bluuebunny/crossref_metadata_2025 huggingface dataset:
Modelling stem cell ageing: a multi-compartment continuum approach
Authors: Wang Yanli , Lo Wing-Cheong , Chou Ching-Shan
Published: March 2020

Stem cells are important to generate all specialized tissues at an early life stage, and in some systems, they also have repair functions to replenish the adult tissues. Repeated cell divisions lead to the accumulation of molecular damage in stem cells, which are commonly recognized as drivers of ageing. In this paper, a novel model is proposed to integrate stem cell proliferation and differentiation with damage accumulation in the stem cell ageing process. A system of two structured PDEs is used to model the population densities of stem cells (including all multiple progenitors) and terminally differentiated (TD) cells. In this system, cell cycle progression and damage accumulation are modelled by continuous dynamics, and damage segregation between daughter cells is considered at each division. Analysis and numerical simulations are conducted to study the steady-state populations and stem cell damage distributions under different damage segregation strategies. Our simulations suggest that equal distribution of the damaging substance between stem cells in a symmetric renewal and less damage retention in stem cells in the asymmetric division are favourable strategies, which reduce the death rate of the stem cells and increase the TD cell populations. Moreover, asymmetric damage segregation in stem cells leads to less concentrated damage distribution in the stem cell population, which may be more robust to the stochastic changes in the damage. The feedback regulation from stem cells can reduce oscillations and population overshoot in the process, and improve the fitness of stem cells by increasing the percentage of cells with less damage in the stem cell population.
Heaps’ Law and Heaps functions in tagged texts: evidences of their linguistic relevance
Authors: Chacoma A. , Zanette D. H.
Published: March 2020

We study the relationship between vocabulary size and text length in a corpus of 75 literary works in English, authored by six writers, distinguishing between the contributions of three grammatical classes (or ‘tags,’ namely,
nouns
,
verbs
and
others
), and analyse the progressive appearance of new words of each tag along each individual text. We find that, as prescribed by Heaps’ Law, vocabulary sizes and text lengths follow a well-defined power-law relation. Meanwhile, the appearance of new words in each text does not obey a power law, and is on the whole well described by the average of random shufflings of the text. Deviations from this average, however, are statistically significant and show systematic trends across the corpus. Specifically, we find that the appearance of new words along each text is predominantly retarded with respect to the average of random shufflings. Moreover, different tags add systematically distinct contributions to this tendency, with
verbs
and
others
being respectively more and less retarded than the mean trend, and
nouns
following instead the overall mean. These statistical systematicities are likely to point to the existence of linguistically relevant information stored in the different variants of Heaps’ Law, a feature that is still in need of extensive assessment.
Cognitive appraisal in fish: stressor predictability modulates the physiological and neurobehavioural stress response in sea bass
Authors: Cerqueira M. , Millot S. , Felix A. , Silva T. , Oliveira G. A. , Oliveira C. C. V. , Rey S. , MacKenzie S. , Oliveira R.
Published: March 2020

The role of cognitive factors in triggering the stress response is well established in humans and mammals (aka cognitive appraisal theory) but very seldom studied in other vertebrate taxa. Predictability is a key factor of the cognitive evaluation of stimuli. In this study, we tested the effects of stressor predictability on behavioral, physiological and neuromolecular responses in the European sea bass (Dicentrarchus labrax). Groups of four fish were exposed to a predictable (signalled) or unpredictable (unsignalled) stressor. Stressor predictability elicited a lower behavioural response and reduced cortisol levels. Using the expression of immediate early genes (c-fos,egr-1,bdnfandnpas4) as markers of neuronal activity, we monitored the activity of three sea bass brain regions known to be implicated in stressor appraisal: the dorsomedian telencephalon, Dm (putative homologue of the pallial amygdala); and the dorsal (Dld) and ventral (Dlv) subareas of the dorsolateral telencephalon (putative homologue of the hippocampus). The activity of both the Dm and Dlv significantly responded to stressor predictability, suggesting an evolutionarily conserved role of these two brain regions in information processing related to stressor appraisal. These results indicate that stressor predictability plays a key role in the activation of the stress response in a teleost fish, hence highlighting the role of cognitive processes in fish stress.
A bird's-eye view of phylosymbiosis: weak signatures of phylosymbiosis among all 15 species of cranes
Authors: Trevelline Brian K. , Sosa Jahree , Hartup Barry K. , Kohl Kevin D.
Published: March 2020

In numerous animal clades, the evolutionary history of host species drives patterns of gut microbial community structure, resulting in more divergent microbiota with increasing phylogenetic distance between hosts. This phenomenon, termed phylosymbiosis, has been observed in diverse evolutionary lineages, but has been difficult to detect in birds. Previous tests of phylosymbiosis among birds have been conducted using wild individuals, and thus interspecific differences in diet and environment may have masked a phylogenetic signal. Therefore, we tested for phylosymbiosis among all 15 species of cranes (family Gruidae) housed in the same captive environment and maintained on identical diets. 16S rRNA sequencing revealed that crane species harbour distinct gut microbiota. Overall, we detected marginally significant patterns of phylosymbiosis, the strength of which was increased when including the estimates of absolute microbial abundance (rather than relative abundance) derived from microbial densities determined by flow cytometry. Using this approach, we detected the statistically significant signatures of phylosymbiosis only after removing male cranes from our analysis, suggesting that using mixed-sex animal cohorts may prevent the detection of phylosymbiosis. Though weak compared with mammals (and especially insects), these results provide evidence of phylosymbiosis in birds. We discuss the potential differences between birds and mammals, such as transmission routes and host filtering, that may underlie the differences in the strength of phylosymbiosis.
Colour dimorphism in labrid fishes as an adaptation to life on coral reefs
Authors: Hodge J. R. , Santini F. , Wainwright P. C.
Published: March 2020

