bluuebunny/crossref_metadata_2025 huggingface dataset:
Sports Related Concussion Impacts Speech Rate and Muscle Function
Authors: Banks Russell E. , Beal Deryk S. , Hunter Eric J.
Published: June 2020

Objective

To examine speech rate and muscle function in athletes with and without sports related concussion (SRC).

Methods

We recruited 30 athletes aged 19-22 years-old who had sustained a SRC within the past 2 years and 30 pair-wise matched controls with no history of SRC from the student community at Michigan State University. Speech rate and muscle function were evaluated during diadochokinetic (DDK) tasks. Speech rate was measured via average time per syllable, average unvoiced time per syllable, and expert perceptual judgement. Speech muscle function was measured via surface electromyography over the obicularis oris, masseter, and segmental triangle. Group differences were assessed using MANOVA, bootstrapping and predictive ROC analyses.

Results

Athletes with SRC had slower speech rates during DDK tasks than controls as evidenced by longer average time per syllable (F(1, 52) = 11.072, p =.002, [95% CI : .01 to .04]), longer average unvoiced time per syllable (F(1, 52) = 16.031, p < .000, [95% CI : .01 to .029] and expert judgement of slowed rate (F(1, 22) = 9.782, p = .005, [95% CI : .163 to .807]). Rate measures were predictive of concussion history. Further, athletes with SRC required more speech muscle activation than controls to complete the DDK tasks (F(1, 3) = 17.12, p =.000, [95% CI: .003 to .006]).

Conclusion

We found clear evidence of slowed speech and increased muscle activation during the completion of DDK tasks in athletes with SRC histories relative to controls. Speech rate and muscle assessment should be incorporated into clinical evaluation of concussion.
An Extended Laboratory Validation Study and Comparative Performance Evaluation of the Abbott ID NOW™ COVID-19 Assay in a Coastal California Tertiary Care Medical Center
Authors: Comer Stewart , Fisk David
Published: June 2020

The Abbott ID NOW™ COVID-19 assay is a rapid molecular diagnostic test particularly designed for on-site, rapid turnaround point of care (POC) testing. The utilization of rapid diagnostic tests is integral to optimizing workflow within the hospital and/or procedural-based clinics. The capability to provide both rapid disposition and correct patient classification during this COVID-19 pandemic is critically important with broad infection control implications for both patients and healthcare staff. A tightly controlled, extended laboratory validation was performed at our medical center to determine the negative test agreement of the Abbott ID NOW™ compared with the BD MAX™ analyzer, a laboratory-based, two target, molecular analyzer with a sensitive cycle threshold (Ct) positive cutoff value of ≤ 42. There was strict adoption of the procedures listed in the Abbott ID NOW™ Instruction for Use (IFU)1 insert delineating preferred practices for “optimal test performance.” Under these conditions, our institution demonstrated a significant negative percent agreement with 116 out of 117 patients correlating, which equates to a 99.1% concordance similar to a recently reported correlation study2.
Impact of weather indicators on the COVID-19 outbreak: A multi-state study in India
Authors: Singh Kuldeep , Agarwal Aryan
Published: June 2020

The present study examines the impact of weather indicators on the COVID-19 outbreak in the majorly affected states of India. In this study, we hypothesize that the weather indicators could significantly influence the impact of the corona virus. The Kendall and Spearman rank correlation tests were chosen to conduct the statistical analysis. In this regard, we compiled a daily dataset including confirmed case counts, Recovered case counts, Deceased cases, Average Temperature, Maximum Relative Humidity, Maximum Wind Speed for six most affected states of India during the period of March 25, 2020 to April 24, 2020. We investigated that the average Humidity and Average Temperature seven days ago play a significant role in the recovery of coronavirus cases. The rise in average temperature will improve the recovery rate in the days to come. The cities with very high humidity levels or dry weather conditions have high probabilities of recovery from COVID-19. The findings of this research will help the policymakers to identify risky geographic areas and enforce timely preventive measures.
Risk factors for critical-ill events of patients with COVID-19 in Wuhan, China: a retrospective cohort study
Authors: Yang Sen , Ma Le , Wang Yu-Lan , Wang Qian , Tong Qiang , Chen Miao , Zhang Hua , Yu De-Hua , Dai Sheng-Ming , Cui Ran
Published: June 2020

Background

Little is known about the risk factors for critical-ill events (intensive care, invasive ventilation, or death) in patients with COVID-19.

Methods

Patients with laboratory-confirmed COVID-19 admitted to the Wuhan Leishenshan Hospital from February 13 to March 14 was retrospectively analyzed. Demographic data, symptoms, laboratory values at baseline, comorbidities, treatments and clinical outcomes were extracted from electronic medical records and compared between patients with and without critical-ill events. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression models were developed to explore the risk factors for critical-ill events. A risk nomogram was established to predict the probability for the critical-ill events. Survival analysis of patients with critical-ill events was performed by the Kaplan-Meier method.

