bluuebunny/crossref_metadata_2025 huggingface dataset:
Interneuron origins in the embryonic porcine medial ganglionic eminence
Authors: Casalia Mariana L. , Li Tina , Ramsay Harrison , Ross Pablo J. , Paredes Mercedes F. , Baraban Scott C.
Published: December 2020

Interneurons contribute to the complexity of neural circuits and maintenance of normal brain function. Rodent interneurons originate in embryonic ganglionic eminences, but developmental origins in other species are less understood. Here, we show that transcription factor expression patterns in porcine embryonic subpallium are similar to rodents, delineating a distinct medial ganglionic eminence (MGE) progenitor domain. On the basis of Nkx2.1, Lhx6 and Dlx2 expression,in vitrodifferentiation into neurons expressing GABA and robust migratory capacity in explant assays, we propose that cortical and hippocampal interneurons originate from a porcine MGE region. Following xenotransplantation into adult male and female rat hippocampus, we further demonstrate that porcine MGE progenitors, like those from rodents, migrate and differentiate into morphologically distinct interneurons expressing GABA. Our findings reveal that basic rules for interneuron development are conserved across species, and that porcine embryonic MGE progenitors could serve as a valuable source for interneuron-based xenotransplantation therapies.

Significance Statement

Here we demonstrate that porcine MGE, like rodents, exhibit a distinct transcriptional and pallial interneuron-specific antibody profile,in vitromigratory capacity and are amenable to xenotransplantation. This is the first comprehensive examination of embryonic pallial interneuron origins in the pig, and because a rich neurodevelopmental literature on embryonic mouse MGE exists (with some additional characterizations in other species like monkey and human) our work allows direct neurodevelopmental comparisons with this literature.
Optimizing ventilation cycles to control airborne transmission risk of SARS-CoV2 in school classrooms
Authors: Zivelonghi Alessandro , Lai Massimo
Published: December 2020

Open schools in winter in highly epidemic areas pose a controversial issue: ventilation of classrooms (an essential mitigation factor for airborne transmission) is expected to sensibly decrease due to outdoor temperatures getting colder and regulators going to allow less restrictive policies on windows closure. Fundamental questions to be addressed are therefore: to which extent can we contain airborne transmission risk in schools? what would be the optimal ventilation strategy during the cold season considering the fact that most schools are not provided with mechanical ventilation systems? To try answering these questions a risk model for airborne transmission of covid-19 in classrooms has been develped based on previous models for tubercolosis and influenza. The separate cases of infective student and infective teacher, as well as infective teacher with microphone are investigated. We explored 3500 different air ventilation cycles for different lesson+break times and carried out a numerical optimization of the risk function. Safety risk-zones for breaks and lessons durations were estimated combining the effect of surgical masks and optimal windows opening cycles.
SARS-CoV-2 infections in people with PCD: neither frequent, nor particularly severe
Authors: Pedersen Eva SL , Goutaki Myrofora , Harris Amanda L , Dixon Lucy , Manion Michele , Rindlisbacher Bernhard ,   COVID-PCD patient advisory group, Lucas Jane S , Kuehni Claudia E
Published: December 2020

People with pre-existing chronic health conditions are reportedly at high risk of getting the coronavirus disease (COVID-19) and of having a severe disease course but little data exist on rare diseases such as Primary Ciliary Dyskinesia (PCD). We studied risk and severity of SARS-CoV-2 infections among people with PCD using data from the COVID-PCD, a participatory study that collects data in real-time directly from people with PCD. Data was collected using online questionnaires. A baseline questionnaire collected information on demographic data, information about the PCD diagnosis and severity. A short weekly questionnaire collected information about current symptoms and incident SARS-CoV-2 infections. 578 people participated in the COVID-PCD by December 7, 2020, with a median number of follow-up weeks of 9 (interquartile range: 4-19 weeks). 256 (45%) of the participants had been tested for SARS-CoV-2 and 12 tested positive prior to study entry or during study follow up (2.1% of the total included population, 95% confidence interval (CI) 1.1-3.6%). 4 people tested positive during the study follow-up, corresponding to an incidence rate of 2.5 per 100 person-years (95% CI: 0.9-6.5). Overall, reported severity was mild with two reporting no symptoms, eight reporting mild symptoms, one reporting severe symptom without hospitalisation, and one reporting hospitalisation for 9 days. The study suggests that with careful personal protection, people with PCD do not seem to have an increased risk of infection with SARS-COV-2, nor an especially severe disease course.

Take home message

In this longitudinal study of people with PCD followed weekly via online questionnaires, the incidence rate of COVID-19 and the proportion of participants infected were low, and the observed severity mostly mild.
Polaratio: A magnitude-contingent monotonic correlation metric and its improvements to scRNA-seq clustering
Authors: Wang Victor , Cicalese Pietro Antonio , Louis Sam Titus Anto Sam Crosslee , Mohan Chandra
Published: December 2020

Motivation

Single-cell RNA sequencing (scRNA-seq) technologies and analysis tools have allowed researchers to achieve remarkably detailed understandings of the roles and relationships between cells and genes. However, conventional distance metrics, such as Euclidean, Pearson, and Spearman distances, fail to simultaneously take into account the high dimensionality, monotonicity, and magnitude of gene expression data. To address several shortcomings in these commonly used metrics, we present a magnitude-contingent monotonic correlation metric called Polaratio which is designed to enhance the quality of scRNA-seq data analysis.

