bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress granules display bistable dynamics modulated by Cdk
Authors: Yahya G , Pérez AP , Mendoza MB , Parisi E , Moreno DF , Gallego C , Aldea M
Published: May 2020

Stress granules are conserved biomolecular condensates that originate in response to many stress conditions. These membraneless organelles contain nontranslating mRNAs and a diverse subproteome, but our knowledge on their regulation and functional relevance is still incipient. Here we describe a mutual-inhibition interplay between stress granules and Cdc28, the budding yeast Cdk. Amongst Cdc28 interactors acting as negative modulators of Start we have identified Whi8, an RNA-binding protein that localizes to SGs and recruits the mRNA ofCLN3, the most upstream G1 cyclin, for efficient translation inhibition and Cdk inactivation under stress. However, Whi8 also contributes to recruiting Cdc28 to SGs, where it acts to promote their dissolution. As predicted by a mutual-inhibition framework, the SG constitutes a bistable system that is modulated by Cdk. Since mammalian cells display a homologous mechanism, we propose that the opposing functions of specific mRNA-binding proteins and Cdks subjugate SG dynamics to a conserved hysteretic switch.
Furry is required for cell movements during gastrulation and functionally interacts with NDR1
Authors: Cervino Ailen S. , Moretti Bruno , Stuckenholz Carsten , Grecco Hernán E. , Davidson Lance A. , Cirio M. Cecilia
Published: May 2020

Gastrulation is a key event in animal embryogenesis during which the germ layers precursors are rearranged and the embryonic axes are established. Cell polarization is essential during gastrulation driving asymmetric cell division, cell movements and cell shape changes. Furry (Fry) gene encodes an evolutionarily conserved protein with a wide variety of cellular functions mostly related to cell polarization and morphogenesis in invertebrates. However, little is known about its function in vertebrate development. Here we show that inXenopus, Fry participates in the regulation of morphogenetic processes during gastrulation. Using morpholino knock-down, we demonstrate a role of Fry in blastopore closure and dorsal axis elongation. Loss of Fry function drastically affects the movement and morphological polarization of cells during gastrulation, in addition to dorsal mesoderm convergent extension, responsible for head-to-tail elongation. Finally, we demonstrate a functional interaction between Fry and NDR1 kinase, providing evidence of an evolutionarily conserved complex required for morphogenesis.
HUMAN BREAST TUMOUR CELLS VIABILITY EFFECT OF AFRICAN DIOSCOREA ROTUNDATA TUBER EXTRACTS IN MCF-7 AND MDA-MB231 CELL LINES
Authors: Odimegwu Joy Ifunanya , Odukoya Olukemi Abiodun , Español Alejandro , Sales Maria Elena
Published: May 2020

Objective

We aim to test the efficacy of edibleDioscorea speciesgrown and consumed in Nigeria, Africa on two breast cancer cell lines; MCF-7 and MDA-MB231 derived from a luminal and a triple-negative breast cancer (TNBC) respectively and to confirm safety in non-tumour cells MCF-10A using a well established cytotoxic compound paclitaxel as a standard. Metastatic breast cancer is a prevalent cause of mortality in women around the world. Breast cancer therapies have greatly advanced in recent years, but many patients develop cancer re-occurrence and metastasis and subsequently yield to the disease because of chemoresistance.

Methods

Ethanolic extracts ofDioscorea rotundataboiled and raw (DiosB and DiosR) respectively were chemically analysed for the presence of diosgenin using HPLC and the cytotoxic activity of the extracts were tested on MCF-7, MDA-MB-231 and MCF-10A cellsIn vitroby MTT assay.

Results

DiosB and DiosR extracts showed a higher maximal effect on MCF-7 cells than on MDA-MB231 after 24 h and 48 h treatments (p<0.0001 and p<0.05 respectively). DiosR, if applied at a range between 50-70 g/ml, can be effective to reduce breast tumor cell viability without affecting non tumorigenic MCF-10A cells either at 24 h or at 48 h. DiosB showed an IC50of 38.83μg/ml while DiosR showed an IC50of 41.80μg/ml.

Conclusion

These results show that ethanolic extracts ofDioscorea rotundatatubers could be used effectively to treat breast cancer tumors and this is in sync with its diosgenin content as otherDioscorea speciesapplied for similar treatments in Asia and elsewhere.
Song sparrows do not discriminate between their own song and stranger song
Authors: Akçay Çağlar , Beecher Michael D.
Published: May 2020

Bird song is socially learned. During song learning, the bird’s hearing its own vocalization is important for normal development of song. Whether bird’s own song is represented and recognized as a special category in adult birds, however, is unclear. If birds respond differently to their own songs when these are played back to them, this would be evidence for auditory self-recognition. To test this possibility, we presented song sparrow males (Melospiza melodia) playbacks of their own songs or stranger songs and measured aggressive responses as well as type matching. We find no evidence of behavioral discrimination of bird’s own song relative to the (non-matching) stranger song. These findings cast doubt on an earlier proposal that song sparrows display auditory self-recognition and support the common assumption in playback experiments that bird’s own song is perceived as stranger song.
Intuitive, reproducible high-throughput molecular dynamics in Galaxy: a tutorial
Authors: Bray Simon A. , Senapathi Tharindu , Barnett Christopher B. , Grüning Björn A.
Published: May 2020

