bluuebunny/crossref_metadata_2025 huggingface dataset:
Chlamydia trachomatisEncodes a Dynamic, Ring-Forming Bactofilin Critical for Maintaining Cell Size and Shape
Authors: Brockett Mary R. , Lee Junghoon , Cox John V. , Liechti George W. , Ouellette Scot P.
Published: October 2020

Bactofilins are polymer-forming cytoskeletal proteins that are widely conserved in bacteria. Members of this protein family have diverse functional roles such as orienting subcellular molecular processes, establishing cell polarity, and aiding in cell shape maintenance.Chlamydiaspecies are obligate intracellular bacteria that undergo a developmental cycle alternating between an infectious, non-dividing EB and a non-infectious, dividing RB. AsChlamydiadivides by a polarized division process, we hypothesized that BacACTmay function to establish polarity in these unique bacteria. Using sequence alignment to the conserved bactofilin domain, we identified a bactofilin ortholog, BacACT, in the obligate intracellular pathogenChlamydia trachomatis. Utilizing a combination of fusion constructs and high-resolution fluorescence microscopy, we determined that BacACTforms a dynamic, membrane-associated, ring-like structure inChlamydia’sreplicative RB form. Contrary to our hypothesis, this filamentous ring structure is distinct from the microbe’s cell division machinery and does not colocalize with septal peptidoglycan or MreB, the major organizer of the bacterium’s division complex. Bacterial two-hybrid assays demonstrated BacACTinteracts homotypically but does not directly interact with proteins involved in cell division or peptidoglycan biosynthesis. To investigate the function of BacACTin chlamydial development, we constructed a conditional knockdown strain using a newly developed CRISPR interference system. We observed that reducingbacACTexpression significantly impacted chlamydial cell size and morphology. Normal RB morphology was restored when an additional copy of BacACTwas expressedin transduring knockdown. These data reveal a novel function for chlamydial bactofilin in maintaining cell shape in this obligate intracellular bacterium.

IMPORTANCE

Chlamydiais an ancient, obligate intracellular bacterium with a unique biphasic developmental cycle. As a result of its evolution within the osmotically stable environment of a host cell,Chlamydiahas lost its dependence on side-wall peptidoglycan, and maintains only a fraction of the components thought to be required for regulating bacterial cell size and division. As such, very little is known about howChlamydiaspecies carry out these critical processes in the absence of a stabilizing peptidoglycan layer. In the current study, we identify a novel cytoskeletal element, termed a bactofilin, that is critical for maintaining the morphology of the bacteria. Using state-of-the-art genetic techniques for this organism, we demonstrate that chlamydial bactofilin forms a dynamic ring structure independent of the microbe’s division machinery and that abrogating its expression level using CRISPR interference results in abnormal morphologic forms. These findings enhance our understanding of chlamydial biology and bactofilins more generally.
Prevalence of SARS-CoV-2 antibodies in France: results from nationwide serological surveillance
Authors: Vu Stéphane Le , Jones Gabrielle , Anna François , Rose Thierry , Richard Jean-Baptiste , Bernard-Stoecklin Sibylle , Goyard Sophie , Demeret Caroline , Helynck Olivier , Robin Corinne , Monnet Virgile , Facci Louise Perrin de , Ungeheuer Marie-Noelle , Léon Lucie , Guillois Yvonnick , Filleul Laurent , Charneau Pierre , Lévy-Bruhl Daniel , van der Werf Sylvie , Noel Harold
Published: October 2020

Background

Assessment of cumulative incidence of SARS-CoV-2 infections is critical for monitoring the course and the extent of the epidemic. As asymptomatic or mild cases were typically not captured by surveillance data in France, we implemented nationwide serological surveillance. We present estimates for prevalence of anti-SARS-CoV-2 antibodies in the French population and the proportion of infected individuals who developed potentially protective neutralizing antibodies throughout the first epidemic wave.

Methods

We performed serial cross-sectional sampling of residual sera over three periods: prior to (9-15 March), during (6-12 April) and following (11-17 May) a nationwide lockdown. Each sample was tested for anti-SARS-CoV-2 IgG antibodies targeting the Nucleoprotein and Spike using two Luciferase-Linked ImmunoSorbent Assays, and for neutralising antibodies using a pseudo-neutralisation assay. We fitted a general linear mixed model of seropositivity in a Bayesian framework to derive prevalence estimates stratified by age, sex and region.

Findings

In total, sera from 11 021 individuals were analysed. Nationwide seroprevalence of SARS-CoV-2 antibodies was estimated at 0.41% [0.05−0.88] mid-March, 4.14% [3.31−4.99] mid-April and 4.93% [4.02−5.89] mid-May. Approximately 70% of seropositive individuals had detectable neutralising antibodies. Seroprevalence was higher in regions where circulation occurred earlier and was more intense. Seroprevalence was lowest in children under 10 years of age (2.72% [1.10−4.87]).

Interpretation

Seroprevalence estimates confirm that the nationwide lockdown substantially curbed transmission and that the vast majority of the French population remains susceptible to SARS-CoV-2. Low seroprevalence in school age children suggests limited susceptibility and/or transmissibility in this age group. Our results show a clear picture of the progression of the first epidemic wave and provide a framework to inform the ongoing public health response as viral transmission is picking up again in France and globally.

