bluuebunny/crossref_metadata_2025 huggingface dataset:
The untapped potential of conservation journals to promote freshwater biodiversity
Authors: He Fengzhi , Jähnig Sonja C. , Wetzig Annett , Langhans Simone D.
Published: July 2020

Freshwater ecosystems are amongst the most diverse ecosystems on the planet. They are subject to intense and increasing threats and have a higher proportion of threatened and extinct species than terrestrial or marine realms. Concurrently, freshwater ecosystems are largely underrepresented in both conservation research and actions arguably as a consequence of less popularity and promotion. To test this assumption, we used cover images as a proxy of exposure and promotion opportunities provided by conservation journals. We collected information on cover images of 18 conservation journals from 1997 to 2016 and data on citations and Altmetric scores of papers published in them. We found that freshwater ecosystems (10.4%) were featured less often than marine (15.2%) or terrestrial (74.4%) ecosystems on covers of these journals. All 15 most featured species are from terrestrial or marine ecosystems, with 14 of them being large vertebrates such as elephants, big cats, rhinos, polar bears, and marine turtles. None of the 95 species featured more than once on the covers of conservation journals spend their whole life history in fresh waters, i.e. they are at least partly associated with terrestrial or marine ecosystems. Our results indicated that cover-featured studies received more attention from academia and the general public, i.e. showed higher citations and Altmetric scores, than non-featured ones within the same issue. By featuring freshwater species and habitats on covers, therewith providing more exposure opportunities, conservation journals hold the potential to promote biodiversity conservation in fresh waters. Scientists can help that endeavour by submitting freshwater-related photos together with their manuscripts for review, therewith providing more options for editors to portray freshwater species and habitats and to ultimately raise awareness and appreciation of freshwater life.
Inhibitors of L-type calcium channels show therapeutic potential for treating SARS-CoV-2 infections by preventing virus entry and spread
Authors: Straus Marco R. , Bidon Miya K. , Tang Tiffany , Jaimes Javier A. , Whittaker Gary R. , Daniel Susan
Published: July 2020

COVID-19 is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus (CoV)-2 (SARS-CoV-2). The virus is responsible for an ongoing pandemic and concomitant public health crisis around the world. While vaccine development is proving to be highly successful, parallel drug development approaches are also critical in the response to SARS-CoV-2 and other emerging viruses. Coronaviruses require Ca2+ions for host cell entry and we have previously shown that Ca2+modulates the interaction of the viral fusion peptide with host cell membranes. In an attempt to accelerate drug development, we tested a panel of L-type calcium channel blocker (CCB) drugs currently developed for other conditions, to determine whether they would inhibit SARS-CoV-2 infection in cell culture. All the CCBs tested showed varying degrees of inhibition, with felodipine and nifedipine strongly limiting SARS-CoV-2 entry and infection in epithelial lung cells at concentrations where cell toxicity was minimal. Further studies with pseudo-typed particles displaying the SARS-CoV-2 spike protein suggested that inhibition occurs at the level of virus entry. Overall, our data suggest that certain CCBs have potential to treat SARS-CoV-2 infections and are worthy of further examination for possible treatment of COVID-19.
Experience-dependent plasticity in an innate social behavior is mediated by hypothalamic LTP
Authors: Stagkourakis Stefanos , Spigolon Giada , Liu Grace , Anderson David J.
Published: July 2020

All animals can perform certain survival behaviors without prior experience, suggesting a “hard wiring” of underlying neural circuits. Experience, however, can alter the expression of innate behaviors. Where in the brain and how such plasticity occurs remains largely unknown. Previous studies have established the phenomenon of “aggression training,” in which the repeated experience of winning successive aggressive encounters across multiple days leads to increased aggressiveness. Here we show that this procedure also leads to long-term potentiation (LTP) at an excitatory synapse, derived from the Anterior Hippocampus/Posterior Medial amygdala (AHiPM), onto estrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). We demonstrate further that the optogenetic induction of such LTPin vivofacilitates, while optogenetic long-term depression (LTD) diminishes, the behavioral effect of aggression training, implying a causal role for potentiation at AHiPM➔VMHvlEsr1synapses in mediating the effect of this training. Interestingly, ∼25% of inbred C57BL/6 mice fail to respond to aggression training. We show that these individual differences are correlated both with lower levels of testosterone, relative to mice that respond to such training, and with a failure to exhibit LTPin vivoafter aggression training. Administration of exogenous testosterone to such non-aggressive mice restores both behavioral and physiological plasticityin vivo. Together, these findings reveal that LTP at a hypothalamic circuit node mediates a form of experience-dependent plasticity in an innate social behavior, and a potential hormone-dependent basis for individual differences in such plasticity among genetically identical mice.