This paper is a tutorial developed for the data analysis platform Galaxy. The purpose of Galaxy is to make high-throughput computational data analysis, such as molecular dynamics, a structured, reproducible and transparent process. In this tutorial we focus on 3 questions: How are protein-ligand systems parameterized for molecular dynamics simulation? What kind of analysis can be carried out on molecular trajectories? How can high-throughput MD be used to study multiple ligands? After finishing you will have learned about force-fields and MD parameterization, how to conduct MD simulation and analysis for a protein-ligand system, and understand how different molecular interactions contribute to the binding affinity of ligands to the Hsp90 protein.
Alterations in odor hedonics in the 5XFAD Alzheimer’s disease mouse model and the influence of sex
Authors: Roberts Elizabeth R. , Dossat Amanda M. , Mar Cortijo María del , Brundin Patrik , Wesson Daniel W.
Published: May 2020

Olfactory impairments, including deficits in odor detection, discrimination, recognition, and changes in odor hedonics are reported in the early stages of Alzheimer’s disease (AD). Rodent models of AD display deficits in odor learning, detection, and discrimination – recapitulating the clinical condition. However, the impact of familial AD genetic mutations on odor hedonics is unknown. We tested 2-, 4-, and 6-months old 5XFAD (Tg6799) mice in the five-port odor multiple-choice task designed to assay a variety of odor-guided behaviors, including odor preferences/hedonics. We found that 5XFAD mice investigated odors longer than controls, an effect that was driven by 6-months old mice. Interestingly, this effect was carried by females in the 5XFAD group, who investigated odors longer than age-matched males. Upon examining behavior directed towards individual odors to test for aberrant odor preferences, we uncovered that 5XFAD females at several ages displayed heightened preferences towards some of the odors, indicating aberrant hedonics. We observed no impairments in the ability to engage in the task in 5XFAD mice. Taken together, 5XFAD mice, particularly 5XFAD females, displayed prolonged odor investigation behavior and enhanced preferences to certain odors. The data provide insight into hedonic alterations which may occur in AD mouse models, and how these are influenced by biological sex.
Extending the Martini coarse-grained forcefield to N-glycans
Authors: Shivgan Aishwary T. , Marzinek Jan K. , Huber Roland G. , Krah Alexander , Henchman Richard H. , Matsudaira Paul , Verma Chandra S. , Bond Peter J.
Published: May 2020

Glycans play a vital role in a large number of cellular processes. Their complex and flexible nature hampers structure-function studies using experimental techniques. Molecular dynamics (MD) simulations can help in understanding dynamic aspects of glycans if the forcefield (FF) parameters used can reproduce key experimentally observed properties. Here, we present optimized coarse-grained (CG) Martini FF parameters for N-glycans, calibrated against experimentally derived binding affinities for lectins. The CG bonded parameters were obtained from atomistic (ATM) simulations for different glycan topologies including high mannose and complex glycans with various branching patterns. In the CG model, additional elastic networks are shown to improve maintenance of the overall conformational distribution. Solvation free energies and octanol-water partition coefficients were also calculated for various n-glycan disaccharide combinations. When using standard Martini non-bonded parameters, we observed that glycans spontaneously aggregated in the solution and required down-scaling of their interactions for reproduction of ATM model radial distribution functions. We also optimised the non-bonded interactions for glycans interacting with seven lectin candidates and show that scaling down the glycan-protein interactions can reproduce free energies obtained from experimental studies. These parameters should be of use in studying the role of glycans in various glycoproteins, carbohydrate binding proteins (CBPs) as well as their complexes, while benefiting from the efficiency of CG sampling.
Strategy guides feature recall of a single object in working memory task
Authors: Sengupta Rakesh , lewis Christelle M.
Published: May 2020

Over past couple of decades our understanding of visual working memory (VWM), and working memory in general, has been predominantly in line with the capacity debate. We recently opened a new line of inquiry regarding the recall of a single object to go beyond the capacity debate, and showed that a series of feature probe questions about a single object yields poorer recall later in the sequence (Sengupta et al, 2020). In the current work we focused on another aspect of sequential feature recall - mainly regarding whether recall can be improved by asking the same question twice. To that end, we chose to focus on two features - color and location, and we contrasted repeat and non-repeat (from the standpoint of feature questions) trials in a series of two experiments. In repeat trials either color or location would be probed twice consecutively. In non-repeat trials color and location probes were presented one after the other in random order. In all trials the stimulus was a small colored oriented line presented for 1 sec in a location within 4o of visual angle. The recall of color and location were mapped onto continuous variable like Sengupta et al, 2020 - for instance, color recall was mapped onto a color wheel. In the first experiment, we used an unaltered color wheel when the color question was repeated. For the second experiment, we used a rotated color wheels for two consecutive color recall trials. We observed an increase in recall error for both repeat and non-repeat condition for location when the probe was at the second question in both experiments. However, color recall error did not increase for second repeat question condition in Experiment 1 as opposed to the non-repeat condition. On the other hand, in Experiment 2 we observed the expected increase in recall error for both repeat and non repeat condition for color probe at the second question. This maybe due to the fact that participants used an ‘anchoring’ strategy in Experiment 1 by remembering where they clicked on the color wheel in the first question. The rotation of color wheel in second experiment destroys the anchor leading to the aforementioned result. The results show that trying to recall the same feature again leads to degradation of recall accuracy for both color and location, and human beings may use different strategies for recall in working memory tasks.
Psychological morbidities and fatigue in patients with confirmed COVID-19 during disease outbreak: prevalence and associated biopsychosocial risk factors
Authors: Qi Rongfeng , Chen Wei , Liu Saiduo , Thompson Paul M. , Zhang Long Jiang , Xia Fei , Cheng Fang , Hong Ailing , Surento Wesley , Luo Song , Sun Zhi Yuan , Zhou Chang Sheng , Li Lingjiang , Jiang Xiangao , Lu Guang Ming
Published: May 2020

Objective

The coronavirus disease 2019 (COVID-19) – a novel and highly infectious pneumonia – has now spread across China and beyond for over four months. However, its psychological impact on patients is unclear. We aim to examine the prevalence and associated risk factors for psychological morbidities and fatigue in patients with confirmed COVID-19 infection.