Funding

Santé publique France.
ASSOCIATION BETWEEN VITAMIN D LEVEL AND SERUM LIPID PARAMETERS AMONG INDIAN ADULTS WORKING IN IT SECTOR: A RETROSPECTIVE OBSERVATIONAL STUDY
Authors: Anantharamakrishnan Bhavani , Benansia Jisha
Published: October 2020

Background & objectives

Association between serum vitamin D levels and lipid levels has been focus of research in recent times. The relationship of 25(OH)D and Atherogenic Index of Plasma is not well established among Indian population. We investigated the prevalence of vitamin D deficiency, its relation with serum lipids and AIP among IT employees.

Methods

A retrospective observational study was conducted among employees of multiple IT firms in Bangalore, India. Participants were selected by convenient sampling from annual comprehensive health screening at work place. Serum lipid levels were assessed auto-analyser (ADVIA1650; Siemens, NY, USA). Serum 25(OH)D was assessed by Chemiluminescent microparticle immunoassay. AIP was calculated as log [Triglycerides/HDL-Cholesterol].

Results

Among 533 subjects included final analysis, mean of age was 33.18±6.6 with Male: female ratio of 1.8:1. Vitamin D deficiency and AIP > 0.15 was observed in 405 (75.98%) and 450 (84.43%) participants respectively. Median HDL-cholesterol was significantly lower (42 Vs 45.5, P value 0.004) and LDL cholesterol was significantly higher (90 Vs 52, P value <0.001) among people with vitamin-D deficiency. LDL (Spearman Rho=-0.18, P <0.001) had weak negative correlation, Total cholesterol (Spearman Rho=-0.1, P Value <0.01) and VLDL (Spearman Rho=-0.18, P Value <0.001) had weak positive correlation with 25(OH)D. No statistically significant association was observed between AIP and vitamin-D.

Conclusions

More than two thirds of IT employees were deficient in vitamin D. Vitamin D deficiency was associated with significantly higher LDL, lower HDL and VLDL levels. No statistically significant association was observed between vitamin D and AIP.
Changes of evening exposure to electronic devices during the COVID-19 lockdown affect the time course of sleep disturbances
Authors: Salfi Federico , Amicucci Giulia , Corigliano Domenico , D’Atri Aurora , Viselli Lorenzo , Tempesta Daniela , Ferrara Michele
Published: October 2020

Study Objectives

During the COVID-19 lockdown, there was a worldwide increase in electronic devices’ daily usage. The exposure to backlit screens before falling asleep leads to negative consequences on sleep health through its influence on the circadian system. We investigated the relationship between the changes in evening screen exposure and the time course of sleep disturbances during the home confinement period due to COVID-19.

Methods

2123 Italians were longitudinally tested during the third and the seventh week of lockdown. The web-based survey evaluated sleep quality and insomnia symptoms through the Pittsburgh Sleep Quality Index and the Insomnia Severity Index. During the second assessment, respondents reported the changes in the backlit screen exposure in the two hours before falling asleep.

Results

Participants who increased electronic device usage showed decreased sleep quality, exacerbated insomnia symptoms, reduced sleep duration, higher sleep onset latency, and delayed bedtime and rising time. In this subgroup, the prevalence of poor sleepers and clinical insomniacs increased. Conversely, respondents reporting decreased screen exposure exhibited improved sleep quality and insomnia symptoms. In this subgroup, the prevalence of poor sleepers and clinical insomniacs decreased. Respondents preserving their screen time habits did not show any change in the sleep parameters.

Conclusions

Our investigation demonstrated a strong relationship between the modifications of the evening electronic device usage and the time course of sleep disturbances during the lockdown period. Interventions to raise public awareness about the risks of excessive exposure to backlit screens are necessary to prevent sleep disturbances and foster well-being during the home confinement due to COVID-19.

Statement of Significance

The present investigation is the first to provide insights about the relationship between the changes in evening electronic device usage and the time course of sleep disturbances during the COVID-19 lockdown. Consistent with the well-known negative effect of backlit screen lights on circadian physiology, we demonstrated a strong relationship between the screen time modifications in the hours before falling asleep, the development and exacerbation of sleep disturbances, and the changes of sleep/wake patterns during the period of home confinement due to COVID-19 pandemic. To date, hundreds of thousands of people are subjected to restraining measures worldwide. Our findings have large scale and broad-spectrum implications, considering the unavoidable increase of electronic device usage during the current period of limited social interactions.
Classification of submandibular salivary stones based on ultrastructural studies
Authors: Tretiakow Dmitry , Skorek Andrzej , Wysocka Joanna , Darowicki Kazimierz , Ryl Jacek
Published: October 2020

Introduction

Sialolithiasis remains a clinical problem with unclear etiopathogenesis, lack of prevention methods and only surgical treatment.

Materials and Methods

An ultrastructure examination of submandibular sialoliths obtained from patients with chronic sialolithiasis was conducted using a scanning electron microscope and X-ray photoelectron spectroscopy.

Results

Based on the results, we divided sialoliths into three types: calcified (CAL), organic/lipid (LIP) and mixed (MIX). The core structure of the CAL and MIX is very similar. The core of the LIP has a prevalence of organic components. The intermediate layers’ structure of the CAL is different from LIP and MIX. In LIP and MIX, the organic component begins to increase in intermediate layers rapidly. The structure of the superficial layers for all types of sialoliths is similar.