Results

We integrate three interpretable clustering algorithms – Single-Cell Consensus Clustering (SC3), Hierarchical Clustering (HC), and K-Medoids (KM) – through a consensus cell clustering procedure, which we evaluate on various biological datasets to benchmark Polaratio against several well-known metrics. Our results demonstrate Polaratio’s ability to improve the accuracy of cell clustering on 5 out of 7 publicly available datasets.

Availability

https://github.com/dubai03nsr/Polaratio

Contact

pcicalese@uh.edu
The CP110-CEP97-CEP290 module orchestrates a centriolar satellite dependent response to proteotoxic stress
Authors: Prosser Suzanna L. , Tkach Johnny , Gheiratmand Ladan , Morrison Ciaran G. , Pelletier Laurence
Published: December 2020

Protein degradation at the centrosome, the primary microtubule organizing centre of the cell, is critical to a myriad of cellular processes. Perturbation of the ubiquitin proteasome system causes the formation of an inclusion, or aggresome, at the centrosome. By systematic microscopy analysis, we have placed a subset of centrosomal proteins within the aggresome. Centriolar satellites, proteinaceous granules found in the vicinity of centrosomes, also became incorporated into this structure. Through high-resolution quantitative analysis, we have defined aggresome assembly at the centrosome, demonstrating a requirement for satellites in this process. Furthermore, a module consisting of CP110-CEP97-CEP290 was required to recruit aggresome components early in the pathway and senescent cells were defective in aggresome formation due to limiting amounts of CP110. Finally, satellites and the CP110-CEP97-CEP290 module were required for the aggregation of mutant huntingtin. The accumulation of protein aggregates is central to the pathology of a range of human disorders. These data thereby reveal new roles for CP110, its interactors, and centriolar satellites in controlling cellular proteostasis and the aggregation of disease relevant proteins.
Quantitative Control of Noise in Mammalian Gene Expression by Dynamic Histone Regulations
Authors: Tan Deng , Chen Rui , Mo Yuejian , Xu Wei , Lu Xibin , He Huiyu , Gu Shu , Jiang Fan , Fan Weimin , Wang Yilin , Chen Xi , Huang Wei
Published: December 2020

Fluctuation (‘noise’) in gene expression is critical for mammalian cellular processes. Numerous mechanisms contribute to its origins, yet large noises induced by single transcriptional activator species remain to be experimentally understood. Here, we combined the dynamic regulation of transcriptional activator binding, histone regulator inhibitors, and single-cell quantification of chromatin accessibility, mRNA, and protein to probe putative mechanisms. Using a light-induced expression system, we show that the transcriptional activator forms a positive feedback loop with histone acetyltransferases CBP/p300. It generates epigenetic bistability in H3K27ac, which contributes to large noise. Disable of the positive feedback loop by CBP/p300 and HDAC4/5 inhibitors also reduces heterogeneity in endogenous genes, suggesting a universal mechanism. We showed that the noise was reduced by pulse-wide modulation of transcriptional activator binding due to alternating the system between high and low monostable states. Our findings could provide a mechanism-based approach to modulate noise in synthetic and endogenous gene expressions.
Cross-covariance isolate detect: a new change-point method for estimating dynamic functional connectivity
Authors: Anastasiou Andreas , Cribben Ivor , Fryzlewicz Piotr
Published: December 2020

Evidence of the non stationary behavior of functional connectivity (FC) networks has been observed in task based functional magnetic resonance imaging (fMRI) experiments and even prominently in resting state fMRI data. This has led to the development of several new statistical methods for estimating this time-varying connectivity, with the majority of the methods utilizing a sliding window approach. While computationally feasible, the sliding window approach has several limitations. In this paper, we circumvent the sliding window, by introducing a statistical method that finds change-points in FC networks where the number and location of change-points are unknown a priori. The new method, calledcross-covariance isolate detect(CCID), detects multiple change-points in the second-order (cross-covariance or network) structure of multivariate, possibly high-dimensional time series. CCID allows for change-point detection in the presence of frequent changes of possibly small magnitudes, can assign change-points to one or multiple brain regions, and is computationally fast. In addition, CCID is particularly suited to task based data, where the subject alternates between task and rest, as it firstly attempts isolation of each of the change-points within subintervals, and secondly their detection therein. Furthermore, we also propose a new information criterion for CCID to identify the change-points. We apply CCID to several simulated data sets and to task based and resting state fMRI data and compare it to recent change-point methods. CCID may also be applicable to electroencephalography (EEG), magentoencephalography (MEG) and electrocorticography (ECoG) data. Similar to other biological networks, understanding the complex network organization and functional dynamics of the brain can lead to profound clinical implications. Finally, the R packageccidimplementing the method from the paper is available from CRAN.
Alternate Grainy head isoforms regulateDrosophilamidgut intestinal stem cell differentiation
Authors: Dominado Nicole , Casagranda Franca , Heaney James , Siddall Nicole A. , Abud Helen E. , Hime Gary R.
Published: December 2020