Methods

Amidst the disease outbreak, 41 out of 105 COVID-19 patients in a local designated hospital in China were successfully assessed using a constellation of psychometric questionnaires to determine their psychological morbidities and fatigue. Several potential biopsychosocial risk factors (including pre-existing disabilities, CT severity score of pneumonia, social support, coping strategies) were assessed through multivariable logistic regression analyses to clarify their association with mental health in patients.

Results

43.9% of 41 patients presented with impaired general mental health, 12.2% had post-traumatic stress disorder (PTSD) symptoms, 26.8% had anxiety and/or depression symptoms, and 53.6% had fatigue. We did not find any association between pneumonia severity and psychological morbidities or fatigue in COVID-19 patients. However, high perceived stigmatization was associated with an increased risk of impaired general mental health and high perceived social support was associated with decreased risk. Besides, negative coping inclination was associated with an increased risk of PTSD symptoms; high perceived social support was associated with a decreased risk of anxiety and/or depression symptoms.

Conclusions

Psychological morbidities and chronic fatigue are common among COVID-19 patients. Negative coping inclination and being stigmatized are primary risk factors while perceived social support is the main protective factor.
Early detection of severe COVID-19 disease patterns define near real-time personalised care, bioseverity in males, and decelerating mortality rates
Authors: Vizcaychipi Marcela P. , Shovlin Claire L , Hayes Michelle , Singh Suveer , Christie Linsey , Sisson Alice , Davies Roger , Lockie Christopher , Howard Alice , Brown Alexander , McCarthy Alex , Popescu Monica , Gupta Amandeep , Armstrong James , Said Hisham , Peters Timothy , Keays Richard T ,   ChelWest COVID-19 Consortium
Published: May 2020

Background

COVID-19 is a global health emergency. Recent data indicate a 50% mortality rate across UK intensive care units.

Methods

A single institution, two-centre retrospective analysis following implementation of a Decision Support tool and real-time data dashboard for early detection of patients requiring personalised enhanced care, focussing on respiratory rate, diastolic blood pressure, oxygenation indices, C-reactive protein, D-dimer and ferritin. Protocols differing from conventional practice included high-dose prophylactic anticoagulation for all COVID-19 positive patients and prescription of antioxidants.

Results

By 22/04/2020, 923 patients tested COVID-19 positive. 569 patients (61.7%) were male. The majority presented with advanced disease: interquartile ranges were C-reactive protein 44.9-179mg/L, D-dimer 1070-3802ng/mL, and ferritin 261-1208µg/L. Completed case fatality rates were 25.1% [95% CI 20.0, 30.0] in females, 40.5% [95% CI 35.9, 45.0] in males. 139 patients were admitted to intensive care where current death rates are 16.2% [95% CI 3.8, 28.7] in females, 38.2% [95% CI 28.6, 47.8] in males with no trends for differences based on ethnicity. A real-time traffic lights dashboard enabled rapid assessment of patients using critical parameters to accelerate adjustments to management protocols. In total 513 (55.6%) of patients were flagged as high risk for thromboembolic disease, exceeding the numbers flagged for respiratory deteriorations (N=391, 42.4%), or cytokine storm (N=68, 7.4%). There was minimal evidence that age was associated with disease severity, but males had higher levels of all dashboard indices, particularly C-reactive protein and ferritin (p<0.0001) which displayed no relationship with age.

Conclusions

Survival rates are encouraging. Protocols employed (traffic light-driven personalised care, protocolised early therapeutic anticoagulation based on D-dimer >1,000ng/mL and/or CRP>200 mg/L, personalised ventilatory strategies and antioxidants) are recommended to other units. Males are at greater risk of severe disease, most likely as the obligate SARS-CoV-2 receptor is encoded by the X-chromosome, and require especially close, and early attention.
Replicating extensive brain structural heterogeneity in individuals with schizophrenia and bipolar disorder
Authors: Wolfers Thomas , Rokicki Jaroslav , Alnæs Dag , Berthet Pierre , Agartz Ingrid , Kia Seyed Mostafa , Kaufmann Tobias , Zabihi Mariam , Moberget Torgeir , Melle Ingrid , Beckmann Christian F , Andreassen Ole A , Marquand Andre F , Westlye Lars T
Published: May 2020

