bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of bottlenecks and inbreeding on the genome of the endangered Pyrenean desman
Authors: Escoda Lídia , Castresana Jose
Published: July 2020

The Pyrenean desman (Galemys pyrenaicus) is a small semiaquatic mammal endemic to the Iberian Peninsula. Despite its limited range, this species presents a strong genetic structure due to past isolation in glacial refugia and subsequent bottlenecks. Additionally, some populations are highly fragmented today as a consequence of river barriers, causing substantial levels of inbreeding. These features make the Pyrenean desman a unique model in which to study the genomic footprints of differentiation, bottlenecks and extreme isolation in an endangered species. The complete genome of the Pyrenean desman was assembled using a Bloom filter-based approach. An analysis of the 1.83 Gb reference genome and the sequencing of five additional individuals from different evolutionary units allowed us to detect its main genomic characteristics. The population differentiation of the species was reflected in highly distinctive demographic trajectories. A severe population bottleneck during the postglacial recolonization of the eastern Pyrenees created the lowest genomic heterozygosity ever recorded in a mammal. Moreover, isolation and inbreeding gave rise to a high proportion of runs of homozygosity (ROH). Despite these extremely low levels of genetic diversity, two key multigene families from an eco-evolutionary perspective that need to be genetically variable, the major histocompatibility complex and olfactory receptor genes, showed heterozygosity excess in the majority of individuals. Furthermore, these two classes of genes were significantly less abundant than expected within ROH. These results allow us to characterize important genomic health indicators for each individual, information that may be crucial for the conservation and management of the species.
Mapping social distancing measures to the reproduction number for COVID-19
Authors: Brooks-Pollock Ellen , Read Jonathan M. , McLean Angela R. , Keeling Matt J. , Danon Leon
Published: July 2020

Background

In the absence of a vaccine, SARS-CoV-2 transmission has been controlled by preventing person-to-person interactions via social distancing measures. In order to re-open parts of society, policy-makers need to consider how combinations of measures will affect transmission and understand the trade-offs between them.

Methods

We use age-specific social contact data, together with epidemiological data, to quantify the components of the COVID-19 reproduction number. We estimate the impact of social distancing policies on the reproduction number by turning contacts on and off based on context and age. We focus on the impact of re-opening schools against a background of wider social distancing measures.

Results

We demonstrate that pre-collected social contact data can be used to provide a time-varying estimate of the reproduction number (R). We find that following lockdown (when R=0.7 (95% CI 0.6, 0.8)), opening primary schools as a modest impact on transmission (R = 0.89 (95%CI: 0.82 − 0.97)) as long as other social interactions are not increased. Opening secondary and primary schools is predicted to have a larger impact (R = 1.22, 95%CI: 1.02 − 1.53)). Contact tracing and COVID security can be used to mitigate the impact of increased social mixing to some extent, however social distancing measures are still required to control transmission.

Conclusions

Our approach has been widely used by policy-makers to project the impact of social distancing measures and assess the trade-offs between them. Effective social distancing, contact tracing and COVID-security are required if all age groups are to return to school while controlling transmission.
Epidemiological investigation and prevention control analysis of longitudinal distribution of COVID-19 in Henan province, China
Authors: Yang Xianguang , Chen Xuelin , Ding Cuihong , Bai Zhibo , Zhu Jingyi , Sun Gege , Yu Guoying
Published: July 2020

Objective

To analyze the vertical distribution of six cities in Henan Province,China from January 21, 2020 to June17, 2020: Xinyang City (including Gushi County), Nanyang City (including Dengzhou City), Zhumadian City (including XincaiCounty), Zhengzhou City (including Gongyi City), Puyang City and Anyang City (including Hua County) corona virus disease 2019(COVID-19) epidemiological characteristics and local prevention and control measures.

Methods

Data were collected and analyzed through the COVID-19 information published on the official websites of health commissions of Henan Province and six cities.

Results

As of June 17, 2020, the cumulative incidence rate of COVID-19 in Henan province was 1.33/100,000, the cumulative cure rate was 98.27%, the cumulative mortality rate was 1.73%, the age range of diagnosed cases was 5days-85years old, and the male to female ratio was 1.09:1.The confirmed cases of COVID-19 in Henan province were mainly imported cases from Hubei, accounting for 87.74%, of which the highest number was 70.50% in Zhumadian. The contact cases and local cases increased in a fluctuating manner over time.

Significance

In this paper, epidemiological characteristics of COVID-19 in Henan province from the outbreak to the effective control within 60 days were analyzed, and effective and distinctive prevention and control measures in various cities were summarized, so as to provide a favorable reference for the further formulation and implementation of epidemic prevention and control and a valuable theoretical basis for effectively avoiding the second outbreak.

