bluuebunny/crossref_metadata_2025 huggingface dataset:
Endocannabinoid response in acute ischemic stroke: elevated 2-arachidonoylglycerol
Authors: Buciuc Marina , Conte Gian Marco , Scharf Eugene L.
Published: November 2020

Background and purpose

Endocannabinoids are hypothesized to have anti-inflammatory and neuroprotective properties and hold therapeutic potential in the acute phase response mechanisms during acute cerebral ischemia and closed head injury. We set to describe the plasma levels of endocannabinoids and related ethanolamides during acute and subacute phases of cerebral ischemia.

Methods

We conducted a prospective observational study of plasma endocannabinoid levels in patients with acute ischemic stroke or transient ischemic attack. Two blood samples were collected: T1 (<12 hours from symptom onset) and T2 (>24 hours from symptom onset). N-arachidonoylethanolamine (AEA), 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were quantified by liquid chromatography mass spectrometry.

Results

Twenty-three patients met inclusion criteria. Median (interquartile range): Age – 76 years (60-81); body mass index - 25.6 (23.6-30.4); National Institutes of Health Stroke Scale score-5(3-13); infarct volume - 1.4 cm3 (0.5-8.6). Higher 2-AG levels at T1 were correlated with smaller infarct volumes (Spearman ƿ=-0.48, p=0.0206). Levels of 2-AG were elevated at T2 compared to T1 in 48% of patients (median difference - 310.3nM, 95% CI 194.1-497.3; p=0.001); AEA, PEA and OEA did not differ between T1 and T2, p>0.05. Patients with elevated 2-AG at T2 had larger infarct volumes, p=0.0178, lower frequency of embolectomy performed, p=0.0373, but no difference in neurological disability 90 days after the ischemic event compared to patients without 2-AG elevation.

Conclusion

2-AG increases significantly in early phases of ischemic stroke. The final mechanistic role of 2-AG in acute ischemic stroke is to be determined in further studies.
Prevalence and expressivity of loss of function mutations in the Melanocortin 4 Receptor (MC4R) in a UK birth cohort
Authors: Wade KH , Lam BYH , Melvin A , Pan W , Corbin LJ , Hughes DA , Rainbow K , Chen JH , Duckett K , Liu X , Mokrosiński J , Mörseburg A , Neaves S , Williamson A , Zhang C , Farooqi IS , Yeo GSH , Timpson NJ , O’Rahilly S
Published: November 2020

Mutations in the melanocortin 4 receptor gene (MC4R) have frequently been reported in severe early-onset human obesity but the prevalence and extent of phenotypic impact of such mutations are unclear. In a large UK birth cohort, we found that 17 of 5724 unrelated participants (∼1/337; 0.30%) were heterozygous for functionally deleterious mutations. At age 18 years, the mean difference in body weight, body mass index (BMI) and fat mass was 17.76kg (95% CI: 9.41, 26.10), 4.84kg/m2(95% CI: 2.19, 7.49) and 14.78kg (95% CI: 8.56, 20.99), respectively, in carriers of loss of function (LoF) mutations compared to non-LoF carriers. Carriage of LoF mutations increased adiposity from as early as 5 years.MC4RLoF was associated with an impact on BMI at age 18 years that was approximately double that of a genome-wide polygenic risk score (comparing the upper 10thand lower 90thpercentile). An extrapolation of incidence forMC4RLoF mutations from this birth cohort suggests that up to ∼200,000 people in the UK are likely to carry such mutations. This frequency, combined with the substantial impact of these variants on adiposity, has implications for public health, and drug development.
Prevalence of missing data in the National Cancer Database and association with overall survival
Authors: Yang Daniel X. , Khera Rohan , Miccio Joseph A. , Jairam Vikram , Chang Enoch , Yu James B. , Park Henry S. , Krumholz Harlan M. , Aneja Sanjay
Published: November 2020

Importance

Cancer registries are important real-world data (RWD) sources that rely on data abstraction from the medical record, however, patients with unknown or missing data are under-represented in studies that use such data sources.

Objective

To determine the prevalence of missing data and its associated overall survival among cancer patients

Design, Setting, and Participants

In this retrospective cohort study, all variables within the National Cancer Database (NCDB) were reviewed for missing or unknown values for the three most common cancers in the United States diagnosed from 2006 to 2015. Prevalence of patient records with missing data and their associated overall survival were determined. Data analysis was performed from February to August 2020.

Exposures

Any missing data field within a patient record among 63 variables of interest, from over 130 variables total in the NCDB.

Main Outcome and Measure

Prevalence of cancer patient records with missing data and associated two-year overall survival

Results

A total of 1,198,749 non-small cell lung cancer (NSCLC) patients (mean [SD] age, 68.5 [10.9] years; 569,938 [47.5%] women), 2,120,775 breast cancer patients (mean [SD] age, 61.0 [13.3] years; 2,101,758 [99.1%] women), and 1,158,635 prostate cancer patients (mean [SD] age, 65.2 [9.0] years; 0 [0%] women) were included for analysis. For NSCLC, there were 851,295 (71.0%) patients with missing data in variables of interest; 2-year overall survival was 33.2% for patients with missing data and 51.6% for patients with complete data (p<0.001). For breast cancer, there were 1,161,096 (54.7%) patients with missing data; 2-year overall survival was 93.2% for patients with missing data and 93.9% for patients with complete data (p<0.001). For prostate cancer, there were 460,167 (39.7%) patients with missing data; 2-year overall survival was 91.0% for patients with missing data and 95.6% for patients with complete data (p<0.001).

