bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paracoccidioidesgenomes reflect high levels of species divergence and little interspecific gene flow
Authors: Mavengere Heidi , Mattox Katlheen , Teixeira Marcus M , Sepúlveda Victoria E. , Gomez Oscar M. , Hernandez Orville , McEwen Juan , Matute Daniel R. 
Published: July 2020

ABSTRACTThe fungusParacoccidioidesspp. is a prevalent human pathogen endemic to South America. The genus is composed of five species. In this report, we use 37 whole genome sequences to study the allocation of genetic variation inParacoccidioides. We tested three genome-wide predictions of advanced speciation, namely, that all species should be reciprocally monophyletic, that species pairs should be highly differentiated along the whole genome, and that there should be low rates of interspecific gene exchange. We find support for these three hypotheses. Species pairs with older divergences show no evidence of gene exchange, while more recently diverged species pairs show evidence of modest rates of introgression. Our results indicate that as divergence progresses, species boundaries become less porous amongParacoccidioidesspecies. Our results suggest that species inParacoccidioidesare at different stages along the divergence continuum.IMPORTANCEParacoccidioidesis the causal agent of the most frequent systemic mycosis in Latin America. Most of the inference of the evolutionary history ofParacoccidioideshas used only a handful of molecular markers. In this report, we evaluate the extent of genome divergence amongParacoccidioidesspecies and study the possibility of interspecific gene exchange. We find that all species are highly differentiated. We also find that the amount of gene flow between species is low and in some cases even completely absent in spite of geographic overlap. Our study constitutes a systematic effort to identify species boundaries in fungal pathogens, and determine the extent of gene exchange among fungal species.
Multiple spatial codes for navigating 2-D semantic spaces
Authors: Viganò Simone , Rubino Valerio , Di Soccio Antonio , Buiatti Marco , Piazza Manuela 
Published: July 2020

SummaryWhen mammals navigate in the physical environment, specific neurons such as grid-cells, head-direction cells, and place-cells activate to represent the navigable surface, the faced direction of movement, and the specific location the animal is visiting. Here we test the hypothesis that these codes are also activated when humans navigate abstract language-based representational spaces. Human participants learnt the meaning of novel words as arbitrary signs referring to specific artificial audiovisual objects varying in size and sound. Next, they were presented with sequences of words and asked to process them semantically while we recorded the activity of their brain using fMRI. Processing words in sequence was conceivable as movements in the semantic space, thus enabling us to systematically search for the different types of neuronal coding schemes known to represent space during navigation. By applying a combination of representational similarity and fMRI-adaptation analyses, we found evidence of i) a grid-like code in the right postero-medial entorhinal cortex, representing the general bidimensional layout of the novel semantic space; ii) a head-direction-like code in parietal cortex and striatum, representing the faced direction of movements between concepts; and iii) a place-like code in medial prefrontal, orbitofrontal, and mid cingulate cortices, representing the Euclidean distance between concepts. We also found evidence that the brain represents 1-dimensional distances between word meanings along individual sensory dimensions: implied size was encoded in secondary visual areas, and implied sound in Heschl’s gyrus/Insula. These results reveal that mentally navigating between 2D word meanings is supported by a network of brain regions hosting a variety of spatial codes, partially overlapping with those recruited for navigation in physical space.
Altered bacteria community dominance reduces tolerance to resident fungus and seed to seedling growth performance in maize (Zea maysL. var. DBK 177)
Authors: dos Santos Lidiane Figueiredo , Souta Julie Fernandes , da Rocha Letícia Oliveira , de Paula Soares Cleiton , Santos Maria Luiza Carvalho , de Matos Clicia Grativol Gaspar , Roesch Luiz Fernando Wurdig , Olivares Fabio Lopes 
Published: July 2020

AbstractSeeds are reservoirs of beneficial and harmful microorganism that modulates plant growth and health. Here, we access seed to seedling bacteriome assembly modified by seed-disinfection and the underlined effect over maize germination performance and root-seedlings microbial colonization. Seed-disinfection was performed with sodium hypochlorite (1.25%, 30 min), resulting in a reduction of the cultivable-dependent fraction of seed-borne bacteria population, but not significantly detected by real-time PCR, microscopy, and biochemical analysis of the roots on germinated seeds. 16S rRNA sequencing revealed that the seed and root bacteriome exhibited similar diversity and did not differ in the structure concerning seed-disinfection. On the other hand, the abundance reduction of the genera f_Enterobacteriaceae_922761 (unassigned genus),Azospirillum,andAcinetobacterin disinfected-seed prior germination seems to display changes in prominence of several new taxa in the roots of germinated seeds. Interestingly, this reduction in the bacteriome negatively affected the germination speed and growth of maize plantlets. Additionally, bacteriome re-shape increased the maize var DKB 177 susceptible to the seed-borne plant pathogenPenicilliumsp. Such changes in the natural seed-borne composition removed the natural barrier, increasing susceptibility to pathogens, impairing disinfected seeds to germinate, and develop. We conclude that bacteria borne in seeds modulate the relative abundance of taxa in the root, promote germination, seedling growth, and protect the maize against fungal pathogens.
Genome-scale functional profiling of cell cycle controls in African trypanosomes
Authors: Marques Catarina A. , Tinti Michele , Cassidy Andrew , Horn David 
Published: July 2020