Importance

Epidemic prevention and control in China has entered the normalized this new stage, this article analyze the epidemiological characteristics of COVID - 19 in henan province, and summarizes the prefecture level and effective disease prevention and control means and measures, the normalized private provide the theoretical reference to the prevention and control work, formulate and carry out, at the same time in other countries and regions of epidemic prevention and control work can also be used for reference.
Pathological uptake with 18-Fluorocholine versus 99mTc-MIBI in the location of the parathyroid glands in hyperparathyroidism. Systematic review and meta-analysis
Authors: Refoyo José Luis Pardal , Alonso Pilar Tamayo , Cendón Sofía Ferreira , Gómez Esther Martín
Published: July 2020

Introduction

The location of the pathological parathyroid glands in hyperparathyroidism is usually carried out by means of 99mTc-sestamibi scintigraphy, which increases its precision by adding the ultrasound examination. The non-localization of the parathyroid glands increases the difficulties for surgical removal. To increase the detection of pathological glands, other radioactive tracers are used, such as methionine, fluorocholine or 18F-flurpiridaz.

Objective

To establish if PET / CT with 18-Fluorocholine in patients with hyperparathyroidism increases the number of uptakes compared to the 99mTc-sestamibi scan.

Method

Systematic review and meta-analysis. Two subgroups were analyzed. Subgroup 1: trials comparing both techniques as an initial exploration. Thirteen studies including 1131 examinations were selected (596 PET / CT with 18-Fluorocholine vs. 535 scintigraphy with 99mTc-sestamibi). Meta-analysis was performed following the random effects model and the odds ratio was calculated. Subgroup 2: studies that include 18-Fluorocholine as a rescue examination in patients with a previous negative study with a 99mTc-sestamibi scan. 17 articles including 412 examinations with 359 patients in which there was at least one uptake were selected. Meta-analysis of the prevalence of the number of patients in whom there was at least one uptake was performed using the random effects model.

Results

Subgroup 1: The number of patients in which at least one uptake occurs is significantly higher with the 18-Fluorocholine examinations (OR 4.264, 95% CI 2.400-7.577). The prevalence of uptake with 18-Fluorocholine is 0.91 [0.86, 0.95] and with sestamibi 0.68 [0.56, 0.80]. Subgroup 2: the prevalence of uptake among patients with previous negative MIBI studies was 0.90 [0.87, 0.94]. The probability of detection of both techniques in this group reaches 0.98. Publication bias in the meta-analyzes is low.

Discussion

18-Fluorocholine protocols provide higher precision, clearer images, with faster acquisition as well as being readily available for most PET / CT centers.

Conclusion

The PET / CT study with 18-Fluorocholine can be recommended as a study for the location of pathological parathyroid glands after studies with negative MIBI.
An integrated, modular approach to data science education in the life sciences
Authors: Dill-McFarland Kimberly A , König Stephan G , Mazel Florent , Oliver David , McEwen Lisa M , Hong Kris Y , Hallam Steven J
Published: July 2020

We live in an increasingly data-driven world, where high-throughput sequencing and mass spectrometry platforms are transforming biology into an information science. This has shifted major challenges in biological research from data generation and processing to interpretation and knowledge translation. However, post-secondary training in bioinformatics, or more generally data science for life scientists, lags behind current demand. In particular, development of accessible, undergraduate data science curricula has potential to improve research and learning outcomes and better prepare students in the life sciences to thrive in public and private sector careers. Here, we describe the Experiential Data science for Undergraduate Cross-Disciplinary Education (EDUCE) initiative, which aims to progressively build data science competency across several years of integrated practice. Through EDUCE, students complete data science modules integrated into required and elective courses augmented with coordinated co-curricular activities. The EDUCE initiative draws on a community of practice consisting of teaching assistants, postdocs, instructors and research faculty from multiple disciplines to overcome several reported barriers to data science for life scientists, including instructor capacity, student prior knowledge, and relevance to discipline-specific problems. Preliminary survey results indicate that even a single module improves student self-reported interest and/or experience in bioinformatics and computer science. Thus, EDUCE provides a flexible and extensible active learning framework for integration of data science curriculum into undergraduate courses and programs across the life sciences.

Availability and implementation

The EDUCE teaching and learning framework is accessible ateduce-ubc.github.io
Waking experience modulates sleep need in mice
Authors: Milinski Linus , Fisher Simon P. , Cui Nanyi , McKillop Laura E. , Blanco Duque Cristina , Ang Gauri , Yamagata Tomoko , Bannerman David M. , Vyazovskiy Vladyslav V.
Published: July 2020

