bluuebunny/crossref_metadata_2025 huggingface dataset:
Enriched G-quadruplexes on the Drosophila Male X Chromosome Function as Insulators of Dosage Compensation Complex
Authors: Qian Sheng-Hu , Chen Lu , Chen Zhen-Xia
Published: June 2019

The evolution of sex chromosomes has resulted in half X chromosome dosage in males as females. Dosage compensation, or the two-fold upregulation in males, was thus evolved to balance the gene expression between sexes. However, the step-wise evolutionary trajectory of dosage compensation during Y chromosome degeneration is still unclear. Here, we show that the specific structured elements G-quadruplexes (G4s) are enriched on the X chromosome in Drosophila melanogaster. Meanwhile, on the X chromosome, the G4s are underrepresented on the H4K16 acetylated regions and the binding sites of dosage compensation complex male-specific lethal (MSL) complex. Peaks of G4 density and potential are observed at the flanking regions of MSL binding sites, suggesting G4s act as insulators to precisely up-regulate certain regions in males. Thus, G4s may be involved in the evolution of dosage compensation process through fine-tuning one-dose proto-X chromosome regions around MSL binding sites during the gradual Y chromosome degeneration.

One Sentence Summary

G-quadruplexes act as insulators to precisely up-regulate X chromosome in males.
Genetic background modifies CNS-mediated sensorimotor decline in the AD-BXD mouse population
Authors: O’Connell Kristen M.S. , Ouellette Andrew R. , Neuner Sarah M. , Dunn Amy R. , Kaczorowski Catherine C.
Published: June 2019

Many patients with Alzheimer’s dementia also exhibit non-cognitive symptoms such as sensorimotor deficits, which can precede the onset of the hallmark cognitive deficits and significantly impact daily activities and an individual’s ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and the relationship between sensorimotor and cognitive decline remain poorly understood, due in part to a lack of translationally relevant animal models. To address this, we recently developed a novel model of genetic diversity in Alzheimer’s disease, the AD-BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD-BXDs and their relationship to cognitive decline in these mice. We found that both age- and AD-related declines in coordination, balance, and vestibular function vary significantly across the panel, indicating that genetic background strongly influences the expressivity of the familial AD mutations used in the AD-BXD panel and their impact on motor function. Further, we found that motor decline is not associated withcognitive decline in either AD or aging, suggesting that sensorimotor deficits in AD occur – in part - through distinct mechanisms. Overall, the results presented here suggest that AD-related sensorimotor decline is strongly dependent on background genetics and is independent of dementia and cognitive deficits, suggesting that effective therapeutics for the entire spectrum of AD symptoms will likely require interventions targeting each distinct domain involved in the disease.
Unconventional cell division cycles from marine-derived yeasts
Authors: Mitchison-Field Lorna M.Y. , Vargas-Muñiz José M. , Stormo Benjamin M. , Vogt Ellysa J.D. , Van Dierdonck Sarah , Ehrlich Christoph , Lew Daniel J. , Field Christine M. , Gladfelter Amy S.
Published: June 2019

Fungi have been found in every marine habitat that has been explored, however, the diversity and functions of fungi in the ocean are poorly understood. In this study, fungi were cultured from the marine environment in the vicinity of Woods Hole, MA, USA including from plankton, sponge and coral. Our sampling resulted in 36 unique species across 20 genera. We observed many isolates by time-lapse differential interference contrast (DIC) microscopy and analyzed modes of growth and division. Several black yeasts displayed highly unconventional cell division cycles compared to those of traditional model yeast systems. Black yeasts have been found in habitats inhospitable to other life and are known for halotolerance, virulence, and stress-resistance. We find that this group of yeasts also shows remarkable plasticity in terms of cell size control, modes of cell division, and cell polarity. Unexpected behaviors include division through a combination of fission and budding, production of multiple simultaneous buds, and cell division by sequential orthogonal septations. These marine-derived yeasts reveal alternative mechanisms for cell division cycles that seem likely to expand the repertoire of rules established from classic model system yeasts.
Toward computational design of protein crystals with improved resolution
Authors: Jeliazkov Jeliazko R. , Robinson Aaron C. , García-Moreno E. Bertrand , Berger James M. , Gray Jeffrey J.
Published: June 2019

Substantial advances have been made in the computational design of protein interfaces over the last 20 years. However, the interfaces targeted by design have typically been stable and high affinity. Here, we report the development of a generic computational design method to stabilize the weak interactions at crystallographic interfaces. Initially, we analyzed structures reported in the Protein Data Bank (PDB) to determine whether crystals with more stable interfaces result in higher resolution structures. We found that, for twenty-two variants of a single protein crystallized by a single individual, Rosetta score correlates with resolution. We next developed and tested a computational design protocol, seeking to identify point mutations that would improve resolution on a highly stable variant of staphylococcal nuclease (SNase Δ+PHS). Only one of eleven initial designs crystallized, forcing us to re-evaluate our strategy and base our designs on an ensemble of protein backbones. Using this strategy, four of the five designed proteins crystallized. Collecting diffraction data for multiple crystals per design and solving crystal structures, we found that designed crystals improved resolution modestly and in unpredictable ways, including altering crystal space group. Post-hoc, in silico analysis showed that crystal space groups could have been predicted for four of six variants (including WT), but that resolution did not correlate with interface stability, as it did in the preliminary results. Our results show that single point mutations can have significant effects on crystal resolution and space group, and that it is possible to computationally identify such mutations, suggesting a potential design strategy to generate high-resolution protein crystals from poorly diffracting ones.
Single Nanoparticle Tracking Reveals Efficient Long-Distance Undercurrent Transport above Swarming Bacteria
Authors: Feng Jingjing , Zhang Zexin , Wen Xiaodong , Xue Jianfeng , He Yan
Published: June 2019