Conclusions and Relevance

Within a large cancer registry-based RWD source, missing data that was unable to be ascertained from the medical record was highly prevalent. Missing data among cancer patients was associated with heterogeneous differences in overall survival. Improving documentation and data quality are needed to best leverage RWD for clinical advancements.
Deep Learning Model for Improving the Characterization of Coronavirus on Chest X-ray Images Using CNN
Authors: Oyelade Olaide N. , Ezugwu Absalom E.
Published: November 2020

The novel Coronavirus, also known as Covid19, is a pandemic that has weighed heavily on the socio-economic affairs of the world. Although researches into the production of relevant vaccine are being advanced, there is, however, a need for a computational solution to mediate the process of aiding quick detection of the disease. Different computational solutions comprised of natural language processing, knowledge engineering and deep learning have been adopted for this task. However, deep learning solutions have shown interesting performance compared to other methods. This paper therefore aims to advance the application deep learning technique to the problem of characterization and detection of novel coronavirus. The approach adopted in this study proposes a convolutional neural network (CNN) model which is further enhanced using the technique of data augmentation. The motive for the enhancement of the CNN model through the latter technique is to investigate the possibility of further improving the performances of deep learning models in detection of coronavirus. The proposed model is then applied to the COVID-19 X-ray dataset in this study which is the National Institutes of Health (NIH) Chest X-Ray dataset obtained from Kaggle for the purpose of promoting early detection and screening of coronavirus disease. Results obtained showed that our approach achieved a performance of 100% accuracy, recall/precision of 0.85, F-measure of 0.9, and specificity of 1.0. The proposed CNN model and data augmentation solution may be adopted in pre-screening suspected cases of Covid19 to provide support to the use of the well-known RT-PCR testing.
Modeling COVID-19 Transmissions and Evaluation of Large Scale Social Restriction in Jakarta, Indonesia
Authors: Hasan A. , Nasution Y. , Susanto H. , Putri E.R.M. , Tjahjono V.R. , Puspita D. , Sukandar K. , Nuraini N. , Widyastuti W.
Published: November 2020

This paper presents mathematical modeling and quantitative evaluation of Large Scale Social Restriction (LSSR) in Jakarta between 10 April and 4 June 2020. The special capital region of Jakarta is the only province among 34 provinces in Indonesia with an average Testing Positivity Rate (TPR) below 5% recommended by the World Health Organization (WHO). The transmission model is based on a discrete-time compartmental epidemiological model incorporating suspected cases. The quantitative evaluation is measured based on the estimation of the time-varying effective reproduction number (ℛt). Our results show the LSSR has been successfully suppressed the spread of COVID-19 in Jakarta, which was indicated by ℛt < 1. However, once the LSSR was relaxed, the effective reproduction number increased significantly. The model is further used for short-term forecasting to mitigate the course of the pandemic.
Availability of personal protective equipment and satisfaction of healthcare professionals during COVID-19 pandemic in Ethiopia
Authors: Deressa Wakgari , Worku Alemayehu , Abebe Workeabeba , Gizaw Muluken , Amogne Wondwosson
Published: November 2020

Healthcare professionals (HCPs) are at the frontline in the fight against COVID-19 and are at an increased risk of becoming infected with coronavirus. Risk of infection can be minimized by use of proper personal protective equipment (PPE). This study assessed the availability of PPE and satisfaction of HCPs in six public hospitals in Addis Ababa, Ethiopia. A cross-sectional study was conducted from 9th to 26th June 2020. The study hospitals included: Tikur Anbessa Specialized Hospital, Zewditu Memorial Hospital, Ghandi Memorial Hospital, Menelik II Hospital, Yekatit 12 Hospital Medical College and St. Paul Hospital Millennium Medical College. Data were collected using a self-administered questionnaire. Descriptive statistics were used to describe the data and Chi-square test was used to assess the association between the groups. Bivariate and multivariable logistic regression models were used to assess factors associated with the satisfaction level of healthcare workers with regard to the availability and use of proper PPE during the current COVID-19 pandemic. A total of 1,134 (92.3%) valid questionnaires from a possible 1,228 were included in the analysis. The mean (±SD) age of the participants was 30.26±6.43 year and 52.6% were females. Nurses constituted about 40% of the overall sample, followed by physicians (22.2%), interns (10.8%), midwives (10.3%) and others (16.7%). An overall shortage of PPE was reported in all study hospitals. The majority (77%) of the healthcare professionals reported that their hospital did not have adequate PPE. A critical shortage of N95 respirator was particularly reported, the self-reported availability of N95 increased from 13% to 24% before and during COVID-19, respectively. The self-reported use of N95 increased from 9% to 21% before and during COVID-19, respectively. Almost 72% of the respondents were dissatisfied with the availability of PPE in their hospital. The independent predictors of the respondents’ satisfaction level about PPE were male gender (adjusted OR=1.39, 95% CI:1.05-1.85), healthcare workers who reported that PPE was adequately available in the hospital (adjusted OR=7.53, 95% CI:5.08-11.16), and preparedness to provide care to COVID-19 cases (adjusted OR=1.65, 95% CI:1.22-2.12). A critical shortage of appropriate PPE both before and during COVID-19 was identified. The high level of dissatisfaction with the availability of PPE might potentially lead to a lower level of preparedness and readiness to fight against COVID-19. Therefore, urgent efforts are needed to adequately supply the healthcare facilities with appropriate PPE to alleviate the challenges.
Senotherapeutic peptide reduces skin biological age and improves skin health markers
Authors: Zonari Alessandra , Brace Lear E. , Al-Katib Kallie Z. , Porto William F. , Foyt Daniel , Guiang Mylieneth , Cruz Edgar Andres Ochoa , Marshall Bailey , Salgueiro Willian G. , Inan Mehmet Dinçer , Rahman Mizanur , Anupom Taslim , Vanapalli Siva , Mori Marcelo A. , Franco Octavio L. , Oliveira Carolina R. , Boroni Mariana , Carvalho Juliana L.
Published: November 2020