Homeostatic regulation of sleep is reflected in the maintenance of a daily balance between sleep and wake. Although numerous internal and external factors can influence sleep, it is unclear whether and to what extent the process that keeps track of time spent awake is determined by the content of the waking experience. We hypothesised that alterations in environmental conditions may elicit different types of wakefulness, which will in turn influence both the capacity to sustain continuous wakefulness as well the rates of accumulating sleep pressure. To address this, we performed two experiments, where we compared wakefulness dominated by novel object exploration with either (i) the effects of voluntary wheel running (Experiment 1) or (ii) performance in a simple touchscreen task (Experiment 2). We find that voluntary wheel running results in longer wake episodes, as compared with exploratory behaviour; yet it does not lead to higher levels of EEG slow wave activity (SWA) during subsequent sleep. On the other hand, engagement in a touchscreen task, motivated by a food reward, results in lower SWA during subsequent sleep, as compared to exploratory wakefulness, even though the total duration of wakefulness was similar. Overall, our study suggests that sleep-wake behaviour is highly flexible within an individual, and that the homeostatic process that keeps track of time spent awake is sensitive to the nature of the waking experience. We therefore conclude that sleep dynamics are determined, to a large degree, by the interaction between the organism and the environment.
Endocardial/endothelial angiocrines regulate cardiomyocyte development and maturation and induce features of ventricular non-compaction
Authors: Rhee Siyeon , Paik David T. , Yang Johnson Y. , Nagelberg Danielle , Williams Ian , Tian Lei , Roth Robert , Chandy Mark , Ban Jiyeon , Belbachir Nadjet , Kim Seokho , Zhang Hao , Phansalkar Ragini , Wong Ka Man , King Devin A. , Valdez Caroline , Winn Virginia D. , Morrison Ashby J. , Wu Joseph C. , Red-Horse Kristy
Published: July 2020

Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We have previously shown that endothelial cell-specific deletion of the chromatin remodeler geneIno80results in defective coronary vessel development that leads to ventricular noncompaction in embryonic mouse hearts. Here, we used single-cell RNA-sequencing to characterize endothelial and endocardial defects inIno80-deficient hearts. We observed a pathological endocardial cell population in the non-compacted hearts, and identified multiple dysregulated angiocrine factors that dramatically affected cardiomyocyte behavior. We identifiedCol15A1as a coronary vessel-secreted angiocrine factor, downregulated byIno80-deficiency, that functioned to promote cardiomyocyte proliferation. Furthermore, mutant endocardial and endothelial cells (ECs) upregulated expression of secreted factors, such asTgfbi, Igfbp3, Isg15, andAdm, which decreased cardiomyocyte proliferation and increased maturation. These findings support a model where coronary ECs normally promote myocardial compaction through secreted factors, but that endocardial and ECs can secrete factors that contribute to non-compaction under pathological conditions.
A unified atlas of CD8 T cell dysfunctional states in cancer and infection
Authors: Pritykin Yuri , van der Veeken Joris , Pine Allison , Zhong Yi , Sahin Merve , Mazutis Linas , Pe’er Dana , Rudensky Alexander , Leslie Christina
Published: July 2020

CD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by the conspicuous heterogeneity of CD8 T cell states described across different experimental and clinical settings. By carrying out a unified analysis of over 300 ATAC-seq and RNA-seq experiments from twelve independent studies of CD8 T cell dysfunction in cancer and infection we defined a shared differentiation trajectory towards terminal dysfunction and its underlying transcriptional drivers and revealed a universal early bifurcation of functional and dysfunctional T cell activation states across models. Experimental dissection of acute and chronic viral infection using scATAC-seq and allele-specific scRNA-seq identified state-specific transcription factors and captured the early emergence of highly similar TCF1+progenitor-like populations at an early branch point, at which epigenetic features of functional and dysfunctional T cells diverge. Our atlas of CD8 T cell states will facilitate mechanistic studies of T cell immunity and translational efforts.
The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in anin vitroALS Model
Authors: Sannigrahi Achinta , Chowdhury Sourav , Das Bidisha , Banerjee Amrita , Halder Animesh , Naganathan Athi N. , Karmakar Sanat , Chattopadhyay Krishnananda
Published: July 2020

Aggregation of Cu-Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, ALS. Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysiology. Here, we use multiple mutational variants of SOD1 to show that the absence of Zn, and not Cu, significantly impacts membrane attachment of SOD1 through two loop regions facilitating aggregation driven by lipid induced conformational changes. These loop regions influence both the primary (through Cu intake) and the gain of function (through aggregation) of SOD1 presumably through a shared conformational landscape. Combining experimental and theoretical frameworks using representative ALS disease mutants, we develop a ‘co-factor derived membrane association model’ wherein mutational stress closer to the Zn (but not to the Cu) pocket is responsible for membrane association mediated toxic aggregation and survival time scale after ALS diagnosis.
Role for novel family of pathogen-induced cysteine-rich transmembrane proteins in disease resistance
Authors: Mendes Marciel Pereira , Hickman Richard , Van Verk Marcel C. , Nieuwendijk Nicole , Reinstädler Anja , Panstruga Ralph , Pieterse Corné M.J. , Van Wees Saskia C.M.
Published: July 2020