Flagellated bacteria move collectively in a swirling pattern on agar surfaces immersed in a thin layer of viscous “swarm fluid”, but the role of this fluid in mediating the cooperation of the bacterial population is not well understood. Herein, we use gold nanorods (AuNRs) as single particle tracers to explore the spatiotemporal structure of the swarm fluid. We observed that individual AuNRs are transported in a plane of ~2 μm above the motile cells. They can travel for long distances (>700 μm) in a 2D plane at high speed (often >50 μm2/s) without interferences from bacterial movements. The particles are apparently lifted up and transported by collective mixing of the small vortices around bacteria during localized clustering and de-clustering of the motile cells, exhibiting superdiffusive and non-Gaussian characteristics with alternating large-step jumps and confined lingering. Their motions are consistent with the Lévy walk (LW) model, revealing efficient transport flows above swarms. These flows provide obstacle-free highways for long-range material transportations, shed light on how swarming bacteria perform population-level communications, and reveal the essential role of the fluid phase on the emergence of large-scale synergy. This approach is promising for probing complex fluid dynamics and transports in other collective systems.
Automated Threshold Selection for Cryo-EM Density Maps
Authors: Pfab Jonas , Si Dong
Published: June 2019

Recent advances in cryo-EM have made it possible to create protein density maps with a near-atomic resolution. This has contributed to its wide popularity, resulting in a rapidly growing number of available cryo-EM density maps. In order to computationally process them, an electron density threshold level is required which defines a lower bound for density values. In the context of this paper the threshold level is required in a pre-processing step of the backbone structure prediction project which predicts the location of Cα atoms of the backbone of a protein based on its cryo-EM density map using deep learning techniques. A custom threshold level has to be selected for each prediction in order to reduce noise that could irritate the deep learning model. Automatizing this threshold selection process makes it easier to run predictions as well as it removes the dependency of the prediction accuracy to the ability of someone to choose the right threshold value. This paper presents a method to automatize the threshold selection for the previously mentioned project as well as for other problems which require a density threshold level. The method uses the surface area to volume ratio and the ratio of voxels that lie above the threshold level to non-zero voxels as metrics to derive characteristics about suitable threshold levels based on a training dataset. The threshold level selection was tested by integrating it in the backbone prediction project and evaluating the accuracy of predictions using automatically as well as manually selected thresholds. We found that there was no loss in accuracy using the automatically selected threshold levels indicating that they are equally good as manually selected ones. The source code related to this paper can be found at https://github.com/DrDongSi/Auto-Thresholding.
Age-dependent changes in electrophysiology and calcium handling – implications for pediatric cardiac research
Authors: Swift Luther M. , Burke Morgan , Guerrelli Devon , Ramadan Manelle , Reilly Marissa , McCullough Damon , Chaluvadi Ashika , Mulvany Colm , Jaimes Rafael , Posnack Nikki Gillum
Published: June 2019

Rationale

The heart continues to develop and mature after birth and into adolescence. Accordingly, cardiac maturation is likely to include a progressive refinement in both organ morphology and function during the postnatal period. Yet, age-dependent changes in cardiac electrophysiology and calcium handling have not yet been fully characterized.

Objective

The objective of this study, was to examine the relationship between cardiac maturation, electrophysiology, and calcium handling throughout postnatal development in a rat model.

Methods

Postnatal rat cardiac maturation was determined by measuring the expression of genes involved in cell-cell coupling, electrophysiology, and calcium handling. In vivo electrocardiograms were recorded from neonatal, juvenile, and adult animals. Simultaneous dual optical mapping of transmembrane voltage and calcium transients was performed on isolated, Langendorff-perfused rat hearts (postnatal day 0–3, 4-7, 8-14, adult).

Results

Younger, immature hearts displayed slowed electrical conduction, prolonged action potential duration and increased ventricular refractoriness. Slowed calcium handling in the immature heart increased the propensity for calcium transient alternans which corresponded to alterations in the expression of genes encoding calcium handling proteins. Developmental changes in cardiac electrophysiology were associated with the altered expression of genes encoding potassium channels and intercalated disc proteins.