Significance Statement

Modification of instinctive behaviors occurs through experience, yet the mechanisms through which this happens have remained largely unknown. Recent studies have shown that potentiation of aggression, an innate behavior, can occur through repeated winning of aggressive encounters. Here we show that synaptic plasticity at a specific excitatory input to a hypothalamic cell population is correlated with, and required for, the expression of increasingly higher levels of aggressive behavior following successful aggressive experience. We additionally show that the amplitude and persistence of long-term potentiation at this synapse are influenced by serum testosterone, administration of which can normalize individual differences among genetically identical inbred mice, in the expression of intermale aggression.
Drosophila p53isoforms have overlapping and distinct functions in germline genome integrity and oocyte quality control
Authors: Chakravarti Ananya , Thirimanne Heshani N. , Calvi Brian R.
Published: July 2020

p53 gene family members in humans and other organisms encode a large number of protein isoforms whose functions are largely undefined. UsingDrosophilaas a model, we find that a p53B isoform is expressed predominantly in the germline where it colocalizes with p53A into subnuclear bodies. It is only p53A, however, that mediates the apoptotic response to ionizing radiation in the germline and soma. In contrast, p53A and p53B both respond to meiotic DNA breaks and are required during oogenesis to prevent persistent germline DNA breaks, an activity that is more crucial when meiotic recombination is defective. We find that in oocytes with persistent DNA breaks p53A is required to activate a meiotic pachytene checkpoint. Our findings indicate thatDrosophilap53 isoforms have DNA lesion and cell type-specific functions, with parallels to the functions of mammalian p53 family members in the genotoxic stress response and oocyte quality control.
cDC1 Coordinate Innate and Adaptive Responses in the Omentum required for T cell Priming and Memory
Authors: Christian David A. , Adams Thomas A. , Smith Tony E. , Shallberg Lindsey A. , Theisen Derek J. , Phan Anthony T. , Abraha Mosana , Perry Joseph , Ruthel Gordon , Clark Joseph T. , Murphy Kenneth M. , Kedl Ross M. , Hunter Christopher A.
Published: July 2020

The omentum in the peritoneal cavity contains fat associated lymphoid clusters (FALCs) whose role in the response to microbial challenge are poorly understood. After intraperitoneal immunization withToxoplasma gondii, type I dendritic cells (cDC1) were critical to induce innate sources of IFN-γ required to recruit monocytes to the FALCs. The migration of infected peritoneal macrophages into T and B cell rich areas of the FALCs allowed the TCR-induced activation of parasite-specific T cells. Unexpectedly, cDC1 were not required for T cell priming but rather supported the expansion of parasite-specific CD8+T cells. An agent-based mathematical model predicted that the lack of cDC1 would impact the early proliferative burst, and we confirmed that cDC1 were required for optimal T cell expression of nutrient uptake receptors and cell survival. These studies highlight that cDC1 in the FALCs have distinct roles in the co-ordination of the innate and adaptive responses to microbial challenge.
Early life imprints the hierarchy of T cell clone sizes
Authors: Gaimann Mario U. , Nguyen Maximilian , Desponds Jonathan , Mayer Andreas
Published: July 2020

The adaptive immune system responds to pathogens by selecting clones of cells with specific receptors. While clonal selection in response to particular antigens has been studied in detail, it is unknown how a lifetime of exposures to many antigens collectively shape the immune repertoire. Here, through mathematical modeling and statistical analyses of T cell receptor sequencing data we demonstrate that clonal expansions during a perinatal time window leave a long-lasting imprint on the human T cell repertoire. We demonstrate how the empirical scaling law relating the rank of the largest clones to their size can emerge from clonal growth during repertoire formation. We statistically identify early founded clones and find that they are indeed highly enriched among the largest clones. This enrichment persists even after decades of human aging, in a way that is quantitatively predicted by a model of fluctuating clonal selection. Our work presents a quantitative theory of human T cell dynamics compatible with the statistical laws of repertoire organization and provides a mechanism for how early clonal dynamics imprint the hierarchy of T cell clone sizes with implications for pathogen defense and autoimmunity.
Understanding the antiviral effects of RNAi-based therapy on chronic hepatitis B infection
Authors: Kadelka Sarah , Dahari Harel , Ciupe Stanca M
Published: July 2020

Reaching hepatitis B surface antigen (HBsAg) loss (called functional cure) with approved treatment with pegylated interferon-α(IFN) and/or nucleos(t)ide analogues (NAs) in chronic hepatitis B virus (HBV) infected patients is suboptimal. The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum HBV DNA, HBsAg and hepatitis B e antigen (HBeAg) in chimpanzees and small animals. A recent clinical study (Heparc-2001) showed reduction of serum HBV DNA, HBeAg and HBsAg in HBeAg-positive patients treated with a single dose of ARC-520 and daily NA (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a a multi-compartmental pharmacokinetic-pharamacodynamic model and calibrated it with measured HBV data. We showed that the time-dependent ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1-4 months. The combined ARC-520 and entecavir effect on HBV DNA is constant over time, with efficacy of more than 99.8%. HBV DNA loss is entecavir mediated and the strong but transient HBsAg and HBeAg decays are solely ARC-520 mediated. We added complexity to the model in order to reproduce current long-term therapy outcomes with NAs by considering the tradeoff between hepatocyte loss and hepatocyte division, and used it to makein-silicolong-term predictions for virus, HBsAg and HBeAg titer dynamics. These results may help assess ongoing RNAi drug development for hepatitis B virus infection.