Regeneration of theDrosophilamidgut epithelium depends upon differential expression of transcription factors in intestinal stem cells and their progeny. Thegrainy headlocus produces multiple splice forms that result in production of two classes of transcription factor, designated Grh.O and Grh.N.grainy headexpression is associated with epithelial tissue and has roles in epidermal development and regeneration but had not been examined for a function in the midgut epithelium. Null mutant clones had a limited effect on intestinal stem cell (ISC) maintenance and proliferation, but specific loss of the Grh.O isoform results in loss of ISCs from the epithelium. This was confirmed by generation of a new Grh.O mutant to control for genetic background effects. Grh.O mutant ISCs were not lost due to cell death but were forced to differentiate. Ectopic expression of the Grh.N isoform also resulted in ISC differentiation suggesting that the two isoforms act in an opposing manner. Grh.O expression must be tightly regulated as high-level ectopic expression in enteroblasts, but not ISCs, resulted in cells with confused identity and promoted excess proliferation in the epithelium. Thus, midgut regeneration is not only dependent upon signalling pathways that regulate transcription factor expression, but also upon regulated mRNA splicing of these genes.
Spatiotemporal modelling and mapping of cervical cancer incidence among HIV positive women in South Africa: A nationwide study
Authors: Tafadzwa Dhokotera , Julien Riou , Lina Bartels , Eliane Rohner , Frederique Chammartin , Leigh Johnson , Elvira Singh , Victor Olago , Mazvita Muchengeti , Matthias Egger , Julia Bohlius , Garyfallos Konstantinoudis
Published: December 2020

Disparities in invasive cervical cancer (ICC) incidence exist globally, particularly in HIV positive women who are at elevated risk compared to HIV negative women. We aimed to determine the spatial, temporal, and spatiotemporal incidence of ICC and the associated factors among HIV positive women in South Africa. We included ICC cases in women diagnosed with HIV from the South African HIV cancer match study during 2004-2014. We used the Thembisa model to estimate women diagnosed with HIV per municipality, age group and calendar year. We fitted Bayesian hierarchical models to estimate the spatiotemporal distribution of ICC incidence among women diagnosed with HIV. We also examined the association of deprivation, access to health (using the number of health facilities per municipality) and urbanicity with ICC incidence. We included 17,821 ICC cases and demonstrated a decreasing trend in ICC incidence, from 306 to 312 in 2004 and from 160 to 191 in 2014 per 100,000 person-years across all corrections. The spatial relative rate (RR) ranged from 0.27 to 4.43. In the model adjusting for covariates, the most affluent municipalities had a RR of 3.18 (95% Credible Interval 1.82, 5.57) compared to the least affluent ones, and municipalities with better access to health care had a RR of 1.52 (1.03, 2.27) compared to municipalities with worse access to health. More efforts should be made to ensure equitable access to health services, including mitigating physical barriers, such as transportation to health centres and strengthening of screening programmes.

Novelty and Impact

This is the first nationwide study in South Africa to evaluate spatial and spatiotemporal distribution of cervical cancer in women diagnosed with HIV. The results show an increased incidence of cervical cancer in affluent municipalities and in those with better access to health care. This is likely driven by better access to health care in more affluent areas. More efforts should be made to ensure equitable access to health services, including mitigating physical barriers.
Telehealth Applied to Deliver In-situ Behavioral Skills Training to Reduce Car Seat Misuse During the Covid-19 Pandemic
Authors: DeCarli James M.
Published: December 2020

Objective

The use of telehealth has been a common approach to deliver health education before and during the COVID-19 pandemic. However, its ability to apply behavioral skills training (BST) for CRS education has been undocumented. This study assessed the efficacy of telehealth to deliver in-situ behavioral skills training (BST) to teach expectant parents how to install and use their child restraint system (CRS) to reduce misuse and improve retention during the COVID-19 pandemic.

Method

A repeated measures group design was used to evaluate 171 individual participants, in a 37-step CRS task analysis for baseline, BST, and follow-up. Performance across all participants was aggregated for each task analysis. Participants were recruited from National Highway Traffic Safety Administration car seat fitting stations during the Covid-19 pandemic between March through July, 2020.

Results

Baseline results identified significant critical misuse across participants. With BST, delivered with telehealth, misuse decreased by 97% among 37 task objectives. A 2-week follow-up evaluation concluded that 100% of participants retained the skills they mastered during BST.