Conclusion

Using an intact whole heart model, this study highlights chronological changes in cardiac electrophysiology and calcium handling throughout postnatal development. Results of this study can serve as a comprehensive baseline for future studies focused on pediatric cardiac research, safety assessment and/or preclinical testing using rodent models.
Gap junctions in theC. elegansnervous system regulate ageing and lifespan
Authors: Vladis Nathalie Alexandra , Fischer Katharina Elisabeth , Digalaki Eva , Marcu Daniel-Cosmin , Bimpos Modestos Nakos , Greer Peta , Ayres Alice , Li Qiaochu , Busch Karl Emanuel
Published: June 2019

The nervous system is a central regulator of longevity, but how neuronal communication interfaces with ageing pathways is not well understood. Gap junctions are key conduits that allow voltage and metabolic signal transmission across cellular networks, yet it has remained unexplored whether they play a role in regulating ageing and longevity. We show that the innexin genes encoding gap junction subunits inCaenorhabditis eleganshave extensive and diverse impacts on lifespan. Loss of the neural innexinunc-9increases longevity by a third and also strongly benefits healthspan.Unc-9acts specifically in a glutamatergic circuit linked to mechanosensation. Absence ofunc-9depends on a functional touch-sensing machinery to regulate lifespan and alters the age-dependent decline of mechanosensory neurons. The life extension produced by removal ofunc-9requires reactive oxygen species. Our work reveals for the first time that gap junctions are important regulators of ageing and lifespan.
Microstructural plasticity in the bilingual brain
Authors: Luo Daiyi , Kwok Veronica P.Y. , Li Ping , Liu Qing , Li Wenlong , Yang Yang , Zhou Ke , Xu Min , Gao Jia-Hong , Tan Li Hai
Published: June 2019

The human brain has been uniquely equipped with the remarkable ability to acquire more than one language, as in bilingual individuals. Previous neuroimaging studies have indicated that learning a second language (L2) induced neuroplasticity at the macrostructural level. In this study, using the quantitative MRI (qMRI) combined with functional MRI (fMRI) techniques, we quantified the microstructural properties and tested whether second language learning modulates the microstructure in the bilingual brain. We found significant microstructural variations related to age of acquisition of second language in the left inferior frontal region and the left fusiform gyrus that are crucial for resolving lexical competition of bilinguals’ two languages. Early second language acquisition contributes to enhance cortical development at the microstructural level.

Significant statement

The ability to communicate in two languages is becoming more and more important in the increasingly global community. Does learning a second language (L2) affect the human brain development? At the macrostructural level, there has been neuroimaging evidence revealing neuroplasticity induced by the acquisition of L2. Here, we employed the quantitative MRI technique to investigate the microstructural variations related to L2 learning, and found that age of acquisition of L2, but not its proficiency, is associated with cortical proliferation. Early second language acquisition seems to enhance cortical development at the microstructural level.
Tolerance of nonsynonymous variation is closely correlated between human and mouse orthologues
Authors: Powell George , Simon Michelle , Pulit Sara , Mallon Ann-Marie , Lindgren Cecilia M.
Published: June 2019

Genic constraint describes how tolerant a gene is of nonsynonymous variation before it is removed from the population by negative selection. Here, we provide the first estimates of intraspecific constraint for mouse genes genome-wide, and show constraint is positively correlated between human and mouse orthologues (r = 0.806). We assess the relationships between mouse gene constraint and knockout phenotypes, showing gene constraint is positively associated with pleiotropy (ie an increased number of phenotype associations (R2= 0.65)), in addition to an enrichment in lethal, developmental, and craniofacial knockout phenotypes amongst the most constrained genes. Finally, we show mouse constraint can be used to predict human genes associated with Mendelian disease, and is positively correlated with an increase in the number of known pathogenic variants in the human orthologue (R2= 0.23). Our metrics of mouse and human constraint are available to inform future research using mouse models.
Hyperdiverse archaea near life limits at the polyextreme geothermal Dallol area
Authors: Belilla Jodie , Moreira David , Jardillier Ludwig , Reboul Guillaume , Benzerara Karim , López-García José M. , Bertolino Paola , López-Archilla Ana I. , López-García Purificación
Published: June 2019

Microbial life has adapted to various individual extreme conditions; yet, organisms simultaneously adapted to very low pH, high salt and high temperature are unknown. We combined environmental 16S/18S rRNA-gene metabarcoding, cultural approaches, fluorescence-activated cell sorting, scanning electron microscopy and chemical analyses to study samples along such unique polyextreme gradients in the Dallol-Danakil area (Ethiopia). We identify two physicochemical barriers to life in the presence of surface liquid water defined by: i) high chaotropicity-low water activity in Mg2+/Ca2+-dominated brines and ii) hyperacidity-salt combinations (pH~0/ NaCl-dominated salt-saturation) When detected, life was dominated by highly diverse ultrasmall archaea widely distributed across phyla with and without previously known halophilic members. We hypothesize that high cytoplasmic K+-level was an original archaeal adaptation to hyperthermophily, subsequently exapted during multiple transitions to extreme halophily. We detect active silica encrustment/fossilization of cells but also abiotic biomorphs of varied chemistry. Our work helps circumscribing habitability and calls for cautionary interpretations of morphological biosignatures on Earth and beyond.
Expectation pooling: An effective and interpretable pooling method for predicting DNA-protein binding
Authors: Luo Xiao , Tu Xinming , Ding Yang , Gao Ge , Deng Minghua
Published: June 2019

Motivation

Convolutional neural networks (CNNs) have outperformed conventional methods in modeling the sequence specificity of DNA-protein binding. While previous studies have built a connection between CNNs and probabilistic models, simple models of CNNs cannot achieve sufficient accuracy on this problem. Recently, some methods of neural networks have increased performance using complex neural networks whose results cannot be directly interpreted. However, it is difficult to combine probabilistic models and CNNs effectively to improve DNA-protein binding predictions.