Identifying brain processes involved in the risk and development of mental disorders is a major aim. We recently reported substantial inter-individual heterogeneity in brain structural aberrations among patients with schizophrenia and bipolar disorder. Estimating the normative range of voxel-based morphometry (VBM) data among healthy individuals using a gaussian process regression (GPR) enables us to map individual deviations from the healthy range in unseen datasets. Here we aim to replicate our previous results in two independent samples of patients with schizophrenia (n1=94; n2=105), bipolar disorder (n1=116; n2=61) and healthy individuals (n1=400; n2=312). In line with previous findings with exception of the cerebellum our results revealed robust group level differences between patients and healthy individuals, yet only a small proportion of patients with schizophrenia or bipolar disorder exhibited extreme negative deviations from normality in the same brain regions. These direct replications support that group level-differences in brain structure disguise considerable individual differences in brain aberrations, with important implications for the interpretation and generalization of group-level brain imaging findings to the individual with a mental disorder.
Analysis and annotation of genome-wide DNA methylation patterns in two nonhuman primate species using the Infinium Human Methylation 450K and EPIC BeadChips
Authors: Pichon Fabien , Busato Florence , Jochems Simon , Jacquelin Beatrice , Le Grand Roger , Deleuze Jean-Francois , Müller-Trutwin Michaela , Tost Jörg
Published: May 2020

The Infinium Human Methylation450 and Methylation EPIC BeadChips are useful tools for the study of the methylation state of hundreds of thousands of CpG across the human genome at affordable cost. However, in a wide range of experimental settings in particular for studies in infectious or brain-related diseases, human samples cannot be easily obtained. Hence, due to their close developmental, immunological and neurological proximity with humans, non-human primates are used in many research fields of human diseases and for preclinical research. Few studies have used DNA methylation microarrays in simian models. Microarrays designed for the analysis of DNA methylation patterns in the human genome could be useful given the genomic proximity between human and nonhuman primates. However, there is currently information lacking about the specificity and usability of each probe for many nonhuman primate species, including rhesus macaques (Macaca mulatta), originating from Asia, and African green monkeys originating from West-Africa (Chlorocebus sabaeus). Rhesus macaques and African green monkeys are among the major nonhuman primate models utilized in biomedical research. Here, we provide a precise evaluation and re-annotation of the probes of the two microarrays for the analysis of genome-wide DNA methylation patterns in these two Cercopithecidae species. We demonstrate that up to 162,000 of the 450K and 255,000 probes of the EPIC BeadChip can be reliably used inMacaca mulattaorChlorocebus sabaeus. The annotation files are provided in a format compatible with a variety of preprocessing, normalization and analytical pipelines designed for data analysis from 450K/EPIC arrays, facilitating high-throughput DNA methylation analyses inMacaca mulattaandChlorocebus sabaeus. They provide the opportunity to the research community to focus their analysis only on those probes identified as reliable. The described analytical workflow leaves the choice to the user to balance coverage versus specificity and can also be applied to other Cercopithecidae species.
Developmental chromatin programs determine oncogenic competence in melanoma
Authors: Baggiolini Arianna , Callahan Scott J. , Trieu Tuan , Tagore Mohita M. , Montal Emily , Weiss Joshua M. , Tischfield Sam E. , Fan Yujie , Campbell Nathaniel R. , Saurat Nathalie , Hollmann Travis , Simon-Vermot Theresa , Tickoo Satish K. , Taylor Barry S. , Koche Richard , Khurana Ekta , Studer Lorenz , White Richard M.
Published: May 2020

Oncogenes are only transforming in certain cellular contexts, a phenomenon called oncogenic competence. The mechanisms regulating this competence remain poorly understood. Here, using a combination of a novel human pluripotent stem cell (hPSC)-based cancer model along with zebrafish transgenesis, we demonstrate that the transforming ability of BRAFV600Edepends upon the intrinsic transcriptional program present in the cell of origin. Remarkably, in both systems, melanocytes (MC) are largely resistant to BRAF. In contrast, both neural crest (NC) and melanoblast (MB) populations are readily transformed. Molecular profiling reveals that NC/MB cells have markedly higher expression of chromatin modifying enzymes, and we discovered that the chromatin remodeler ATAD2 is required for response to BRAF and tumor initiation. ATAD2 forms a complex with SOX10, allowing for expression of downstream oncogenic programs. These data suggest that oncogenic competence is mediated by developmental regulation of chromatin factors, which then allow for proper response to those oncogenes.
Measuring context dependency in birdsong using artificial neural networks
Authors: Morita Takashi , Koda Hiroki , Okanoya Kazuo , Tachibana Ryosuke O.
Published: May 2020

Context dependency is a key feature in sequential structures of human language, which requires reference between words far apart in the produced sequence. Assessing how long the past context has an effect on the current status provides crucial information to understand the mechanism for complex sequential behaviors. Birdsongs serve as a representative model for studying the context dependency in sequential signals produced by non-human animals, while previous reports were upper-bounded by methodological limitations. Here, we newly estimated the context dependency in birdsongs in a more scalable way using a modern neural-network-based language model whose accessible context length is sufficiently long. The detected context dependency was beyond the order of traditional Markovian models of birdsong, but was consistent with previous experimental investigations. We also studied the relation between the assumed/auto-detected vocabulary size of birdsong (i.e., fine-vs. coarse-grained syllable classifications) and the context dependency. It turned out that the larger vocabulary (or the more fine-grained classification) is assumed, the shorter context dependency is detected.
Functional requirement of theArabidopsisimportin-α nuclear transport receptor family in autoimmunity mediated by the NLR protein SNC1
Authors: Lüdke Daniel , Roth Charlotte , Kamrad Sieglinde A. , Messerschmidt Jana , Hartken Denise , Appel Jonas , Hörnich Bojan F. , Yan Qiqi , Kusch Stefan , Klenke Melanie , Gunkel Annette , Wirthmueller Lennart , Wiermer Marcel
Published: May 2020

