlapping responses, which can be mathematically separated using least-squares deconvolution.

The DEA paradigm allowed the evaluation of the neural representation in the auditory cortex of responses to stimuli presented at syllabic rates (i.e., SOAs between 120 and 260 ms). Analysis of the neuromagnetic responses in each cortex offered a sensitive technique to study hemispheric lateralization, ear representation (right versus left), pathway advantage (contra- versus ipsi-lateral) and cortical binaural interaction.

To provide a proof-of-concept of the DEA paradigm, data was recorded from three normal-hearing adults. Results showed good test-retest reliability, and indicated that the difference score between hemispheres can potentially be used to assess central auditory processing. This suggests that the method could be a potentially valuable tool for generating an objective “auditory profile” by assessing individual fine-grained auditory processing using a non-invasive recording method.
Wide spectrum of neuronal and network phenotypes in human stem cell-derived excitatory neurons with Rett syndrome-associatedMECP2mutations
Authors: Mok Rebecca SF , Zhang Wenbo , Sheikh Taimoor I , Pradeepan Kartik , Fernandes Isabella R , DeJong Leah C , Benigno Gabriel , Hildebrandt Matthew R , Mufteev Marat , Rodrigues Deivid C , Wei Wei , Piekna Alina , Liu Jiajie , Muotri Alysson R , Vincent John B , Muller Lyle , Martinez-Trujillo Julio , Salter Michael W , Ellis James
Published: July 2020

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by heterozygous loss-of-function mutations in the X-linked geneMECP2that is a global transcriptional regulator. Mutations in the methyl-CpG binding domain (MBD) of MECP2 disrupt its interaction with methylated DNA. Here, we investigate the effect ofMECP2L124W missense mutation in the MBD of an atypical RTT patient in comparison to severeMECP2null mutations. L124W protein had a limited ability to disrupt heterochromatic chromocenters due to decreased binding dynamics. We isolated two pairs of isogenic WT and L124W induced pluripotent stem cells. L124W induced excitatory neurons expressed stable protein, exhibited increased input resistance and decreased voltage-gated Na+and K+currents, and their neuronal dysmorphology was limited to decreased dendritic complexity. Three isogenic pairs ofMECP2null neurons had the expected more extreme morphological and electrophysiological phenotypes. We examined development and maturation of L124W andMECP2null excitatory neural network activity using micro-electrode arrays. Relative to isogenic controls, L124W neurons had an increase in synchronous network burst frequency, in contrast toMECP2null neurons that suffered a significant decrease in synchronous network burst frequency and a transient extension of network burst duration. We capture these findings in a computational neural network model that shows the observed changes in network dynamics are best explained by changes in intrinsic adaptation currents in individual neurons. Our multilevel results demonstrate that RTT excitatory neurons show a wide spectrum of morphological, electrophysiological and circuitry phenotypes that are dependent on the severity of theMECP2mutation.
Evolutionary conserved multifunctional nitric oxide synthesis proteins responding to bacterial MAMPs are located at the endoplasmic reticulum
Authors: Zheng Wenhui , Li Hongchen , Fang Wenqin , Ipcho Simon , Hennessy Rosanna C. , Hansen Bjoern Oest , Lu Guodong , Wang Zonghua , Newman Mari-Anne , Olsson Stefan
Published: July 2020

Most Eukaryotic organisms produce nitric oxide (NO); however, the mechanisms underpinning NO’s biosynthesis are only known in animals. In animals, there seems to be a non-described additional system for producing NO in many cell types, including blood vessels where NO is essential for blood pressure control. NO is known to be a signalling molecule of the innate immunity system in plants and fungi although no NO generation has yet been described. In the plant pathogenic fungusFusarium graminearum,we demonstrate an extra NO-producing system in fungi that seems also present in mammals and plants and, thus, likely the evolutionary original. The discovered NO-producing enzymes are already well-known sterol-producing enzymes with more than one function. Both these enzymes are targets for statins and the major fungicides; thus, the NO production of the new system has consequences for agriculture (pathogen resistance and control) and medicine (blood pressure control, immunity and sepsis).
Ventricular, atrial and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak
Authors: Ivanovitch Kenzo , Soro-Barrio Pablo , Chakravarty Probir , Jones Rebecca A , Bell Donald M , Gharavy S. Neda Mousavy , Stamataki Despina , Delile Julien , Smith James C , Briscoe James
Published: July 2020

The heart develops from two sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single cell transcriptomic assay in combination with genetic lineage tracing, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Moreover, a subset of atrial progenitors are gradually incorporated in posterior locations of the FHF. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract cells originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are pre-patterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function and disease.
Combination of loop-mediated isothermal amplification and AuNP-oligoprobe colourimetric assay for pork authentication in processed-meat products
Authors: Thangsunan Pattanapong , Temisak Sasithon , Morris Phattaraporn , Rios-Solis Leonardo , Suree Nuttee
Published: July 2020

Pork adulteration is a major concern for Muslims and Jews whose diets are restricted by religious beliefs, as well as those who are allergic to pork meat and its derivatives. Accurate pork authentication is of great importance to assist this demographic group of people in making decision on their product purchase. The aim of this study was to develop a new analytical method for pork authentication in processed-meat products based on a combination of loop-mediated isothermal amplification (LAMP) and AuNP-nanoprobe colourimetric assay. The LAMP conditions were first optimised to obtain the highest yield of amplified DNA products within the shortest time. Oligoprobe-functionalised AuNPs were then hybridised with LAMP-DNA amplicons, and subsequently challenged with MgSO4at a high concentration to induce AuNP aggregation. In the presence of pork DNA, the colloidal AuNPs-probe remained unchanged in its red colour, which indicates the dispersion of AuNPs. In contrast, in the absence of pork DNA, the colour was changed to colourless as a result from the aggregation of AuNPs. The LAMP-AuNP-nanoprobe assay offers a high sensitivity with a limit of detection as low as 100 pg of pork DNA. The assay is highly specific to pork content without cross-reactivity with the other meat species tested. The assay developed herein can become a simple, inexpensive, precise, and rapid analytical tool for small laboratories or the general public interested in halal food authentication.