Conspicuous coloration displayed by animals that express sexual colour dimorphism is generally explained as an adaptation to sexual selection, yet the interactions and relative effects of selective forces influencing colour dimorphism are largely unknown. Qualitatively, colour dimorphism appears more pronounced in marine fishes that live on coral reefs where traits associated with strong sexual selection are purportedly more common. Using phylogenetic comparative analysis, we show that wrasses and parrotfishes exclusive to coral reefs are the most colour dimorphic, but surprisingly, the effect of habitat is not influenced by traits associated with strong sexual selection. Rather, habitat-specific selective forces, including clear water and structural refuge, promote the evolution of pronounced colour dimorphism that manifests colours less likely to be displayed in other habitats. Our results demonstrate that environmental context ultimately determines the evolution of conspicuous coloration in colour-dimorphic labrid fishes, despite other influential selective forces.
Efficient inactivation of SARS-CoV-2 by WHO-recommended hand rub formulations and alcohols
Authors: Kratzel Annika , Todt Daniel , V’kovski Philip , Steiner Silvio , Gultom Mitra L. , Thao Tran Thi Nhu , Ebert Nadine , Holwerda Melle , Steinmann Jörg , Niemeyer Daniela , Dijkman Ronald , Kampf Günter , Drosten Christian , Steinmann Eike , Thiel Volker , Pfaender Stephanie
Published: March 2020

The recent emergence of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 is a major burden for health care systems worldwide. It is important to address if the current infection control instructions based on active ingredients are sufficient. We therefore determined the virucidal activity of two alcohol-based hand rub solutions for hand disinfection recommended by the World Health Organization (WHO), as well as commercially available alcohols. Efficient SARS-CoV-2 inactivation was demonstrated for all tested alcohol-based disinfectants. These findings show the successful inactivation of SARS-CoV-2 for the first time and provide confidence in its use for the control of COVID-19.

Importance

The current COVID-19 outbreak puts a huge burden on the world’s health care systems. Without effective therapeutics or vaccines being available, effective hygiene measure are of utmost importance to prevent viral spreading. It is therefore crucial to evaluate current infection control strategies against SARS-CoV-2. We show the inactivation of the novel coronavirus for the first time and endorse the importance of disinfectant-based hand hygiene to reduce SARS-CoV-2 transmission.
Nephrotic Syndrome Disease Activity Predicts Severity of the Associated Hypercoagulopathy
Authors: Waller Amanda P. , Troost Jonathan P. , Parikh Samir V. , Wolfgang Katelyn J. , Rovin Brad H. , Nieman Marvin T. , Smoyer William E. , Kretzler Matthias , Kerlin Bryce A. ,   for The NEPTUNE Investigators
Published: March 2020

Nephrotic syndrome (NS) is associated with an acquired hypercoagulopathy and strong predilection for life-threatening thrombotic complications. Current anticoagulant prophylaxis guidelines are based upon controversial hypoalbuminemia thresholds. Anticoagulant prophylaxis is thus inconsistently implemented due to a lack of high-grade safety and efficacy data. Development of evidence-based clinical parameters that define thrombosis risk may thus refine safe and effective anticoagulant use. Endogenous thrombin potential (ETP) is a recognized measure of hypercoagulopathy and established predictor of both incident and recurrent thrombosis. This study utilized biorepository samples from a prospective longitudinal cohort study to demonstrate that ETP is proportional to NS disease activity, resulting in multivariable models that are significantly correlated with ETP. The relationship with disease activity was confirmed in a separate cohort. These models revealed that ETP is related to disease activity in a manner dependent on remission status and that proteinuria and hypercholesterolemia exert the strongest influence on ETP. In contrast to prior epidemiology studies, which did not include hypercoagulopathy measures, we found that hypoalbuminemia was less predictive of ETP. These findings are consistent with our previously reported animal model observations and are expected to inform the design of clinical trials that will generate high-grade evidence to guide more effective and safer anticoagulant use and thus reduce life-threatening thrombotic events in patients with NS.
Tracking the Covid-19 pandemic : Simple visualization of the epidemic states and trajectories of select European countries & assessing the effects of delays in official response
Authors: Kévorkian A. , Grenet T. , Gallée H.
Published: March 2020

We present a self-synchronizing and robust method for comparing the progression of the Covid-19 epidemics among multiple countries. In their growth phase the epidemics show power law rather than exponential law time dependences. They are similar enough for the earlier China outbreak to guide other countries projections. The delayed reaction of European countries is shown to produce a significantly worse outcome compared to China.
Morphognostic honey bees communicating nectar location through dance movements
Authors: Portegys Thomas E.
Published: March 2020