Conclusions

This study suggests the use of telehealth, as a method of BST delivery for CRS education, is an effective approach to reduce CRS misuse and the burden of child occupant motor vehicle injury. It was found to empower participants and improve their self-confidence, while ensuring the safety of their child occupant. While it was found to be an effective approach for expectant parents during the COVID-19 pandemic, it also has broader child passenger safety program and train-the-trainer implications beyond the COVID-19 pandemic.
Simultaneous in vitro simulation of multiple antimicrobial agents with different elimination half-lives in a pre-clinical infection model
Authors: Kesisoglou Iordanis , Eales Brianna M , Ledesma Kimberly R. , Merlau Paul R. , Tam Vincent H , Wang Weiqun , Nikolaou Michael
Published: December 2020

Combination therapy for treatment of multi-drug resistant bacterial infections is becoming increasingly common. In vitro testing of drug combinations under realistic pharmacokinetic conditions is needed before a corresponding combination is eventually put into clinical use. The current standard for in vitro simulation of the pharmacokinetics of two drugs with distinct elimination half-lives cannot be extended for combinations of three or more agents, posing a growing need. To address that need we develop a general method to design an in vitro model for simultaneous simulation of the kinetics of an arbitrary number ofNdrugs with different half-lives. The method developed entails two possible configurations: (a) An in-series configuration, which generalizes the standard two-drug design forNdrugs and offers additional flexibility even for two drugs, and (b) an in-parallel configuration, which is new, and offers yet additional flexibility over the in-series configuration. Corresponding design equations for sizing and operation of each configuration are rigorously developed for immediate use by experimenters. These equations were used for experimental verification using a combination of three antibiotics with distinctly different half-lives (meropenem, ceftazidime, and levofloxacin). While experimental verification involved antibiotics, the method is applicable to any anti-infective or anti-cancer drugs with distinct elimination pharmacokinetics. With increasing importance of in vitro simulation of the kinetics of an arbitrary number of drugs in combination, the methods developed here are an important new tool for the design of such in vitro models.
Multicohort Analysis of Publicly-available Monocyte Expression Data Identifies Gene Signatures to Accurately Monitor Subset-specific Changes in Human Diseases
Authors: Vallania Francesco , Zisman Liron , Macaubas Claudia , Hung Shu-Chen , Rajasekaran Narendiran , Mason Sonia , Graf Jonathan , Nakamura Mary , Mellins Elizabeth D , Khatri Purvesh
Published: December 2020

Monocytes and monocyte-derived cells play important roles in the regulation of inflammation, both as precursors as well as effector cells. Monocytes are heterogeneous and characterized by three distinct subsets in humans. Classical and non-classical monocytes represent the most abundant subsets, each carrying out distinct biological functions. Consequently, altered frequencies of different subsets have been associated with inflammatory conditions, such as infections and autoimmune disorders including lupus, rheumatoid arthritis, inflammatory bowel disease, and, more recently, COVID-19. Dissecting the contribution of different monocyte subsets to disease is currently limited by samples and cohorts, often resulting in underpowered studies and, consequently, poor reproducibility. Public transcriptomes provide an alternative source of data characterized by high statistical power and real world heterogeneity. However, most transcriptome datasets profile bulk blood or tissue samples, requiring the use ofin silicoapproaches to quantify changes in the levels of specific cell types.

Here, we integrated 853 publicly available microarray expression profiles of sorted human monocyte subsets from 45 independent studies to identify robust and parsimonious gene expression signatures, consisting of 10 genes specific to each subset. These signatures, although derived using only datasets profiling healthy individuals, maintain their accuracy independent of the disease state in an independent cohort profiled by RNA-sequencing (AUC = 1.0). Furthermore, we demonstrate that our signatures are specific to monocyte subsets compared to other immune cells such as B, T, dendritic cells (DCs) and natural killer (NK) cells (AUC = 0.87~0.88, p<2.2e-16). This increased specificity results in estimated monocyte subset levels that are strongly correlated with cytometry-based quantification of cellular subsets (r = 0.69, p = 6.7e-4). Consequently, we show that these monocyte subset-specific signatures can be used to quantify changes in monocyte subsets levels in expression profiles from patients in clinical trials. Finally, we show that proteins encoded by our signature genes can be used in cytometry-based assays to specifically sort monocyte subsets. Our results demonstrate the robustness, versatility, and utility of our computational approach and provide a framework for the discovery of new cellular markers.
Inferring within-flock transmission dynamics of highly pathogenic avian influenza (H5N8) in France, 2020
Authors: Vergne Timothée , Gubbins Simon , Guinat Claire , Bauzile Billy , Delpont Mattias , Chakraborty Debapriyo , Gruson Hugo , Roche Benjamin , Andraud Mathieu , Paul Mathilde , Guérin Jean-Luc
Published: December 2020