Author summary

With about 300 million persons infected worldwide and 800,000 deaths annually, chronic infection with hepatitis B virus (HBV) is a major public health burden with high endemic areas around the world. Current treatment options focus on removing circulating HBV DNA but are suboptimal in removing hepatitis B s- and e-antigens. ARC-520, a RNA interference drug, had induced substantial hepatitis B s- and e- antigen reductions in animals and patients receiving therapy. We study the effect of ARC-520 on hepatitis B s- and e-antigen decline by developing mathematical models for the dynamics of intracellular and serum viral replication, and compare it to patient HBV DNA, hepatitis B s- and e-antigen data from a clinical trial with one ARC-520 injection and daily nucleoside analogue therapy. We examine biological parameters describing the different phases of HBV DNA, s-antigen and e-antigen decline and rebound after treatment initiation, and estimate treatment effectiveness. Such approach can inform the RNA interference drug therapy.
dN/dSdynamics quantify tumour immunogenicity and predict response to immunotherapy
Authors: Zapata Luis , Caravagna Giulio , Williams Marc J , Lakatos Eszter , AbdulJabbar Khalid , Werner Benjamin , Graham Trevor A , Sottoriva Andrea
Published: July 2020

Immunoediting is a major force during cancer evolution that selects for clones with low immunogenicity (adaptation), or clones with mechanisms of immune evasion (escape). However, quantifying immunogenicity in the cancer genome and how the tumour-immune coevolutionary dynamics impact patient outcomes remain unexplored. Here we show that the ratio of nonsynonymous to synonymous mutations (dN/dS) in the immunopeptidome quantifies tumor immunogenicity and differentiates between adaptation and escape. We analysed 8,543 primary tumors from TCGA and validated immune dN/dS as a measure of selection associated with immune infiltration in immune-adapted tumours. In a cohort of 308 metastatic patients that received immunotherapy, pre-treatment lesions in non-responders showed increased immune selection (dN/dS<1), whereas responders did not and instead harboured a higher proportion of genetic escape mechanisms. Ultimately, these findings highlight the potential of evolutionary genomic measures to predict clinical response to immunotherapy.
Flagellar perturbations activate adhesion through two distinct pathways inCaulobacter crescentus
Authors: Hershey David M. , Fiebig Aretha , Crosson Sean
Published: July 2020

Bacteria carry out sophisticated developmental programs to colonize exogenous surfaces. The rotary flagellum, a dynamic machine that drives motility, is a key regulator of surface colonization. The specific signals recognized by flagella and the pathways by which those signals are transduced to coordinate adhesion remain subjects of debate. Mutations that disrupt flagellar assembly in the dimorphic bacteriumCaulobacter crescentusstimulate the production of a polysaccharide adhesin called the holdfast. Using a genome-wide phenotyping approach, we compared surface adhesion profiles in wild-type and flagellar mutant backgrounds ofC. crescentus. We identified a diverse set of flagellar mutations that enhance adhesion by inducing a hyper-holdfast phenotype and discovered a second set of mutations that suppress this phenotype. Epistasis analysis of theflagellar signaling suppressor(fss) mutations demonstrated that the flagellum stimulates holdfast production via two genetically distinct pathways. The developmental regulator PleD contributes to holdfast induction in mutants disrupted at both early and late stages of flagellar assembly. Mutants disrupted at late stages of flagellar assembly, which assemble an intact rotor complex, induce holdfast production through an additional process that requires the MotAB stator and its associated diguanylate cyclase, DgcB. We have assigned a subset of thefssgenes to either the stator- orpleD-dependent networks and characterized two previously unidentified motility genes that regulate holdfast production via the stator complex. We propose a model through which the flagellum integrates mechanical stimuli into theC. crescentusdevelopmental program to coordinate adhesion.

Importance

Understanding how bacteria colonize solid surfaces is of significant clinical, industrial and ecological importance. In this study, we identified genes that are required forCaulobacter crescentusto activate surface attachment in response to signals from a macromolecular machine called the flagellum. Genes involved in transmitting information from the flagellum can be grouped into separate pathways, those that control theC. crescentusmorphogenic program and those that are required for flagellar motility. Our results support a model in which a developmental and a mechanical signaling pathway operate in parallel downstream of the flagellum and converge to regulate adhesion. We conclude that the flagellum serves as a signaling hub by integrating internal and external cues to coordinate surface colonization and emphasize the role of signal integration in linking complex sets of environmental stimuli to individual behaviors.
An accessible, efficient and global approach for the large-scale sequencing of bacterial genomes
Authors: Perez-Sepulveda Blanca M. , Heavens Darren , Pulford Caisey V. , Predeus Alexander V. , Low Ross , Webster Hermione , Schudoma Christian , Rowe Will , Lipscombe James , Watkins Chris , Kumwenda Benjamin , Shearer Neil , Costigan Karl , Baker Kate S. , Feasey Nicholas A. , Hinton Jay C. D. , Hall Neil ,   The 10KSG consortium
Published: July 2020

We have developed an efficient and inexpensive pipeline for streamlining large-scale collection and genome sequencing of bacterial isolates. Evaluation of this method involved a worldwide research collaboration focused on the model organismSalmonella enterica, the 10KSG consortium. By optimising a logistics pipeline that collected isolates as thermolysates, permitting shipment in ambient conditions, the project assembled a diverse collection of 10,419 clinical and environmental isolates from low- and middle-income countries in less than one year. The bacteria were obtained from 51 countries/territories dating from 1949 to 2017, with a focus on Africa and Latin-America. All isolates were collected in barcoded tubes and genome sequenced using an optimised DNA extraction method and the LITE pipeline for library construction. After Illumina sequencing, the total reagent cost was less than USD$10 per genome. Our method can be applied to genome-sequence other large bacterial collections at a relatively low cost, within a limited timeframe, to support global collaborations.
The soluble glutathione transferase superfamily: Role of Mu class in Triclabendazole sulphoxide challenge inFasciola hepatica
Authors: Stuart Rebekah B. , Zwaanswijk Suzanne , MacKintosh Neil D. , Witikornkul Boontarikaan , Prescott Mark , Brophy Peter M. , Morphew Russell M.
Published: July 2020