Abstract

Honey bees are social insects that forage for flower nectar cooperatively. When an individual forager discovers a flower patch rich in nectar, it returns to the hive and performs a “waggle dance” in the vicinity of other bees that consists of movements communicating the direction and distance to the nectar source. The dance recruits “witnessing” bees to fly to the location of the nectar to retrieve it, thus cooperatively exploiting the environment. Replicating such complex animal behavior is a step forward on the path to artificial intelligence. This project simulates the bee foraging behavior in a cellular automaton using the Morphognosis machine learning model. The model features hierarchical spatial and temporal contexts that output motor responses from sensory inputs. Given a set of bee foraging and dancing exemplars, and exposing only the external input-output of these behaviors to the Morphognosis learning algorithm, a hive of artificial bees can be generated that forage as their biological counterparts do. A comparison of Morphognosis foraging performance with that of an artificial recurrent neural network is also presented.
A high efficient hospital emergency responsive mode is the key of successful treatment of 100 COVID-19 patients in Zhuhai
Authors: Huang Jin , Li Zhonghe , Qu Xiujuan , Zheng Xiaobin , Tu Changli , Chen Meizhu , Tan Cuiyan , Liu Jing , Shan Hong
Published: March 2020

Background

Since December 2019, Coronavirus Disease 2019 (COVID-19) emerged in Wuhan city and rapidly spread throughout China. The mortality of novel coronavirus pneumonia (NCP) in severe and critical cases is very high. Facing this kind of public health emergency, high efficient administrative emergency responsive mode in designated hospital is needed.

Method

As an affiliated hospital of Sun Yat-sen University, our hospital is the only designated one for diagnosis and treatment of COVID-19 in Zhuhai, a medium-sized city. Novel coronavirus pneumonia department, which is administrative led by the president of hospital directly, has been established at early stage of epidemic crisis in my hospital. In NCP department, there are core members of Pulmonary and Critical Care Medicine (PCCM) specialist and multidisciplinary team. Don’t stick to national guidelines of NCP, based on professional opinion by respiratory professor and expert group, we focused on individualized treatment and timely adjustment of treatment and management strategies in working about COVID-19 patients.

Results

1. High working efficiency: By Mar 02, 2020, we have completed 2974 citywide consultations and treatment of 366 inpatients, including 101 patients diagnosed with COVID-19. 2. Excellent therapeutic effect: Among 101 hospitalized patients with confirmed COVID-19, all were cured and discharged, except for one death. No secondary hospital infection, no pipeline infection and no pressure sore were found in all patients. 3. Finding and confirming person-to-person transmission characteristic of COVID-19 prior to official release conference: Strengthened protection is key point to zero infection in healthcare group and medical faculty and lower rate of second generation infectious patients. 4. Timely adjustment management and treatment strategy prior to guideline update: The first evidence of digestive tract involvement in COVID-19 has been found, and the earliest clinical trial of chloroquine in the treatment of COVID-19 has been carried out in our hospital.

Conclusions

In our hospital, establishment of NCP department, which is administratively led by the president of hospital directly and specialized conduct by respiratory professor, is the key to success in management and treatment of COVID-19 patients. This hospital emergency responsive mode could provide reference for other hospitals and cities in epidemic situation.
Routes for COVID-19 importation in Brazil
Authors: Candido Darlan Da S , Watts Alexander , Abade Leandro , Kraemer Moritz UG , Pybus Oliver G , Croda Julio , Oliveira Wanderson de , Khan Kamran , Sabino Ester C , Faria Nuno R
Published: March 2020

Highlight

The global outbreak caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been declared a pandemic by the WHO. As the number of imported SARS-CoV-2 cases is on the rise in Brazil, we use incidence and historical air travel data to estimate the most important routes of importation into the country.
Understanding Epidemic Data and Statistics: A Case Study of COVID-19
Authors: Dehkordi Amirhoshang Hoseinpour , Alizadeh Majid , Derakhshan Pegah , Babazadeh Peyman , Jahandideh Arash
Published: March 2020

The 2019-Novel-Coronavirus (COVID-19) has affected 181 countries and out of about 1197405 confirmed cases (By April 5). Understanding the transmission dynamics of the infection in each country which affected on a daily basis and evaluating the effectiveness of control policies is critical for our further actions. To date, the statistics of COVID-19 reported cases show more than 80 percent of infected had a mild case of disease, while around 14 percent of infected experienced a severe one and about 5 percent are categorized as critical disease victims. Today’s report (2020-04-05; daily updates in the prepared website) shows the confirmed cases of COVID-19 in US, Spain, Italy, and Germany are 308850, 126168, 124632 and 96092; respectively. Calculating the total Case Fatality Rate (CFR) of Italy (2020-04-04), about 13.3% of confirmed cases passed away. Compared to South Korea’s rate of 1.8% (7 times lower than Italy) and China’s 4% (69% lower than Italy), the CFR of Italy is too high. There are some effective policies that yield significant changes in the trend of cases. The lockdown policy in China, Italy and Spain (the effect observed after some days), Shutdown of all non-essential companies in Hubei (the effect observed after 5 days), combined policy in South Korea and reducing working hours in Iran.
US Mortality Due To Congenital Heart Disease Across the Lifespan from 1999-2017 Exposes Persistent Racial/Ethnic Disparities
Authors: Lopez Keila N. , Morris Shaine A. , Tejtel Kristen Sexson , Espaillat Andre , Salemi Jason L.
Published: March 2020

Background

Congenital heart disease (CHD) accounts for approximately 40% percent of deaths in United States (US) children with birth defects. Previous US data from 1999-2006 demonstrated an overall decrease in CHD mortality. The objective of our study was to assess current trends in US mortality related to CHD from infancy to adulthood over the last 19 years and determine differences by sex and race/ethnicity.