Results

463 COVID-19 patients were included in this study, of whom 397 were non-critically ill and 66 were critically ill (all from the intensive care unit). The LASSO regression identified four variables (hypersensitive cardiac troponin I, blood urea nitrogen, haemoglobin, and interleukin-6) contributing to the critical-ill events. Multivariable regression showed increasing odds of in-hospital critical-ill events associated with hypersensitive cTnI greater than 0.04 ng/mL (OR 20.98,95% CI 3.51-125.31), blood urea nitrogen greater than 7.6 mmol/L (OR 5.22, 95% CI 1.52-17.81, decreased haemoglobin (OR 1.06, 95% CI 1.04-1.10), and higher interleukin-6 (OR 1.05, 95% CI 1.02-1.08) on admission.

Conclusions

Hypersensitive cTnI greater than 0.04 ng/mL, blood urea nitrogen greater than 7.6 mmol/L, decreased haemoglobin, and high IL-6 were risk factors of critical-ill events in patients with COVID-19.

Main point

Hypersensitive cTnI greater than 0.04 ng/mL, BUN greater than 7.6 mmol/L, decreased haemoglobin, and high IL-6 were risk factors of critical-ill events (intensive care, invasive ventilation, or death) in patients with COVID-19.
Innate immune signaling in the olfactory epithelium reduces odorant receptor levels: modeling transient smell loss in COVID-19 patients
Authors: Rodriguez Steven , Cao Luxiang , Rickenbacher Gregory T. , Benz Eric G. , Magdamo Colin , Gomez Liliana Ramirez , Holbrook Eric H. , Albers Alefiya D. , Gallagher Rose , Westover M. Brandon , Evans Kyle E. , Tatar Daniel J. , Mukerji Shibani , Zafonte Ross , Boyer Edward W , Yu C. Ron , Albers Mark W.
Published: June 2020

Post-infectious anosmias typically follow death of olfactory sensory neurons (OSNs) with a months-long recovery phase associated with parosmias. While profound anosmia is the leading symptom associated with COVID-19 infection, many patients regain olfactory function within days to weeks without distortions. Here, we demonstrate that sterile induction of anti-viral type I interferon signaling in the mouse olfactory epithelium is associated with diminished odor discrimination and reduced odor-evoked local field potentials. RNA levels of all class I, class II, and TAAR odorant receptors are markedly reduced in OSNs in a non-cell autonomous manner. We find that people infected with COVID-19 rate odors with lower intensities and have odor discrimination deficits relative to people that tested negative for COVID-19. Taken together, we propose that inflammatory-mediated loss of odorant receptor expression with preserved circuit integrity accounts for the profound anosmia and rapid recovery of olfactory function without parosmias caused by COVID-19.
Long time frames to detect the impact of changing COVID-19 control measures
Authors: Stockdale Jessica E , Doig Renny , Min Joosung , Mulberry Nicola , Wang Liangliang , Elliott Lloyd T , Colijn Caroline
Published: June 2020

Background

Many countries have implemented population-wide interventions such as physical distancing measures, in efforts to control COVID-19. The extent and success of such measures has varied. Many jurisdictions with declines in reported COVID-19 cases are moving to relax measures, while others are continuing to intensify efforts to reduce transmission.

Aim

We aim to determine the time frame between a change in COVID-19 measures at the population level and the observable impact of such a change on cases.

Methods

We examine how long it takes for there to be a substantial difference between the cases that occur following a change in control measures and those that would have occurred at baseline. We then examine how long it takes to detect a difference, given delays and noise in reported cases. We use changes in population-level (e.g., distancing) control measures informed by data and estimates from British Columbia, Canada.

Results

We find that the time frames are long: it takes three weeks or more before we might expect a substantial difference in cases given a change in population-level COVID-19 control, and it takes slightly longer to detect the impacts of the change. The time frames are shorter (11-15 days) for dramatic changes in control, and they are impacted by noise and delays in the testing and reporting process, with delays reaching up to 25-40 days.

Conclusion

The time until a change in broad control measures has an observed impact is longer than is typically understood, and is longer than the mean incubation period (time between exposure than onset) and the often used 14 day time period. Policy makers and public health planners should consider this when assessing the impact of policy change, and efforts should be made to develop rapid, consistent real-time COVID-19 surveillance.
First SARS-CoV-2 detection in river water: implications in low sanitation countries
Authors: Guerrero-Latorre Laura , Ballesteros Isabel , Villacrés Irina M. , Granda M. Genoveva , Freire Byron P. , Ríos-Touma Blanca
Published: June 2020

Since the beginning of SARS-CoV-2 pandemic studies on viral shedding have reported that this virus is excreted in feces in most patients. High viral loads are found at the sewage pipeline or at the entrance of wastewater treatment plants from cities where the number of COVID-19 cases are significant. In Quito (Ecuador) as in many other cities worldwide, wastewater is directly discharged into natural waters. The aim of this study was to evaluate SARS-CoV-2 presence in urban streams from a low sanitation context. Three river locations along the urban rivers of Quito were sampled on the 5th of June during a peak of COVID-19 cases. River samples were evaluated for water quality parameters and afterwards, concentrated for viral analysis using skimmed milk flocculation method. The viral concentrates were quantified for SARS-CoV-2 (N1 and N2 genes) and Human Adenovirus as a human viral indicator. The results showed that SARS-CoV-2 was detected for both target genes in all samples analyzed in a range of 2,91E+05 to 3,19E+06 GC/L for N1 and from 2,07E+05 to 2,22E+06 GC/L for N2. The high values detected in natural waters from a low sanitation region have several implications in health and ecology that should be further assessed.
stLFRsv: a germline SV analysis pipeline using co-barcoded reads
Authors: Guo Junfu , Shi Chang , Chen Xi , Wang Ou , Liu Ping , Yang Huanming , Xu Xun , Zhang Wenwei , Zhu Hongmei
Published: June 2020