Fasciola hepatica(liver fluke), a significant threat to food security, causes global economic loss for the livestock production industry and is re-emerging as a food borne disease of humans. In the absence of vaccines the commonly used method of treatment control is by anthelmintics; with only Triclabendazole (TCBZ) currently effective against all stages ofF. hepaticain livestock and humans. There is widespread resistance to TCBZ and detoxification by flukes might contribute to the mechanism. However, there is limited Phase I capacity in adult parasitic helminths and the major Phase II detoxification system in adults is the soluble Glutathione transferases (GST) superfamily. Previous global proteomic studies have shown that the levels of Mu class GST from pooledF. hepaticaparasites respond under TCBZ-Sulphoxide (TCBZ-SO), the likely active metabolite, challenge duringin vitroculture ex-host. We have extended this finding by using a sub-proteomic lead approach to measure the change in the total soluble GST profile (GST-ome) of individual TCBZ susceptibleF. hepaticaon TCBZ-SO-exposurein vitroculture. TCBZ-SO exposure demonstrated a FhGST-Mu29 and FhGST-Mu26 response following affinity purification using both GSH and S-hexyl GSH affinity resins. Furthermore, a low affinity Mu class GST (FhGST-Mu5) has been identified and recombinantly expressed and represents a novel low affinity mu class GST. Low affinity GST isoforms within the GST-ome was not limited to FhGST-Mu5 with second likely low affinity sigma class GST (FhGST-S2) uncovered through genome analysis. This study represents the most completeFasciolaGST-ome generated to date and has supported the sub proteomic analysis on individual adult flukes.
From people toPanthera: Natural SARS-CoV-2 infection in tigers and lions at the Bronx Zoo
Authors: McAloose Denise , Laverack Melissa , Wang Leyi , Killian Mary Lea , Caserta Leonardo C. , Yuan Fangfeng , Mitchell Patrick K. , Queen Krista , Mauldin Matthew R. , Cronk Brittany D. , Bartlett Susan L. , Sykes John M. , Zec Stephanie , Stokol Tracy , Ingerman Karen , Delaney Martha A. , Fredrickson Richard , Ivančić Marina , Jenkins-Moore Melinda , Mozingo Katie , Franzen Kerrie , Bergeson Nichole Hines , Goodman Laura , Wang Haibin , Fang Ying , Olmstead Colleen , McCann Colleen , Thomas Patrick , Goodrich Erin , Elvinger François , Smith David C. , Tong Suxiang , Slavinski Sally , Calle Paul P. , Terio Karen , Torchetti Mia Kim , Diel Diego G.
Published: July 2020

We describe the first cases of natural SARS-CoV-2 infection detected in animals in the United States. In March 2020, four tigers and three lions at the Bronx Zoo developed mild respiratory signs. SARS-CoV-2 RNA was detected by rRT-PCR in respiratory secretions and/or feces from all seven affected animals; viral RNA and/or antibodies were detected in their keepers. SARS-CoV-2 was isolated from respiratory secretions or feces from three affected animals;in situhybridization co-localized viral RNA with cellular damage. Whole genome sequence and haplotype network analyses showed tigers and lions were infected with two different SARS-CoV-2 strains, suggesting independent viral introductions. The source of SARS-CoV-2 infection in the lions is unknown. Epidemiological data and genetic similarities between keeper and tiger viruses indicate human to animal transmission.
Host responses in anex-vivohuman skin model challenged withMalassezia sympodialis
Authors: Corzo Leon Dora E. , MacCallum Donna M. , Munro Carol A.
Published: July 2020

Malasseziaspecies are a major part of the normal mycobiota and colonise mainly sebum-rich skin regions of the body. This group of fungi cause a variety of infections such as pityriasis versicolour, folliculitis and fungaemia. In particular,Malassezia sympodialisand its allergens have been associated with non-infective inflammatory diseases such as seborrheic dermatitis and atopic eczema. The aim of this study was to investigate the host response toM. sympodialison oily skin (supplemented with oleic acid) and non-oily skin using anex-vivohuman skin model. Host-pathogen interactions were analysed by SEM, histology, gene expression, immunoassays and dual species proteomics. The skin response toM. sympodialiswas characterised by increased expression of the genes encoding β-defensin 3 and RNase7, and by high levels of S100 proteins in tissue. Supplementation of oleic acid onto skin was associated with direct contact of yeasts with keratinocytes and epidermal damage. In oily conditions, skin response toM. sympodialisshowed no gene expression of AMPs, but increased expression ofIL18. In supernatants from inoculated skin plus oleic acid, TNFα levels were decreased and IL-18 levels were significantly increased.
Genome-wide association study and polygenic risk score analysis for hearing measures in children
Authors: Schmitz Judith , Abbondanza Filippo , Paracchini Silvia
Published: July 2020