Methods

We conducted an analysis of death certificates from 1999-2017 to calculate annual CHD mortality by age at death, race/ethnicity, and sex. Population estimates used as denominators in mortality rate calculation for infants were based on National Center for Health Statistics live birth data. Mortality rates in individuals>1 year of age utilized US Census Bureau bridged-race estimates as denominators for population estimates. We characterized temporal trends in all-cause mortality, mortality resulting directly due to and related to CHD by age, race/ethnicity, and sex using joinpoint regression.

Results

There were 47.7 million deaths with 1 in 814 deaths due to CHD (n=58,599). While all-cause mortality decreased 16.4% across all ages, mortality resulting from CHD declined 39.4% overall. The mean annual decrease in CHD mortality was 2.6%, with the largest decrease for those age >65years. The age-adjusted mortality rate decreased from 1.37 to 0.83 per 100,000. Males had higher mortality due to CHD than females throughout the study, although both sexes declined at a similar rate (∼40% overall), with a 3-4% annual decrease between 1999 and 2009, followed by a slower annual decrease of 1.4% through 2017. Mortality resulting from CHD significantly declined among all race/ethnicities studied, although disparities in mortality persisted for non-Hispanic Blacks versus non-Hispanic Whites (mean annual decrease 2.3% versus 2.6%, respectively; age-adjusted mortality rate 1.67 to 1.05 versus 1.35 to 0.80 per 100,000, respectively).

Conclusions

While overall US mortality due to CHD has decreased over the last 19 years, disparities in mortality persist for males compared to females and for non-Hispanic Blacks compared to non-Hispanic Whites. Determining factors that contribute to these disparities such as access to quality care, timely diagnosis, and maintenance of insurance will be important moving into the next decade.
The Effect of Visual Uncertainty on Implicit Motor Adaptation
Authors: Tsay Jonathan S. , Avraham Guy , Kim Hyosub E. , Parvin Darius E. , Wang Zixuan , Ivry Richard B.
Published: March 2020

Sensorimotor adaptation is driven by sensory prediction errors, the difference between the predicted and actual feedback. When the position of the feedback is made uncertain, adaptation is attenuated. This effect, in the context of optimal sensory integration models, has been attributed to a weakening of the error signal driving adaptation. Here we consider an alternative hypothesis, namely that uncertainty alters the perceived location of the feedback. We present two visuomotor adaptation experiments to compare these hypotheses, varying the size and uncertainty of a visual error signal. Uncertainty attenuated learning when the error size was small but had no effect when the error size was large. This pattern of results favors the hypothesis that uncertainty does not impact the strength of the error signal, but rather, leads to mis-localization of the error. We formalize these ideas to offer a novel perspective on the effect of visual uncertainty on implicit sensorimotor adaptation.

SIGNIFICANCE STATEMENT

Current models of sensorimotor adaptation assume that the rate of learning will be related to properties of the error signal (e.g., size, consistency, relevance). Recent evidence has challenged this view, pointing to a rigid, modular system, one that automatically recalibrates the sensorimotor map in response to movement errors, with minimal constraint. In light of these developments, this study revisits the influence of feedback uncertainty on sensorimotor adaptation. Adaptation was attenuated in response to a noisy feedback signal, but the effect was only manifest for small errors and not for large errors. This interaction suggests that uncertainty does not weaken the error signal. Rather, it may influence the perceived location of the feedback and thus the change in the sensorimotor map induced by that error. These ideas are formalized to show how the motor system remains exquisitely calibrated, even if adaptation is largely insensitive to the statistics of error signals.
Computational analysis of microRNA-mediated interactions in SARS-CoV-2 infection
Authors: Saçar Demirci Müşerref Duygu , Adan Aysun
Published: March 2020

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that have been found in more than 200 diverse organisms. Although it is still not fully established if RNA viruses could generate miRNAs that would target their own genes or alter the host gene expression, there are examples of miRNAs functioning as an antiviral defense mechanism. In the case of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there are several mechanisms that would make miRNAs impact the virus, like interfering with replication, translation and even modulating the host expression. In this study, we performed a machine learning based miRNA prediction analysis for the SARS-CoV-2 genome to identify miRNA-like hairpins and searched for potential miRNA – based interactions between the viral miRNAs and human genes and human miRNAs and viral genes. Our PANTHER gene function analysis results indicate that viral derived miRNA candidates could target various human genes involved in crucial cellular processes including transcription. For instance, a transcriptional regulator, STAT1 and transcription machinery might be targeted by virus-derived miRNAs. In addition, many known human miRNAs appear to be able to target viral genes. Considering the fact that miRNA-based therapies have been successful before, comprehending mode of actions of miRNAs and their possible roles during SARS-CoV-2 infections could create new opportunities for the development and improvement of new therapeutics.
Detecting sample swaps in diverse NGS data types using linkage disequilibrium
Authors: Javed Nauman , Farjoun Yossi , Fennell Tim J. , Epstein Charles B. , Bernstein Bradley E. , Shoresh Noam
Published: March 2020