Skin aging has been primarily related to aesthetics and beauty. Therefore, interventions have focused on reestablishing skin appearance, but not necessarily skin health, function, and resilience. Recently, cellular senescence was shown to play a role in age-related skin function deterioration and influence organismal health and, potentially, longevity. In the present study, a two-step screening was performed to identify peptides capable of reducing cellular senescence in human dermal fibroblasts (HDF) from Hutchinson-Gilford Progeria (HGPS) patients. From the top four peptides of the first round of screening, we built a 764-peptide library using amino acid scanning, of which the second screen led to the identification of peptide 14. Peptide 14 effectively decreased HDF senescence induced by HGPS, chronological aging, ultraviolet-B radiation, and etoposide treatment, without inducing significant cell death, and likely by modulating longevity and senescence pathways. We further validated the effectiveness of peptide 14 using human skin equivalents and skin biopsies, where peptide 14 promoted skin health and reduced senescent cell markers, as well as the biological age of samples, according to the Skin-Specific DNA methylation clock, MolClock. Topical application of peptide 14 outperformed Retinol treatment, the current gold-standard in “anti-aging” skin care. Finally, we determined that peptide 14 is safe for long-term applications and also significantly extends both the lifespan and healthspan ofC. elegansworms tested in two independent testings. This highlights the potential for geroprotective applications of the senotherapeutic compounds identified using our screening platform beyond the skin.
TMExplorer: A Tumour Microenvironment Single-cell RNAseq Database and Search Tool
Authors: Christensen Erik , Naidas Alaine , Husic Mia , Shooshtari Parisa
Published: November 2020

Tumour microenvironments (TME) contain a variety of cells including but not limited to stromal fibroblasts, endothelial cells, immune cells, malignant cells, and cells of the tissues of origin, whose interactions likely influence tumour behaviour and response to cancer treatment. The specific composition of the TME can be elucidated using single-cell RNA sequencing (scRNA-seq) by measuring expression profiles of individual cells. Several scRNA-seq datasets from multiple cancer types have been published in recent years, yet we still lack a comprehensive database for the collection and presentation of TME data from these studies in an easily accessible format. We have thus built a database of TME scRNA-seq data, containing 21 TME scRNA-seq datasets from 12 different cancer types. We have also created an R package called TMExplorer, which provides an interface to easily search and access all available datasets and their metadata. Data and metadata are kept in a consistent format across all datasets, with multiple expression formats available depending on the use case. Users can view a table of metadata and select individual datasets or filter them by specific characteristics. Users may also select a specific type of cancer and view all published scRNA-seq data for that cancer type available in our database. Users are provided with an option to save the data in multiple formats in order to view or process it outside of R. Thus, the TMExplorer database and search tool allows for thorough examination of the TME using scRNA-seq in a way that is streamlined and allows for easy integration into already existing scRNA-seq analysis pipelines.
A plausible mechanism for longitudinal lock-in of the plant cortical microtubule array after light-induced reorientation
Authors: Saltini Marco , Mulder Bela M.
Published: November 2020

The light-induced reorientation of the cortical microtubule array in dark-grownA. thalianahypocotyl cells is a striking example of the dynamical plasticity of the microtubule cytoskeleton. A consensus model, based onkatanin-mediated severing at microtubule crossovers, has been developed that successfully describes the onset of the observed switch between a transverse and longitudinal array orientation. However, we currently lack an understanding of why the newly-populated longitudinal array direction remains stable for longer times and re-equilibration effects would tend to drive the system back to a mixed orientation state. Using both simulations and analytical calculations, we show that the assumption of a small orientation-dependent shift in microtubule dynamics is sufficient to explain the long term lock-in of the longitudinal array orientation. Furthermore, we show that the natural alternative hypothesis that there is a selective advantage in severing longitudinal microtubules, is neither necessary nor sufficient to achieve cortical array reorientation, but is able to accelerate this process significantly.
Characterization of structural and energetic differences between conformations of the SARS-CoV-2 spike protein
Authors: Moreira Rodrigo A. , Guzman Horacio V. , Boopathi Subramanian , Baker Joseph L. , Poma Adolfo B.
Published: November 2020