An efficient auditory system contributes to cognitive and psychosocial development. A right ear advantage in hearing thresholds (HT) has been described in adults and atypical patterns of left/right hearing threshold asymmetry (HTA) have been described for psychiatric and neurodevelopmental conditions. Previous genome-wide association studies (GWAS) on HT have mainly been conducted in elderly participants whose hearing is more likely to be affected by external environmental factors. We analyzed HT and HTA in a children population cohort (ALSPAC,n= 6,743). Better hearing was associated with better cognitive performance and higher socioeconomic status (SES). At the group level, HTA suggested a left ear advantage (mean = -0.28 dB) that was mainly driven by females. SNP heritability for HT and HTA was 0.17 and 0.01, respectively (n= 5,344). Genetic correlation analysis confirmed associations between HT, reading ability, listening comprehension, and GCSE scores. GWAS for HT did not yield significant hits but polygenic risk score (PRS) analysis showed significant associations of higher educational attainment (EA, ß = -1564.72, p = .008) and risk for schizophrenia (ß = -241.14, p = .004) with lower HT, i.e. better hearing. In summary, we report new data supporting associations between hearing measures and cognitive abilities at the behavioral level. Genetic analysis suggests shared biological pathways between cognitive and sensory systems and provides evidence for a positive outcome of genetic risk for schizophrenia.
Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization
Authors: Matsumura Kazuki , Shimomura Takushi , Kubo Yoshihiro , Oka Takayuki , Kobayashi Naohiro , Imai Shunsuke , Yanase Naomi , Akimoto Madoka , Fukuda Masahiro , Yokogawa Mariko , Ikeda Kazuyoshi , Kurita Jun-ichi , Nishimura Yoshifumi , Shimada Ichio , Osawa Masanori
Published: July 2020

Humanether-à-go-go-related gene potassium channel 1 (hERG) is a voltage-gated potassium channel, the voltage-sensing domain (VSD) of which is targeted by a gating-modifier toxin, APETx1. Although it is known that APETx1 inhibits hERG by stabilizing the resting state, it remains unclear where and how APETx1 interacts with the VSD in the resting state. Here, we prepared a recombinant APETx1, which is structurally and functionally equivalent to the natural product. Electrophysiological analyses using wild type and mutants of APETx1 and hERG revealed that their hydrophobic residues, in addition to a previously reported acidic hERG residue, play key roles in the inhibition of hERG by APETx1. Docking models of the APETx1-VSD complex that satisfy the results of mutational analysis suggest a molecular recognition mode between APETx1 and the resting state of hERG; this would provide a structural basis for designing ligands that control hERG function by binding to the VSD.
Distinct networks coupled with parietal cortex for spatial representations inside and outside the visual field
Authors: Zhang Bo , Wang Fan , Zhang Qi , Yuji Naya
Published: July 2020

Our mental representation of egocentric space is influenced by the disproportionate sensory perception of the body. Previous studies have focused on the neural architecture for egocentric representations within the visual field. However, the space representation underlying the body is still unclear. To address this problem, we applied both fMRI and MEG to a spatial-memory paradigm by using a virtual environment in which human participants remembered a target location left, right, or back relative to their own body. Both experiments showed larger involvement of the frontoparietal network in representing a retrieved target on the left/right side than on the back. Conversely, the medial temporal lobe (MTL)-parietal network was more involved in retrieving a target behind the participants. The MEG data showed preferential connectivity in the alpha-band frequency in both networks. These findings suggest that the parietal cortex may represent the entire space around the self-body by coordinating two distinct brain networks.
Identifying transcription patterns of histology and radiomics features in NSCLC with neural networks
Authors: Smedley Nova F. , Aberle Denise R. , Hsu William
Published: July 2020

Purpose

To investigate the use of deep neural networks to learn associations between gene expression and radiomics or histology in non-small cell lung cancer (NSCLC).

Materials and Methods

Deep feedforward neural networks were used for radio-genomic mapping, where 21,766 gene expressions were inputs to individually predict histology and 101 CT radiomic features. Models were compared against logistic regression, support vector machines, random forests, and gradient boosted trees on 262 training and 89 testing patients. Neural networks were interpreted using gene masking to derive the learned associations between subsets of gene expressions to a radiomic feature or histology type.

Results

Neural networks outperformed other classifiers except in five radiomic features, where training differences were <0.026 AUC. In testing, neural networks classified histology with AUCs of 0.86 (adenocarcinoma), 0.91 (squamous), and 0.71 (other); and 14 radiomics features with >= 0.70 AUC. Gene masking of the models showed new and previously reported histology-gene or radiogenomic associations. For example, hypoxia genes could predict histology with >0.90 test AUC and published gene signatures for histology prediction were also predictive in our models (>0.80 test AUC). Gene sets related to the immune or cardiac systems and cell development processes were predictive (>0.70 test AUC) of several different radiomic features while AKT signaling, TNF, and Rho gene sets were each predictive of tumor textures.

Conclusion

We demonstrate the ability of neural networks to map gene expressions to radiomic features and histology in NSCLC and interpret the models to identify predictive genes associated with each feature or type.