As the number of genomics datasets grows rapidly, sample mislabeling has become a high stakes issue. We present CrosscheckFingerprints (Crosscheck), a tool for quantifying sample-relatedness and detecting incorrectly paired sequencing datasets from different donors. Crosscheck outperforms similar methods and is effective even when data are sparse or from different assays. Application of Crosscheck to 8851 ENCODE ChIP-, RNA-, and DNase-seq datasets enabled us to identify and correct dozens of mislabeled samples and ambiguous metadata annotations, representing ∼1% of ENCODE datasets.
Quantification of lactoyl-CoA by liquid chromatography mass spectrometry in mammalian cells and tissues
Authors: Varner Erika L , Trefely Sophie , Bartee David , von Krusenstiern Eliana , Izzo Luke , Bekeova Carmen , O’Connor Roddy S , Seifert Erin L. , Wellen Kathryn , Meier Jordan L. , Snyder Nathaniel W.
Published: March 2020

Lysine lactoylation is a recently described protein post-translational modification (PTM). However, the biochemical pathways responsible for this acylation remain unclear. Two metabolite-dependent mechanisms have been proposed: enzymatic histone lysine lactoylation derived from lactoyl-coenzyme A (lactoyl-CoA, also termed lactyl-CoA), and non-enzymatic lysine lactoylation resulting from acyl-transfer via lactoyl-glutathione. While the former has precedent in the form of enzyme-catalyzed lysine acylation, the lactoyl-CoA metabolite has not been previously quantified in mammalian systems. Here we use liquid chromatography-high resolution mass spectrometry (LC-HRMS) together with a synthetic standard to detect and validate the presence of lactoyl-CoA in cell and tissue samples. Conducting a retrospective analysis of data from previously analyzed samples revealed the presence of lactoyl-CoA in diverse cell and tissue contexts. In addition, we describe a biosynthetic route to generate13C315N1-isotopically-labeled lactoyl-CoA, providing a co-eluting internal standard for analysis of this metabolite. We estimate lactoyl-CoA concentrations of 1.14×10−8pmol/cell in cell culture and 0.0172 pmol/mg tissue wet weight in mouse heart. These levels are similar to crotonyl-CoA, but between 20-350 times lower than predominant acyl-CoAs such as acetyl-, propionyl-, and succinyl-CoA. Overall our studies provide the first quantitative measurements of lactoyl-CoA and provide a methodological foundation for the interrogation of this novel metabolite in biology and disease.

Highlights

- Detection of lactoyl-CoA at picomole concentrations across tissues and cells

- Lactoyl-CoA was detected at concentrations similar to crontonyl-CoA within HepG2 cells

- Isotopically labeled13C315N1-lactoyl-CoA can be prepared by SILEC
Queryfuse is a sensitive algorithm for detection of gene-specific fusions
Authors: Tan Yuxiang
Published: March 2020

Recurrent chromosomal translocations, known as fusions, play important roles in carcinogenesis. They can serve as valuable diagnostic and therapeutic targets. RNA-seq is an ideal platform for detecting transcribed fusions, and computational methods have been developed to identify fusion transcripts from RNA-seq data. However, some transciptome realignment procedures for these methods are unnecessary, making this task computationally expensive and time consuming. Therefore, we have developed QueryFuse, a novel hypothesis-based algorithm that identifies gene-specific fusion from pre-aligned RNA-seq data. It is designed to help biologists quickly find and/or computationally validate fusions of interest, together with visualization and detailed properties of supporting reads. By aligning reads to Query genes at the pre-processing step with a more sensitive, memory intensive local aligner, QueryFuse can reduce alignment time and improve detection sensitivity.

QueryFuse performed better or at comparable levels with two popular tools (deFuse and TopHatFusion) on both simulated and well-annotated cell-line datasets. Finally, using QueryFuse, we identified a novel fusion event with a potential therapeutic implication in clinical samples. Taken together, our results showed that QueryFuse is efficient and reliable for detecting gene-specific fusion events.
Acute myelitis after SARS-CoV-2 infection: a case report
Authors: Zhao Kang , Huang Jucun , Dai Dan , Feng Yuwei , Liu Liming , Nie Shuke
Published: March 2020

We report a case of acute myelitis in a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A 66-year-old man with coronavirus disease 2019 was admitted with acute flaccid paralysis of the bilateral lower limbs and urinary and bowel incontinence. All serum microbiological test results were negative, except for SARS-CoV-2 nucleic acid testing. Clinical findings indicated post-infectious acute myelitis. He received treatment containing ganciclovir, lopinavir/ritonavir, moxifloxacin, dexamethasone, human immunoglobulin, and mecobalamin. With a diagnosis of post-infectious acute myelitis and comprehensive treatment, paralysis of the bilateral lower extremities ameliorated. After two negative novel coronavirus RNA nasopharyngeal swab tests, he was discharged and transferred to a designated hospital for isolation and rehabilitation therapy.
Optimization of skeletal protein preparation for LC-MS/MS sequencing yields additional coral skeletal proteins inStylophora pistillata
Authors: Peled Yanai , Drake Jeana , Malik Assaf , Almuly Ricardo , Lalzar Maya , Morgenstern David , Mass Tali
Published: March 2020