Plants possess a sophisticated immune system to protect themselves against pathogen attack. The defense hormone salicylic acid (SA) is an important player in the plant immune gene regulatory network. Using RNA-seq time series data ofArabidopsis thalianaleaves treated with SA, we identified a largely uncharacterized SA-responsive gene family of eight members that are all activated in response to various pathogens or their immune elicitors and encode small proteins with cysteine-rich transmembrane domains. Based on their nucleotide similarity and chromosomal position, the designatedPathogen-inducedCysteine-rich transMembrane protein (PCM) genes were subdivided into three subgroups consisting ofPCM1-3(subgroup I),PCM4-6(subgroup II), andPCM7-8 (subgroup III). Of thePCMgenes, onlyPCM4(also known asPCC1) has previously been implicated in plant immunity. Transient expression assays inNicotiana benthamianaindicated that most PCM proteins localize to the plasma membrane. Ectopic overexpression of thePCMsin Arabidopsis resulted in all eight cases in enhanced resistance against the biotrophic oomycete pathogenHyaloperonospora arabidopsidisNoco2. Additionally, overexpression ofPCMsubgroup I genes conferred enhanced resistance to the hemi-biotrophic bacterial pathogenPseudomonas syringaepv.tomatoDC3000. Ectopic overexpression of thePCMsalso affected the expression of genes related to light signaling and development, and accordingly PCM-overexpressing seedlings displayed elongated hypocotyl growth. These results point to a function of PCMs in both disease resistance and photomorphogenesis, connecting both biological processes, possibly via effects on membrane structure or activity of interacting proteins at the plasma membrane.
No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor
Authors: Shilts Jarrod , Wright Gavin J.
Published: July 2020

The spike protein of SARS-CoV-2 is known to enable viral invasion into human cells through direct binding to host receptors including ACE2. An alternate entry receptor for the virus was recently proposed to be basigin/CD147. These early studies have already prompted a clinical trial and multiple published hypotheses of the role of this host receptor in viral infection and pathogenesis. We sought to independently characterize the basigin-spike protein interaction. After conducting several lines of experiments, we report that we are unable to find evidence supporting the role of basigin as a putative spike-binding receptor. Recombinant forms of both the entire ectodomain and S1 domain of the SARS-CoV-2 spike protein that directly bind ACE2 do not interact with basigin expressed on the surface of human cells. Using specialized assays tailored to detect receptor interactions as weak or weaker than the proposed basigin-spike binding, we report no evidence for direct binding of the viral spike to either of the two common isoforms of basigin. Given the pressing need for clarity on which targets of SARS-CoV-2 may lead to promising therapeutics, we present these findings to allow more informed decisions about the translational relevance of this putative mechanism in the race to understand and treat COVID-19.
The sleep-wake distribution contributes to the peripheral rhythms in PERIOD-2
Authors: Hoekstra Marieke M.B. , Jan Maxime , Emmenegger Yann , Franken Paul
Published: July 2020

In the mouse,Period-2(Per2) expression in tissues peripheral to the suprachiasmatic nuclei (SCN) increases during sleep deprivation and at times of the day when animals are predominantly awake spontaneously, suggesting that the circadian sleep-wake distribution directly contributes to the daily rhythms inPer2. We found support for this hypothesis by recording sleep-wake state alongside PER2 bioluminescence in freely behaving mice, demonstrating that PER2 increases during spontaneous waking and decreases during sleep. The temporary reinstatement of PER2 rhythmicity in behaviorally arrhythmic SCN-lesioned mice submitted to daily recurring sleep deprivations substantiates our hypothesis. Mathematical modelling revealed that PER2 dynamics can be described by a damped harmonic oscillator driven by two forces: a sleep-wake-dependent force and a SCN-independent circadian force. Our work underscores the notion that in peripheral tissues the clock gene circuitry integrates sleep-wake information and could thereby contribute to behavioral adaptability to respond to homeostatic requirements.
Optimal inaccuracy: estimating male fitness in the movement-assisted dichogamous speciesClerodendrum infortunatum
Authors: Mukhopadhyay Amritendu , Quader Suhel
Published: July 2020

In hermaphroditic species, sexual interference can drive the evolution of dichogamy, where sporophylls (reproductive parts) are separated in time. However, the separation of sporophylls can lead to pollination inaccuracy, especially in movement-assisted dichogamy, where sporophylls alter their position over time. Is pollination inaccuracy minimised by the second sporophyll taking the exact position of the first? Are the sporophylls optimally positioned and stable in their respective active phases? We address these questions inClerodendrum infortunatum, a protandrous, movement-assisted dichogamous species. We made predictions from optimality arguments, and tested these by measuring sporophyll angles over time, by experimentally manipulating flowers, and by estimating correlates of the resultant fitness, taking into account pollen export, pollination inaccuracy and the resultant total pollen delivered. Contrary to expectation, anthers do not have a fixed position in the male phase, and pollination inaccuracy is high. Further, when pollen load is highest, anthers are paradoxically not positioned at the pollen export peak. Also, pollen export and pollination accuracy peaks do not align. This seeming maladaptiveness of anther positioning nevertheless results in highest overall male fitness, measured as the total pollen delivered over the entire male phase. Instead of a simple positional exchange of sporophylls, stamens display a more complicated dynamic strategy which appears close to optimal even though naive measures of pollination inaccuracy are high. Such a strategy of maximising overall male fitness, integrating over the dynamics of stamen trajectory, could well be a general characteristic of protandrous movement-assisted dichogamy.
We think what we eat: Animal-based diet influences cerebral and microbiota networks connectivity in early ages. A study case of an indigenous community in Mexico
Authors: Elvia Ramirez-Carrillo , Isaac G-Santoyo , Oliver López-Corona , Rojas-Ramos Olga A. , Falcón Luisa I. , Gaona Osiris , Cerqueda-García Daniel , Sánchez-Quinto Andrés , de la Fuente Rodríguez Rosa María , Castillo Ariatna Hernández , Javier Nieto
Published: July 2020