Co-barcoded reads originated from long DNA fragment (mean length larger than 50Kbp) with barcodes, maintain both single base level accuracy and long range genomic information. We propose a pipeline stLFRsv to detect structure variation using co-barcoded reads. stLFRsv identifies abnormally large gaps between co-barcoded reads to detect potential breakpoints and reconstruct complex structure variations. The barcodes enabled co-barcoded reads phasing increases the signal to noise ratio and barcode sharing profiles are used to filter out false positives. We integrate the short reads SV caller smoove for smaller variations with stLFRsv. The integrated pipeline was evaluated on the well characterized genome HG002/NA24385 and obtained precision and recall rate of 74.2% and 22.3% for deletion on the whole genome. stLFR found some large variations not included in the benchmark set and verified by means of long reads or assembly. Our work indicates that co-barcoded reads technology has the potential to improve genome completeness.
Modulation of Aplnr signaling is required during the development and maintenance of the hematopoietic system
Authors: Jackson Melany , Fidanza Antonella , Taylor A. Helen , Rybtsov Stanislav , Axton Richard , Kydonaki Maria , Meek Stephen , Burdon Tom , Medvinsky Alexander , Forrester Lesley M.
Published: June 2020

Apelin receptor (Aplnr/Agtrl1/Apj) marks a transient cell population during the differentiation of hematopoietic progenitor cells (HPCs) from pluripotent stem cells but the function of this signalling pathway during hematopoietic development both in vitro and in vitro is poorly understood. We generated an Aplnr-null mouse embryonic stem cell (mESC) line and demonstrated that they are significantly impaired in the production of HPCs indicating that the Aplnr pathway is required for their formation. Using Aplnr-tdTomato reporter mESCs we demonstrated that is expressed in a population of differentiating mesodermal cells committed to a hematopoietic and endothelial fate. Activation of this signaling pathway by the addition of the Apelin ligand to differentiating ESCs has no effect on the production of HPCs but the addition toex vivoAGM cultures impaired the generation of long term reconstituting hematopoietic stem cells and appeared to drive myeloid differentiation. Taken together, our data suggest that the Aplnr pathway is required for the generation of cells that give rise to HSCs during development but its subsequent down regulation is required for their maintenance.

HIGHLIGHTS

Hematopoietic differentiation is impaired in Aplnr-null ESCs

Aplnr-tdTomato reporter marks a subpopulation of ESC-derived mesoderm.

Aplnr signaling drives the maturation of lineage-committed myeloid progenitors

In AGM explant cultures HSC activity is reduced in the presence of Aplnr ligands.
Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution
Authors: Overholt Kalon J. , Krog Jonathan R. , Bryson Bryan D.
Published: June 2020

As the global COVID-19 pandemic continues to escalate, no effective treatment has yet been developed for the severe respiratory complications of this disease. This may be due in large part to the unclear immunopathological basis for the development of immune dysregulation and acute respiratory distress syndrome (ARDS) in severe and critical patients. Specifically, it remains unknown whether the immunological features of the disease that have been identified so far are compartment-specific responses or general features of COVID-19. Additionally, readily detectable biological markers correlated with strata of disease severity that could be used to triage patients and inform treatment options have not yet been identified. Here, we leveraged publicly available single-cell RNA sequencing data to elucidate the common and compartment-specific immunological features of clinically severe COVID-19. We identified a number of transcriptional programs that are altered across the spectrum of disease severity, few of which are common between the lung and peripheral immune environments. In the lung, comparing severe and moderate patients revealed severity-specific responses of enhanced interferon, A20/IκB, IL-2, and IL-6 pathway signatures along with broad signaling activity ofIFNG, SPP1, CCL3, CCL8, andIL18across cell types. These signatures contrasted with features unique to ARDS observed in the blood compartment, which included depletion of interferon and A20/IκB signatures and a lack of IL-6 response. The cell surface markerS1PR1was strongly upregulated in patients diagnosed with ARDS compared to non-ARDS patients in γδ T cells of the blood compartment, and we nominate S1PR1 as a potential marker for immunophenotyping ARDS in COVID-19 patients using flow cytometry.

HIGHLIGHTS

COVID-19 disease severity is associated with a number of compositional shifts in the cellular makeup of the blood and lung environments.

Transcriptional data suggest differentially expressed cell surface proteins as markers for COVID-19 immunophenotyping from BALF and PBMC samples.

Severity-specific features COVID-19 manifest at the pathway level, suggesting distinct changes to epithelia and differences between local and systemic immune dynamics.

Immune-epithelial cellular communication analysis identifies ligands implicated in transcriptional regulation of proto-oncogenes in the lung epithelia of severe COVID-19 patients.