IMPORTIN-α3/MOS6 (MODIFIER OF SNC1, 6) is one of nine importin-α isoforms inArabidopsisthat recruit nuclear localization signal (NLS)-containing cargo proteins to the nuclear import machinery.IMP-α3/MOS6is required genetically for full autoimmunity of the nucleotide-binding leucine-rich repeat (NLR) immune receptor mutantsnc1(suppressor of npr1-1, constitutive 1) andMOS6also contributes to basal disease resistance. Here, we investigated the contribution of the otherimportin-α genes to both types of immune responses, and we analyzed potential interactions of all importin-α isoforms with SNC1. By using reverse-genetic analyses inArabidopsisand protein-protein interaction assays inN. benthamianawe provide evidence that among the nine α-importins inArabidopsis, IMP-α3/MOS6 is the main nuclear transport receptor of SNC1, and thatIMP-α3/MOS6is required selectively for autoimmunity ofsnc1and basal resistance to mildly virulentPseudomonas syringaeinArabidopsis.

SIGNIFICANCE STATEMENT

Specific requirement for theArabidopsisα-importin MOS6 insnc1-mediated autoimmunity is explained by selective formation of MOS6-SNC1 nuclear import complexes.
Clinical Knowledge Graph Integrates Proteomics Data into Clinical Decision-Making
Authors: Santos Alberto , Colaço Ana R. , Nielsen Annelaura B. , Niu Lili , Geyer Philipp E. , Coscia Fabian , Albrechtsen Nicolai J Wewer , Mundt Filip , Jensen Lars Juhl , Mann Matthias
Published: May 2020

The promise of precision medicine is to deliver personalized treatment based on the unique physiology of each patient. This concept was fueled by the genomic revolution, but it is now evident that integrating other types of omics data, like proteomics, into the clinical decision-making process will be essential to accomplish precision medicine goals. However, quantity and diversity of biomedical data, and the spread of clinically relevant knowledge across myriad biomedical databases and publications makes this exceptionally difficult. To address this, we developed the Clinical Knowledge Graph (CKG), an open source platform currently comprised of more than 16 million nodes and 220 million relationships to represent relevant experimental data, public databases and the literature. The CKG also incorporates the latest statistical and machine learning algorithms, drastically accelerating analysis and interpretation of typical proteomics workflows. We use several biomarker studies to illustrate how the CKG may support, enrich and accelerate clinical decision-making.

Graphical Abstract
Bioengineered ciprofloxacin loaded chitosan nanoparticles for the treatment of Bovine Mastitis
Authors: Yadav Preeti , Gaur Preksha , Yadav Awadh B. , Huma Z. I. , Sharma Neelesh
Published: May 2020

Mastitis is the most devastating economic disease of dairy cattle. Mastitis in dairy cattle frequently occurs during the dry period or in early lactation. E. coli. andS. aureusis the main causative agent of mastitis. S. aureushas an ability to form encapsulated focuses in the udder and develop subclinical form of mastitis. This property of bacteria hinders the effective cure during lactation period. Antibiotics used for treatments have a short half-life span at the site of action because of frequent milking, therefore unable to maintain desired drug concentration for effective clearance of bacteria. We demonstrated the potential of ciprofloxacin encapsulated nanocarriers which can improve availability of drugs and could provide effective means of the treatment of mastitis. These drug loaded nanoparticles show low toxicity & slow clearance from the site of action. Antimicrobial studied against clinical strain ofE.coli.andStaphylococcus aureuszone of inhibition depend on dose 0.5 mg to 2 mg/ml nanoparticles solution from 11.6 to 14.5 mm and 15 to 18mm. These nanoparticles show good antimicrobial activity in broth culture as well against bacteria.
Resynthesis: Marker-based partial reconstruction of elite genotypes in clonally-reproducing plant species
Authors: Eduardo Iban , Alegre Simó , Alexiou Konstantinos G. , Arús Pere
Published: May 2020

We propose a method for marker-based selection of cultivars of clonally-reproducing plant species which keeps the basic genetic architecture of a top-performing cultivar (usually a partly heterozygous genotype), with some agronomically relevant differences (such as production time, product appearance or quality), providing added value to the product or cultivation process. The method is based on selecting a) two complementary nearly-inbred lines from successive selfing generations (ideally only F2 and F3) of large size, that may generate individuals with most of their genome identical to the original cultivar but being homozygous for either of the two component haplotypes in the rest, and b) individuals with such characteristics already occurring in the F2. Option a) allows for introgressing genes from other individuals in one or both of these nearly-inbred lines.

Peach, a woody-perennial, clonally-reproduced species, was chosen as a model for a proof of concept of the Resynthesis process due to its biological characteristics: self-compatibility, compact and genetically well-known genome, low recombination rates and relatively short intergeneration time (3-4 years). From 416 F2seedlings from cultivar Sweet Dream (SD), we obtained seven individuals with 76-94% identity with SD, and selected five pairs of complementary lines with average homozygosity of the two parents ≥0.70 such that crossing would produce some individuals highly similar to SD. The application of this scheme to other species with more complex genomes or biological features, including its generalization to F1 hybrids, is discussed.
Rapid Population Decline of the Pillar CoralDendrogyra cylindrusAlong the Florida Reef Tract
Authors: Neely Karen L. , Lewis Cynthia L.
Published: May 2020