Conclusions

We introduced a new classification of the submandibular salivary gland stones. Based on the results, it can be said that sialoliths type CAL and LIP have their separate path of origin and development, while MIX is formed as CAL stone, and the further pathway of their growth passes as LIP stones. Organic components was much more than inorganic in all layers of salivary gland stones, which highly prevents their dissolution in the patient’s salivary gland duct.
Predicting the efficacy of exenatide in Parkinson’s disease using genetics – a Mendelian randomization study
Authors: Storm Catherine S. , Kia Demis A. , Almramhi Mona , Athauda Dilan ,   International Parkinson’s Disease Genomics Consortium (IPDGC), Burgess Stephen , Foltynie Thomas , Wood Nicholas W.
Published: October 2020

Background

Exenatide is a glucagon-like peptide 1 receptor (GLP1R) agonist used in type 2 diabetes mellitus that has shown promise for Parkinson’s disease in a phase II clinical trial. Drugs with genetic evidence are more likely to be successful in clinical trials. In this study we investigated whether the genetic technique Mendelian randomization (MR) can “rediscover” the effects of exenatide on diabetes and weight, and predict its efficacy for Parkinson’s disease.

Methods

We used genetic variants associated with increased expression ofGLP1Rin blood to proxy exenatide, as well as variants associated with expression ofDPP4, TLR4and 15 genes thought to act downstream of GLP1R or mimicking alternative actions of GLP-1 in blood and brain tissue. Using an MR approach, we predict the effect of exenatide on type 2 diabetes risk, body mass index (BMI), Parkinson’s disease risk and several Parkinson’s disease progression markers.

Results

We found that genetically-raisedGLP1Rexpression in blood was associated with lower BMI and possibly type 2 diabetes mellitus risk, but not Parkinson’s disease risk, age at onset or progression. ReducedDPP4expression in brain tissue was significantly associated with increased Parkinson’s disease risk.

Conclusions

We demonstrate the usefulness of MR using expression data in predicting the efficacy of a drug and exploring its mechanism of action. Our data suggest that GLP-1 mimetics like exenatide, if ultimately proven to be effective in Parkinson’s disease, will be through a mechanism that is independent of GLP1R in blood.
When governments spread lies, the fight is against two viruses: A study on the novel coronavirus pandemic in Brazil
Authors: Biancovilli Priscila , Jurberg Claudia
Published: October 2020

Background

One of the challenges posed by the novel coronavirus pandemic is theinfodemic risk, that is, a huge amount of information being published on the topic, along with misinformation and rumours. Around 100 million people in Brazil (50% of the inhabitants) are users of social media networks, and a substantial amount of false information about the disease circulates in these media.

Objectives

In this study, we examine the agenda-setting, media frame and content of misinformation published on the topic.

Methods

We analysed all pieces of misinformation published by the Brazilian fact-checking service “Agência Lupa”, during six months of 2020. We used content analysis to classify the texts into categories, and three types of rumours were identified: Misleading content; fabricated content; false context.

Results

We analysed 232 pieces of misinformation. Most were published on Facebook (76%), followed by Whatsapp, with 10% of total cases. Half of the stories (47%) are classified as “real-life”, that is, the focus is on everyday situations, or circumstances involving people. Regarding the type of misinformation, there is a preponderance of fabricated content, with 53% of total, followed by false context (34%) and misleading content (13%). Wrong information was mostly published in text format (47%). We discuss the influence that misinformation can have on the behaviour of the Brazilian population during the pandemic and how the media’s agenda-setting is influenced by false information published on social media.

Conclusions

This study shows that misinformation about COVID-19 in Brazil seem to help establish an agenda-setting in the country, and the media frame is aligned with President Bolsonaro’s political position.
Mendelian randomization of dyslipidemia on cognitive impairment among older Americans
Authors: Fu Mingzhou , Bakulski Kelly M. , Higgins Cesar , Ware Erin B.
Published: October 2020

Background

Altered lipid metabolism may be a risk factor for dementia, and blood cholesterol level has a strong genetic component. We tested the hypothesis that dyslipidemia (either low levels of high-density lipoprotein cholesterol (HDL-C) or high total cholesterol) is associated with cognitive status and domains, and assessed inferred causality using genetic predisposition to dyslipidemia as an instrumental variable.

Methods

Using data from European and African genetic ancestry participants in the Health and Retirement Study, we selected observations at the first non-missing biomarker assessment (waves 2006 to 2012). Cognition domains were assessed using episodic memory, mental status, and vocabulary tests. Overall cognitive status was categorized in three levels (normal, cognitive impairment non-dementia, dementia). Based on 2018 clinical guidelines, we compared low HDL-C or high total cholesterol to normal levels. Polygenic scores for dyslipidemia were used as instrumental variables in a Mendelian randomization framework. Multivariable logistic regressions and Wald-type ratio estimators were used to examine associations.

Results

Among European ancestry participants (n = 8781), at risk HDL-C levels were associated with higher odds of cognitive impairment (OR = 1.20, 95%CI: 1.03, 1.40) and worse episodic memory, specifically. Using cumulative genetic risk for HDL-C levels as a valid instrumental variable, a significant causal estimate was observed between at risk low HDL-C levels and higher odds of dementia (OR = 2.15, 95%CI: 1.16, 3.99). No significant associations were observed between total cholesterol levels and cognitive status. No significant associations were observed in the African ancestry sample (n = 2101).