AbstractTrypanosomatids, which include major pathogens of humans and livestock, are divergent eukaryotes for which cell cycle controls and the underlying mechanisms are not completely understood. Here, we describe a genome-wide RNA-interference library screen for cell cycle regulators in bloodstream formTrypanosoma brucei. We induced massive parallel knockdown and sorted the perturbed population into cell cycle stages using flow cytometry. RNAi-targets were deep-sequenced from each stage and cell cycle profiles were digitally reconstructed at a genomic scale. We identify hundreds of proteins that impact cell cycle progression; glycolytic enzymes required for G1S progression, DNA replication factors, mitosis regulators, proteasome and kinetochore complex components required for G2M progression, flagellar and cytoskeletal components required for cytokinesis, mRNA-binding factors, protein kinases and many previously uncharacterised proteins. The outputs facilitate functional annotation and drug-target prioritisation and provide comprehensive functional genomic evidence for the machineries, pathways and regulators that coordinate progression through the trypanosome cell cycle.The data can be searched and browsed using an interactive, open access, online data visualization tool (https://tryp-cycle.onrender.com).
Trade-off between reducing mutational accumulation and increasing commitment to differentiation determines tissue organization
Authors: Demeter Márton , Derényi Imre , Szöllősi Gergely J. 
Published: July 2020

AbstractSpecies-specific differences control cancer risk across orders of magnitude variation in body size and lifespan, e.g., by varying the copy numbers of tumor suppressor genes. It is unclear, however, how different tissues within an organism can control somatic evolution despite being subject to markedly different constraints, but sharing the same genome. Hierarchical differentiation, characteristic of self-renewing tissues, can restrain somatic evolution both by limiting divisional load, thereby reducing mutation accumulation, and by increasing cells’ commitment to differentiation, which can “wash out” mutants. Here, we explore the organization of hierarchical tissues that have evolved to limit their lifetime incidence of cancer. Estimating the likelihood of cancer in the presence of mutations that enhance self-proliferation, we demonstrate that a trade-off exists between mutation accumulation and the strength of washing out. Our results explain differences in the organization of widely different hierarchical tissues, such as colon and blood.
Translation regulation of Japanese encephalitis virus revealed by ribosome profiling
Authors: Rizvi Vaseef A. , Sarkar Maharnob , Roy Rahul 
Published: July 2020

AbstractJapanese encephalitis virus (JEV), a neurotropic flavivirus, is the leading cause of viral encephalitis in endemic regions of Asia. Although the mechanisms modulating JEV virulence and neuroinvasiveness are poorly understood, several acquired mutations in the live attenuated vaccine strain (SA14-14-2) point towards translation regulation as a key strategy. Using ribosome profiling, we identify multiple mechanisms including frameshifting, tRNA dysregulation and alternate translation initiation sites that regulate viral protein synthesis. A significant fraction (~ 40%) of ribosomes undergo frameshifting on NS1 coding sequence leading to early termination, translation of NS1′ protein and modulation of viral protein stoichiometry. Separately, a tRNA subset (glutamate, serine, leucine and histidine) was found to be associated in high levels with the ribosomes upon JEV infection. We also report a previously uncharacterised translational initiation event from an upstream UUG initiation codon in JEV 5′ UTR. A silent mutation at this start site in the vaccine strain has been shown to abrogate neuroinvasiveness suggesting the potential role of translation from this region. Together, our study sheds light on distinct mechanisms that modulate JEV translation with likely consequences for viral pathogenesis.
Demography, education, and research trends in the interdisciplinary field of disease ecology
Authors: Brandell Ellen E. , Becker Daniel J. , Sampson Laura , Forbes Kristian M. 
Published: July 2020