Following the emergence of highly pathogenic avian influenza (H5N8) in France in early December 2020, we used duck mortality data of the index case to investigate within-flock transmission dynamics. A stochastic epidemic model was adjusted to the daily mortality data and model parameters were estimated using an approximate Bayesian computation sequential Monte Carlo (ABC-SMC) algorithm. Results suggested that the virus was introduced 4 days (95% credible interval: 3 – 5) prior to the day suspicion was reported and that the transmission rate was 3.7 day-1(95%CI: 2.6 – 5.3). On average, ducks started being infectious 3.1 hours (95%CI: 0.4 – 8.0) after infection and remained infectious for 4.4 days (95%CI: 3.1 – 5.6). Model outputs also suggested that the number of infectious ducks was already 3239 (95%CI: 26 – 3706) the day before suspicion, emphasising the substantial latent threat this virus could pose to other poultry farms and to neighbouring wildlife. These estimations can be applied to upcoming outbreaks and made available to veterinary services within few hours. This study illustrates how mechanistic models can provide rapid relevant insights to contribute to the management of infectious disease outbreaks of farmed animals.
Density and temperature controlled fluid extraction in a bacterial biofilm is determined by poly-γ-glutamic acid production
Authors: Morris Ryan J. , Sukhodub Tetyana , MacPhee Cait E. , Stanley-Wall Nicola R.
Published: December 2020

A hallmark of microbial biofilms is the self-production of extracellular matrix that encases the cells resident within the community. The matrix provides protection from the environment, while spatial heterogeneity of expression influences the structural morphology and colony spreading dynamics.Bacillus subtilisis a model bacterial system used to uncover the regulatory pathways and key building blocks required for biofilm growth and development. Previous reports have suggested that poly-γ-glutamic acid (PGA) production is suppressed during biofilm formation and does not play a major role in biofilm morphology of the undomesticated isolate NCIB 3610. In this work we report on the observation of multiple travelling fronts that develop during the early stage ofB. subtiliscolony biofilm formation. We find the emergence of a highly motile population of bacteria that is facilitated by the extraction of fluid from the underlying agar substrate. Motility develops behind a moving front of fluid that propagates from the boundary of the biofilm towards the interior. The extent of proliferation is strongly modulated by the presence of extracellular polysaccharides (EPS). We trace the origin of this moving front of fluid to the production of PGA. We find that PGA production is correlated with higher temperatures, resulting in a mature biofilm morphology that is distinct from the biofilm architecture typically associated withB. subtilis. Our results suggest thatB. subtilisNCIB 3610 produces distinct biofilm matrices in response to environmental conditions.
Systematic analysis of goal-related movement sequences during maternal behavior in a female mouse model for Rett syndrome
Authors: Stevenson Parker K. , Casenhiser Devin M. , Krishnan Keerthi
Published: December 2020

Parenting is an ethologically relevant social behavior consisting of stereotypic components involving the care and nourishment of young. First-time rodent dams seek and gather wandering/scattered pups back to the nest (pup retrieval), an essential aspect of maternal care. Over the decades, qualitative observations of the behaving animal have been presented in quantitative discrete units. However, systematic analysis of the dynamic sequences of goal-related movements that comprise the entire behavioral sequence, which would be ultimately essential for understanding the underlying neurobiology, is usually not analyzed. Here, we present systematic analysis of pup retrieval behavior across three days in alloparental female mice (Surrogates or Sur) of two genotypes;Mecp2Heterozygotes(Het), a female mouse model for a neuropsychiatric disorder called Rett syndrome and their wild type (WT) siblings. Additionally, we analyzed CBA/CaJ and C57BL/6J WT surrogates for within-strain comparisons. Frame-by-frame analysis over different phases was performed manually using DataVyu software.

We previously showed that Het are inefficient, by measuring latency and errors, at pup retrieval. Here, we show that the sequence of searching, pup-approach and good retrieval crystallizes over time for WT; this sequence does not crystallize in Het. We found that goal-related movements of Het in different phases were similar to WT, suggesting context-driven atypical dynamic patterns in Het. We also identified pup approach and pup grooming as atypical tactile interactions between pups and Het, which contribute to inefficient pup retrieval. Day-by-day analysis showed dynamic changes in goal-related movements in individual animals across genotypes and strains in response to the growing pups. Overall, our approach 1) embraces natural variation in individual mice on different days of pup retrieval behavior, 2) establishes a “gold-standard” manually curated dataset to next build behavioral repertoires using machine learning approaches, and 3) identifies distinct atypical tactile sensory processing in a female mouse model for Rett syndrome.
The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147-receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease
Authors: Avolio Elisa , Carrabba Michele , Milligan Rachel , Williamson Maia Kavanagh , Beltrami Antonio P , Gupta Kapil , Elvers Karen T , Gamez Monica , Foster Rebecca , Gillespie Kathleen , Hamilton Fergus , Arnold David , Berger Imre , Caputo Massimo , Davidson Andrew D , Hill Darryl , Madeddu Paolo
Published: December 2020

Severe coronavirus disease 2019 (COVID-19) manifests as a life-threatening microvascular syndrome. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the Spike (S) protein to engage with its receptors and infect host cells. To date, it is still not known whether heart vascular pericytes (PCs) are infected by SARS-CoV-2, and if the S protein alone provokes PC dysfunction. Here, we aimed to investigate the effects of the S protein on primary human cardiac PC signalling and function. Results show, for the first time, that cardiac PCs are not permissive to SARS-CoV-2 infectionin vitro, whilst a recombinant S protein alone elicits functional alterations in PCs. This was documented as: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in thecytokine storm, and (4) production of pro-apoptotic factors responsible for EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation and rescued PC function in the presence of the S protein. In conclusion, our findings suggest that circulating S protein prompts vascular PC dysfunction, potentially contributing to establishing microvascular injury in organs distant from the site of infection. This mechanism may have clinical and therapeutic implications.