Conclusion

Our study demonstrates low blood HDL-C is a potential causal risk factor for impaired cognition during aging in non-Hispanic whites of European ancestry. Dyslipidemia can be modified by changing diets, health behaviors, and therapeutic strategies, which can improve cognitive aging. Studies on low density lipoprotein cholesterol, the timing of cholesterol effects on cognition, and larger studies in non-European ancestries are needed.
Nanotube mediated cell-to-cell communication and cannibalism in Halobacillus sp. GSS1 isolated from Sundarbans, India: A cryptic story of survival under nutrient-limiting condition
Authors: Guria Manas Kumar , Sengupta Sohan , Bhattacharyya Maitree , Karmakar Parimal
Published: October 2020

Microorganisms play a self-protective role by evolving their genetic and metabolic machinery to thrive in extreme environmental habitats. Halophiles are such salt-loving extremophilic microorganisms able to adapt, survive, and tend to grow at high salt concentrations. In this study, we have isolated Halobacillus sp. GSS1 from Sundarbans mangrove, India having a strong salt-tolerant ability (up to 4M) in Zobell Marine 2216 medium. The salt adaptation mechanism of Halobacillus sp. was investigated by Confocal microscopy using [Na+] specific dye, ‘Sodium Green’ indicating the ‘salt-in’ strategy for their osmoadaptation. Electron microscopic studies revealed that a contact-dependent cell-to-cell communication was profound among the Halobacillus sp. under nutrient limiting condition. This communication is mediated by ‘nanotube’, which is highly recommended for the exchange of molecular information between the two individual bacteria. The existence of the ‘ymdB’ gene strongly supports our claim for nanotube formation by Halobacillus sp. GSS1. Surprisingly, Halobacillus sp. not only utilizing the nanotubes for communication, rather they desperately use nanotubes as a survival weapon under nutrient limiting conditions by triggering cannibalism. This is the first-ever report on the existence of nanotube mediated cell-to-cell communication and cannibalism in any halophilic bacteria, isolated from Sundarbans mangrove forest, India.

Highlights

The existence of nanotube mediated cell-to-cell communication was discovered in Halobacillus sp. GSS1, isolated from Sundarbans mangrove, India.

The communication of Halobacillus sp. GSS1 was established through single or multiple nanotubes with the neighboring cells.

Intercellular nanotube communication was possible only after the participation of two individual bacteria.

Halobacillus sp. GSS1 also uses these nanotubes as a survival weapon by triggering the cannibalism to kill their genetically identical siblings.

The presence of the ymdB gene in Halobacillus sp. GSS1 strongly confers the evidence of nanotube formation.

Graphical Abstract
Ceragenins and antimicrobial peptides kill bacteria through distinct mechanisms
Authors: Mitchell Gabriel , Silvis Melanie R. , Talkington Kelsey C. , Budzik Jonathan M. , Dodd Claire E. , Paluba Justin M. , Oki Erika A. , Trotta Kristine L. , Licht Daniel J. , Jimenez-Morales David , Chou Seemay , Savage Paul B. , Gross Carol A. , Marletta Michael A. , Cox Jeffery S.
Published: October 2020

Ceragenins are a family of synthetic amphipathic molecules designed to mimic the properties of naturally-occurring cationic antimicrobial peptides (CAMPs). Although ceragenins have potent antimicrobial activity, whether their mode of action is similar to that of CAMPs has remained elusive. Here we report the results of a comparative study of the bacterial responses to two well-studied CAMPs, LL37 and colistin, and two ceragenins with related structures, CSA13 and CSA131. Using transcriptomic and proteomic analyses, we found thatEscherichia coliresponds similarly to both CAMPs and ceragenins by inducing a Cpx envelope stress response. However, whereasE. coliexposed to CAMPs increased expression of genes involved in colanic acid biosynthesis, bacteria exposed to ceragenins specifically modulated functions related to phosphate transport, indicating distinct mechanisms of action between these two classes of molecules. Although traditional genetic approaches failed to identify genes that confer high-level resistance to ceragenins, using a Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) approach we identifiedE. coliessential genes that when knocked down modify sensitivity to these molecules. Comparison of the essential gene-antibiotic interactions for each of the CAMPs and ceragenins identified both overlapping and distinct dependencies for their antimicrobial activities. Overall, this study indicates that while some bacterial responses to ceragenins overlap with those induced by naturally-occurring CAMPs, these synthetic molecules target the bacterial envelope using a distinctive mode of action.