The novel coronavirus disease 2019 (COVID-19) pandemic has disrupted modern societies and their economies. The resurgence in COVID-19 cases as part of the second wave is observed across Europe and the Americas. The scientific response has enabled a complete structural characterization of the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS-CoV-2). Among the most relevant proteins required by the novel coronavirus to facilitate the cell entry mechanism is the spike protein trimer. This protein possesses a receptor-binding domain (RBD) that binds the cellular angiotensin-converting enzyme 2 (ACE2) and then triggers the fusion of viral and host cell membranes. In this regard, a comprehensive characterization of the structural stability of the spike protein is a crucial step to find new therapeutics to interrupt the process of recognition. On the other hand, it has been suggested the participation of more than one RBD as a possible mechanism to enhance cell entry. Here we discuss the protein structural stability based on the computational determination of the dynamic contact map and the energetic difference of the spike protein conformations via the mapping of the hydration free energy by the Poisson-Boltzmann method. We expect our result to foster the discussion of the number of RBD involved during recognition and the repurposing of new drugs to disable the recognition by discovering new hotspots for drug targets apart from the flexible loop in the RBD that binds the ACE2.
Silencing of E-cadherin in induced human pluripotent stem cells promotes extraembryonic fates accompanying multilineage differentiation
Authors: Libby Ashley RG , Vasic Ivana , Joy David A , Krakora Martina Z , Mendoza-Camacho Fredrico N , Conklin Bruce R , McDevitt Todd C
Published: November 2020

Summary/Abstract

In embryonic development, symmetry breaking events and the mechanical milieus in which they occur coordinate the specification of separate cell lineages. Here, we use 3D aggregates of human pluripotent stem cells (hPSCs) encapsulated in alginate microbeads to model the early blastocyst prior to zona pellucida hatching. We demonstrate that 3D confinement combined with modulation of cell-cell adhesions is sufficient to drive differentiation and collective migration reminiscent of the pre-implantation embryo. Knockdown of the cell adhesion protein CDH1 in encapsulated hPSC aggregates resulted in protrusion morphologies and emergence of extra-embryonic lineages, whereas unencapsulated CDH1(-) aggregates displayed organized radial delamination and mesendoderm specification bias. Transcriptomic similarities between single-cell RNA-sequencing data of early human embryos and encapsulated CDH1(-) aggregates establishes thisin vitrosystem as a competent surrogate for studying early embryonic fate decisions and highlights the relationship between cell-cell adhesions and the mechanical microenvironment in directing cell fate and behavior.

Highlights

Generation of embryonic scale 3D morphogenesis using hydrogel encapsulation

Manipulating adhesion triggers emergence of specific morphologies and cell fates

Acquisition of germ layer cell fates mimics early human embryonic diversity
Temporal patterns in the evolutionary genetic distance of SARS-CoV-2 during the COVID-19 pandemic
Authors: Lou Jingzhi , Zhao Shi , Cao Lirong , Chen Zigui , Chan Renee WY , Chong Marc KC , Zee Benny CY , Chan Paul KS , Wang Maggie H
Published: November 2020

Background

During the pandemic of coronavirus disease 2019 (COVID-19), the genetic mutations occurred in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cumulatively or sporadically. In this study, we employed a computational approach to identify and trace the emerging patterns of the SARS-CoV-2 mutations, and quantify accumulative genetic distance across different periods and proteins.

Methods

Full-length human SARS-CoV-2 strains in United Kingdom were collected. We investigated the temporal variation in the evolutionary genetic distance defined by the Hamming distance since the start of COVID-19 pandemic.

Findings

Our results showed that the SARS-CoV-2 was in the process of continuous evolution, mainly involved in spike protein (S protein), the RNA-dependent RNA polymerase (RdRp) region of open reading frame 1 (ORF1) and nucleocapsid protein (N protein). By contrast, mutations in other proteins were sporadic and genetic distance to the initial sequenced strain did not show an increasing trend.
Glucose and NAADP trigger elementary intracellular β-cell Ca2+signals
Authors: Heister Paula Maria , Powell Trevor , Galione Antony
Published: November 2020