We are not individuals, we are much better described as ecosystems due to trillions of bacteria and other microorganisms that inhabit us. We now know that gut microbiota can greatly influence many physiological parameters that in turn may impact several cognitive functions, such as learning, memory, and decision making processes. This mutualistic symbiotic relation known as the gut-brain axis is also constrained by external factors such as dietary habits such as animal protein and lipids intake. Using a novel combination of Machine Learning and Network Theory techniques, we provide evidence from an indigenous population in Guerrero Mexico, that both brain and gut-microbiota connectivity, evaluated by Minimum Spanning Tree as the critical backbone of information flow, diminish under either low protein or lipids intake. We discuss then how this loss of connectivity may translate into a reduction of the individual’s capacity to cope with perturbations as loss of connectivity may be linked with losses in antifragility.
Identification of clinical combination therapies to induce durable responses in kidney cancers
Authors: Lue Hui-wen , Derrick Daniel S. , Rao Soumya , Van Gaest Anna , Cheng Larry , Podolak Jennifer , Lawson Samantha , Xue Changhui , Garg Devin , White Ralph , Ryan Christopher W. , Drake Justin M. , Ritz Anna , Heiser Laura M. , Thomas George V.
Published: July 2020

The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high throughput drug screen to multiple human kidney cancer cells, we identified the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acted synergistically in cells to markedly reduce cell viability. Importantly, the combination was well tolerated and caused tumor regressionin vivo. Transcriptional and phosphoproteomic profiling revealed that the combination converged to downregulate the MAPK-ERK signaling pathway, a result not predicted by single agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergized with either dasatinib or cabozantinib to increase its efficacy. This study, by employing approved, clinically relevant drugs provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.
Structure and function of a novel osmoregulated periplasmic fiber-forming high-molecular-weight carbohydrate ofMyxococcus xanthus
Authors: Agrawal Sapeckshita , Heiss Christian , Zuckerman David M. , So Jeffery M. T. , Semeijn Koen , Naran Radnaa , Azadi Parastoo , Hoiczyk Egbert
Published: July 2020

Osmoregulation is of central importance for living cells. In Gram-negative bacteria, strategies for osmoregulation and turgor maintenance in hypotonic environments include the synthesis, accumulation, and modification of periplasmic oligosaccharides. These osmoregulated periplasmic glucans (OPGs, formerly known as membrane-derived oligosaccharides or MDOs) promote water uptake and retention, keeping the cells in an optimal state of hydration. While our understanding of OPG-dependent osmoregulation in a number of model organisms likeEscherichia coliis quite detailed, less is known about these processes in bacteria that live in environments characterized by strongly fluctuating osmolarity, such as soil. Here we describe that the soil bacteriumMyxococcus xanthuslacks a canonical low-molecular-weight OPG, but instead possesses a novel high-molecular-weight, fiber-forming polysaccharide. Chemical analysis reveals that this polysaccharide is several thousand kilodaltons in size, composed of a highly branched decasaccharide repeat unit containing mannose, glucose, N-acetylglucosamine, and rhamnose. Physiological experiments indicate that the polysaccharide is osmoregulated thereby functionally replacing the canonical OPG. Moreover, experiments indicate that this high-molecular-weight periplasmic polysaccharide forms a fibrillar meshwork that stabilizes the cell envelope during glycerol spore formation, a process during which the entire peptidoglycan of the cell is degraded and the rod-shaped vegetative cells convert into spherical spores.

Significance

Osmoprotection is a necessity for every living cell, particularly in an environment with fluctuating osmolarity. In Gram-negative bacteria, low-molecular-weight osmoregulated periplasmic glucans (OPGs) are an important component of the osmotic stress response in hypotonic environments. Here, we describe that the soil bacteriumMyxococcus xanthusdoes not possess such an OPG but instead accumulates a novel high-molecular-weight fiber-forming polysaccharide in the periplasm in response to hypotonic conditions. This polymer is important for osmoprotection of the cells and plays a key role in the stabilization of the cell envelope during the conversion of rod-shaped vegetative cells into spherical spores. These results indicate that bacteria may use non-OPG carbohydrates for osmoprotection and cell wall stabilization during processes like cellular differentiation.
Cell-free DNA as a biomarker for prostate cancer: elevated concentration and decreased fragment size
Authors: Chen Emmalyn , Cario Clinton L. , Leong Lancelote , Lopez Karen , Márquez César P. , Chu Carissa , Li Patricia S. , Oropeza Erica , Tenggara Imelda , Cowan Janet , Simko Jeffry P. , Chan June M. , Friedlander Terence , Wyatt Alexander W. , Aggarwal Rahul , Paris Pamela L. , Carroll Peter R. , Feng Felix , Witte John S.
Published: July 2020

Purpose

Prostate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer. Here we investigated whether differences in cfDNA concentration and cfDNA fragment size could improve the sensitivity for detecting more advanced and aggressive prostate cancer.