Author Summary

Non-small-cell lung cancer (NSCLC) patients can have different presentations as seen in the CT scans, tumor gene expressions, or histology types. To improve the understanding of these complementary data types, this study attempts to map tumor gene expressions associated with a patient’s CT radiomic features or a histology type. We explore a deep neural network approach to learn gene-radiomic associations (i.e., the subsets of co-expressed genes that are predictive of a value of an individual radiomic feature) and gene-histology associations in two separate public cohorts. Our modeling approach is capable of learning relevant information by showing the model can predict histology and that the learned relationships are consistent with prior works. The study provides evidence for coherent patterns between gene expressions and radiomic features and suggests such integrated associations could improve patient stratification.
Sensory processing and participation in childhood occupation in Autism and Typically developing children - A cross sectional case control
Authors: Loh Siew Yim , Ee Su Im , Marret Mary J. , Chinna Karuthan
Published: July 2020

Background

Sensory processing difficulties and participation in childhood occupation in children impact their development, but the association among Malaysian children is unknown. The aim of this study is to provide empirical evidences on sensory processing and participation in childhood occupation, in children with autism and compare them with typical children without autism /’typical’.

Method

Two groups of participants (parents of children with autism and parents of ‘normal’ children were recruited from 5 hospitals, and from tuition/care centre/school respectively. Children with autism, age 6 to 10 years were matched (age/gender) with ‘typical’ children. The Participation of childhood occupation (PICO) and Sensory Processing (SSP) measures were used. Data were analysed descriptively for patterns, and Chi-square cross tabs used to compare sensory processing and participation (categorical variables) between the two groups.

Results

186 parents (93 children with autism and 93 typically developing children) participated. In the autism group, 77.4 percent (n=72) were males, or 4:1 male to female ratio. Children with autism compared with typical group experienced- a) higher sensory processing difficulties and b) less participation in childhood occupation (except basic activities like eating and sleep). Sensory processing difficulties in the autism children is lower compared to developed countries, but, the prevalence of sensory processing difficulties in the ‘typical’ children (21.5 percent) was higher than data from USA and Israel (9-15%). There were significant differences in sensory processing difficulties between the two group (p<0.05), except for movement sensitivity (p=0.28). Auditory filtering section were most affected in children with autism.

Conclusion

Differences were found in the sensory processing difficulties (especially auditory filtering) and lower participation in autism group compared to ‘normal’ group. A higher percentage of sensory processing difficulties was also found in the ‘normal/ typically developing children’, which may be attributed to cultural or geographical factors (living in high rise flats with less playing space). More studies are needed comparing rural and urban children.
Pain burden, sensory profile and inflammatory cytokines of dogs with naturally-occurring neuropathic pain treated with gabapentin alone or with meloxicam
Authors: Ruel Hélène L.M. , Watanabe Ryota , Evangelista Marina C. , Beauchamp Guy , Auger Jean-Philippe , Segura Mariela , Steagall Paulo V.
Published: July 2020

Canine neuropathic pain (NeuP) has been poorly investigated. This study aimed to evaluate the pain burden, sensory profile and inflammatory cytokines in dogs with naturally-occurring NeuP. Twenty-nine client-owned dogs with NeuP were included in a prospective, partially masked, randomized crossover clinical trial, and treated with gabapentin/placebo/gabapentin-meloxicam or gabapentin-meloxicam/placebo/gabapentin (each treatment block of 7 days; total 21 days). Pain scores, mechanical (MNT) and electrical (ENT) nociceptive thresholds and descending noxious inhibitory controls (DNIC) were assessed at baseline, days 7, 14, and 21. DNIC was evaluated using ΔMNT (after-before conditioning stimulus). Positive or negative ΔMNT corresponded to inhibitory or facilitatory pain profiles, respectively. Data from baseline were compared to those of sixteen healthy controls. ΔMNT, but not MNT and ENT, was significantly larger in controls (2.3 ± 0.9 N) than in NeuP (−0.2 ± 0.7 N). The percentage of dogs with facilitatory sensory profile was similar at baseline and after placebo (61.5-63%), and between controls and after gabapentin (33.3-34.6%). Pain scores were lower than baseline after gabapentin or gabapentin-meloxicam. Cytokine levels were not different between groups or treatments. Dogs with NeuP have deficient inhibitory pain mechanisms. Pain burden was reduced after gabapentin and gabapentin-meloxicam depending on the pain scoring instrument used.
Protective mutation A673T as a potential gene therapy for most forms of APP Familial Alzheimer’s Disease
Authors: Guyon Antoine , Rousseau Joël , Lamothe Gabriel , Tremblay Jacques P.
Published: July 2020