Coral reefs worldwide are in a state of decline, but the status of populations and stressors for rare species are generally not well documented using broad-scale monitoring protocol. We fate-tracked all known colonies of the pillar coralDendrogyra cylindruson the Florida Reef Tract from 2013 – 2020 to assess the population and document the impacts of chronic and acute stressors. Large average colony size, an absence of juveniles, and large geographic distances between genotypes suggest that the FloridaD. cylindruspopulation has been reproductively extinct for decades. During the study period, low-intensity chronic stressors were balanced by regrowth, while back-to-back years of coral bleaching and thermally-exacerbated disease led to declines that the subsequent years of recovery suggest would take 11 uninterrupted years to overcome. The most recent stressor on Florida’sD. cylindruspopulation is “stony coral tissue loss disease.” Following the appearance of the disease in Florida in 2015, it resulted in unrecoverable losses to theD. cylindruspopulation as tissue, colonies, and whole genotypes were driven to extinction. Losses of 91% of coral tissue, 88% of colonies, and 73% of genotypes between 2014 and early 2020 have led to functional extinction ofD. cylindruson the Florida Reef Tract.
Mechanical Tension in Syndecan-1 is Regulated by Extracellular Mechanical Cues and Fluidic Shear Stress
Authors: Le Victoria , Mei Lei , Voyvodic Peter L. , Zhao Chi , Busch David J. , Stachowiak Jeanne C. , Baker Aaron B.
Published: May 2020

The endothelium plays a central role in regulating vascular homeostasis and is key in determining the response to materials implanted in the vascular system. Endothelial cells are uniquely sensitive to biophysical cues from applied forces and their local cellular microenvironment. The glycocalyx is a layer of proteoglycans, glycoproteins and glycosaminoglycans that lines the luminal surface of the vascular endothelium, interacting directly with the components of the blood and the forces of blood flow. In this work, we examined the changes in mechanical tension of syndecan-1, a cell surface proteoglycan that is an integral part of the glycocalyx, in response to substrate stiffness and fluidic shear stress. Our studies demonstrate that syndecan-1 is mechanically responsive to extracellular mechanical cues and alters its association with cytoskeletal and adhesion-related proteins in response to substrate stiffness and physiological flow.
Converting endogenous genes of the malaria mosquito into simple non-autonomous gene drives for population replacement
Authors: Hoermann Astrid , Tapanelli Sofia , Capriotti Paolo , Masters Ellen K. G. , Habtewold Tibebu , Christophides George K. , Windbichler Nikolai
Published: May 2020

Gene drives for mosquito population replacement are promising tools for malaria control. However, there is currently no clear pathway for safely testing such tools in endemic countries. The lack of well-characterized promoters for infection-relevant tissues and regulatory hurdles are further obstacles for their design and use. Here we explore how minimal genetic modifications of endogenous mosquito genes can convert them directly into non-autonomous gene drives without disrupting their expression. We co-opted the native regulatory sequences of three midgut-specific loci of the malaria vectorAnopheles gambiaeto host a prototypical antimalarial molecule and guide-RNAs encoded within artificial introns, that support efficient gene drive. We assess the propensity of these modifications to interfere with the development ofPlasmodium falciparumand their effect on fitness. Because of their inherent simplicity and passive mode of drive such traits could form part of an accepted testing pathway of gene drives for malaria eradication.
Mitochondrial fatty acid synthesis coordinates mitochondrial oxidative metabolism
Authors: Nowinski Sara M. , Solmonson Ashley , Rusin Scott F. , Maschek J. Alan , Bensard Claire L. , Fogarty Sarah , Jeong Mi-Young , Lettlova Sandra , Berg Jordan A. , Morgan Jeffrey T. , Ouyang Yeyun , Naylor Bradley C. , Paulo Joao A. , Funai Katsuhiko , Cox James E. , Gygi Steven P. , Winge Dennis R. , Deberardinis Ralph J. , Rutter Jared
Published: May 2020

Cells harbor two systems for fatty acid synthesis, one in the cytoplasm (catalyzed by fatty acid synthase, FASN) and one in the mitochondria (mtFAS). In contrast to FASN, mtFAS is poorly characterized, especially in higher eukaryotes, with the major product(s), metabolic roles, and cellular function(s) being essentially unknown. Here we show that hypomorphic mtFAS mutants display a severe loss of electron transport chain (ETC) complexes and exhibit compensatory metabolic activities including reductive carboxylation. This effect on ETC complexes appears to be independent of protein lipoylation, the best characterized function of mtFAS, as mutants lacking lipoylation have an intact ETC. Finally, mtFAS impairment blocks the differentiation of skeletal myoblasts in vitro. Together, these data suggest that ETC activity in mammals is profoundly controlled by mtFAS function, thereby connecting anabolic fatty acid synthesis with the oxidation of carbon fuels.
Impact of industrial production system parameters on chicken microbiomes: mechanisms to improve performance and reduceCampylobacter
Authors: McKenna Aaron , Ijaz Umer Zeeshan , Kelly Carmel , Linton Mark , Sloan William T. , Green Brian D. , Lavery Ursula , Dorrell Nick , Wren Brendan W. , Richmond Anne , Corcionivoschi Nicolae , Gundogdu Ozan
Published: May 2020

Background

The factors affecting host-pathogen ecology in terms of the microbiome remain poorly studied. Chickens are a key source of protein with gut health heavily dependent on the complex microbiome which has key roles in nutrient assimilation and vitamin and amino acid biosynthesis. The chicken gut microbiome may be influenced by extrinsic production system parameters such asPlacement Birds/m2(stocking density), feed type and additives. Such parameters, in addition to on-farm biosecurity may influence performance and also pathogenic bacterial numbers such asCampylobacter. In this study, three different production systems ‘Normal’ (N), ‘Higher Welfare’ (HW) and ‘Omega-3 Higher Welfare’ (O) were investigated “in a natural environment” at day 7 and day 30 with a range of extrinsic parameters assessing performance in correlation with microbial dynamics andCampylobacterpresence.