Materials and Methods

This study included 268 individuals: 34 healthy controls, 112 men with localized prostate cancer who underwent radical prostatectomy (RP), and 122 men with metastatic castration-resistant prostate cancer (mCRPC). Plasma cfDNA concentration and fragment size were quantified with the Qubit 3.0 and the 2100 Bioanalyzer. The potential relationship between cfDNA concentration or fragment size and localized or mCRPC prostate cancer was evaluated with descriptive statistics, logistic regression, and area under the curve analysis with cross-validation.

Results

Plasma cfDNA concentrations were elevated in mCRPC patients in comparison to localized disease (OR5 ng/mL= 1.34, P = 0.027) or to being a control (OR5 ng/mL= 1.69, P = 0.034). Decreased average fragment size was associated with an increased risk of localized disease compared to controls (OR5bp= 0.77, P = 0.0008).

Conclusion

This study suggests that cfDNA concentration and average cfDNA fragment size may provide a quick, cost-effective approach to help determine which patients will benefit most from further screening and/or disease monitoring to help improve prostate cancer outcomes.
Variants atRNF212andRNF212Bare associated with recombination rate variation in Soay sheep (Ovis aries)
Authors: Johnston Susan E. , Stoffel Martin A. , Pemberton Josephine M.
Published: July 2020

Meiotic recombination is a ubiquitous feature of sexual reproduction, ensuring proper disjunction of homologous chromosomes, and creating new combinations of alleles upon which selection can act. By identifying the genetic drivers of recombination rate variation, we can begin to understand its evolution. Here, we revisit an analysis investigating the genetic architecture of gamete autosomal crossover counts (ACC) in a wild population of Soay sheep (Ovis aries) using a much larger dataset (increasing from 3,300 to 7,235 gametes and from ∼39,000 to ∼415,000 SNPs for genome-wide association analysis). Animal models fitting genomic relatedness confirmed that ACC was heritable in both females (h2= 0.18) and males (h2= 0.12). Genome-wide association studies identified two regions associated with ACC variation. A region on chromosome 6 containingRNF212explained 46% of heritable variation in female ACC, but was not associated with male ACC, confirming the previous finding. A region on chromosome 7 containingRNF212Bexplained 20-25% of variation in ACC in both males and females. BothRNF212andRNF212Bhave been repeatedly associated with recombination rate in other mammal species. These findings confirm that moderate to large effect loci can underpin ACC variation in wild mammals, and provide a foundation for further studies on the evolution of recombination rates.
Dynamic control over feedback regulation identifies pyruvate-ferredoxin oxidoreductase as a central metabolic enzyme in stationary phaseE. coli
Authors: Li Shuai , Ye Zhixia , Lebeau Juliana , Moreb Eirik A. , Lynch Michael D.
Published: July 2020

We demonstrate the use of two-stage dynamic metabolic control to manipulate feedback regulation in central metabolism and improve stationary phase biosynthesis in engineeredE. coli. Specifically, we report the impact of dynamic control over two enzymes: citrate synthase, and glucose-6-phosphate dehydrogenase, on stationary phase fluxes. Firstly, reduced citrate synthase levels lead to a reduction inα-ketoglutarate, which is an inhibitor of sugar transport, resulting in increased stationary phase glucose uptake and glycolytic fluxes. Reduced glucose-6-phosphate dehydrogenase activity activates the SoxRS regulon and expression of pyruvate-ferredoxin oxidoreductase, which is in turn responsible for large increases in acetyl-CoA production. The combined reduction in citrate synthase and glucose-6-phosphate dehydrogenase, leads to greatly enhanced stationary phase metabolism and the improved production of citramalic acid enabling titers of 126±7g/L. These results identify pyruvate oxidation via the pyruvate-ferredoxin oxidoreductase as a “central” metabolic pathway in stationary phaseE. coli, which coupled with ferredoxin reductase comprise a pathway whose physiologic role is maintaining NADPH levels.

Highlights

Dynamic reduction inα-keto-glutarate pools alleviate inhibition of PTS dependent transport improving stationary phase sugar uptake.

Dynamic reduction in glucose-6-phosphate dehydrogenase activates pyruvate flavodoxin/ferredoxin oxidoreductase and improves stationary acetyl-CoA flux.

Pyruvate flavodoxin/ferredoxin oxidoreductase is responsible for large stationary phase acetyl-CoA fluxes under aerobic conditions.