The accumulation of plaque in the brain leads to the onset and development of Alzheimer’s disease. The Amyloid precursor protein (APP) is usually cut by α-secretase, however an abnormal cleavage profile by β-secretase (BACE1) leads to the accumulation of Aβ peptides, which forms these plaques. Numerous APP gene mutations favor plaque accumulation, causing Familial Alzheimer Disease (FAD). However, a variant of the APP gene (A673T) in Icelanders reduces BACE1 cleavage by 40 %. A library of plasmids containing APP genes with 29 FAD mutations with or without the additional A673T mutation was generated and transfected in neuroblastomas to assess the effect of this mutation on Aβ peptide production. In most cases the production of Aβ peptides was decreased by the co-dominant A673T mutation. The reduction of Aβ peptide concentrations for the London mutation (V717I) even reached the same level as A673T carriers. These results suggest that the insertion of A673T in the APP gene of genetically susceptible FAD patients may prevent the onset of, slow down, or stop the progression of the disease.
Long-reads assembly of theBrassica napusreference genome, Darmor-bzh
Authors: Rousseau-Gueutin Mathieu , Belser Caroline , Silva Corinne Da , Richard Gautier , Istace Benjamin , Cruaud Corinne , Falentin Cyril , Boideau Franz , Boutte Julien , Delourme Regine , Deniot Gwenaëlle , Engelen Stefan , de Carvalho Julie Ferreira , Lemainque Arnaud , Maillet Loeiz , Morice Jérôme , Wincker Patrick , Denoeud France , Chèvre Anne-Marie , Aury Jean-Marc
Published: July 2020

Background

The combination of long-reads and long-range information to produce genome assemblies is now accepted as a common standard. This strategy not only allow to access the gene catalogue of a given species but also reveals the architecture and organisation of chromosomes, including complex regions like telomeres and centromeres. TheBrassicagenus is not exempt and many assemblies based on long reads are now available. The reference genome forBrassica napus, Darmor-bzh, which was published in 2014, has been produced using short-reads and its contiguity was extremely low if compared to current assemblies of theBrassicagenus.

Findings

Here, we report the new long-reads assembly of Darmor-bzh genome (Brassica napus) generated by combining long-reads sequencing data, optical and genetic maps. Using the PromethION device and six flowcells, we generated about 16M long-reads representing 93X coverage and more importantly 6X with reads longer than 100Kb. This ultralong-reads dataset allows us to generate one of the most contiguous and complete assembly of aBrassicagenome to date (contigs N50 > 10Mb). In addition, we exploited all the advantages of the nanopore technology to detect modified bases and sequence transcriptomic data using direct RNA to annotate the genome and focus on resistance genes.

Conclusion

Using these cutting edge technologies, and in particular by relying on all the advantages of the nanopore technology, we provide the most contiguousBrassica napusassembly, a resource that will be valuable for theBrassicacommunity for crop improvement and will facilitate the rapid selection of agronomically important traits.
The roles of history, chance, and natural selection in the evolution of antibiotic resistance
Authors: Santos-Lopez Alfonso , Marshall Christopher W. , Welp Allison L. , Turner Caroline , Rasero Javier , Cooper Vaughn S.
Published: July 2020

History, chance, and selection are the fundamental factors that drive and constrain evolution. We designed evolution experiments to disentangle and quantify effects of these forces on the evolution of antibiotic resistance. History was established by prior antibiotic selection of the pathogenAcinetobacter baumanniiin both structured and unstructured environments, selection occurred in increasing concentrations of new antibiotics, and chance differences arose as random mutations among replicate populations. The effects of history were reduced by increasingly strong selection in new drugs, but not erased, at times producing important contingencies. Selection in structured environments constrained resistance to new drugs and led to frequent loss of resistance to the initial drug. This research demonstrates that despite strong selective pressures of antibiotics leading to genetic parallelism, history can etch potential vulnerabilities to orthogonal drugs.
A behavioral logic underlying aggression in an African cichlid fish
Authors: Alward Beau A. , Cathers Phillip H. , Blakkan Danielle M. , Fernald Russell D.
Published: July 2020

Social rank in a hierarchy determines which individuals have access to important resources such as food, shelter, and mates. In the African cichlid fishAstatotilapia burtoni, rank is under social control, such that larger males are more likely than smaller males to be dominant in rank. Although it is well known that the relative size ofA. burtonimales is critical in controlling social rank, the specific behavioral strategies underlying responses to males of different sizes are not well understood. In this research, our goal was to characterize these responses by performing resident-intruder assays, in which aggressive behaviors were measured in territorial males in response to the introduction of unfamiliar males that differed in relative standard length (SL). We found that the relative SL of intruders played an important role in determining behavioral performance. Resident males exposed to larger (>5% larger in SL) or matched (between 0 and 5% larger or smaller in SL) intruder males performed more lateral displays, a type of non-physical aggression, compared to resident males exposed to smaller (>5% smaller in SL) intruder males. However, physical aggression, such as chases and bites, did not differ as a function of relative SL. Our results suggest thatA. burtonimales amplify non-physical aggression to settle territorial disputes in response to differences in relative SL that were not previously considered to be behaviorally relevant.

Highlights

Relative size determines social rank in the African cichlidAstatotilapia burtoni

Resident maleA. burtonirespond differently to small size differences in intruder males

Residents perform more non-physical aggression against larger intruders

Residents do not alter physical aggression as a function of differently sized intruders

Distinct behavioral strategies are used against different intruders
A pan-cancer atlas of somatic mutations in miRNA biogenesis genes
Authors: Galka-Marciniak Paulina , Urbanek-Trzeciak Martyna Olga , Nawrocka Paulina Maria , Kozlowski Piotr
Published: July 2020