Clinical perspective

Severe COVID-19 manifests as a microvascular syndrome, but whether SARS-CoV-2 infects and damages heart vascular pericytes (PCs) remains unknown.

We provide evidence that cardiac PCs are not infected by SARS-CoV-2. Importantly, we show that the recombinant S protein alone elicits cellular signalling through the CD147 receptor in cardiac PCs, thereby inducing cell dysfunction and microvascular disruptionin vitro.

This study suggests that soluble S protein can potentially propagate damage to organs distant from sites of infection, promoting microvascular injury. Blocking the CD147 receptor in patients may help protect the vasculature not only from infection, but also from the collateral damage caused by the S protein.
Noise Distorts the Epigenetic Landscape and Shapes Cell Fate Decisions
Authors: Coomer Megan A. , Ham Lucy , Stumpf Michael P. H.
Published: December 2020

The Waddington epigenetic landscape has become an iconic representation of the cellular differentiation process. Recent single-cell transcriptomic data provide new opportunities for quantifying this originally conceptual tool, offering insight into the gene regulatory networks underlying cellular development. While many methods for constructing the landscape have been proposed, by far the most commonly employed approach is based on computing the landscape as the negative logarithm of the steady-state probability distribution. Here, we use simple models to highlight the complexities and limitations that arise when reconstructing the potential landscape in the presence of stochastic fluctuations. We consider how the landscape changes in accordance with different stochastic systems, and show that it is the subtle interplay between the deterministic and stochastic components of the system that ultimately shapes the landscape. We further discuss how the presence of noise has important implications for the identifiability of the regulatory dynamics from experimental data.
CGRP-receptor family reveals endogenous GPCR agonist bias and its significance in primary human cardiovascular cells
Authors: Clark Ashley J. , Mullooly Niamh , Safitri Dewi , Harris Matthew , de Vries Tessa , Van Den Brink Antoinette Maassen , Poyner David R. , Giani Davide , Wigglesworth Mark , Ladds Graham
Published: December 2020

Agonist bias at G protein-coupled receptors has attracted considerable interest, although its relevance for physiologically-produced agonists is not always clear. Here, using primary human cells and gene editing techniques, we demonstrate for the first time, endogenous agonist bias with physiological consequences for the calcitonin-like receptor (CLR). We reveal that by switching the accessory protein: receptor activity-modifying protein (RAMP) associated with CLR we can re-route the physiological pathways activated by the stimulating peptide agonists. These results have revealed a unique role in calcium-mediated nitric oxide signalling for the little-understood peptide adrenomedullin 2 and distinct pro-proliferative effects of calcitonin-gene related peptide (CGRP) and adrenomedullin in cardiovascular cells. This work reveals that CLR-based agonist bias occurs naturally in human cells and has a fundamental purpose for its existence. We anticipate this will be a starting point for more studies into RAMP function in native environments and its importance in endogenous GPCR signalling.
GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer
Authors: Brun Sonia , Pascussi Jean-Marc , Gifu Elena Patricia , Bestion Eloïne , Macek-Jilkova Zuzana , Wang Guanxiong , Bassissi Firas , Mezouar Soraya , Courcambeck Jérôme , Merle Philippe , Decaens Thomas , Pannequin Julie , Halfon Philippe , de Fromentel Claude Caron
Published: December 2020

Patients with advanced hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) have a very poor prognosis due to the lack of efficient treatments. As observed in several other tumors, the effectiveness of treatments is mainly hampered by the presence of a highly tumorigenic sub-population of cancer cells called cancer stem cells (CSCs). Indeed, CSCs are resistant to chemotherapy and radiotherapy and have the ability to regenerate the tumor bulk. Hence, innovative drugs that are efficient against both bulk tumor cells and CSCs would likely improve cancer treatment. In this study, we demonstrated that GNS561, a new autophagy inhibitor that induces lysosomal cell death, showed significant activity against not only the whole tumor population but also a sub-population displaying CSC features (high ALDH activity and tumorsphere formation ability) in HCC and in liver mCRC cell lines. These results were confirmedin vivoin HCC from a DEN-induced cirrhotic rat model in which GNS561 decreased tumor growth and reduced the frequency of CSCs (CD90+CD45-). Accordingly, GNS561, which was in a global phase 1b clinical trial in liver cancers that was recently successful, offers great promise for cancer therapy by exterminating both the tumor bulk and the CSC sub-population.
Population genomics of the maize pathogenUstilago maydis: demographic history and role of virulence clusters in adaptation
Authors: Schweizer Gabriel , Haider Muhammad Bilal , Barroso Gustavo V. , Rössel Nicole , Münch Karin , Kahmann Regine , Dutheil Julien Y.
Published: December 2020