Stony corals generate their calcium carbonate exoskeleton in a highly controlled biomineralization process mediated by a variety of macromolecules including proteins. Fully identifying and classifying these proteins is crucial to understanding their role in exoskeleton formation, yet no optimal method to purify and characterize the full suite of extracted coral skeletal proteins has been established and hence their complete composition remains obscure. Here, we tested four skeletal protein purification protocols using acetone precipitation and ultrafiltration dialysis filters to present a comprehensive scleractinian coral skeletal proteome. We identified a total of 60 proteins in the coral skeleton, 44 of which were not present in previously published stony coral skeletal proteomes. Extracted protein purification protocols carried out in this study revealed that no one method captures all proteins and each protocol revealed a unique set of method-exclusive proteins. To better understand the general mechanism of skeletal protein transportation, we further examined the proteins’ gene ontology, transmembrane domains, and signal peptides. We found that transmembrane domain proteins and signal peptide secretion pathways, by themselves, could not explain the transportation of proteins to the skeleton. We therefore propose that some proteins are transported to the skeleton via non-traditional secretion pathways.
Impact of force function formulations on the numerical simulation of centre-based models
Authors: Mathias Sonja , Coulier Adrien , Bouchnita Anass , Hellander Andreas
Published: March 2020

Centre-based, or cell-centre models are a framework for the computational study of multicellular systems with widespread use in cancer modelling and computational developmental biology. At the core of these models are the numerical method used to update cell positions and the force functions that encode the pairwise mechanical interactions of cells. For the latter there are multiple choices that could potentially affect both the biological behaviour captured, and the robustness and efficiency of simulation. For example, available open-source software implementations of centre-based models rely on different force functions for their default behaviour and it is not straightforward for a modeler to know if these are interchangeable. Our study addresses this problem and contributes to the understanding of the potential and limitations of three popular force functions from a numerical perspective. We show empirically that choosing the force parameters such that the relaxation time for two cells after cell division is consistent between different force functions results in good agreement of the population radius of a growing monolayer. Furthermore, we report that numerical stability is not sufficient to prevent unphysical cell trajectories following cell division, and consequently, that too large time steps can cause geometrical differences at the population level.
Secondary structural characterization of the nucleic acids from circular dichroism spectra using extreme gradient boosting decision-tree algorithm
Authors: Sathyaseelan Chakkarai , Vinothini V , Rathinavelan Thenmalarchelvi
Published: March 2020

Nucleic acids exhibit a repertoire of conformational preference depending on the sequence and environment. Circular dichroism (CD) is an important and valuable tool for monitoring such secondary structural conformations of nucleic acids. Nonetheless, the CD spectral diversity associated with these structures poses a challenge in obtaining the quantitative information about the secondary structural content of a given CD spectrum. To this end, the competence of extreme gradient boosting decision-tree algorithm has been exploited here to predict the diverse secondary structures of nucleic acids. A curated library of 610 CD spectra corresponding to 16 different secondary structures of nucleic acids has been developed and used as a training dataset. For a test dataset of 242 CD spectra, the algorithm exhibited the prediction accuracy of 99%. For the sake of accessibility, the entire process is automated and implemented as a webserver, called CD-NuSS (CD to nucleic acids secondary structure) and is freely accessible athttps://www.iith.ac.in/cdnuss/. The XGBoost algorithm presented here may also be extended to identify the hybrid nucleic acid topologies in future.
Polymorphic SNPs, short tandem repeats and structural variants are responsible for differential gene expression across C57BL/6 and C57BL/10 substrains
Authors: Mortazavi Milad , Ren Yangsu , Saini Shubham , Antaki Danny , Pierre Celine St. , Williams April , Sohni Abhishek , Wilkinson Miles , Gymrek Melissa , Sebat Jonathan , Palmer Abraham A.
Published: March 2020

Mouse substrains are an invaluable model for understanding disease. We compared C57BL/6J, which is the most commonly used inbred mouse strain, with 8 C57BL/6 and 5 C57BL/10 closely related inbred substrains. Whole genome sequencing and RNA-sequencing analysis yielded 352,631 SNPs, 109,096 INDELs, 150,344 short tandem repeats (STRs), 3,425 structural variants (SVs) and 2,826 differentially expressed genes (DEGenes) among these 14 strains. 312,981 SNPs (89%) distinguished the B6 and B10 lineages. These SNPs were clustered into 28 short segments that are likely due to introgressed haplotypes rather than new mutations. Outside of these introgressed regions, we identified 53 SVs, protein-truncating SNPs and frameshifting INDELs that were associated with DEGenes. Our results can be used for both forward and reverse genetic approaches, and illustrate how introgression and mutational processes give rise to differences among these widely used inbred substrains.
Formation of polarized contractile interfaces by self-organized Toll-8/Cirl GPCR asymmetry
Authors: Lavalou Jules , Mao Qiyan , Harmansa Stefan , Kerridge Stephen , Lellouch Annemarie C. , Philippe Jean-Marc , Audebert Stephane , Camoin Luc , Lecuit Thomas
Published: March 2020