IMPORTANCE

The development of novel antibiotics is essential since the current arsenal of antimicrobials will soon be ineffective due to the widespread occurrence of antibiotic resistance. Development of naturally-occurring cationic antimicrobial peptides (CAMPs) for therapeutics to combat antibiotic resistance has been hampered by high production costs and protease sensitivity, among other factors. The ceragenins are a family of synthetic CAMP mimics that kill a broad spectrum of bacterial species but are less expensive to produce, resistant to proteolytic degradation and have been associated with low levels of resistance. Determining how ceragenins function may identify new essential biological pathways of bacteria that are less prone to development of resistance and will further our understanding of the design principles for maximizing the effects of synthetic CAMPs.
A Sea Change in Microbial Enzymes: Heterogeneous latitudinal and depth-related gradients in bulk water and particle-associated enzymatic activities from 30°S to 59°N in the Pacific Ocean
Authors: Balmonte John Paul , Simon Meinhard , Giebel Helge-Ansgar , Arnosti Carol
Published: October 2020

Heterotrophic microbes initiate organic matter degradation using extracellular enzymes. Our understanding of differences in microbial enzymatic capabilities, especially among particle-associated taxa and in the deep ocean, is limited by a paucity of hydrolytic enzyme activity measurements. Here, we measured the activities of a broad range of hydrolytic enzymes (glucosidases, peptidases, polysaccharide hydrolases) in epipelagic to bathypelagic bulk water (non-size fractionated), and on particles (≥ 3 μm) along a 9,800 km latitudinal transect from 30°S in the South Pacific to 59°N in the Bering Sea. Individual enzyme activities showed heterogeneous latitudinal and depth-related patterns, with varying biotic and abiotic correlates. With increasing latitude and decreasing temperature, lower laminarinase activities sharply contrasted with higher leucine aminopeptidase (leu-AMP) and chondroitin sulfate hydrolase activities in bulk water. Endopeptidases (chymotrypsins, trypsins) exhibited patchy spatial patterns, and their activities can exceed rates of the widely-measured exopeptidase, leu-AMP. Compared to bulk water, particle-associated enzymatic profiles featured a greater relative importance of endopeptidases, a broader spectrum of polysaccharide hydrolases, and latitudinal and depth-related trends that paralleled variations in particle fluxes. As water depth increased, enzymatic spectra on particles and in bulk water became narrower, and diverged more from one another. These distinct latitudinal and depth-related gradients of enzymatic activities underscore the biogeochemical consequences of emerging global patterns of microbial community structure and function, from surface to deep waters, and among particle-associated taxa.
The impact of life stage and pigment source on the evolution of novel warning signal traits
Authors: Lindstedt Carita , Bagley Robin , Calhim Sara , Jones Mackenzie , Linnen Catherine
Published: October 2020

Our understanding of how novel color traits evolve in aposematic taxa is based largely on studies of reproductive stages and organisms with endogenously produced pigmentation. In these systems, genetic drift is often required for novel alleles to overcome strong purifying selection stemming from frequency-dependent predation and positive assortative mating. Here we show that the importance of these mechanisms can differ if selective processes are considered in larval stage instead. By integrating population genomic data, predation experiments and phenotypic measurements of larvae and their host plants, we show that novel white alleles inNeodiprion lecontei(pine sawfly) larvae spread via selection rather than drift. The cost of being rare was not offset by an enhanced aposematic display or immune function. Instead, bottom-up selection via host plants may drive divergence among populations as white larvae were disproportionately abundant on a pine species with a reduced carotenoid content relative to other pine hosts.
Cortical inhibitory network selects cerebellar signals for movement initiation
Authors: Nashef Abdulraheem , Cohen Oren , Perlmutter Steve I. , Prut Yifat
Published: October 2020

The onset of voluntary movements is driven by coordinated firing across a large population of motor cortical neurons. This pattern of activity is determined by both local interactions and long-range corticocortical and subcortical inputs. The way remote areas of the brain communicate to effectively drive movement is still unclear. We addressed this question by studying an important pathway through which the cerebellum communicates, via the motor thalamus, with the motor cortex. We found that similar to the sensory cortices, thalamic input to the motor cortex triggers feedforward inhibition by directly contacting inhibitory cells via particularly effective GluR2- lacking AMPA receptors blocked by NASPM. Based on these results, we constructed a classifier for SCP-responsive cortical cells to identify pyramidal and PV interneurons and study their role in controlling movements. The findings indicate that PV and pyramidal cells are co-driven by TC input in response to activation of the CTC pathway. During task performance, PV and pyramidal cells had comparable relations to movement parameters (directional tuning and movement duration). However, PV interneurons exhibited stronger movement-related activity that preceded the firing of pyramidal cells. This seemingly counterintuitive sequence of events where inhibitory cells are recruited more strongly and before excitatory cells may in fact enhance the signal-to-noise ratio of cerebellar signals by suppressing other inputs and prioritizing the excitatory synchronized volley from the TC system which occurs at the right time to overcome the inhibitory signal. In this manner, the CTC system can shape cortical activity in a way that exceeds its sheer synaptic efficacy.
Genetic characterization of a mild isolate of papaya ringspot virus type-P (PRSV-P) and assessment of its cross-protection potential under greenhouse and field conditions
Authors: Medina-Salguero Andres X. , Cornejo-Franco Juan F. , Grinstead Sam , Mowery Joseph , Mollov Dimitre , Quito-Avila Diego F.
Published: October 2020