The tight interaction between pathogens and their hosts results in reciprocal selective forces that impact the genetic diversity of the interacting species. The footprints of this selection differ between pathosystems because of distinct life-history traits, demographic histories, or genome architectures. Here, we studied the genome-wide patterns of genetic diversity of 22 isolates of the causative agent of the corn smut disease,Ustilago maydis, originating from five locations in Mexico, the presumed center of origin of this species. In this species, many genes encoding secreted effector proteins reside in so-called virulence clusters in the genome, an arrangement that is so far not found in other filamentous plant pathogens. Using a combination of population genomic statistical analyses, we assessed the geographical, historical and genome-wide variation of genetic diversity in this fungal pathogen.

We report evidence of two partially admixed subpopulations that are only loosely associated with geographic origin. Using the multiple sequentially Markov coalescent model, we inferred the demographic history of the two pathogen subpopulations over the last 0.5 million years. We show that both populations experienced a recent strong bottleneck starting around 10,000 years ago, coinciding with the assumed time of maize domestication. While the genome average genetic diversity is low compared to other fungal pathogens, we estimated that the rate of non-synonymous adaptive substitutions is three times higher in genes located within virulence clusters compared to non-clustered genes, including non-clustered effector genes. These results highlight the role that these singular genomic regions play in the evolution of this pathogen.

Significance statement

The maize pathogenUstilago maydisis a model species to study fungal cell biology and biotrophic host-pathogen interactions. Population genetic studies of this species, however, were so far restricted to using a few molecular markers, and genome-wide comparisons involved species that diverged more than 20 million years ago. Here, we sequenced the genomes of 22 MexicanU. maydisisolates to study the recent evolutionary history of this species. We identified two co-existing populations that went through a recent bottleneck and whose divergence date overlaps with the time of maize domestication. Contrasting the patterns of genetic diversity in different categories of genes, we further showed that effector genes in virulence clusters display a high rate of adaptive mutations, highlighting the importance of these effector arrangements for the adaptation ofU. maydisto its host.
Cortical entrainment to hierarchical contextual rhythms recomposes dynamic attending in visual perception
Authors: Yuan Peijun , Hu Ruichen , Zhang Xue , Wang Ying , Jiang Yi
Published: December 2020

Temporal regularity is ubiquitous and essential to guiding attention and coordinating behavior within a dynamic environment. Previous researchers have modeled attention as an internal rhythm that may entrain to first-order regularity from rhythmic events to prioritize information selection at specific time points. Using the attentional blink paradigm, here we show that higher-order regularity based on rhythmic organization of contextual features (pitch, color, or motion) may serve as a temporal frame to recompose the dynamic profile of visual temporal attention. Critically, such attentional reframing effect is well predicted by cortical entrainment to the higher-order contextual structure at the delta band as well as its coupling with the stimulus-driven alpha power. These results suggest that the human brain involuntarily exploits multiscale regularities in rhythmic contexts to recompose dynamic attending in visual perception, and highlight neural entrainment as a central mechanism for optimizing our conscious experience of the world in the time dimension.
Hyperbolic matrix factorization reaffirms the negative curvature of the native biological space
Authors: Poleksic Aleksandar
Published: December 2020

Past research in systems biology has taken for granted the Euclidean geometry of biological space. This has not only drawn parallels to other fields but has also been convenient due to the ample statistical and numerical optimization tools available to address the core task and downstream machine learning problems. However, emerging theoretical studies now demonstrate that biological databases exhibit hierarchical topology, characterized by heterogeneous degree distribution and a high degree of clustering, thus contradicting the flat geometry assumption. Namely, since the number of nodes in hierarchical structures grows exponentially with node depth, the biological networks naturally reside in a hyperbolic space where the circle circumference and disk area are the exponential functions of the radius. To test these claims and assess potential benefits of the applications grounded in the above hypothesis, we have developed a mathematical framework and an accompanying computational procedure for matrix factorization and implied biological relationship inference in hyperbolic space. Not only does our study demonstrate a significant increase in the accuracy of hyperbolic embedding compared to Euclidean embedding, but it also shows that the latent dimension of an optimal hyperbolic embedding is by more than an order of magnitude smaller than the latent dimension of an optimal Euclidean embedding. We see this as additional evidence that hyperbolic geometry, rather than Euclidean, underlines the biological system.
Schema-induced shifts in mice navigational strategies are unveiled by a minimal behavioral model of spatial exploration
Authors: Vallianatou Christina-Anna , Alonso Alejandra , Aleman Adrian , Genzel Lisa , Stella Federico
Published: December 2020