During development, interfaces between cells with distinct genetic identities elicit signals to organize local cell behaviors driving tissue morphogenesis. TheDrosophilaembryonic axis extension requires planar polarized enrichment of Myosin-II powering oriented cell intercalations. Myosin-II levels are quantitatively controlled by G protein-coupled receptor (GPCR) signaling whereas Myosin-II polarity requires patterned expression of several Toll receptors. How Toll receptors polarizes Myosin-II, and how this involves GPCRs, remain unknown. Here we report that differential expression of a single Toll receptor, Toll-8, polarizes Myosin-II via a novel binding partner, the adhesion GPCR Cirl/Latrophilin. Asymmetric expression of Cirl is sufficient to enrich Myosin-II and Cirl localization is asymmetric at Toll-8 expression boundaries. Exploring the process dynamically, we reveal that Toll-8 and Cirl exhibit mutually dependent planar polarity in response to quantitative differences in Toll-8 expression between neighboring cells. Collectively, we propose that a novel cell surface protein complex Toll-8/Cirl self-organizes to generate local asymmetric interfaces essential for planar polarization of contractile interfaces.
Amyloid-β oligomers are captured by the DNAJB6 chaperone: Direct detection of interactions that can prevent primary nucleation
Authors: Österlund Nicklas , Lundquist Martin , Ilag Leopold L. , Gräslund Astrid , Emanuelsson Cecilia
Published: March 2020

A human molecular chaperone protein, DNAJB6, is an efficient inhibitor of amyloid aggregation owing to a unique motif with conserved S/T-residues with high capacity for hydrogen bonding. Global analysis of kinetics data previously showed that especially the primary nucleation rate is inhibited. It was concluded that DNAJB6 achieves this remarkably effective and sub-stoichiometric inhibition by interacting not with the monomeric unfolded conformations of the amyloid-β (Aβ) peptide but with aggregated species. The pre-nucleation oligomeric aggregates are transient and difficult to study experimentally. Here we employed an approach to directly detect oligomeric forms of Aβ formed in solution by subsequent analysis with native mass spectrometry (native MS). Results show that the signals from the various forms of Aβ (1-40) oligomers were reduced considerably in the presence of DNAJB6, but not with a mutational variant of DNAJB6 in which the S/T-residues were substituted. With focus on DNAJB6 we could also detect signals that appear to represent DNAJB6 dimers and trimers to which varying amounts of Aβ is bound. These data provide direct experimental evidence that it is the oligomeric forms of Aβ that are captured by DNAJB6 in a manner which is dependent on the S/T residues. Strong binding of Aβ oligomers to DNAJB6 should indeed inhibit the formation of amyloid nuclei, in agreement with the previously observed decrease in primary nucleation rate.
Evidence of the Recombinant Origin and Ongoing Mutations in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Authors: Huang Jiao-Mei , Jan Syed Sajid , Wei Xiaobin , Wan Yi , Ouyang Songying
Published: March 2020

The recent global outbreak of viral pneumonia designated as Coronavirus Disease 2019 (COVID-19) by coronavirus (SARS-CoV-2) has threatened global public health and urged to investigate its source. Whole genome analysis of SARS-CoV-2 revealed ~96% genomic similarity with bat CoV (RaTG13) and clustered together in phylogenetic tree. Furthermore, RaTGl3 also showed 97.43% spike protein similarity with SARS-CoV-2 suggesting that RaTGl3 is the closest strain. However, RBD and key amino acid residues supposed to be crucial for human-to-human and cross-species transmission are homologues between SARS-CoV-2 and pangolin CoVs. These results from our analysis suggest that SARS-CoV-2 is a recombinant virus of bat and pangolin CoVs. Moreover, this study also reports mutations in coding regions of 125 SARS-CoV-2 genomes signifying its aptitude for evolution. In short, our findings propose that homologous recombination has been occurred between bat and pangolin CoVs that triggered cross-species transmission and emergence of SARS-CoV-2, and, during the ongoing outbreak, SARS-CoV-2 is still evolving for its adaptability.
A tissue- and organ-based cell biological atlas of obesity-related human genes and cellular pathways
Authors: Tavassoly Iman , Barbieri Valentina , van Hasselt Coen , Martinez Pedro , Sobie Eric A. , Hansen Jens , Azeloglu Evren , Goldfarb Joseph , Sanseau Philippe , Rajpal Deepak K , Iyengar Ravi
Published: March 2020

Over the last decades, several features of obesity have been identified at behavioral, physiological, endocrine and genomic levels, and they have revealed the complexity of the disease; obesity results from a combination of genetic predisposition, endocrine disorders, and dysregulation of both food intake and energy expenditure. This complexity makes the development of new therapeutic regimens challenging and bariatric surgery is still the treatment of choice for many obese patients. Given the need for noninvasive therapeutic intervention strategies, we sought to systematically study the biological manifestations of obesity in peripheral organs. We analyzed publicly available datasets of genes, genomic determinants, and levels of obesity-related hormones in the blood, using a combination of methodologies, including graph theory and dynamical modeling, that allow for the integration of different types of datasets. The analysis revealed tissue- and organ-specific metabolic impairments and potential new drug targets. All the data are organized into a tissue/organ-based subcellular-function atlas for human obesity. The data show that the complexity of the obesity arises due to the multiplicity of subcellular processes in different peripheral organs.
Low-frequency vibrational modes in G-quadruplexes reveal the mechanical properties of nucleic acids
Authors: González-Jiménez M. , Ramakrishnan G. , Wynne K.
Published: March 2020