Results

In this paper, we present a novel global pooling method: expectation pooling for predicting DNA-protein binding. Our pooling method stems naturally from the EM algorithm, and its benefits can be interpreted both statistically and via deep learning theory. Through experiments, we demonstrate that our pooling method improves the prediction performance DNA-protein binding. Our interpretable pooling method combines probabilistic ideas with global pooling by taking the expectations of inputs without increasing the number of parameters. We also analyze the hyperparameters in our method and propose optional structures to help fit different datasets. We explore how to effectively utilize these novel pooling methods and show that combining statistical methods with deep learning is highly beneficial, which is promising and meaningful for future studies in this field.

Contact

dengmh@pku.edu.cn,gaog@mail.cbi.pku.edu.cn

Supplementary information

All code is public inhttps://github.com/gao-lab/ePooling
Metabolic Alterations in Human Peripheral Blood Mononuclear Cells Associate with Progression to Islet Autoimmunity and Type 1 Diabetes
Authors: Sen Partho , Dickens Alex M. , López-Bascón María Asunción , Lindeman Tuomas , Kemppainen Esko , Lamichhane Santosh , Rönkkö Tuukka , Ilonen Jorma , Toppari Jorma , Veijola Riitta , Hyöty Heikki , Hyötyläinen Tuulia , Knip Mikael , Orešič Matej
Published: June 2019

Previous metabolomics studies suggest that type 1 diabetes (T1D) is preceded by specific metabolic disturbances. Here we asked whether distinct metabolic patterns occur in peripheral blood mononuclear cells (PBMCs) of children later developing pancreaticβ-cell autoimmunity or overt T1D. In a longitudinal cohort setting, PBMC metabolomic analysis was applied in children who either (1) progressed to T1D (PT1D, n=34), (2) seroconverted to ≥1 islet autoantibody without progressing to T1D (P1Ab, n=27), or (3) remained autoantibody negative during follow-up (CTRL, n=10). During the first year of life, levels of most lipids and polar metabolites were lower in PT1D and P1Ab, versus CTRLs. Pathway overrepresentation analysis suggested alanine, aspartate, glutamate, glycerophospholipid and sphingolipid metabolism were overrepresented in PT1D. Genome-scale metabolic models of PBMCs in T1D progression were developed using available transcriptomics data and constrained with metabolomics data from our study. Metabolic modeling confirmed altered ceramide pathways as specifically associated with T1D progression.
Diurnal.plant.tools: comparative transcriptomic and co-expression analyses of diurnal gene expression of the Archaeplastida kingdom
Authors: Xiong Ng Jonathan Wei , Tan Qiao Wen , Ferrari Camilla , Mutwil Marek
Published: June 2019

Almost all organisms coordinate some aspects of their biology through the diurnal cycle. Photosynthetic organisms, and plants especially, have established complex programs that coordinate physiological, metabolic and developmental processes with the changing light. The diurnal regulation of the underlying transcriptional processes is observed when groups of functionally related genes (gene modules) are expressed at a specific time of the day. However, studying the diurnal regulation of these gene modules in the plant kingdom was hampered by the large amount of data required for the analyses. To meet this need, we used gene expression data from 17 diurnal studies spanning the whole Archaeplastida kingdom (Plantae kingdom in the broad sense) to make an online diurnal database. We have equipped the database with tools that allow user-friendly cross-species comparisons of gene expression profiles, entire co-expression networks, co-expressed clusters (involved in specific biological processes), time-specific gene expression, and others. We exemplify how these tools can be used by studying three important biological questions: (i) the evolution of cell division, (ii) the diurnal control of gene modules in algae and (iii) the conservation of diurnally-controlled modules across species. The database is freely available at http://diurnal.plant.tools/.
Incomplete resilience of a shallow lake to a brownification event
Authors: Kazanjian G. , Brothers S. , Köhler J. , Hilt S.
Published: June 2019