Pancreatic β-cells release insulin upon a rise in blood glucose. The precise mechanisms of stimulus-secretion coupling, and its failure in Diabetes Mellitus Type 2, remain to be elucidated. The consensus model, as well as a class of currently prescribed anti-diabetic drugs, are based around the observation that glucose-evoked ATP production in β-cells leads to closure of cell membrane ATP-gated potassium (KATP) channels, plasma membrane depolarisation, Ca2+influx, and finally the exocytosis of insulin granules (Ashcroft et al., 1984; Cook and Hales, 1984). However, it has been demonstrated by the inactivation of this pathway using genetic and pharmacological means that closure of the KATPchannel alone may not be sufficient to explain all β-cell responses to glucose elevation (Henquin, 1998; Seghers et al., 2000). Here we show using total internal reflection fluorescence (TIRF) microscopy (Axelrod, 1981) that glucose as well as the Ca2+mobilising messenger nicotinic acid adenine dinucleotide phosphate (NAADP), known to operate in β-cells (Johnson and Misler, 2002; Masgrau et al., 2003), lead to highly localised elementary intracellular Ca2+signals. These were found to be obscured by measurements of global Ca2+signals and the action of powerful SERCA-based sequestration mechanisms at the endoplasmic reticulum (ER). This is the first demonstration of elemental Ca2+signals in response to NAADP, although they have been suspected (Davis et al., 2020). Optical quantal analysis of these events reveals a unitary event amplitude equivalent to that of known elementary Ca2+signalling events, inositol trisphosphate (IP3) receptor mediated blips (Parker et al., 1996; Parker and Ivorra, 1990), and ryanodine receptor mediated sparks (Cheng et al., 1993). We propose that a mechanism based on these highly localised intracellular Ca2+signalling events mediated by NAADP may initially operate in β-cells when they respond to elevations in blood glucose.
MetaPop: A pipeline formacro- andmicro-diversity analyses and visualization of microbial and viral metagenome-derived populations
Authors: Gregory Ann C. , Gerhardt Kenji , Zhong Zhi-Ping , Bolduc Benjamin , Temperton Ben , Konstantinidis Konstantinos T. , Sullivan Matthew B.
Published: November 2020

Background

Microbes and their viruses are hidden engines driving Earth’s ecosystems from the oceans and soils to humans and bioreactors. Though gene marker approaches can now be complemented by genome-resolved studies of inter- (macrodiversity) and intra- (microdiversity) population variation, analytical tools to do so remain scattered or under-developed.

Results

Here we introduce MetaPop, an open-source bioinformatic pipeline that provides a single interface to analyze and visualize microbial and viral community metagenomes at both themacro- andmicro-diversity levels.Macrodiversity estimates include population abundances and α- and β-diversity.Microdiversity calculations include identification of single nucleotide polymorphisms, novel codon-constrained linkage of SNPs, nucleotide diversity (π and θ) and selective pressures (pN/pS and Tajima’s D) within and fixation indices (FST) between populations. MetaPop will also identify genes with distinct codon usage. Following rigorous validation, we applied MetaPop to the gut viromes of autistic children that underwent fecal microbiota transfers and their neurotypical peers. Themacrodiversity results confirmed our prior findings for viral populations (microbial shotgun metagenomes were not available), that diversity did not significantly differ between autistic and neurotypical children. However, by also quantifyingmicrodiversity, MetaPop revealed lower average viral nucleotide diversity (π) in autistic children. Analysis of the percentage of genomes detected under positive selection was also lower among autistic children, suggesting that higher viral π in neurotypical children may be beneficial because it allows populations to better ‘bet hedge’ in changing environments. Further, comparisons ofmicrodiversity pre- and post-FMT in the autistic children revealed that the delivery FMT method (oral versus rectal) may influence viral activity and engraftment ofmicrodiverseviral populations, with children who received their FMT rectally having highermicrodiversitypost-FMT. Overall, these results show that analyses at themacro-levelalone can miss important biological differences.

Conclusions

These findings suggest that standardized population and genetic variation analyses will be invaluable for maximizing biological inference, and MetaPop provides a convenient tools package to explore the dual impact ofmacro- andmicro-diversity across microbial communities.
Population differentiation and structural variation in theManduca sextagenome across the United States
Authors: Mongue Andrew J. , Kawahara Akito Y.
Published: November 2020

Many species that are extensively studied in the laboratory are less well characterized in their natural habitat, and laboratory strains represent only a small fraction of the variation in a species’ genome. Here we investigate genomic variation in three natural North American populations of an agricultural pest and a model insect for many scientific disciplines, the tobacco hornworm (Manduca sexta). We show that hornworms from Arizona, Kansas, and North Carolina are genetically distinct, with Arizona being particularly differentiated from the other two populations using Illumina whole-genome resequencing. Peaks of differentiation exist across the genome, but here we focus in on the most striking regions. In particular, we identify two likely segregating inversions found in the Arizona population. One inversion on the Z chromosome may enhance adaptive evolution of the sex chromosome. The larger, autosomal inversion contains a pseudogene may be involved in the exploitation of a novel hostplant in Arizona, but functional genetic assays will be required to support this hypothesis. Nevertheless, our results reveal undiscovered natural variation and provide useful genomic data for both pest management and evolutionary genetics of this insect species.
A biophysical limit for quorum sensing in biofilms
Authors: Narla Avaneesh V. , Borenstein David , Wingreen Ned S.
Published: November 2020

Bacteria grow on surfaces in complex immobile communities known as biofilms, which are composed of cells embedded in an extracellular matrix. Within biofilms, bacteria often interact with members of their own species, and cooperate or compete with members of other species via quorum sensing (QS). QS is a process by which microbes produce, secrete, and subsequently detect small molecules called autoinducers (AIs) to assess their local population density. We explore the competitive advantage of QS through agent-based simulations of a spatial model in which colony expansion via extracellular matrix production provides greater access to a limiting diffusible nutrient. We note a significant difference in results based on whether AI production is constitutive or limited by nutrient availability: If AI production is constitutive, simple QS-based matrix-production strategies can be far superior to any fixed strategy. However, if AI production is limited by nutrient availability, QS-based strategies fail to provide a significant advantage over fixed strategies. To explain this dichotomy, we derive a novel biophysical limit for the dynamic range of nutrient-limited AI concentrations in biofilms. This range is remarkably small (less than 10-fold) for the realistic case in which a growth-limiting diffusible nutrient is taken up within a narrow active growth layer. This biophysical limit implies that for QS to be most effective in biofilms, AI production should be a protected function not directly tied to metabolism.