Production of citramalate to titers 126 ± 7g/L at > 90 % of theoretical yield.
Transposable Element-Gene Splicing Modulates the Transcriptional Landscape of Human Pluripotent Stem Cells
Authors: Babarinde Isaac A. , Ma Gang , Li Yuhao , Deng Boping , Luo Zhiwei , Liu Hao , Abdul Mazid Md. , Ward Carl , Chen Minchun , Fu Xiuling , Duttlinger Martha , He Jiangping , Sun Li , Li Wenjuan , Zhuang Qiang , Frampton Jon , Cazier Jean-Baptiste , Chen Jiekai , Jauch Ralf , Esteban Miguel A. , Hutchins Andrew P.
Published: July 2020

Transposable elements (TEs) occupy nearly 50% of mammalian genomes and are both potential dangers to genome stability and functional genetic elements. TEs can be expressed and exonised as part of a transcript, however, their full contribution to the transcript splicing remains unresolved. Here, guided by long and short read sequencing of RNAs, we show that 26% of coding and 65% of non-coding transcripts of human pluripotent stem cells (hPSCs) contain TEs. Different TE families have unique integration patterns with diverse consequences on RNA expression and function. We identify hPSC-specific splicing of endogenous retroviruses (ERVs) as well as LINE L1 elements into protein coding genes that generate TE-derived peptides. Finally, single cell RNA-seq reveals that proliferating hPSCs are dominated by ERV-containing transcripts, and subpopulations express SINE or LINE-containing transcripts. Overall, we demonstrate that TE splicing modulates the pluripotency transcriptome by enhancing and impairing transcript expression and generating novel transcripts and peptides.
partR2: Partitioning R2in generalized linear mixed models
Authors: Stoffel Martin A. , Nakagawa Shinichi , Schielzeth Holger
Published: July 2020

The coefficient of determinationR2quantifies the amount of variance explained by regression coefficients in a linear model. It can be seen as the fixed-effects complement to the repeatabilityR(intra-class correlation) for the variance explained by random effects and thus as a tool for variance decomposition. TheR2of a model can be further partitioned into the variance explained by a particular predictor or a combination of predictors using semi-partial (part)R2and structure coefficients, but this is rarely done due to a lack of software implementing these statistics. Here, we introducepartR2, an R package that quantifies partR2for fixed effect predictors based on (generalized) linear mixed-effect model fits. The package iteratively removes predictors of interest from the model and monitors the change in the variance of the linear predictor. The difference to the full model gives a measure of the amount of variance explained uniquely by a particular predictor or a set of predictors.partR2also estimates structure coefficients as the correlation between a predictor and fitted values, which provide an estimate of the total contribution of a fixed effect to the overall prediction, independent of other predictors. Structure coefficients can be converted to the total variance explained by a predictor, here called ‘inclusive’R2, as the square of the structure coefficients times totalR2. Furthermore, the package reports beta weights (standardized regression coefficients). Finally,partR2implements parametric bootstrapping to quantify confidence intervals for each estimate. We illustrate the use ofpartR2with real example datasets for Gaussian and binomial GLMMs and discuss interactions, which pose a specific challenge for partitioning the explained variance among predictors.
Cytokinetic abscission is part of the mid-blastula transition switch in early zebrafish embryogenesis
Authors: Adar-Levor Shai , Nachmias Dikla , Gal-Oz Shani T. , Jahn Yarden M. , Peyrieras Nadine , Zaritsky Assaf , Birnbaum Ramon Y. , Elia Natalie
Published: July 2020

Animal cytokinesis ends with the formation of a thin intercellular membrane bridge connecting the two newly formed sibling cells that is ultimately resolved by abscission. While mitosis is completed within 15 minutes, the intercellular bridge can persist for hours, maintaining a physical connection between sibling cells and allowing exchange of cytosolic components. Although cell-cell communication is fundamental for development, the potential role of intercellular bridges during embryogenesis have not been fully elucidated. Here, we found that in early zebrafish (Danio rerio) embryogenesis, abscission is delayed and cells do not resolve their intercellular bridges until midblastula transition (MBT), giving rise to the formation of small inter-connected cell clusters. Interestingly, abscission commences during the MBT switch, which is manifested by cell cycle elongation, loss of synchronized divisions and genome activation. Moreover, depletion of Chmp4bb which is an essential ESCRT-III component for scission, delayed abscission beyond the MBT switch. Hallmark features of MBT, including transcription onset and cell shape changes, were similar in sibling cells connected by intercellular bridges, proposing a role for intercellular bridges in maintaining cell-cell communication in the embryo. Taken together, our data suggest that abscission is part of the cellular changes that occur during MBT and that cells coordinate their behavior during this critical embryonic phase through persisted intercellular bridges.

Significance Statement

In this work we show that the last step of cytokinesis, termed abscission, is inhibited in early zebrafish embryos. As a result, sibling cells remain connected to one another for several cycles and mutually time their developmental progress including transcription onset. Abscission commences at the 10thcell cycle, when embryos enter the midblastula transition (MBT) switch in which embryonic cells become individualized and exhibit the characteristics of mature cells. Our data suggest that abscission is part of the MBT switch and that embryonic sibling cells mutually time their developmental progress by maintaining physical connections between them in the early embryo.
COVID-19 and Rheumatoid Arthritis share myeloid pathogenic and resolving pathways
Authors: MacDonald Lucy , Otto Thomas D. , Elmesmari Aziza , Tolusso Barbara , Somma Domenico , McSharry Charles , Gremese Elisa , McInnes Iain B. , Alivernini Stefano , Kurowska-Stolarska Mariola
Published: July 2020

Background

We recently delineated the functional biology of pathogenic and inflammation resolving synovial tissue macrophage clusters in rheumatoid arthritis (RA). Whilst RA is not a viral respiratory syndrome, it represents a pro-inflammatory cytokine-driven chronic articular condition often accompanied by cardiovascular and lung pathologies. We hypothesised that functionally equivalent macrophage clusters in the lung might govern inflammation and resolution of COVID-19 pneumonitis.