Low-frequency vibrations play an essential role in biomolecular processes involving DNA such as gene expression, charge transfer, drug intercalation, and DNA–protein recognition. However, understanding of the vibrational basis of these mechanisms relies on theoretical models due to the lack of experimental evidence. Here we present the low-frequency vibrational spectra of G-quadruplexes (structures formed by four strands of DNA) and B-DNA characterized using femtosecond optical Kerr-effect spectroscopy. Contrary to expectation, we found that G-quadruplexes show several strongly underdamped delocalized phonon-like modes that have the potential to contribute to the biology of the DNA at the atomic level. In addition, G-quadruplexes present modes at a higher frequency than B-DNA demonstrating that changes in the stiffness of the molecule alter its gigahertz to terahertz vibrational profile. These results demonstrate that current theoretical models fail to predict basic properties of the vibrational modes of DNA.

Statement of significance

A number of recent studies have identified thermally excited low-frequency vibrational modes as a key deciding factor in the biological function of DNA. However, the nature of these vibrational modes has never been established. Here, vibrational spectroscopy with unrivalled signal-to-noise in the gigahertz to terahertz range is used to determine the low-frequency Raman spectra of nucleotides and oligomeric DNAs carefully chosen to form G-quadruplexes, structures formed by four strands of DNA common in the genome. These G-quadruplexes exhibit an unusual group of highly-underdamped delocalized vibrational modes—not reproduced by any of the theoretical models in use—which are expected to be the thermally excited. This provides a new perspective on the role of low-frequency vibrational modes in protein interactions and allostery.
Insulin dissociates by diverse mechanisms of coupled unfolding and unbinding
Authors: Antoszewski Adam , Feng Chi-Jui , Vani Bodhi P. , Thiede Erik H. , Hong Lu , Weare Jonathan , Tokmakoff Andrei , Dinner Aaron R.
Published: March 2020

The protein hormone insulin exists in various oligomeric forms, and a key step in binding its cellular receptor is dissociation of the dimer. This dissociation process and its corresponding association process have come to serve as a paradigms of coupled (un)folding and (un)binding more generally. Despite its fundamental and practical importance, the mechanism of insulin dimer dissociation remains poorly understood. Here, we use molecular dynamics simulations, leveraging recent developments in umbrella sampling, to characterize the energetic and structural features of dissociation in unprecedented detail. We find that the dissociation is inherently multipathway with limiting behaviors corresponding to conformational selection and induced fit, the two prototypical mechanisms of coupled folding and binding. Along one limiting path, the dissociation leads to detachment of the C-terminal segment of the insulin B chain from the protein core, a feature believed to be essential for receptor binding. We simulate IR spectroscopy experiments to aid in interpreting current experiments and identify sites where isotopic labeling can be most effective for distinguishing the contributions of the limiting mechanisms.
The Role of Ion Transition from the Pore Cavity to the Selectivity Filter in the Mechanism of Selectivity and Rectification in the Kv1.2 Potassium Channel: Transfer of Ion Solvation from Cavity Water to the Protein and Water of the Selectivity Filter
Authors: Kariev Alisher M , Green Michael E
Published: March 2020

Potassium channels generally have a selectivity filter that includes the sequence threonine-threonine-valine-glycine-tyrosine-glycine (TTVGYG). The last five amino acids are conserved over practically the entire range of evolution, so the sequence obviously is necessary to the function of the channel. Here we show by quantum calculations on the upper part of the channel “cavity” (aqueous compartment between the gate and selectivity filter) and lower part of the selectivity filter (SF) how the channel with two sets of four threonines (the channel is fourfold symmetric) effects rectification and selectivity. The threonines are at the location in which the ion transfers from the cavity into the SF; in this calculation they play a key role in selectivity. The channel is also a rectifier. The wild type channel with K+and three other cases are considered: 1) the upper set of four threonines is replaced by serines. 2) and 3) Related computations with the Na+and NH4+ions help to clarify the important factors in moving the ion from the cavity to the SF. In particular, one set of angles (not bond angles,O(T373–C=O) –O(T374–OH) –H(T374–OH)) flips a hydrogen into and out of the ion path, allowing the K+to go forward but not back. This is essentially a ratchet and pawl mechanism, with the ratchet driven by electrostatics. This also allows a clear path forward for K+but not for Na+or NH4+, nor for K+in a T→S mutant. Atomic charges in the lowest positions in the SF are the driving force moving the ion forward, but the O - O - H angle just specified is key to making the “knock-on” mechanism move the ions forward only, using the ratchet with the pawl formed by the hydrogen in the bonds that flip. A water interacts with threonine hydroxyls to allow ion passage, and another water moves together with the K+.