Dissolved organic carbon (DOC) concentrations in many freshwater ecosystems of the northern hemisphere have increased in recent decades due to additional terrestrial inputs. This phenomenon, known as brownification, can strongly alter the physical, chemical, and biological traits of aquatic ecosystems. Extreme rainfall can also cause sudden brownification, known as blackwater events in rivers, while longer term effects on lakes are unknown. Here, we investigated the resilience of a small, temperate, shallow lake to a strong natural flooding-induced brownification event in 2011-2012. From initial DOC and total phosphorus (TP) concentrations of ~12 and 0.04 mg L−1, respectively, the lake rapidly reached peak DOC and TP concentrations of 60 and 0.35 mg L−1, respectively. By the following year, water levels had returned close to initial values, yet two additional years of monitoring (until summer 2015) and a more recent sample in spring 2019 showed that the lake did not fully return to its pre-brownification state. Instead, DOC and TP concentrations plateaued at concentrations respectively 1.5-fold and twofold greater than pre-brownification values within less than two years and remained at these concentrations in spring 2019. During this initial recovery period the lake exhibited a decline of phytoplankton and a partial recovery of summer periphyton biomass and production, albeit a full return to pre-brownification values was not recorded in either case. DOC and TP concentrations were positively correlated to phytoplankton biomass and negatively to periphyton. As increases in phytoplankton production outpaced decreasing periphyton production, the net result of this brownification event has been an increase in whole-lake areal summertime primary production. This incomplete resilience to a flooding-induced brownification event implies consequences for several ecological and biogeochemical functions of shallow lakes that warrant further investigation and might contribute to the gradual increase of freshwater DOC concentrations in the northern hemisphere.
Rainfall and other meteorological factors as drivers of urban transmission of leptospirosis
Authors: Cunha Marcelo , Costa Federico , Ribeiro Guilherme S. , Carvalho Marília S. , Reis Renato B. , Júnior Nivison N. , Pischel Lauren , Gouveia Edilane L. , Santos Andreia C. , Queiroz Adriano , Wunder Elsio A. , Reis Mitermayer G. , Diggle Peter J , Ko Albert I.
Published: June 2019

Background

Leptospirosis is an important public health problem affecting vulnerable urban slum populations in developing country settings. However, the complex interaction of meteorological factors driving the temporal trends of leptospirosis remain incompletely understood.

Methods and findings

From 1996 to 2010, we investigated the association between the weekly incidence of leptospirosis and climatic variables in the city of Salvador, Brazil by using a dynamic generalized linear model that accounted for time lags, overall trend and seasonal variation. Our model showed an increase of leptospirosis cases associated with rainfall, lower temperature and higher humidity. There was a lag of one-to-two weeks between weekly values for significant meteorological variables and leptospirosis incidence. Independent of the season, a weekly cumulative rainfall of 20 mm increased the risk of the leptospirosis by 10% compared to a week without rain. Finally, over the 14 year study period the incidence of leptospirosis decreased significantly by four fold (12.8 versus 3.6 per 100,000 people), independently of variations in climate.

Conclusions

Strategies to control leptospirosis should focus on avoiding contact with contaminated sources ofLeptospiraas well as on increasing awareness in the population and health professionals within the short time window after both low-level and extreme rainfall events. Increased leptospirosis incidence was restricted to one-to-two weeks after those events suggesting that infectiousLeptospirasurvival may be limited to short time intervals.

Author Summary

To determine the role of meteorological variables, seasonal variation and temporal trends in the incidence of leptospirosis, we investigated the time series of leptospirosis incidence amongst residents of Salvador, Brazil, from 1996 to 2010. Exploratory and confirmatory statistical methods detected associations between meteorological factors and disease incidence. Results showed the importance of extreme meteorological conditions, particularly rainfall, as short-term predictors of leptospirosis incidence. In addition, we found a long-term decreasing trend of in disease incidence over the observation period.
Generation of a Retina Reporter hiPSC Line to Label Progenitor, Ganglion, and Photoreceptor Cell Types
Authors: Lam Phuong T. , Gutierrez Christian , Del Rio-Tsonis Katia , Robinson Michael L.
Published: June 2019

Early in mammalian eye development, VSX2, BRN3b, and RCVRN expression marks neural retina progenitors (NRPs), retinal ganglion cells (RGCs), and photoreceptors (PRs), respectively. The ability to create retinal organoids from human induced pluripotent stem cells (hiPSC) holds great potential for modeling both human retinal development and retinal disease. However, no methods allowing the simultaneous, real-time monitoring of multiple specific retinal cell types during development currently exist. Here, we describe a CRISPR/Cas9 gene editing strategy to generate a triple transgenic reporter hiPSC line (PGP1) that utilizes the endogenous VSX2, BRN3b, and RCVRN promoters to specifically express fluorescent proteins (Cerulean in NRPs, eGFP in RGCs and mCherry in PRs) without disrupting the function of the endogenous alleles. Retinal organoid formation from the PGP1 line demonstrated the ability of the edited cells to undergo normal retina development while exhibiting appropriate fluorescent protein expression consistent with the onset of NRPs, RGCs, and PRs. Organoids produced from the PGP1 line expressed transcripts consistent with the development of all major retinal cell types. The PGP1 line offers a powerful new tool to study retinal development, retinal reprogramming, and therapeutic drug screening.
Optimal markers for the identification ofColletotrichumspecies
Authors: dos Santos Vieira Willie Anderson , Bezerra Priscila Alves , da Silva Anthony Carlos , Silva Veloso Josiene , Paz Saraiva Câmara Marcos , Patrick Doyle Vinson
Published: June 2019