A mild isolate ofPapaya ringspot virustype-P, abbreviated as PRSV-mild, from Ecuador was sequenced and characterized. The most distinguishing symptom induced by PRSV-mild was gray powder-like leaf spots radiating from secondary veins. In greenhouse experiments, PRSV-mild did not confer durable protection against a severe isolate of the virus (PRSV-sev), obtained from the same field. Furthermore, isolate specific detection in cross-protected plants showed that PRSV-sev becomes dominant in infections, rendering PRSV-mild undetectable at 90 - 120 days post superinfection. Virus testing using isolate-specific primers detected PRSV-mild in two out of five surveyed provinces, with 10% and 48% of incidence in Santo Domingo and Los Ríos, respectively. Comparative genomics showed that PRSV-mild lacks two amino acids from the coat protein region, whereas amino acid determinants for asymptomatic phenotypes were not identified. Recombination events were not predicted in the genomes of the Ecuadorean isolates. Phylogenetic analyses placed both PRSV-mild and PRSV-sev in a clade that includes an additional PRSV isolate from Ecuador and others from South America.
Expression analysis of photosynthesis-related genes in albinoArtocarpus heterophyllusseedlings leaves
Authors: Cai Zeping , Dong Junna , Zhang Xi , Qu Qian , Wu Fanhua , Cao Lu , Li Shidong , Wang Zixuan , Zhou Dan , Luo Jiajia , Yu Xudong
Published: October 2020

AlbinoArtocarpus heterophyllusSeedlings (AAS) were found in the preliminary investigation by our group and were used as materials for researching. The phenotype of AAS leaves were observed and measured. In parallel, the photosynthetic physiological parameters were determined under different photosynthetically active radiations (PAR). The results suggested that the length, width, area and thickness of AAS leaves were less than normal seedings. Likewise, the net photosynthetic rate, intercellular CO2concentration, stomatal conductance and transpiration rate of AAS leaves were not susceptible to PAR in contrast to normal individuals. Furthermore, the transcriptome sequencing technology was performed to clarify the expression of genes related to photosynthesis. It is as expected that numerous down-regulated genes were found in the synthesis of photosynthetic pigments, as well as the pathways of photosynthesis - antenna proteins, photoreaction and carbon fixation reaction of AAS leaves. Compared to other albino plants, AAS have a longer life span and more stable phenotypic traits with larger leaves, which could provide ideal materials for investigating photosynthesis of woody plants.
Imeglimin Amplifies Glucose-Stimulated Insulin Release from Diabetic Islets via a Distinct Mechanism of Action
Authors: Hallakou-Bozec Sophie , Kergoat Micheline , Fouqueray Pascale , Bolze Sébastien , Moller David E.
Published: October 2020

Pancreatic islet β-cell dysfunction is characterized by defective glucose-stimulated insulin secretion (GSIS) and is a predominant component of the pathophysiology of diabetes. Imeglimin, a novel first-in-class small molecule tetrahydrotriazine drug candidate, improves glycemia and GSIS in preclinical models and clinical trials in patients with type 2 diabetes; however, the mechanism by which it restores β-cell function is unknown. Here, we show that Imeglimin acutely and directly amplifies GSIS in islets isolated from rodents with Type 2 diabetes via a mode of action that is distinct from other known therapeutic approaches. The underlying mechanism involves increases in the cellular nicotinamide adenine dinucleotide (NAD+) pool – potentially via the salvage pathway and induction of nicotinamide phosphoribosyltransferase (NAMPT) along with augmentation of glucose-induced ATP levels. Further, additional results suggest that NAD+conversion to a second messenger, cyclic ADP ribose (cADPR), via cyclic ADP ribose hydrolase (CD38) is required for Imeglimin’s effects in islets, thus representing a potential link between increased NAD+and enhanced glucose-induced Ca2+ mobilization which - in turn - is known to drive insulin granule exocytosis. Collectively, these findings implicate a novel mode of action for Imeglimin that explains its ability to effectively restore β-cell function and provides for a new approach to treat patients suffering from Type 2 diabetes.
Local adaptation in populations ofMycobacterium tuberculosisendemic to the Indian Ocean Rim
Authors: Menardo Fabrizio , Rutaihwa Liliana K. , Zwyer Michaela , Borrell Sonia , Comas Iñaki , Conceição Emilyn Costa , Coscolla Mireia , Cox Helen , Joloba Moses , Dou Horng-Yunn , Feldmann Julia , Fenner Lukas , Fyfe Janet , Gao Qian , de Viedma Darío García , Garcia-Basteiro Alberto L. , Gygli Sebastian M. , Hella Jerry , Hiza Hellen , Jugheli Levan , Kamwela Lujeko , Kato-Maeda Midori , Liu Qingyun , Ley Serej D. , Loiseau Chloe , Mahasirimongkol Surakameth , Malla Bijaya , Palittapongarnpim Prasit , Rakotosamimanana Niaina , Rasolofo Voahangy , Reinhard Miriam , Reither Klaus , Sasamalo Mohamed , Duarte Rafael Silva , Sola Christophe , Suffys Philip , Lima Karla Valeria Batista , Yeboah-Manu Dorothy , Beisel Christian , Brites Daniela , Gagneux Sebastien
Published: October 2020