ABSTRACTMicro- and macroparasites are a leading cause of mortality for humans, animals, and plants, and there is great need to understand their origins, transmission dynamics, and impacts. Disease ecology formed as an interdisciplinary field in the 1970s to fill this need and has recently rapidly grown in size and influence. Because interdisciplinary fields integrate diverse scientific expertise and training experiences, understanding their composition and research priorities is often difficult. Here, for the first time, we quantify the composition and educational experiences of a subset of disease ecology practitioners and identify topical trends in published research. We combined a large survey of self-declared disease ecologists with a literature synthesis involving machine-learning topic detection of over 18,500 disease ecology research articles. The number of graduate degrees earned by disease ecology practitioners has grown dramatically since the early 2000s. Similar to other science fields, we show that practitioners in disease ecology have diversified in the last decade in terms of gender identity and institution, with weaker diversification in race and ethnicity. Topic detection analysis revealed how the frequency of publications on certain topics have declined (e.g., HIV, serology), increased (e.g., the dilution effect, infectious disease in bats), remained relatively common (e.g., malaria ecology, influenza, vaccine research and development), or have consistently remained relatively infrequent (e.g., theoretical models, field experiments). Other topics, such as climate change, superspreading, emerging infectious diseases, and network analyses, have recently come to prominence. This study helps identify the major themes of disease ecology and demonstrates how publication frequency corresponds to emergent health and environmental threats. More broadly, our approach provides a framework to examine the composition and publication trends of other major research fields that cross traditional disciplinary boundaries.
Empagliflozin inhibits proximal tubule NHE3 activity, preserves GFR and restores euvolemia in nondiabetic rats with induced heart failure
Authors: Borges-Júnior Flávio A. , dos Santos Danúbia Silva , Benetti Acaris , Crajoinas Renato O. , Antonio Ednei L. , Jensen Leonardo , Caramelli Bruno , Malnic Gerhard , Tucci Paulo J. , Girardi Adriana C. 
Published: July 2020

ABSTRACTBackgroundSodium-glucose cotransporter type 2 (SGLT2) inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. We tested the hypothesis that the SGLT2 inhibitor empagliflozin inhibits proximal tubule (PT) Na+/H+ exchanger isoform 3 (NHE3) activity and improves renal salt and water handling in nondiabetic rats with HF.Methods and ResultsMale Wistar rats were subjected to myocardial infarction or sham operation. After four weeks, rats that developed HF and sham rats were treated with empagliflozin (EMPA) or untreated for an additional four weeks. EMPA-treated HF rats displayed lower levels of serum brain natriuretic peptide (BNP) and lower right ventricle and lung weight to tibia length than untreated HF rats. Upon saline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment normalized the glomerular filtration rate and proteinuria in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 function and protein and mRNA abundance were upregulated in the PT of HF rats.ConclusionCollectively, our data show that the prevention of HF progression by empagliflozin is associated with inhibition of PT NHE3 activity and restoration of euvolemia. Moreover, we propose that the dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF.SIGNIFICANCE STATEMENTSGLT2 inhibitors represent a class of drugs that were originally developed for improving glycemic control. Cardiovascular outcome trials that were designed to evaluate cardiovascular safety yielded unexpected and unprecedented evidence of the cardiorenal benefits of SGLT2 inhibitor. Many hypotheses have been proposed to explain the mechanisms underlying these effects. Our study demonstrates that SGLT2 inhibition restores extracellular volume homeostasis in nondiabetic heart failure (HF) rats by preserving GFR and inhibiting proximal tubule NHE3-mediated sodium reabsorption. The attenuation of kidney dysfunction may constitute an essential mechanism by which SGLT2 inhibitors attenuate HF development and progression either in the presence or absence of diabetes.
A series of Orai1 gating checkpoints in transmembrane and cytosolic regions requires clearance for CRAC channel opening: Clearance and synergy of Orai1 gating checkpoints controls pore opening
Authors: Tiffner Adéla , Schober Romana , Höglinger Carmen , Bonhenry Daniel , Pandey Saurabh , Lunz Victoria , Sallinger Matthias , Frischauf Irene , Fahrner Marc , Lindinger Sonja , Maltan Lena , Berlansky Sascha , Stadlbauer Michael , Schindl Rainer , Ettrich Rudiger , Romanin Christoph , Derler Isabella 
Published: July 2020

AbstractThe initial activation step in gating of ubiquitously expressed Orai1 Calcium (Ca2+) ion channels represents the store-dependent coupling to the Ca2+sensor protein STIM1. An array of constitutively active Orai1 mutants gave rise to the hypothesis that STIM1 mediated Orai1 pore opening is accompanied by a global conformational change of all Orai TM helices within the channel complex. Here, we prove that a local conformational change spreads omnidirectionally within the Orai1 complex. Our results demonstrate that a global, opening-permissive allosteric communication of TM helices is indispensable for pore opening and requires clearance of a series of Orai1 gating checkpoints. We discovered these gating checkpoints in middle and cytosolic extended TM domain regions. Our findings are based on a library of double point mutants that contain each one loss-of-function (LoF) with one gain-of-function (GoF) point mutation in a series of possible combinations. We demonstrated that an array of LoF mutations act dominant over most GoF mutations within the same as well as of an adjacent Orai subunit. We further established inter- and intramolecular salt-bridge interactions of Orai subunits as a core element of an opening-permissive Orai channel architecture. Collectively, clearance and synergistic action of all these gating checkpoints is required to allow STIM1 coupling and Orai1 pore opening.Graphical Abstract
Patient-derived glioblastoma cells (GBM) exhibit distinct biomechanical profiles associated with altered activity in the cytoskeleton regulatory pathway
Authors: Foss Amelia , Zanoni Michele , So Woong Young , Jenkins Lisa , Tosatto Luigino , Bartolini Daniela , Gottesman Michael M , Tesei Anna , Tanner Kandice 
Published: July 2020