Methods

To provide insight into the targetable functions of COVID-19 bronchoalveolar lavage (BALF) macrophage clusters, a comparative analysis of BALF macrophage single cell transcriptomics (scRNA-seq) with synovial tissue (ST) macrophage scRNA-seq and functional biology was performed. The function of shared BALF and ST MerTK inflammation-resolving pathway was confirmed with inhibitor in primary macrophage-synovial fibroblast co-cultures.Results. Distinct BALF FCNposand FCNposSPP1posmacrophage clusters emerging in severe COVID-19 patients were closely related to ST CD48highS100A12posand CD48posSPP1posclusters driving synovitis in active RA. They shared transcriptomic profile and pathogenic mechanisms. Healthy lung resident alveolar FABP4posmacrophages shared a regulatory transcriptomic profile, including TAM (Tyro, Axl, MerTK) receptors pathway with synovial tissue TREM2posmacrophages that govern RA remission. This pathway was substantially altered in BALF macrophages of severe COVID-19. In vitro dexamethasone inhibited tissue inflammation via macrophages’ MerTK function.

Conclusion

Pathogenesis and resolution of COVID-19 pneumonitis and RA synovitis might be driven by similar macrophage clusters and pathways. The MerTK-dependent anti-inflammatory mechanisms of dexamethasone, and the homeostatic function of TAM pathways that maintain RA in remission advocate the therapeutic MerTK agonism to ameliorate the cytokine storm and pneumonitis of severe COVID-19.
Perinatal exposure to fluoxetine and maternal adversity affect myelin-related gene expression and epigenetic regulation in the corticolimbic circuit of juvenile rats
Authors: Ramsteijn Anouschka S. , Verkaik-Schakel Rikst Nynke , Houwing Danielle J. , Plösch Torsten , Olivier Jocelien D.A.
Published: July 2020

Many pregnant women experience symptoms of depression, and are often treated with selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine.In uteroexposure to SSRIs and maternal depressive symptoms is associated with sex-specific effects on the brain and behavior. However, knowledge about the neurobiological mechanisms underlying these sex differences is limited. In addition, most animal research into developmental SSRI exposure neglects the influence of maternal adversity. Therefore, we used a rat model relevant to depression to investigate the molecular effects of perinatal fluoxetine exposure in male and female juvenile offspring. We performed RNA sequencing and targeted DNA methylation analyses on the prefrontal cortex and basolateral amygdala; key regions of the corticolimbic circuit. Perinatal fluoxetine enhanced myelin-related gene expression in the prefrontal cortex, while inhibiting it in the basolateral amygdala. SSRI exposure and maternal adversity interacted to affect expression of genes such as myelin−associated glycoprotein (Mag) and myelin basic protein (Mbp). We speculate that altered myelination reflects altered brain maturation. In addition, these effects are stronger in males than in females, resembling known behavioral outcomes. Finally,MagandMbpexpression correlated with DNA methylation, highlighting epigenetic regulation as a potential mechanism for developmental fluoxetine-induced changes in myelination.
The impact of microclimate and soil on the ecology and evolution of an arctic plant
Authors: Wickander Niklas J. , Rasmussen Pil U. , Marteinsdóttir Bryndís , Ehrlén Johan , Tack Ayco J. M.
Published: July 2020

The arctic and alpine regions are predicted to experience one of the highest rates of climate change, and the arctic vegetation is expected to be especially sensitive to such changes. Understanding the ecological and evolutionary responses of arctic plant species to changes in climate is therefore a key objective. Geothermal areas, where temperature gradients naturally occur over small spatial scales, and without many of the confounding environmental factors present in latitudinal and other gradient studies, provide a natural experimental setting to examine the impact of temperature on the response of arctic-alpine plants to increasing temperatures. To test the ecological and evolutionary response of the circumpolar alpine bistort (Bistorta vivipara) to temperature, we collected plant material and soil from areas with low, intermediate, and high soil temperatures and grew them in all combinations at three different temperatures. At higher experimental soil temperatures, sprouting was earlier, and plants had more leaves. Sprouting was earlier in soil originating from intermediate temperature and plants had more leaves when grown in soil originating from low temperatures. We did not find evidence of local adaptation or genetic variation in reaction norms among plants originating from areas with low, intermediate, and high soil temperature. Our findings suggest that the alpine bistort has a strong plastic response to warming, but that differences in soil temperature have not resulted in genetic differentiation. The lack of an observed evolutionary response may, for example, be due to the absence of temperature-mediated selection onB. vivipara, or high levels of gene flow balancing differences in selection. When placed within the context of other studies, we conclude that arctic-alpine plant species often show strong plastic responses to spring warming, while evidence of evolutionary responses varies among species.