Lineage 1 (L1) and 3 (L3) are two lineages of theMycobacterium tuberculosiscomplex (MTBC), causing tuberculosis (TB) in humans. L1 and L3 are endemic to the Rim of the Indian Ocean, the region that accounts for most of the world’s new TB cases. Despite their relevance for this region, L1 and L3 remain understudied. Here we analyzed 2,938 L1 and 2,030 L3 whole genome sequences originating from 69 countries. We show that South Asia played a central role in the dispersion of these two lineages to neighboring regions. Moreover, we found that L1 exhibits signatures of local adaptation at theesxHlocus, a gene coding for a secreted effector that targets the human endosomal sorting complex, and is included in several vaccine candidates. Our study highlights the importance of genetic diversity in the MTBC, and sheds new light on two of the most important MTBC lineages affecting humans.
A lamin A/C variant causing striated muscle disease provides insights into filament organization
Authors: Kronenberg-Tenga Rafael , Tatli Meltem , Eibauer Matthias , Wu Wei , Shin Ji-Yeon , Bonne Gisele , Worman Howard J. , Medalia Ohad
Published: October 2020

TheLMNAgene encodes the A-type lamins that polymerize into ~3.5 nm thick filaments, and together with B-type lamins and lamin binding proteins form the nuclear lamina. Mutations inLMNAare associated with a wide variety of pathologies. In this study, we analyzed the nuclear lamina of embryonic fibroblasts fromLmnaH222P/H222Pmice, which develop cardiomyopathy and muscular dystrophy. Although the organization of the lamina appeared unaltered, there were changes in chromatin and B-type lamin expression. An increase in nuclear size and consequently a relative reduction in heterochromatin near the lamina allowed for a higher resolution structural analysis of lamin filaments using cryo-electron tomography. This was most apparent when visualizing lamin filamentsin situ, and using a nuclear extraction protocol. Averaging of individual segments of filaments inLmnaH222P/H222Pmouse fibroblasts resolved two-polymers that constitute the mature filaments. Our findings provide better views of the organization of lamin filaments and the effect of a striated muscle disease-causing mutation on nuclear structure.
The Halastavi árva virus intergenic region IRES promotes translation by the simplest possible initiation mechanism
Authors: Abaeva Irina S. , Vicens Quentin , Bochler Anthony , Soufari Heddy , Simonetti Angelita , Pestova Tatyana V. , Hashem Yaser , Hellen Christopher U. T.
Published: October 2020

Dicistrovirus intergenic region internal ribosomal entry sites (IGR IRES) do not require initiator tRNA, an AUG codon or initiation factors, and jumpstart translation from the middle of the elongation cycle via formation of IRES/80S complexes resembling the pre-translocation state. eEF2 then translocates the [codon-anticodon]-mimicking pseudoknot I (PKI) from ribosomal A to P sites, bringing the first sense codon into the decoding center. Halastavi árva virus (HalV) contains an IGR that is related to previously described IGR IRESs, but lacks domain 2, which enables these IRESs to bind to individual 40S ribosomal subunits. By employingin vitroreconstitution and cryo-electron microscopy, we now report that the HalV IGR IRES functions by the simplest initiation mechanism that involves binding to 80S ribosomes such that PKI is placed in the P site, so that the A site contains the first codon that is directly accessible for decoding without prior eEF2-mediated translocation of PKI.
Control of archetype BK polyomavirus miRNA expression
Authors: Zou Wei , Vue Gau Shoua , Assetta Benedetta , Manza Heather , Atwood Walter J. , Imperiale Michael J.
Published: October 2020

BK polyomavirus (BKPyV) is a ubiquitous human pathogen, with over 80% of adults worldwide persistently infected. BKPyV infection is usually asymptomatic in healthy people; however, it causes polyomavirus-associated nephropathy in renal transplant patients and hemorrhagic cystitis in bone marrow transplant patients. BKPyV has a circular, double-stranded DNA genome that is divided genetically into three parts: an early region, a late region, and a non-coding control region (NCCR). The NCCR contains the viral DNA replication origin and cis-acting elements regulating viral early and late gene expression. It was previously shown that a BKPyV miRNA expressed from the late strand regulates viral large T antigen expression and limits the replication capacity of archetype BKPyV. A major unanswered question in the field is how expression of the viral miRNA is regulated. Typically, miRNA is expressed from introns in cellular genes but there is no intron readily apparent in the BKPyV from which the miRNA could derive. Here we provide evidence for primary RNA transcripts that circle the genome more than once and include the NCCR. We identified splice junctions resulting from splicing of primary transcripts circling the genome more than once, and Sanger sequencing of RT-PCR products indicates that there are viral transcripts that circle the genome up to four times. Our data suggest that the miRNA is expressed from the intron of these greater-than-genome size primary transcripts.
P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9
Authors: Tian Xiaobing , Ahsan Nagib , Lulla Amriti , Lev Avital , Abbosh Philip , Dicker David T. , Zhang Shengliang , El-Deiry Wafik S.
Published: October 2020

A long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. A novel small-molecule, PG3-Oc, restores p53 pathway-signaling in tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates the p53-transcriptome (13.7% of public p53 target-gene dataset; 15.2% of in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53-/-). Bioinformatic analysis indicates critical p53-effectors of growth-arrest (p21), apoptosis (PUMA, DR5, Noxa), autophagy (DRAM1), and metastasis-suppression (NDRG1) are induced by PG3-Oc. ERK1/2- and CDK9-kinases are required to upregulate ATF4 by PG3-Oc which restores p53 transcriptomic-targets in cells without functional-p53. PG3-Oc represses MYC (ATF4-independent), and upregulates PUMA (ATF4-dependent) in mediating cell death. With largely nonoverlapping transcriptomes, induced-ATF4 restores p53 transcriptomic targets in drug-treated cells including functionally important mediators such as PUMA and DR5. Our results demonstrate novel p53-independent drug-induced molecular reprogramming involving ERK1/2, CDK9, and ATF4 to restore upregulation of p53 effector genes required for cell death and tumor suppression.
Membrane-Dependent Amyloid Aggregation of Human BAX α9 (173-192)
Authors: Price David A. , Hill Tayler D. , Hutson Kaitlyn A. , Rightnowar Blaze W. , Moran Sean D.
Published: October 2020