Colletotrichumis among the most important genera of fungal plant pathogens. Molecular phylogenetic studies over the last decade have resulted in a much better understanding of the evolutionary relationships and species boundaries within the genus. There are now approximately 200 species accepted, most of which are distributed among 13 species complexes. Given their prominence on agricultural crops around the world, rapid identification of a large collection ofColletotrichumisolates is routinely needed by plant pathologists, regulatory officials, and fungal biologists. However, there is no agreement on the best molecular markers to discriminate species in each species complex. Here we calculate the barcode gap distance and intra/inter-specific distance overlap to evaluate each of the most commonly applied molecular markers for their utility as a barcode for species identification. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), histone-3 (HIS3), DNA lyase (APN2), intergenic spacer between DNA lyase and the mating-type locusMAT1-2-1 (APN2/MAT-IGS), and intergenic spacer between GAPDH and a hypothetical protein (GAP2-IGS) have the properties of good barcodes, whereas sequences of actin (ACT), chitin synthase (CHS-1) and nuclear rDNA internal transcribed spacers (nrITS) are not able to distinguish most species. Finally, we assessed the utility of these markers for phylogenetic studies using phylogenetic informativeness profiling, the genealogical sorting index (GSI), and Bayesian concordance analyses (BCA). Although GAPDH, HIS3 and β-tubulin (TUB2) were frequently among the best markers, there was not a single set of markers that were best for all species complexes. Eliminating markers with low phylogenetic signal tends to decrease uncertainty in the topology, regardless of species complex, and leads to a larger proportion of markers that support each lineage in the Bayesian concordance analyses. Finally, we reconstruct the phylogeny of each species complex using a minimal set of phylogenetic markers with the strongest phylogenetic signal and find the majority of species are strongly supported as monophyletic.
Deep-learning-based cell composition analysis from tissue expression profiles
Authors: Menden Kevin , Marouf Mohamed , Oller Sergio , Dalmia Anupriya , Kloiber Karin , Heutink Peter , Bonn Stefan
Published: June 2019

We present Scaden, a deep neural network for cell deconvolution that uses gene expression information to infer the cellular composition of tissues. Scaden is trained on single cell RNA-seq data to engineer discriminative features that confer robustness to bias and noise, making complex data preprocessing and feature selection unnecessary. We demonstrate that Scaden outperforms existing deconvolution algorithms in both precision and robustness. A single trained network reliably deconvolves bulk RNA-seq and microarray, human and mouse tissue expression data and leverages the combined information of multiple data sets. Due to this stability and flexibility, we surmise that deep learning will become an algorithmic mainstay for cell deconvolution of various data types. Scaden’s comprehensive software package is easy to use on novel as well as diverse existing expression datasets available in public resources, deepening the molecular and cellular understanding of developmental and disease processes.
Spontaneous Self-assembly of Amyloid β (1-40) into Dimers
Authors: Hashemi Mohtadin , Zhang Yuliang , Lv Zhengjian , Lyubchenko Yuri L.
Published: June 2019

The self-assembly and fibrillation of amyloid β (Aβ) proteins is the neuropathological hallmark of Alzheimer’s disease. However, the molecular mechanism of how disordered monomers assemble into aggregates remains largely unknown. In this work, we characterize the assembly of Aβ (1-40) monomers into dimers using long-time molecular dynamics simulations. Upon interaction, the monomers undergo conformational transitions, accompanied by change of the structure, leading to the formation of a stable dimer. The dimers are primarily stabilized by interactions in the N-terminal region (residues 5-12), in the central hydrophobic region (residues 16-23), and in the C-terminal region (residues 30-40); with inter-peptide interactions focused around the N- and C- termini. The dimers do not contain long β-strands that are usually found in fibrils.
Interactive Multiresolution Visualization of Cellular Network Processes
Authors: Ortega Oscar O. , Lopez Carlos F.
Published: June 2019

Computational models of network-driven processes have become a standard to explain cellular systems-level behavior and predict cellular responses to perturbations. Modern models can span a broad range of biochemical reactions and species that, in principle, comprise the complexity of dynamic cellular processes. Visualization plays a central role in the analysis of biochemical network processes to identify patterns that arise from model dynamics and perform model exploratory analysis. However, most existing visualization tools are limited in their capabilities to facilitate mechanism exploration of large, dynamic, and complex models. Here, we present PyViPR, a visualization tool that provides researchers static and dynamic representations of biochemical network processes within a Python-based Literate Programming environment. PyViPR embeds network visualizations on Jupyter notebooks, thus facilitating integration with Python modeling, simulation, and analysis workflows. To present the capabilities of PyViPR, we explore execution mechanisms of extrinsic apoptosis in HeLa cells. We show how community-detection algorithms can identify groups of molecular species that represent key biological regulatory functions and simplify the apoptosis network by placing those groups into interactively collapsible nodes. We then show how dynamic execution of a signal, under different kinetic parameter sets that fit the experimental data equally well, exhibit significantly different signal-execution modes in mitochondrial outer-membrane permeabilization – the point of no return in extrinsic apoptosis execution. Therefore, PyViPR aids the conceptual understanding of dynamic network processes and accelerates hypothesis generation for further testing and validation.
Genomic sequencing of the aquaticFusariumspp. QHM and BWC1 and their potential application in environmental protection
Authors: Zhu Hongfei , Zhu Long , Ding Ning
Published: June 2019