It is a well-known and intensively studied phenomenon that the levels of many miRNAs are differentiated in cancer. miRNA biogenesis and functional expression are complex processes orchestrated by many proteins cumulatively called miRNA biogenesis proteins. To characterize cancer somatic mutations in the miRNA biogenesis genes and investigate their potential impact on the levels of miRNAs, we analyzed whole-exome sequencing datasets of over 10,000 cancer/normal sample pairs deposited within the TCGA repository. We identified and characterized over 3,600 somatic mutations in 29 miRNA biogenesis genes and showed that some of the genes are overmutated in specific cancers and/or have recurrent hotspot mutations (e.g., SMAD4 in PAAD, COAD, and READ; DICER1 in UCEC; PRKRA in OV; and LIN28B in SKCM). We identified a list of miRNAs whose level is affected by particular types of mutations in either SMAD4, SMAD2, or DICER1 and showed that hotspot mutations in the RNase domains in DICER1 not only decrease the level of 5p-miRNAs but also increase the level of 3p-miRNAs, including many well-known cancer-related miRNAs. We also showed an association of the mutations with patient survival. Eventually, we created an atlas/compendium of miRNA biogenesis alterations providing a useful resource for different aspects of biomedical research.
Nanotopography controls single-molecule mobility to determine overall cell fate
Authors: Cutiongco Marie FA , Reynolds Paul M , Syme Christopher D , Gadegaard Nikolaj
Published: July 2020

The addition of nanoscale distortion to ordered nanotopographies consistently determines an osteogenic fate in stem cells. Although disordered and ordered nanopit arrays have identical surface areas, array symmetry has opposite effects on cell fate. We aimed to understand how cells sense disorder at the nanoscale. We observed effects in the early formation of cell and focal adhesions that controlled long-term cell fate. Disordered nanopits consistently yielded larger focal adhesions at a faster rate, prompting us to investigate this at the molecular scale. Super-resolution microscopy revealed that the nanopits did not act as nucleation points, as previously thought. Rather, nanopit arrays altered the plasma membrane and acted as barriers that changed molecular diffusion. The local areas corralled by four nanopits were the smallest structures that exerted diverging effects between ordered and disordered arrays. Heterogeneity in the local area on disordered arrays increased the proportion of fastest and slowest diffusing molecules. This resulted in higher quantity, more frequent formation and clustered arrangement of nascent adhesions, i.e., the modular units on which focal adhesions are built. This work presents a new pathway to exploit nanoscale sensing to dictate cell fate.
Transcriptome-wide sites of collided ribosomes reveal principles of translational pausing
Authors: Arpat Alaaddin Bulak , Liechti Angélica , De Matos Mara , Dreos René , Janich Peggy , Gatfield David
Published: July 2020

Translation initiation is the major regulatory step defining the rate of protein production from an mRNA. Meanwhile, the impact of nonuniform ribosomal elongation rates is largely unknown. Using a modified ribosome profiling protocol based on footprints from two closely packed ribosomes (disomes), we have mapped ribosomal collisions transcriptome-wide in mouse liver. We uncover that the stacking of an elongating onto a paused ribosome occurs frequently and scales with translation rate, trapping ∼10% of translating ribosomes in the disome state. A distinct class of pause sites is indicative of deterministic pausing signals. Pause site association with specific amino acids, peptide motifs, and nascent polypeptide structure is suggestive of programmed pausing as a widespread mechanism associated with protein folding. Evolutionary conservation at disome sites indicates functional relevance of translational pausing. Collectively, our disome profiling approach allows unique insights into gene regulation occurring at the step of translation elongation.
Binding specificities of human RNA-binding proteins toward structured and linear RNA sequences
Authors: Jolma Arttu , Zhang Jilin , Mondragón Estefania , Morgunova Ekaterina , Kivioja Teemu , Laverty Kaitlin U. , Yin Yimeng , Zhu Fangjie , Bourenkov Gleb , Morris Quaid , Hughes Timothy R. , Maher Louis James , Taipale Jussi
Published: July 2020

RNA-binding proteins (RBPs) regulate RNA metabolism at multiple levels by affecting splicing of nascent transcripts, RNA folding, base modification, transport, localization, translation, and stability. Despite their central role in RNA function, the RNA-binding specificities of most RBPs remain unknown or incompletely defined. To address this, we have assembled a genome-scale collection of RBPs and their RNA-binding domains (RBDs) and assessed their specificities using high-throughput RNA-SELEX (HTR-SELEX). Approximately 70% of RBPs for which we obtained a motif bound to short linear sequences, whereas ∼30% preferred structured motifs folding into stem–loops. We also found that many RBPs can bind to multiple distinctly different motifs. Analysis of the matches of the motifs in human genomic sequences suggested novel roles for many RBPs. We found that three cytoplasmic proteins—ZC3H12A, ZC3H12B, and ZC3H12C—bound to motifs resembling the splice donor sequence, suggesting that these proteins are involved in degradation of cytoplasmic viral and/or unspliced transcripts. Structural analysis revealed that the RNA motif was not bound by the conventional C3H1 RNA-binding domain of ZC3H12B. Instead, the RNA motif was bound by the ZC3H12B's PilT N terminus (PIN) RNase domain, revealing a potential mechanism by which unconventional RBDs containing active sites or molecule-binding pockets could interact with short, structured RNA molecules. Our collection containing 145 high-resolution binding specificity models for 86 RBPs is the largest systematic resource for the analysis of human RBPs and will greatly facilitate future analysis of the various biological roles of this important class of proteins.