Network analysis suggests broadly-acting dysregulatory ligands in the pulmonary microenvironment as candidate therapeutic targets for the treatment of severe COVID-19.
Untangling stability and gain modulation in cortical circuits with multiple interneuron classes
Authors: Bos Hannah , Miehl Christoph , Oswald Anne-Marie , Doiron Brent
Published: June 2020

Synaptic inhibition is the mechanistic backbone of a suite of cortical functions, not the least of which are maintaining network stability and modulating neuronal gain. In cortical models with a single inhibitory neuron class, network stabilization and gain control work in opposition to one another -- meaning high gain coincides with low stability and vice versa. It is now clear that cortical inhibition is diverse, with molecularly distinguished cell classes having distinct positions within the cortical circuit. We analyze circuit models with pyramidal neurons (E) as well as parvalbumin (PV) and somatostatin (SOM) expressing interneurons. We show how in E -- PV -- SOM recurrently connected networks an SOM-mediated modulation can lead to simultaneous increases in neuronal gain and network stability. Our work exposes how the impact of a modulation mediated by SOM neurons depends critically on circuit connectivity and the network state.
Hypoxia induced sex-difference in zebrafish brain proteome profile reveals the crucial role of H3K9me3 in recovery from acute hypoxia
Authors: Das Tapatee , Kamle Avijeet , Kumar Arvind , Chakravarty Sumana
Published: June 2020

Understanding the molecular basis of sex differences in neural response to acute hypoxic insult has profound implications for the effective prevention and treatment of ischemic stroke. Global hypoxic-ischemic induced neural damage has been studied recently under the well-controlled, non-invasive, reproducible conditions using zebrafish model. Our earlier report on sex difference in global acute hypoxia induced neural damage and recovery in zebrafish prompted us for comprehensive study on the mechanisms underlying the recovery. An omics approach for studying quantitative changes in brain proteome upon hypoxia insult following recovery was undertaken using iTRAQ-based LC-MS/MS approach. The results shed light on altered expression of many regulatory proteins in zebrafish brain upon acute hypoxia following recovery. The sex difference in differentially expressed proteins along with the proteins expressed in uniform direction in both the sexes was studied. Core expression analysis by Ingenuity Pathway analysis (IPA) showed a distinct sex difference in the disease function heatmap. Most of the upstream regulators obtained through IPA were validated at the transcriptional level. Translational upregulation of H3K9me3 in male led us to elucidate the mechanism of recovery by confirming transcriptional targets through ChIP-qPCR. The upregulation of H3K9me3 level in male at 4 hr post-hypoxia appears to affect the early neurogenic markers nestin, klf4 and sox2, which might explain the late recovery in male, compared to female. Acute hypoxia-induced sex-specific comparison of brain proteome led us to reveal many differentially expressed proteins, which can be further studied for the development of novel targets for better therapeutic strategy.
Age-related dedifferentiation and hyperdifferentiation of perceptual and mnemonic representations
Authors: Deng Lifu , Davis Simon W. , Monge Zachary A. , Wing Erik A. , Geib Benjamin R. , Raghunandan Alex , Cabeza Roberto
Published: June 2020

Preliminary evidence indicates that occipito-temporal activation patterns for different visual stimuli are less distinct in older (OAs) than younger (YAs) adults, suggesting a dedifferentiation of visual representations with aging. Yet, it is unclear if this deficit (1) affects only sensory or also categorical aspects of representations during visual perception (perceptual representations), and (2) affects only perceptual or also mnemonic representations. To investigate these issues, we fMRI-scanned YAs and OAs viewing and then remembering visual scenes. First, using representational similarity analyses, we distinguished sensory vs. categorical features of perceptual representations. We found that, compared to YAs, sensory features in early visual cortex were less differentiated in OAs (i.e., age-related dedifferentiation), replicating previous research, whereas categorical features in anterior temporal lobe (ATL) were more differentiated in OAs. This is, to our knowledge, the first report of anage-related hyperdifferentiation. Second, we assessed the quality of mnemonic representations by measuring encoding-retrieval similarity (ERS) in activation patterns. We found that aging impaired mnemonic representations in early visual cortex and hippocampus but enhanced mnemonic representations in ATL. Thus, both perceptual and mnemonic representations in ATL were enhanced by aging. In sum, our findings suggest that aging impairs visual and mnemonic representations in posterior brain regions but enhances them in anterior regions.
An Atlas of Phosphorylation and Proteolytic Processing Events During Excitotoxic Neuronal Death Reveals New Therapeutic Opportunities
Authors: Ameen S. Sadia , Dufour Antoine , Hossain M. Iqbal , Hoque Ashfaqul , Sturgeon Sharelle , Nandurkar Harshal , Draxler Dominik , Medcalf Robert , Kamaruddin Mohd Aizuddin , Lucet Isabelle S. , Leeming Michael G. , Liu Dazhi , Dhillon Amardeep , Lim Jet Phey , Zhu Hong-Jian , Bokhari Laita , Roulston Carli , Kleifeld Oded , Giuseppe D. Ciccotosto , Williamson Nicholas A. , Ang Ching-Seng , Cheng Heung-Chin
Published: June 2020