Fusariumspecies are distributed widely in ecosystems of a wide pH range and play a pivotal role in the aquatic community through the degradation of xenobiotic compounds and secretion of secondary metabolites. The elucidation of their genome would therefore be highly impactful with regard to the control of environmental pollution. Therefore, in this study, two indigenous strains of aquaticFusarium, QHM and BWC1, were isolated from a coal mine pit and a subterranean river respectively, cultured under acidic conditions, and sequenced. Phylogenetic analysis of these two isolates was conducted based on the sequences of internal transcript (ITS1 and ITS4) and encoding β-microtubulin (TUB2), translation elongation factors (TEFs) and the second large sub-unit of RNA polymerase (RPB2).Fusarium, QHM could potentially represent a new species within theFusarium fujikuroispecies complex.FusariumBWC1 were found to form a clade withFusarium subglutinansNRRL 22016, and predicted to beFusarium subglutinans.Shot-gun sequencing on the Illumina Hiseq×10 Platform was used to elucidate the draft genomes of the two species. Gene annotation and functional analyses revealed that they had bio-degradation pathways for aromatic compounds; further, their main pathogenic mechanism was found to be the efflux pump. To date, the genomes of only a limited number of acidic species from theFusarium fujikuroispecies complex, especially from the aquatic species, have been sequenced. Therefore, the present findings are novel and have important potential for the future in terms of environmental control.

IMPORTANCE

Fusarium genus has over 300 species and were distributed in a variety of ecosystem. Increasing attention has been drawn toFusariumdue to the importance in aquatic community, pathogenicity and environmental protection. The genomes of the strains in this work isolated in acidic condition, were sequenced. The analysis has indicated that the isolates were able to biodegrade xenobiotics, which makes it potentially function as environmental bio-agent for aromatic pollution control and remediation. Meanwhile, the virulence and pathogenicity were also predicted for reference of infection control. The genome information may lay foundation for the fungal identification, disease prevention resulting from these isolates and other “-omics” research. The isolates were phylogenetically classified intoFusarium fujikuroispecies complex by means of concatenated gene analysis, serving as new addition to the big complex.
Mps1 releases Mad1 from nuclear pores to ensure a robust mitotic checkpoint and accurate chromosome segregation
Authors: Osswald Mariana , Cunha-Silva Sofia , Goemann Jana , Barbosa João , Santos Luis M , Resende Pedro , Bange Tanja , Sunkel Claudio E , Conde Carlos
Published: June 2019

The strength of the Spindle Assembly Checkpoint (SAC) depends on the amount of the Mad1-C-Mad2 heterotetramer at kinetochores but also on its binding to Megator/Tpr at nuclear pore complexes (NPCs) during interphase. However, the molecular underpinnings controlling the spatiotemporal redistribution of Mad1-C-Mad2 as cells progress into mitosis remain elusive. Here, we show that Mps1-mediated phosphorylation of Megator/Tpr abolishes its interaction with Mad1 in vitro and in Drosophila cells. Timely activation of Mps1 during prophase triggers Mad1 release from NPCs, which we find to be required for competent kinetochore recruitment of Mad1-C-Mad2 and robust checkpoint response. Importantly, preventing Mad1 binding to Megator/Tpr rescues the fidelity of chromosome segregation and aneuploidy in larval neuroblasts of Drosophila mps1-null mutants. Our findings demonstrate that the subcellular localization of Mad1 is stringently coordinated with cell cycle progression by kinetochore-extrinsic activity of Mps1. This ensures that both NPCs in interphase and kinetochores in mitosis can generate anaphase inhibitors to efficiently preserve genomic stability.
Chromatinization ofEscherichia coliwith archaeal histones
Authors: Rojec Maria , Hocher Antoine , Merkenschlager Matthias , Warnecke Tobias
Published: June 2019

Nucleosomes restrict DNA accessibility throughout eukaryotic genomes, with repercussions for replication, transcription, and other DNA-templated processes. How this globally restrictive organization emerged from a presumably more open ancestral state remains poorly understood. Here, to better understand the challenges associated with establishing globally restrictive chromatin, we express histones in a naïve bacterial system that has not evolved to deal with nucleosomal structures:Escherichia coli. We find that histone proteins from the archaeonMethanothermus fervidusassemble on theE. colichromosomein vivoand protect DNA from micrococcal nuclease digestion, allowing us to map binding footprints genome-wide. We provide evidence that nucleosome occupancy along theE. coligenome tracks intrinsic sequence preferences but is disturbed by ongoing transcription and replication. Notably, we show that higher nucleosome occupancy at promoters and across gene bodies is associated with lower transcript levels, consistent with local repressive effects. Surprisingly, however, this sudden enforced chromatinization has only mild repercussions for growth, suggesting that histones can become established as ubiquitous chromatin proteins without interfering critically with key DNA-templated processes. Our results have implications for the evolvability of transcriptional ground states and highlight chromatinization by archaeal histones as a potential avenue for controlling genome accessibility in synthetic prokaryotic systems.
Hsa-mir-210 as a novel signature predicts survival in lung squamous cell carcinoma using bioinformatics analysis
Authors: Liu Yu , Chen Yu , Li Ling-Ling , Wang Shen-Nan , Xia Shu
Published: June 2019