Results

Our data identified production system N as significantly dissimilar from production systems HW and O when comparing the prevalence of genera. An increase inPlacement Birds/m2density led to a decrease in environmental pressure influencing the microbial community structure. Prevalence of genera such asEisenbergiellawithin HW and O, and likewiseAlistipeswithin N were representative. These genera have roles directly relating to energy metabolism, amino acid, nucleotide and short chain fatty acid (SCFA) utilisation. Thus, an association exists between consistent and differentiating parameters of the production systems, that affect feed utilisation, advance our knowledge of mechanistic underpinnings, leading to competitive exclusion of genera based on competition for nutrients and other factors.Campylobacterwas identified within specific production system and presence was linked with the increased diversity and increased environmental pressure on microbial community structure. Addition of Omega-3 though did alter prevalence of specific genera, in our analysis did not differentiate itself from HW production system. However, Omega-3 was linked with a positive impact on weight gain.

Conclusions

Overall, our results show that microbial communities in different industrial production systems are deterministic in elucidating the underlying biological confounders, and these recommendations are transferable to farm practices and diet manipulation leading to improved performance and better intervention strategies againstCampylobacterwithin the food chain.

Graphical Abstract
Mapping fetal brain development based on automated segmentation and 4D brain atlasing
Authors: Li Haotian , Yan Guohui , Luo Wanrong , Liu Tintin , Wang Yan , Liu Ruibin , Zheng Weihao , Zhang Yi , Li Kui , Zhao Li , Limperopoulos Catherine , Zou Yu , Wu Dan
Published: May 2020

Fetal brain MRI has become an important tool for in utero assessment of brain development and disorders. However, quantitative analysis of fetal brain MRI remains difficult, partially due to the limited tools for automated preprocessing and the lack of normative brain templates. In this paper, we proposed an automated pipeline for fetal brain extraction, super-resolution reconstruction, and fetal brain atlasing to quantitatively map in utero fetal brain development during mid-to-late gestation in a Chinese population. First, we designed a U-net convolutional neural network for automated fetal brain extraction, which achieved an average accuracy of 97%. We then generated a developing fetal brain atlas, using an iterative linear and nonlinear registration approach. Based on the 4D spatiotemporal atlas, we quantified the morphological development of the fetal brain between 23-36 weeks of gestation. The proposed pipeline enabled the fully-automated volumetric reconstruction for clinically available fetal brain MRI data, and the 4D fetal brain atlas provided normative templates for quantitative analysis of potential fetal brain abnormalities, especially in the Chinese population.
Removal of repressive histone marks creates epigenetic memory of recurring heat inArabidopsis
Authors: Yamaguchi Nobutoshi , Matsubara Satoshi , Yoshimizu Kaori , Seki Motohide , Hamada Kouta , Kamitani Mari , Kurita Yuko , Inagaki Soichi , Suzuki Takamasa , Gan Eng-Seng , To Taiko , Kakutani Tetsuji , Nagano Atsushi J. , Satake Akiko , Ito Toshiro
Published: May 2020

Acclimation to high temperature increases plants’ tolerance of subsequent lethal high temperatures1-3. Although epigenetic regulation of plant gene expression is well studied, how plants maintain a memory of environmental changes over time remains unclear. Here, we show that JUMONJI (JMJ) proteins4-8, demethylases involved in histone H3 lysine 27 trimethylation (H3K27me3), are necessary forArabidopsis thalianaheat acclimation. Acclimation induces sustained H3K27me3 demethylation at keyHEAT SHOCK PROTEIN(HSP) loci by JMJs, poising theHSPgenes for subsequent activation. Upon sensing heat after a 3-day interval, JMJs directly reactivateHSPgenes. Finally,jmjmutants fail to maintain heat memory under fluctuating field temperature conditions. Our findings of an epigenetic memory mechanism involving histone demethylases may have implications for environmental adaptation of field plants.
SurEau.c : a mechanistic model of plant water relations under extreme drought
Authors: Cochard Hervé , Pimont François , Ruffault Julien , Martin-StPaul Nicolas
Published: May 2020

We describe the operating principle of the detailed version of the soil-plant-atmosphere modelSurEauthat allows, among other things, to predict the risk of hydraulic failure under extreme drought. It is based on the formalization of key physiological processes of plant response to water stress. The hydraulic functioning of the plant is at the core of this model, which focuses on both water flows and water pools using variable hydraulic conductances. The model considers the elementary flow of water from the soil to the atmosphere through different plant organs (roots, trunk branches, leaves and buds) that are described by their symplasm and their apoplasm compartments. Within each organ the flow of water between the apoplasm and the symplasm is also represented; as well as the flow outside the system, from the symplasm of each organ to the atmosphere, through the cuticular conductance. For each organ, the symplasm is described by a pressure volume curves and the apoplasm by the vulnerability curve to cavitation of the xylem. The model can thus compute the loss of conductance caused by cavitation, a leading mechanisms of plant desiccation and drought-induced mortality. Some example simulations are shown to illustrate how the model works.
Silencing of Exosomal miR-181a reverses Pediatric Acute Lymphocytic Leukemia Cell Proliferation
Authors: Haque Shabirul , Vaiselbuh Sarah R.
Published: May 2020