Mitochondrial outer membrane permeabilization, which is a critical step in apoptosis, is initiated upon transmembrane insertion of the C-terminal α-helix (α9) of the pro-apoptotic Bcl-2 family protein BAX. The isolated α9 fragment (residues 173-192) is also competent to disrupt model membranes, and the structures of its membrane-associated oligomers are of interest in understanding the potential roles of this sequence in apoptosis. Here, we used ultrafast two-dimensional infrared (2D IR) spectroscopy, thioflavin T binding, and transmission electron microscopy to show that the synthetic BAX α9 peptide (α9p) forms amyloid aggregates in solution and on the surfaces of anionic small unilamellar vesicles (SUVs). Its inherent amyloidogenicity was predicted by sequence analysis, and 2D IR spectra reveal that SUVs modulate the β-sheet structures of the resulting amyloid species. These results contradict prior models of transmembrane α9p pores and motivate further examination of the formation or suppression of BAX amyloids in apoptosis.
Viral surface geometry shapes influenza and coronavirus spike evolution through antibody pressure
Authors: Amitai Assaf
Published: October 2020

The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the glycoprotein (spike). However, not all antigenic sites are targeted equally by antibodies, leading to complex immunodominance patterns. We used 3D computational models to estimate antibody pressure on the seasonal influenza H1N1 and SARS spikes. Analyzing publically available sequences, we show that antibody pressure, through the geometrical organization of spikes on the viral surface, shaped their mutability. Studying the mutability patterns of SARS-CoV-2 and the 2009 H1N1 pandemic spikes, we find that they are not predominantly shaped by antibody pressure. However, for SARS-CoV-2, we find that over time, it acquired mutations at antibody-accessible positions, which could indicate possible escape as define by our model. We offer a geometry-based approach to predict and rank the probability of surface resides of SARS-CoV-2 spike to acquire antibody escaping mutations.
Rapid coordination of effective learning by the human hippocampus
Authors: Kragel James E. , Schuele Stephan , VanHaerents Stephen , Rosenow Joshua M. , Voss Joel L.
Published: October 2020

Although the human hippocampus is necessary for long-term memory, controversial findings suggest that hippocampal computations support short-term memory in the service of guiding effective behaviors during learning. We tested the counterintuitive theory that the hippocampus contributes to long-term memory through remarkably short-term processing, as reflected in the sequence of eye movements during encoding of naturalistic scenes. While viewing scenes for the first time, participants generated patterns of eye movements that reflected a shift from stimulus-driven to memory-driven viewing and signaled effective spatiotemporal memory formation. Hippocampal theta oscillations recorded from depth electrodes predicted this viewing pattern. Moreover, effective viewing patterns were preceded by shifts towards top-down influence of hippocampal theta on activity within cortical networks that support visual perception and visuospatial attention. The hippocampus thus supports short-term memory processing that coordinates perception, attention, and behavior in the service of effective spatiotemporal learning. These findings motivate re-interpretation of long-term memory disorders as reflecting loss of the organizing influence of hippocampal short-term memory on learning.
High throughput measurements of BMP/BMP receptors interactions using bio-layer interferometry
Authors: Khodr Valia , Machillot Paul , Migliorini Elisa , Reiser Jean-Baptiste , Picart Catherine
Published: October 2020

Bone morphogenetic proteins (BMP) are an important family of growth factors playing a role in a large number of physiological and pathological processes, including bone homeostasis, tissue regeneration and cancers.In vivo, BMPs bind successively to both BMP receptors (BMPR) of type I and type II, and a promiscuity has been reported. In this study, we used bio-layer interferometry to perform parallel real-time biosensing and to deduce the kinetic parameters (ka, kd) and the equilibrium constant (KD) for a large range of BMPs/BMPR combinations in similar experimental conditions. We selected four members of the BMP family (BMP-2, 4, 7, 9) known for their physiological relevance and studied their interactions with five type-I BMP receptors (ALK1, 2, 3, 5, 6) and three type-II BMP receptors (BMPR-II, ACTR-IIA, ACTR-IIB). We reveal that BMP-2 and BMP-4 behave differently, especially regarding their kinetic interactions and affinities with the type-II BMPR. We found that BMP-7 has a higher affinity for ACTR-IIA and a tenfold lower affinity with the type-I receptors. While BMP-9 has a high and similar affinity for all type-II receptors, it can interact with ALK5 and ALK2, in addition to ALK1. Interestingly, we also found that all BMPs can interact with ALK5. The interaction between BMPs and both type-I and type II receptors immobilized on the same surface did not reveal further cooperativity. Our work provides a synthetic view of the interactions of these BMPs with their receptors and paves the way for future studies on their cell-type and receptor specific signaling pathways.