ABSTRACTGlioblastoma multiforme (GBM) is the most commonly diagnosed brain cancer in adults, characterized by rapid proliferation and aggressive invasion into the stroma. Advances in our understanding of the molecular subtypes of GBM have provided attractive druggable targets. However, the high degree of heterogeneity both among patients and within individual tumors has proven a significant challenge for the development of effective therapies. We hypothesized that this heterogeneity is also represented in the mechanical phenotypes of GBM, as the physical properties of tumor tissue strongly influence elements of tumor progression including cell cycle regulation, migration, and therapeutic resistance. To assess these phenotypes, we employed optical trap-based active microrheology to determine the viscoelastic properties of patient-derived GBM cells in 3D hydrogels mimicking the brain ECM. We found that each GBM cell line had a distinct rheological profile as a function of treatment status, and cell lines could be further characterized by strong power law dependence describing intracellular viscoelastic behavior. Single-cell phenotyping according to power law dependence was able to identify subpopulations of cells within the treatment-resistant line. Finally, proteomic analysis indicated that altered mechanical profiles were associated with differential cytoskeletal regulation, particularly in actin - and myosin-binding pathways. This work suggests that evaluating mechanical properties may serve as a valuable strategy for the further stratification of these tumors, and encourages the investigation of cytoskeleton regulation as a potential therapeutic target for GBM.
Success Criteria for Preclinical Testing of Cell-Instructive Hydrogels for Tendon Regeneration
Authors: Locke Ryan C. , Ford Eden M. , Silbernagel Karin G. , Kloxin April M. , Killian Megan L. 
Published: July 2020

ABSTRACTTendon injuries are difficult to heal in part because intrinsic tendon healing, which is dominated by scar tissue formation, does not effectively regenerate the native structure and function of healthy tendon. Further, many current treatment strategies also fall short of producing regenerated tendon with the native properties of healthy tendon. There is increasing interest in the use of cell-instructive strategies to limit the intrinsic fibrotic response following injury and improve the regenerative capacity of tendonin vivo. We have established multi-functional, cell-instructive hydrogels for treating injured tendon that afford tunable control over the biomechanical, biochemical, and structural properties of the cell microenvironments. Specifically, we incorporated integrin-binding domains (RGDS) and assembled multi-functional collagen mimetic peptides (mfCMPs) that enable cell adhesion and elongation of stem cells within synthetic hydrogels of designed biomechanical properties and evaluated these materials using targeted success criteria developed for testing in mechanically-demanding environments like tendon healing. Thein vitroandin situsuccess criteria were determined based on systematic reviews of the most commonly reported outcome measures of hydrogels for tendon repair and established standards for testing of biomaterials. We then showed, using validation experiments, that multi-functional and synthetic hydrogels meet these criteria. Specifically, these hydrogels have mechanical properties comparable to developing tendon; are non-cytotoxic both in 2D bolus exposure (hydrogel components) and 3D encapsulation (full hydrogel); are formed, retained, and visualized within tendon defects over time (two-weeks); and provide mechanical support to tendon defects at the time of injection andin situformation. Ultimately, thein vitroandin situsuccess criteria evaluated in this study were designed for preclinical research to rigorously test the potential to achieve successful tendon repair prior toin vivotesting and indicate the promise of multi-functional and synthetic hydrogels for continued translation.IMPACT STATEMENTTendon healing results in a weak scar that forms due to poor cell-mediated repair of the injured tissue. Treatments that tailor the instructions experienced by cells during healing afford opportunities to regenerate the healthy tendon. Engineered cell-instructive cues, including the biomechanical, biochemical, and structural properties of the cell microenvironment, within multi-functional synthetic hydrogels are promising therapeutic strategies for tissue regeneration. In this paper, the preclinical efficacy of multi-functional synthetic hydrogels for tendon repair is tested against rigorousin vitroandin situsuccess criteria. This study indicates the promise for continued preclinical translation of synthetic hydrogels for tissue regeneration.