Excitotoxicity, a neuronal death process in neurological disorders, is initiated by over-stimulation of neuronal ionotropic glutamate receptors. The over-stimulated receptors dysregulate proteases, protein kinases and phosphatases, which in turn modify target neuronal proteins to induce cell death. To decipher this cell death mechanism, we used quantitative proteomics, phosphoproteomics and N-terminomics to identify modified proteins in excitotoxic neurons. Data, available in ProteomeXchange (identifiers: PXD019527 and PXD019211), enabled us to identify over one thousand such proteins with calpains, cathepsins and over twenty protein kinases as their major modifiers. These protein modification events can potentially perturb signalling pathways governing cell survival, synaptogenesis, axonal guidance and mRNA processing. Importantly, blocking the modification of Src protein kinase, a signalling hub in excitotoxic neurons, protected against neuronal lossin vivoin a rat model of neurotoxicity. Besides offering new insights into excitotoxic neuronal death mechanism, our findings suggest potential neuroprotective therapeutic targets for treating neurological disorders.

Graphical abstract

Highlights

Multi-dimensional proteomic analysis identified proteins modified by proteolysis and altered phosphorylation in neurons undergoing excitotoxic cell death.

Calpains, cathepsins and over twenty protein kinases are major modifiers of these proteins.

These protein modification events are predicted to impact cell survival, axonal guidance, synaptogenesis and mRNA processing.

Blocking modification of an identified protein Src, which acts as a major signalling hub in neurons, was protective against excitotoxic injuryin vivo.

In Brief

Using multidimensional proteomic approaches, Ameen,et al. mapped the changes of proteome, phosphoproteome and N-terminome of cultured primary neurons during excitotoxicity, a crucial neuronal death process in neurological disorders. These proteomic changes document new excitotoxicity-associated molecular events, and offer insights into how these events are organized to induce neuronal death. Potential therapeutic relevance of these molecular events is illustrated by the demonstration thatin vivoblockade of one of these events could protect against excitotoxic neuronal loss.
Effect of Phosphorylation on the Collision Cross Sections of Peptide Ions in Ion Mobility Spectrometry
Authors: Ogata Kosuke , Chang Chih-Hsiang , Ishihama Yasushi
Published: June 2020

The insertion of ion mobility spectrometry (IMS) between LC and MS can improve peptide identification in both proteomics and phosphoproteomics by providing structural information that is complementary to LC and MS, because IMS separates ions on the basis of differences in their shapes and charge states. However, it is necessary to know how phosphate groups affect the peptide collision cross sections (CCS) in order to accurately predict phosphopeptide CCS values and to maximize the usefulness of IMS. In this work, we systematically characterized the CCS values of 4,433 pairs of mono-phosphopeptide and corresponding unphosphorylated peptide ions using trapped ion mobility spectrometry (TIMS). Nearly one-third of the mono-phosphopeptide ions evaluated here showed smaller CCS values than their unphosphorylated counterparts, even though phosphorylation results in a mass increase of 80 Da. Significant changes of CCS upon phosphorylation occurred mainly in structurally extended peptides with large numbers of basic groups, possibly reflecting intramolecular interactions between phosphate and basic groups.
Genome-wide mapping of therapeutically-relevant SARS-CoV-2 RNA structures
Authors: Manfredonia Ilaria , Nithin Chandran , Ponce-Salvatierra Almudena , Ghosh Pritha , Wirecki Tomasz K. , Marinus Tycho , Ogando Natacha S. , Snider Eric J. , van Hemert Martijn J. , Bujnicki Janusz M. , Incarnato Danny
Published: June 2020

SARS-CoV-2 is a betacoronavirus with a linear single-stranded, positive-sense RNA genome of ∼30 kb, whose outbreak caused the still ongoing COVID-19 pandemic. The ability of coronaviruses to rapidly evolve, adapt, and cross species barriers makes the development of effective and durable therapeutic strategies a challenging and urgent need. As for other RNA viruses, genomic RNA structures are expected to play crucial roles in several steps of the coronavirus replication cycle. Despite this, only a handful of functionally conserved structural elements within coronavirus RNA genomes have been identified to date.

Here, we performed RNA structure probing by SHAPE-MaP to obtain a single-base resolution secondary structure map of the full SARS-CoV-2 coronavirus genome. The SHAPE-MaP probing data recapitulate the previously described coronavirus RNA elements (5′ UTR, ribosomal frameshifting element, and 3′ UTR), and reveal new structures. Secondary structure-restrained 3D modeling of highly-structured regions across the SARS-CoV-2 genome allowed for the identification of several putative druggable pockets. Furthermore, ∼8% of the identified structure elements show significant covariation among SARS-CoV-2 and other coronaviruses, hinting at their functionally-conserved role. In addition, we identify a set of persistently single-stranded regions having high sequence conservation, suitable for the development of antisense oligonucleotide therapeutics.