In recent years, more and more studies have shown that the expression of miRNAs is closely related to the occurrence of tumors and plays an irreplaceable role in the development and metastasis of tumors. The research was focused on lung squamous cell carcinoma. The data information is downloaded from the TCGA database and analyzed for variance, which is then verified in the GEO database. Then differential expression of miRNAs was found and survival analysis was performed, through the cut – off standard(P<0.05,|logFC|≥2), we screen the 38 up-regulated miRNAs and 14 down-regulated miRNAs from the TCGA. Finally, after the verification on the GEO database, four up-regulated miRNAs (hsa-mir-205, hsa-mir-210, hsa-mir-182, hsa-mir-224) and one down-regulated miRNA (hsa-mir-451) were obtained, which provide a new direction for the diagnosis of lung squamous cell carcinoma. In the survival analysis, it was found that the expression state of hsamir-210 was significantly correlated with patient survival. The results in the univariate and multivariate Cox analysis indicated that hsa-mir-210 was an independent prognostic factor on lung squamous cell carcinoma. The functional enrichment analysis showed that hsa-mir-210 was closely related to positive and negative regulation of cell proliferation, DNA transcription, VEGF signaling pathway, MAPK signaling pathway, hif-1 signaling pathway and choline metabolic pathway. In summary, this study suggested that hsa-mir-210 could be a potential prognostic factor for lung squamous cell carcinoma.

Author Summary

MicroRNAs are single-stranded small molecular RNA that participate in the regulation of various biological functions through indirect regulation of gene expression, and have been reported to play an important role in the occurrence, development, invasion and metastasis of tumors. In recent years, the research on miRNAs has become increasingly hot, and the role of miRNAs in tumor has been proved more and more. The subjects of this study were squamous cell carcinoma in lung cancer with relatively few studies on miRNAs. Through high-throughput data analysis, miRNAs with differential expression between lung squamous cell carcinoma tissues and normal tissues were found. These differentially expressed miRNAs provide a new direction for the early diagnosis of patients. Then, survival analysis was conducted to find the miRNAs significantly correlated with the total survival time of patients, and multi-factor analysis was conducted to exclude the influence of other clinical factors, and independent risk factors (miRNAs) affecting the survival of patients were determined, so as to provide new targets for the treatment and survival prediction of patients.
Inhibition of a Selective SWI/SNF Function Synergizes with ATR Inhibitors in Cancer Cell Killing
Authors: Chory Emma J. , Kirkland Jacob G. , Chang Chiung-Ying , D’Andrea Vincent D. , Gourinsankar Sai , Dykhuizen Emily C. , Crabtree Gerald R.
Published: June 2019

SWI/SNF (BAF) complexes are a diverse family of ATP-dependent chromatin remodelers produced by combinatorial assembly that are mutated in and thought to contribute to 20% of human cancers and a large number of neurologic diseases. The gene-activating functions of BAF complexes are essential for viability of many cell types, limiting the development of small molecule inhibitors. To circumvent the potential toxicity of SWI/SNF inhibition, we identified small molecules that inhibit the specific repressive function of these complexes but are relatively non-toxic and importantly synergize with ATR inhibitors in killing cancer cells. Our studies suggest an avenue for therapeutic enhancement of ATR/ATM inhibition and provide evidence for chemical synthetic lethality of BAF complexes as a therapeutic strategy in cancer.
Roadmap layers and processes: resilient and sustainable care facilities
Authors: Pantzartzis Efthimia , Price Andrew , Edum Fotwe Francis
Published: June 2019

Purpose

Health and social care facilities are usually complex buildings that require continuous effort to provide resilient and sustainable responses to changes in demographics, technologies, diseases and models of care. Despite resilience and sustainability concepts being frequently used by practitioners and researchers, ambiguities in their definitions often result in a lack of operational solutions to record, monitor and improve the resilience and sustainability of health and social care facilities. Although the importance and complexity of the issues are widely acknowledged, there is little strategic guidance as to how they should be achieved. The purpose of this paper is to assess the suitability of developing a roadmap for improving the resilience and sustainability of UK health and social care facilities, and to identify the layers and processes needed to construct such a roadmap.

Design/methodology/approach

A qualitative approach was adopted, starting with a literature review of different types of roadmaps and their suitability to support the desired improvement objectives. Layers and processes were thus developed using the key issues identified in three recent research streams, and the roadmap was structured.

Findings

The major findings have been captured within a three-layer, four-step process generic roadmap for improving the resilience and sustainability of health and social care facilities that can be used to monitor performance, plans future actions and implement response to change.

Practical implications

This paper targets decision makers, especially estate managers, but the proposed layers and processes can be modified for other stakeholders.

Originality/value

This paper suggests an original approach for the development of a roadmap for resilience and sustainability of health and social care facilities, and specifically of how to structure layers and processes, envisioning a more integrated development of service provision and infrastructure asset management.