Shifts in spatial patterns produced during the execution of a navigational task can be used to track the effects of the accumulation of knowledge and the acquisition of structured information about the environment. Here we provide a quantitative analysis of mice behavior while performing a novel goal localization task in a large, modular arena, the HexMaze. To demonstrate the effects of different forms of previous knowledge we first obtain a precise statistical characterization of animals’ paths with sub-trial resolution and over different phases of learning. The emergence of a flexible representation of the task is accompanied by a progressive improvement of performance, mediated by multiple, multiplexed time scales. We then use a generative mathematical model of the animal behavior to isolate the specific contributions to the final navigational strategy. We find that animal behavior can be accurately reproduced by the combined effect of a goal-oriented component, becoming stronger with the progression of learning, and of a random walk component, producing choices unrelated to the task and only partially weakened in time.
Design of novel Cyanovirin-N variants by modulation of binding dynamics through distal mutations
Authors: Kazan I. Can , Sharma Prerna , Rahman Mohammad Imtiazur , Bobkov Andrey , Fromme Raimund , Ghirlanda Giovanna , Ozkan S. Banu
Published: December 2020

We develop integrated coevolution and dynamic coupling (ICDC) approach to identify, mutate, and assess distal sites to modulate function. We validate the approach first by analyzing the existing mutational fitness data of TEM-1 β-lactamase and show that allosteric positions co-evolved and dynamically coupled with the active site significantly modulate function. We further apply ICDC approach to identify positions and their mutations that can modulate binding affinity in a lectin, Cyanovirin-N (CV-N), that selectively binds to dimannose, and predict binding energies of its variants through Adaptive BP-Dock. Computational and experimental analyses reveal that binding enhancing mutants identified by ICDC impact the dynamics of the binding pocket, and show that rigidification of the binding residues compensates for the entropic cost of binding. This work suggests a general mechanism by which distal mutations modulate function through dynamic allostery and provides a blueprint to identify candidates for mutagenesis in order to optimize protein function.
osr1maintains renal progenitors and regulates podocyte development by promotingwnt2bathrough antagonism ofhand2
Authors: Drummond Bridgette E. , Chambers Brooke E. , Wesselman Hannah M. , Ulrich Marisa N. , Gerlach Gary F. , Kroeger Paul T. , Leshchiner Ignaty , Goessling Wolfram , Wingert Rebecca A.
Published: December 2020

Knowledge about the genetic pathways that control renal cell lineage development is essential to better understand the basis of congenital malformations of the kidney and design regenerative medicine therapies. The embryonic zebrafish kidney, or pronephros, contains two nephrons that are conserved with humans. Recently, the transcription factors Osr1 and Hand2 were found to exert antagonistic influences to balance kidney specification (Perens et al., 2016). Here, we performed a forward genetic screen in zebrafish to identify nephrogenesis regulators, where whole genome sequencing of the noveloceanside(ocn) mutant revealed a nonsense mutation inosr1. ocnmutants evince severe pronephros defects including abrogation of podocytes and proximal tubule cells. Our studies reveal thatosr1is not needed to specify renal progenitors, but rather required to maintain their survival. Additionally,osr1is requisite for expression of the canonical Wnt ligandwnt2ba, wherewnt2bais expressed in the intermediate mesoderm (IM) and later restricts to podocytes. Deficiency ofwnt2bareduced podocyte progenitors, where overexpression ofwnt2bawas sufficient to rescue the podocyte lineage as well asosr1loss of function. Finally, we demonstrate that reciprocal antagonism betweenosr1andhand2mediates podocyte development specifically by controllingwnt2baexpression in the IM. Together, our data show that Osr1 is essential for a sequence of temporal functions that mediate the survival and lineage decisions of IM progenitors, and subsequently the maintenance of podocytes and proximal tubule epithelium in the embryonic nephron.
Ribosome profiling inStreptococcus pneumoniaereveals the role of methylation of 23S rRNA nucleotide G748 on ribosome stalling
Authors: Shoji Tatsuma , Takaya Akiko , Kusuya Yoko , Takahashi Hiroki , Kawashima Hiroto
Published: December 2020

2.

(1) Background

Many nucleotides in 23S rRNA are methylated post-transcriptionally by methyltransferases and cluster around the peptidyltransferase center (PTC) and the nascent peptidyl exit tunnel (NPET) located in 50S subunit of 70S ribosome. Biochemical interactions between a nascent peptide and the tunnel may stall ribosome movement and affect expression levels of the protein. However, no studies have shown a role for NPET on ribosome stalling using an NPET mutant.

(2) Results

A ribosome profiling assay inStreptococcus pneumoniaedemonstrates for the first time that an NPET mutant exhibits completely different ribosome occupancy compared to wild-type. We demonstrate, using RNA footprinting, that changes in ribosome occupancy correlate with changes in ribosome stalling. Further, statistical analysis shows that short peptide sequences that cause ribosome stalling are species-specific and evolutionarily selected. NPET structure is required to realize these specie-specific ribosome stalling.

(3) Conclusions

Results support the role of NPET on ribosome stalling. NPET structure is required to realize the species-specific and evolutionary conserved ribosome stalling. These findings clarify the role of NPET structure on the translation process.