Significance Statement

Biofilms are a ubiquitous form of bacterial community. Within biofilms, bacteria communicate via chemical signals in a process called quorum sensing (QS). However, if signal production is nutrient-limited, then the nutrient-deficient interior of a biofilm cannot contribute to QS, which limits the ability of bacteria to assess their own population and behave accordingly. Numerical simulations of competitions among biofilm bacteria led us to discover a novel biophysical limit on the efficacy of nutrient-limited QS. In view of this limit, we conclude that to be most effective, QS signal production should be a prized function that is not metabolically slaved.
Regulatory diversity contributes to a divergent transcriptional response to dietary changes in mammals
Authors: Costello Kevin R. , Shin Heon , Trac Candi , Varlamov Oleg , Schones Dustin E.
Published: November 2020

BACKGROUND

Regulatory innovation is central to the evolution of species. Different nutritional sources are one environmental pressure that can lead to selection for novel regulatory elements. Dietary composition changes, including exposure to “western” diets with excess fat and sugar content, can lead to transcriptional regulatory changes in the liver. In order to investigate how transcriptional regulatory changes in response to a high fat diet diverge across species, we profiled chromatin accessibility, histone modifications and the transcriptome in livers of rhesus macaques and mice fed high fat and normal diets.

RESULTS

While the majority of elements exhibiting changes in chromatin accessibility in response to a high fat diet are enriched for similar transcription factors across species, the loci that change are mostly species specific. These unique responsive regulatory elements are largely derived from transposable elements and are enriched for liver-specific transcription factors, such as HNF4α. Furthermore, the majority of genes that respond to a high fat diet in rhesus macaques do not have a shared response in mice and are proximal to regulatory elements that display changes in chromatin accessibility only in rhesus macaques.

CONCLUSIONS

Our study demonstrates that most of the liver regulatory elements that exhibit changes in chromatin accessibility in response to a high fat diet do so in a species-specific manner. These findings illustrate how a similar environmental stimulus can drive a divergent chromatin and transcriptional responses in evolutionary distinct mammalian species.
Climate warming weakens local adaptation
Authors: Bontrager M. , Muir C. D. , Mahony C. , Gamble D. E. , Germain R. M. , Hargreaves A. L. , Kleynhans E. J. , Thompson K. A. , Angert A. L.
Published: November 2020

Anthropogenic climate change is generating mismatches between the environmental conditions that populations historically experienced and those in which they reside. Understanding how climate change affects population performance is a critical scientific challenge. We combine a quantitative synthesis of field transplant experiments with a novel statistical approach based in evolutionary theory to quantify the effects of temperature and precipitation variability on population performance. We find that species’ average performance is affected by both temperature and precipitation, but populations show signs of local adaptation to temperature only. Contemporary responses to temperature are strongly shaped by the local climates under which populations evolved, resulting in performance declines when temperatures deviate from historic conditions. Adaptation to other local environmental factors is strong, but temperature deviations as small as 2°C erode the advantage that these non-climatic adaptations historically gave populations in their home sites.

One sentence summary

Climate change is pulling the thermal rug out from under populations, reducing average performance and eroding their historical home-site advantage.
Phylogenomic insights into distribution and adaptation of Bdellovibrionota in marine waters
Authors: Li Qing-Mei , Zhou Ying-Li , Wei Zhan-Fei , Wang Yong
Published: November 2020

Bdellovibrionota is composed of obligate predators that can consume some gram-negative bacteria inhabiting various environments. However, whether genomic traits influence their distribution and marine adaptation remains to be answered. In this study, we performed phylogenomics and comparative genomics studies on 82 Bdellovibrionota genomes along with five metagenome-assembled genomes (MAGs) from deep sea zones. Four phylogenetic groups, Oligoflexia, Bdello-group1, Bdello-group2 and Bacteriovoracia, were revealed by constructing a phylogenetic tree, of which 53.84% of Bdello-group2 and 48.94% of Bacteriovoracia were derived from ocean. Bacteriovoracia was more prevalent in deep sea zones, whereas Bdello-group2 was largely distributed in the epipelagic zone. Metabolic reconstruction indicated that genes involved in chemotaxis, flagellar (mobility), type II secretion system, ABC transporters and penicillin-binding protein were necessary for predatory lifestyle of Bdellovibrionota. Genes involved in glycerol metabolism, hydrogen peroxide (H2O2) degradation, cell wall recycling and peptide utilization were ubiquitously present in Bdellovibrionota genomes. Comparative genomics between marine and non-marine Bdellovibrionota demonstrated that betaine as an osmoprotectant is probably widely used by marine Bdellovibrionota, meanwhile, all the marine genomes have a number of related genes for adapting marine environment. The chitinase and chitin-binding protein encoding genes were identified for the first time in Oligoflexia, which implied that Oligoflexia may prey a wider spectrum of microbes. This study expanded our knowledge on adaption strategies of Bdellovibrionota inhabiting deep sea and their potential usage for biological control.