Exosomes are cell-generated nano-vesicles (30-150 nm) found in most biological fluids. Major components of their cargo are lipids, proteins, RNA, DNA, and non-coding RNAs. Exosomes carry the fingerprint of the parental tumor and as such, may regulate tumor growth, progression and metastasis. We investigated the impact of exosomes on cell proliferation in pediatric acute lymphocytic leukemia and its reversal by silencing of exo-miR-181a.We isolated exosomes from serum of acute lymphocytic leukemia pediatric patients (Exo-PALL) and conditioned medium of leukemic cell lines (Exo-CM) by ultracentrifugation. Gene expression was carried out by q-PCR. We found that Exo-PALL promote cell proliferation in leukemic B cell lines as well as in the control B cell line. This exosome-induced cell proliferation is a precise event with up-regulation of proliferative (PCNA, Ki-67) and pro-survival genes (MCL-1, and BCL2), and suppression of pro-apoptotic genes (BAD, BAX). Exo-PALL and Exo-CM both show over expression of miR-181a compared to controls (Exo-HD). Specific silencing ofexosomalmiR-181a using a miR-181a inhibitor confirms that miR-181a inhibitor treatment reverses Exo-PALL/Exo-CM-induced leukemic cell proliferationin vitro. Altogether, this study suggests that exosomal miR-181a inhibition can be a novel target for growth suppression in pediatric lymphatic leukemia.
Speeding up Inference of Homologous Recombination in Bacteria
Authors: Medina-Aguayo Felipe J , Didelot Xavier , Everitt Richard G
Published: May 2020

Bacteria reproduce clonally but most species recombine frequently, so that the ancestral process is best captured using an ancestral recombination graph. This graph model is often too complex to be used in an inferential setup, but it can be approximated for example by the ClonalOrigin model. Inference in the ClonalOrigin model is performed via a Reversible-Jump Markov Chain Monte Carlo algorithm, which attempts to jointly explore: the recombination rate, the number of recombination events, the departure and arrival points on the clonal genealogy for each recombination event, and the range of genomic sites affected by each recombination event. However, the Reversible-Jump algorithm usually performs poorly due to the complexity of the target distribution since it needs to explore spaces of different dimensions. Recent developments in Bayesian computation methodology have provided ways to improve existing methods and code, but are not well-known outside the statistics community. We show how exploiting one of these new computational methods can lead to faster inference under the ClonalOrigin model.
Rational design of human cathepsin L with efficient collagenolytic activity
Authors: Choudhury Debi , Biswas Sampa
Published: May 2020

Collagens are the main structural components of ECM and collagenolysis is vital for ECM remodelling, which is essential for normal organ homeostasis. Any dysregulation of this process can result in various pathological conditions. The degradation of the interstitial collagens is generally mediated by specific collagenases which are capable of cleaving at specific loci in the collagen triple helix. Lysosomal cysteine cathepsins have general housekeeping as well as some highly specialized functions. Amongst them, human cathepsin K is the only lysosomal cysteine protease which has potent collagenolytic activity against type I collagen. In this study, we have imparted collagenolytic property to another human cysteine protease, cathepsin L, by systematically engineering proline-specificity and GAG-binding surface in the protease. The designed proline-specific mutant shows high specificity for peptidyl substrate containing proline at P2 position but is incapable of cleaving collagen. However, when the proline-specific mutant is further engineered for GAG-binding surface, it can degrade type I collagen in presence of Chondroitin 4-Sulfate (C4-S). We also present high resolution crystal structures of these proline-specific (1.4 Å) and collagen-specific (1.8 Å) mutants. Finally docking studies with prolyl-peptidic substrate (Ala-Gly-Pro-Arg-Ala) at the active site and a GAG molecule (C4-S) at the GAG binding site enables us to identify key structural features responsible for collagenolytic activity of papain-like cysteine proteases. This study provides a rational approach to engineer an efficient collagenase from a human template enzyme which may have various noninvasive therapeutic implications with an expected additional advantage of immuno-compatiblity.
Identification of MAZ as a novel transcription factor regulating erythropoiesis
Authors: Deen Darya , Butter Falk , Holland Michelle L. , Samara Vasiliki , Sloane-Stanley Jacqueline A. , Ayyub Helena , Mann Matthias , Garrick David , Vernimmen Douglas
Published: May 2020

Erythropoiesis requires a combination of ubiquitous and tissue-specific transcription factors. Here, through DNA affinity purification followed by mass spectrometry, we have identified the widely expressed protein MAZ (Myc-associated zinc finger) as a transcription factor that binds to the promoter of the erythroid-specific human α-globin gene. Genome-wide mapping in primary human erythroid cells revealed that MAZ also occupies active promoters as well as GATA1-bound enhancer elements of key erythroid genes. Consistent with an important role during erythropoiesis, knockdown of MAZ in primary human erythroid cells impairs erythroid differentiation, and genetic variants in theMAZlocus are associated with clinically important human erythroid traits. Taken together, these findings reveal the Zinc-finger transcription factor MAZ to be a previously unrecognised regulator of the erythroid differentiation program.