Collectively, our work lays the foundation for the development of innovative RNA-targeted therapeutic strategies to fight SARS-related infections.
Oriented Soft DNA Curtains for Single Molecule Imaging
Authors: Kopūstas Aurimas , Ivanovaitė Šarūnė , Rakickas Tomas , Pocevičiūtė Ernesta , Paksaitė Justė , Karvelis Tautvydas , Zaremba Mindaugas , Manakova Elena , Tutkus Marijonas
Published: June 2020

Over the past twenty years, single-molecule methods have become extremely important for biophysical studies. These methods, in combination with new nanotechnological platforms, can significantly facilitate experimental design and enable faster data acquisition. A nanotechnological platform, which utilizes flow-stretch of immobilized DNA molecules, called DNA Curtains, is one of the best examples of such combinations. Here, we employed new strategies to fabricate a flow-stretch assay of stably immobilized and oriented DNA molecules using protein template-directed assembly. In our assay a protein template patterned on a glass coverslip served for directional assembly of biotinylated DNA molecules. In these arrays, DNA molecules were oriented to one another and maintained extended either by single- or both-ends immobilization to the protein templates. For oriented both-end DNA immobilization we employed heterologous DNA labeling and protein template coverage with the anti-digoxigenin antibody. In contrast to the single-end, both-ends immobilization does not require constant buffer flow for keeping DNAs in an extended configuration, allowing us to study protein-DNA interactions at more controllable reaction conditions. Additionally, we increased immobilization stability of the biotinylated DNA molecules using protein templates fabricated from traptavidin. Finally, we demonstrated that double-tethered Soft DNA Curtains can be used in nucleic acid-interacting protein (e.g. CRISPR-Cas9) binding assay that monitors binding location and position of individual fluorescently labeled proteins on DNA.
FEM-Based Mechanics Modeling of Bio-Inspired Compliant Mechanisms for Medical Applications
Authors: Sun Yilun , Zhang Dingzhi , Liu Yuqing , Lueth Tim C.
Published: June 2020

Compliant mechanisms are widely used in the design of medical robotics and devices because of their monolithic structure and high flexibility. Many compliant mechanisms derive their design ideas from nature, since the structure of biological organisms sometimes offers a better solution than the conventional mechanisms. However, the bio-inspired structures usually have very complex geometries which cannot be easily modeled and analyzed using traditional methods. In this paper, we present a novel finite element method (FEM) based modeling framework in Matlab to analyze the mechanics of different bio-inspired compliant mechanisms. Since the basic linear FEM formulation can only be employed to model small displacements of compliant mechanisms, a non-linear FEM formulation that integrates the modeling of large displacements, tendon-driven mechanisms and contact problems was implemented in the proposed framework to overcome the limitations. Simulations and experiments were also conducted to evaluate the performance of the modeling framework. Results have demonstrated the accuracy and plausibility of the proposed non-linear FEM formulation. Furthermore, the proposed framework can also be used to achieve structural optimization of bio-inspired compliant mechanisms.
Principal curve approaches for inferring 3D chromatin architecture
Authors: Tuzhilina Elena , Hastie Trevor J. , Segal Mark R.
Published: June 2020

Three dimensional (3D) genome spatial organization is critical for numerous cellular processes, including transcription, while certain conformation-driven structural alterations are frequently oncogenic. Genome architecture had been notoriously difficult to elucidate, but the advent of the suite of chromatin conformation capture assays, notably Hi-C, has transformed understanding of chromatin structure and provided downstream biological insights. Although many findings have flowed from direct analysis of the pairwise proximity data produced by these assays, there is added value in generating corresponding 3D reconstructions deriving from superposing genomic features on the reconstruction. Accordingly, many methods for inferring 3D architecture from proximity d hyperrefata have been advanced. However, none of these approaches exploit the fact that single chromosome solutions constitute a one dimensional (1D) curve in 3D. Rather, this aspect has either been addressed by imposition of constraints, which is both computationally burdensome and cell type specific, or ignored with contiguity imposed after the fact. Here we target finding a 1D curve by extending principal curve methodology to the metric scaling problem. We illustrate how this approach yields a sequence of candidate solutions, indexed by an underlying smoothness or degrees-of-freedom parameter, and propose methods for selection from this sequence. We apply the methodology to Hi-C data obtained on IMR90 cells and so are positioned to evaluate reconstruction accuracy by referencing orthogonal imaging data. The results indicate the utility and reproducibility of our principal curve approach in the face of underlying structural variation.
Chip-seq and gene expression data for the identification of functional sub-pathways: a proof of concept in lung cancer
Authors: Atsalaki Xanthoula , Koumakis Lefteris , Potamias George , Tsiknakis Manolis
Published: June 2020

High-throughput technologies, such as chromatin immunoprecipitation (ChIP) with massively parallel sequencing (ChIP-seq) have enabled cost and time efficient generation of immense amount of genome data. The advent of advanced sequencing techniques allowed biologists and bioinformaticians to investigate biological aspects of cell function and understand or reveal unexplored disease etiologies. Systems biology attempts to formulate the molecular mechanisms in mathematical models and one of the most important areas is the gene regulatory networks (GRNs), a collection of DNA segments that somehow interact with each other. GRNs incorporate valuable information about molecular targets that can be corellated to specific phenotype.