Importance

Bdellovibrionota can prey gram-negative bacteria proposed as biocontrol agent. Available Bdellovibrionota genomes showed that most are from marine environment. However, vertical distribution and adaption of Bdellovibrionota in deep sea has not been reported. Our study of Bdellovibrionota revealed four groups (Oligoflexia, Bdello-group1, Bdello-group2 and Bacteriovoracia) and their distribution pattern in oceans. We also identified the genes for different phases of predation and adaptation in deep-sea environment. Moreover, Oligoflexia genomes contain more genes for carbohydrates utilization and particularly those encoding chitin-binding protein and chitinase. Our analyses of Bdellovibrionota genomes may help understand their special lifestyle and deep-sea adaptation.
“High resolution discovery of regulatory DNA with synthetic wild-type and ablated genome constructs”
Authors: Holmes Benjamin , Lin Lin , Sherwood Richard , Gifford David
Published: November 2020

Genomic enhancer elements play a role in modulating gene expression by interacting with effector proteins known as transcription factors. We present a new computational method, “STARR-scan”, which identifies transcription factor motif appearances in synthetic DNA constructs that are correlated with enhancer activity. Using a tiled STARR-seq assay, we demonstrate that STARR-scan can suggest the biological function of transcription factors previously suspected to activate the APOBEC-3B gene. Using the same methodology, STARR-scan can suggest transcription factors with previously unknown biological activity which may regulate the APOBEC-3B gene. These novel factors may have biological significance in our understanding of cancer biology.
Novel nuclear role of HDAC6 in prognosis and therapeutic target for colorectal cancer
Authors: García-Domínguez Daniel J. , Hontecillas-Prieto Lourdes , Kaliszczak Maciej , He Miaomiao , Burguillos Miguel Angel , Bekay Rajaa , Abdul-Salam Vahitha B. , Khozoie Combiz , Shah Khalid , O’Neill Kevin , de Álava Enrique , Silver Andrew , Syed Nelofer , Aboagye Eric O. , Hajji Nabil
Published: November 2020

Histone deacetylase 6 (HDAC6) inhibition is a potential treatment of a wide range of cancer typesviathe acetylation of diverse proteins in the cytoplasm. However, the regulation of histone acetylation and the maintenance of higher-order chromatin structure remains unidentified. Here, we investigated the effect of selective inhibition of HDAC6 by histone acetylation, chromatin relaxation assays, co-immunoprecipitation, acetylome peptide array andin vivoRNA microarray. Our data shows that nuclear HDAC6 physically interacts with the Histone 4 lysine 12 residue, and that HDAC6 inhibition increases acetylation specifically at this residue in several cancer types. Inhibition induces major chromatin structure modulation, but has no equivalent effect on knockout HDAC6-/-MEF cells. We identified several novel HDAC6-deacetylated substrates and high expression of HDAC6 in colorectal cancer (CRC) tissue association with reduced levels of H4K12ac and independent of the key CRC driver mutations, but positively associated withEGFRexpression. Furthermore,in vivoHDAC6 inhibition induces significant tumor regression in a CRC xenograft mice model with significant changes in the expression of functional nuclear genes. We also demonstrated that a DNA damaging agent in combination with selective HDAC6 inhibition is effective and acts synergistically, inducing chromatin relaxation and increased cell death in CRC cells. CRC tissues (Normal versus tumor; n=58 matched pairs) together with TCGA data analysis of 467 CRC patients showed that high HDAC6 expression is associated with metastasis, overall and disease-free survival, and is an independent risk factor of CRC stage progression. Our findings designate a new role for nuclear HDAC6 both in cancer prognosis and as a new therapeutic target for CRC and other types of cancer.

Highlight

Histone deacetylases 6 activity; Chromatin relaxation; Histone modifications; Gene array; DOX: doxorubicin; OXA: oxaliplatin; 5-FU: fluorouracil; Ac: acetylation; MNase: Micrococal nuclease.
A Two-Step Bioreactor for Lung Recellularization
Authors: Young Bethany , Antczak Leigh-Ann M. , Shankar Keerthana , Heise Rebecca L.
Published: November 2020

Bioreactors for reseeding of decellularized lung scaffolds have evolved with a wide variety of advancements. These include biomimetic mechanical stimulation, constant nutrient flow, multi-output monitoring, and large mammal scaling. Although dynamic bioreactors are not new to the field of bioengineered lungs, ideal conditions during cell seeding have not been extensively studied or controlled. To address the lack of cell dispersal in traditional seeding methods, we have designed a two-step bioreactor. The first step rotates a seeded lung every 20 minutes at different angles to ensure 20 percent of cells are anchored to a particular location based on the known rate of attachment. The second step involves perfusion culture to ensure nutrient dispersion and cellular growth. Compared to statically seeded lungs followed by conventional perfusion, rotationally seeded lungs followed by perfusion had significantly increased dsDNA content and more uniform cellular distribution. This new bioreactor system will aid in recellularizing the lung and other geometrically complex organs for tissue engineering.
Small-scale commercial chicken production: A risky business for farmers in the Mekong Delta of Vietnam
Authors: Bao Truong Dinh , Van Cuong Nguyen , Phu Hoang Doan , Dung Nguyen Thi Thuy , Kiet Bach Tuan , Rushton Jonathan , Carrique-Mas Juan
Published: November 2020