In our study we highlight the need to develop new explorative tools and approaches for the integration of different types of -omics data such as ChIP-seq and GRNs using pathway analysis methodologies. We present an integrative approach for ChIP-seq and gene expression data on GRNs. Using public microarray expression samples for lung cancer and healthy subjects along with the KEGG human gene regulatory networks, we identified ways to disrupt functional sub-pathways on lung cancer with the aid of CTCF ChIP-seq data, as a proof of concept.We expect that such a systems biology pipeline could assist researchers to identify corellations and causality of transcription factors over functional or disrupted biological sub-pathways.
Cannabidiol Interactions with Voltage-Gated Sodium Channels
Authors: Sait Lily Goodyer , Sula Altin , Hollingworth David , Whalley Benjamin J. , Rana Rohini R. , Wallace B.A.
Published: June 2020

Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for treatment of neurological diseases. Cannabidiol (CBD), the non-psychoactive compound isolated from cannabis plants, was recently approved for treatment of two types of epilepsy associated with sodium channel mutations. This study used high resolution X-ray crystallography to demonstrate the detailed nature of the interactions between CBD and the NavMs voltage-gated sodium channel, showing CBD binds at a novel site at the interface of the fenestrations and the central hydrophobic cavity of the channel. Binding at this site blocks the transmembrane-spanning sodium ion translocation pathway, providing a molecular mechanism for channel inhibition. Modelling studies illuminate why the closely-related psychoactive compound THC may not bind to these channels. Finally, comparisons are made with the TRPV2 channel, also recently proposed as a target site for CBD. In summary, this study provides novel insight into a possible mechanism for CBD with sodium channels.
Efficient population coding depends on stimulus convergence and source of noise
Authors: Röth Kai , Shao Shuai , Gjorgjieva Julijana
Published: June 2020

Sensory organs transmit information to downstream brain circuits using a neural code comprised of spikes from multiple neurons. According to the prominent efficient coding framework, the properties of sensory populations have evolved to encode maximum information about stimuli given biophysical constraints. How information coding depends on the way sensory signals from multiple channels converge downstream is still unknown, especially in the presence of noise which corrupts the signal at different points along the pathway. Here, we calculated the optimal information transfer of a population of nonlinear neurons under two scenarios. First, a lumped-coding channel where the information from different inputs converges to a single channel, thus reducing the number of neurons. Second, an independent-coding channel when different inputs contribute independent information without convergence. In each case, we investigated information loss when the sensory signal was corrupted by two sources of noise. We determined critical noise levels at which the optimal number of distinct thresholds of individual neurons in the population changes. Comparing our system to classical physical systems, these changes correspond to first- or second-order phase transitions for the lumped- or the independent-coding channel, respectively. We relate our theoretical predictions to coding in a population of auditory nerve fibers recorded experimentally, and find signatures of efficient coding. Our results yield important insights into the diverse coding strategies used by neural populations to optimally integrate sensory stimuli in the presence of distinct sources of noise.
Dietary and pharmacological induction of serine synthesis genes
Authors: Vazquez Alexei
Published: June 2020

There is an increasing interest in the pathway of L-serine synthesis and its. Although L-serine and downstream products can be obtained from the diet, serine deficiency has been documented in neurological disorders, macular degeneration and aging. This evidence calls for strategies to induce serine synthesis. Here I address this problem taking advantage of the wealth of data deposited in the gene expression omnibus database. I uncover that low protein and ketogenic diets increase the expression of serine synthesis genes in the liver and the brain relative to control diets. I discover oestrogen medications, the antifolate methotrexate and serine synthesis inhibitors as classes of compounds inducing the expression of serine synthesis genes in the liver. Future work is required to investigate the use of these interventions for the management of serine deficiency disorders.
Uncovering candidate genes involved in photosynthetic capacity using unexplored genetic variation in Spring Wheat
Authors: Joynson Ryan , Molero Gemma , Coombes Benedict , Gardiner Laura-Jayne , Rivera-Amado Carolina , Piñera-Chávez Francisco J , Evans John R , Furbank Robert T , Reynolds Matthew P , Hall Anthony
Published: June 2020

To feed an ever-increasing population we must leverage advances in genomics and phenotyping to harness the variation in wheat breeding populations for traits like photosynthetic capacity which remains unoptimized. Here we survey a diverse set of wheat germplasm containing elite, introgression and synthetic derivative lines uncovering previously uncharacterised variation. We demonstrate how strategic integration of exotic material alleviates the D genome genetic bottleneck in wheat, increasing SNP rate by 62% largely due to Ae. tauschii synthetic wheat donors. Across the panel, 67% of the Ae. tauschii donor genome is represented as introgressions in elite backgrounds. We show how observed genetic variation together with hyperspectral reflectance data can be used to identify candidate genes for traits relating to photosynthetic capacity using association analysis. This demonstrates the value of genomic methods in uncovering hidden variation in wheat and how that variation can assist breeding efforts and increase our understanding of complex traits.
Sex-specific variation in the use of vertical habitat by a resident Antarctic top predator
Authors: Photopoulou Theoni , Heerah Karine , Pohle Jennifer , Boehme Lars
Published: June 2020