Small-scale farming of meat chicken flocks using local native breeds contributes to the economy of many rural livelihoods in Vietnam and many other low- and middle-income countries (LMICs). These systems are also the target of high levels of antimicrobial use (AMU); however little is known about the profitability and sustainability of such systems. Since small scale farms are commercial enterprises, this knowledge is essential in order to develop successful strategies aimed at curbing excessive AMU. Using longitudinal data from 203 randomly selected small-scale (100-2,000 chickens) native chicken flocks raised in 102 farms in Dong Thap province (Mekong Delta, Vietnam), we investigated the financial and economic parameters of such systems and the main constraints to their sustainability. Feed accounted for the largest financial cost (flock median 49.5% [Inter-quartile range (IQR) 41.5-61.8%]) of total costs, followed by day-old-chicks (DOCs) (median 30.3% [IQR 23.2-38.4%]), non-antimicrobial health-supporting products (median 7.1% [IQR 4.7-10.5%]), vaccines (median 3.1% [IQR 2.2-4.8%]), equipment (median 1.9% [IQR 0.0-4.9%]) and antimicrobials (median 1.9% [IQR 0.7-3.6%]). Excluding labor costs, farmers achieved a positive return on investment (ROI) from 120 (59.1%) flocks, the remainder generated a loss (median ROI 124% [IQR 36-206%]). Higher ROI was associated with higher flock size and low mortality. There was no statistical association between use of medicated feed and flock mortality or chicken bodyweight. The median daily income per person dedicated to raising chickens was 202,100 VND, lower than alternative rural labour activities in the Mekong Delta. In a large proportion of farms (33.4%), farmers decided to stop raising chickens after completing one cycle. Farmers who dropped off chicken production purchased more expensive feed (in 1,000 VND per kg) (11.1 [10.6-11.5] vs. 10.8 [10.4-11.3] for farms that continued production (p=0.039) and experienced higher chicken mortality (28.5% [12.0-79.0%] vs. 16 [7.5-33.0%] (p=0.004). The turnover of farmers raising chickens in such systems represents a challenge in targeting messages on appropriate AMU and on chicken health. In order to ensure sustainability of small-scale commercial systems, advisory services need to be available as farmer initiate new flocks, and support them in the early stages to help overcome their limited experience and skills. This targeted approach would support profitability whilst reducing risk of emergence of AMR and other disease problems from these systems.
The hourglass model of evolutionary conservation during embryogenesis extends to developmental enhancers with signatures of positive selection
Authors: Liu Jialin , Viales Rebecca R. , Khoueiry Pierre , Reddington James P. , Girardot Charles , Furlong Eileen E. M. , Robinson-Rechavi Marc
Published: November 2020

Inter-species comparisons of both morphology and gene expression within a phylum have revealed a period in the middle of embryogenesis with more similarity between species compared to earlier and later time-points. This ‘developmental hourglass’ pattern has been observed in many phyla, yet the evolutionary constraints on gene expression, and underlying mechanisms of how this is regulated, remains elusive. Moreover, the role of positive selection on gene regulation in the more diverged earlier and later stages of embryogenesis remains unknown. Here, using DNase-seq to identify regulatory regions in two distantDrosophilaspecies (D. melanogasterandD. virilis), we assessed the evolutionary conservation and adaptive evolution of enhancers throughout multiple stages of embryogenesis. This revealed a higher proportion of conserved enhancers at the phylotypic period, providing a regulatory basis for the hourglass expression pattern. Using anin silicomutagenesis approach, we detect signatures of positive selection on developmental enhancers at early and late stages of embryogenesis, with a depletion at the phylotypic period, suggesting positive selection as one evolutionary mechanism underlying the hourglass pattern of animal evolution.
Hindbrain neuropore tissue geometry determines asymmetric cell-mediated closure dynamics
Authors: Maniou Eirini , Staddon Michael F , Marshall Abigail , Greene Nicholas DE , Copp Andrew J , Banerjee Shiladitya , Galea Gabriel L
Published: November 2020

Gap closure is a common morphogenetic process. In mammals, failure to close the embryonic hindbrain neuropore (HNP) gap causes fatal anencephaly. We observed that surface ectoderm cells surrounding the mouse HNP assemble high-tension actomyosin purse-strings at their leading edge and establish the initial contacts across the embryonic midline. The HNP gap closes asymmetrically, faster from its rostral than caudal extreme, while maintaining an elongated aspect ratio. Cell-based physical modelling identifies two closure mechanisms sufficient to describe tissue-level HNP closure dynamics; purse-string contraction and directional cell crawling. Combining both closure mechanisms hastens gap closure and produces a constant rate of gap shortening. Purse-string contraction reduces, whereas crawling increases gap aspect ratio, and their combination maintains it. Closure rate asymmetry can be explained by embryo tissue geometry, namely a narrower rostral gap apex. At the cellular level, our model predicts highly directional cell migration with a constant rate of cells leaving the HNP rim. These behaviours are reproducibly live-imaged in mouse embryos. Thus, mammalian embryos coordinate cellular and tissue-level mechanics to achieve this critical gap closure event.