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Patterns of habitat use are commonly studied in horizontal space, but this does not capture the four-dimensional nature of ocean habitats. There is strong seasonal variation in vertical ocean structuring, particularly at the poles, and deep-diving marine animals encounter a range of oceanographic conditions. We use hidden Markov models fitted to telemetry data from an air-breathing top predator to identify different diving behaviours and understand usage patterns of vertically distributed habitat. We show that preference for oceanographic conditions in the Weddell Sea, Antarctica, varies by sex in Weddell seals, and present the first evidence that both sexes use high-density, continental shelf water masses. Males spend more time in the colder, unique high-salinity shelf water masses found at depth, while females also venture off the continental shelf and visit warmer, shallower pelagic water masses. Both sexes exhibit a diurnal pattern in diving behaviour that persists from austral autumn into winter. These findings provide insights into the Weddell Sea shelf and open ocean ecosystem from a top predator perspective. The differences in habitat use in a resident, sexually monomorphic Antarctic top predator suggest a different set of needs and constraints operating at the intraspecific level, which are not driven by body size.
Genomic selection strategies for clonally propagated crops
Authors: Werner Christian R. , Gaynor R. Chris , Sargent Daniel J. , Lillo Alessandra , Gorjanc Gregor , Hickey John M.
Published: June 2020

For genomic selection in clonal breeding programs to be effective, crossing parents should be selected based on genomic predicted cross performance unless dominance is negligible. Genomic prediction of cross performance enables a balanced exploitation of the additive and dominance value simultaneously. Here, we compared different strategies for the implementation of genomic selection in clonal plant breeding programs. We used stochastic simulations to evaluate six combinations of three breeding programs and two parent selection methods. The three breeding programs included i) a breeding program that introduced genomic selection in the first clonal testing stage, and ii) two variations of a two-part breeding program with one and three crossing cycles per year, respectively. The two parent selection methods were i) selection of parents based on genomic estimated breeding values, and ii) selection of parents based on genomic predicted cross performance. Selection of parents based on genomic predicted cross performance produced faster genetic gain than selection of parents based on genomic estimated breeding values because it substantially reduced inbreeding when the dominance degree increased. The two-part breeding programs with one and three crossing cycles per year using genomic prediction of cross performance always produced the most genetic gain unless dominance was negligible. We conclude that i) in clonal breeding programs with genomic selection, parents should be selected based on genomic predicted cross performance, and ii) a two-part breeding program with parent selection based on genomic predicted cross performance to rapidly drive population improvement has great potential to improve breeding clonally propagated crops.
Mainly on the Plane: Deep Subsurface Bacterial Proteins Bind and Alter Clathrate Structure
Authors: Johnson Abigail M. , Huard Dustin J.E. , Kim Jongchan , Raut Priyam , Dai Sheng , Lieberman Raquel L. , Glass Jennifer B.
Published: June 2020

Gas clathrates are both a resource and a hindrance. They store massive quantities of natural gas but also can clog natural gas pipelines, with disastrous consequences. Eco-friendly technologies for controlling and modulating gas clathrate growth are needed. Type I Antifreeze Proteins (AFPs) from cold-water fish have been shown to bind to gas clathrates via repeating motifs of threonine and alanine. We tested whether proteins encoded in the genomes of bacteria native to natural gas clathrates bind to and alter clathrate morphology. We identified putative clathrate-binding proteins (CBPs) with multiple threonine/alanine motifs in a putative operon (cbp) in metagenomes from natural clathrate deposits. We recombinantly expressed and purified five CbpA proteins, four of which were stable, and experimentally confirmed that CbpAs bound to tetrahydrofuran (THF) clathrate, a low-pressure analog for structure II gas clathrate. When grown in the presence of CbpAs, THF clathrate was polycrystalline and plate-like instead of forming single, octahedral crystals. Two CbpAs yielded branching clathrate crystals, similar to the effect of Type I AFP, while the other two produced hexagonal crystals parallel to the [1 1 1] plane, suggesting two distinct binding modes. Bacterial CBPs may find future utility in industry, such as maintaining a plate-like structure during gas clathrate transportation.

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Ancient evolutionary origin of intrinsically disordered cancer risk regions
Authors: Pajkos Mátyás , Zeke András , Dosztányi Zsuzsanna
Published: June 2020

Cancer is a heterogeneous genetic disease that alters the proper functioning of proteins involved in key regulatory processes such as cell cycle, DNA repair, survival or apoptosis. Mutations often accumulate in hot-spots regions, highlighting critical functional modules within these proteins that need to be altered, amplified or abolished for tumor formation. Recent evidence suggests that these mutational hotspots can not only correspond to globular domains but also to intrinsically disordered regions (IDRs), which play a significant role in a subset of cancer types. IDRs have distinct functional properties that originate from their inherent flexibility. Generally, they correspond to more recent evolutionary inventions and show larger sequence variations across species. In this work we analyzed the evolutionary origin of disordered regions that are specifically targeted in cancer. Surprisingly, the majority of these disordered cancer risk regions showed remarkable conservation with ancient evolutionary origin, stemming from the earliest multicellular animals or even beyond. Nevertheless, we encountered several examples, where the mutated region emerged at a later stage compared to the origin of the gene family. We also showed the cancer risk regions become quickly fixated after their emergence, but evolution continues to tinker with their genes with novel regulatory elements introduced even at the level of humans. Our concise analysis provides a much clearer picture of the emergence of key regulatory elements in proteins and highlights the importance of taking into account the modular organisation of proteins for the analyses of evolutionary origin.