bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paranode stability requires UNC5B expression by oligodendrocytes
Authors: de Faria Omar , Nakamura Diane S. , Clemot Samuel , Kim Doyeun , Mocanu Mihai Victor , Pilgram Roland , Bin Jenea M. , Wong Edwin W. , Shmuel Amir , Sadikot Abbas , Ackerman Susan L. , Kennedy Timothy E. 
Published: August 2020

ABSTRACTIn the mature CNS, netrin-1 is expressed by neurons and oligodendrocytes and implicated in the stability of axo-oligodendroglial paranodal junctions. Here we report that the netrin receptor UNC5B is highly expressed by mature oligodendrocytes and enriched at paranodes. We demonstrate that paranodes become disorganized following conditional deletion of UNC5B in oligodendrocytes, with disruption of the interface between glial loops and detachment of loops from the axon. As a result, Caspr1 and Kv1.1 disperse along the axon, internodes fail to lengthen and compact myelin periodicity is reduced. Paranodal and axoglial domain disorganization progressively worsens and a delay in motor learning develops in aged mice lacking oligodendroglial UNC5B. Altered glial loop ultrastructure and reduced levels of claudin-11 and JAM-C tight junction proteins support the conclusion that disruption of autotypic junctions between paranodal loops underlies paranode disorganization. Our findings reveal an essential contribution of oligodendroglial UNC5B at paranodes that is required for the stability of mature myelin.
Random searchers cope with cognitive errors and uncertainty better than path planners
Authors: Campos Daniel , Méndez Vicenç , Palmer John , Cristín Javier , Bartumeus Frederic 
Published: August 2020

AbstractThere is a widespread belief in ecology that the capacity of animals to orchestrate systematic and planned paths should represent a significant benefit for efficient search and exploration. Within this view, stochasticity observed in real animal trajectories is mostly understood as undesirable noise caused by internal or external effects. Far less is known, however, about the case when cognitive errors and limitations inherent to living systems are explicitly put into play. Here we compare within this context the search efficiency of (i) walkers driven by Bayesian rules generating deterministic paths, (ii) standard random walkers, and (iii) human trajectories obtained from search experiments in a soccer field and on the computer screen. Our results clearly challenge the view that deterministic paths are generally better for exploration than random strategies, as the latter are more resilient to cognitive errors. Instead, we provide numerical and experimental evidence that stochasticity would provide living organisms with a sufficient and cognitively simple exploration solution to the problem of uncertainty.
Resistance to clothianidin reduces the efficacy of SumiShield® 50WG, a neonicotinoid formulation for indoor residual spraying, againstAnopheles gambiae
Authors: Fouet Caroline , Ashu Fred A. , Ambadiang Marilene M. , Tchapga Williams , Wondji Charles S. , Kamdem Colince 
Published: August 2020

AbstractChronic exposure of mosquito larvae to pesticide residues in agricultural areas is often associated with evolution of resistance to insecticides used for vector control. This presents a concern for the efficacy of clothianidin, an agricultural neonicotinoid qualified for Indoor Residual Spraying (IRS). Using standard bioassays, we tested if reduced susceptibility to clothianidin affects the efficacy of SumiShield® 50WG, one of the two newly approved formulations, which contains 50% clothianidin. We simultaneously monitored susceptibility to clothianidin and to SumiShield® 50WG, testing adults ofAnopheles gambiae,An. coluzziiandCulexsp collected from urban, suburban and agricultural areas of Yaoundé. We found that the level of susceptibility to the active ingredient predicted the efficacy of SumiShield® 50WG. This formulation was very potent against populations that achieved 100% mortality within 72 h of exposure to a discriminating dose of clothianidin. By contrast, mortality leveled off at 75.4 ± 3.5 % within 7 days of exposure to SumiShield® 50WG inAn. gambiaeadults collected from a farm where spraying of acetamiprid and imidacloprid is driving cross-resistance to clothianidin. These findings indicate that more potent formulations of clothianidin or different insecticides should be prioritized in areas where resistance is emerging.
Cellular barcoding of protozoan pathogens reveals the within-host population dynamics ofToxoplasma gondiihost colonization
Authors: Wincott Ceire J. , Sritharan Gayathri , Benns Henry J. , Liakath Farzana B. , Gilabert-Carbajo Carla , Bunyan Monique , Fairweather Aisling R. , Alves Eduardo , Andrew Ivan , Game Laurence , Frickel Eva M. , Tiengwe Calvin , Ewald Sarah E. , Child Matthew A. 
Published: August 2020

AbstractMolecular barcoding techniques have emerged as powerful tools to understand microbial pathogenesis. However, barcoding strategies have not been extended to protozoan parasites, which have unique genomic structures and virulence strategies compared to viral and bacterial pathogens. Here, we present a versatile CRISPR-based method to barcode protozoa, which we successfully apply toToxoplasma gondiiandTrypanosoma brucei. The murine brain is an important transmission niche forT. gondii, and brain persistence is a clinically untreatable feature of infection. The blood-brain barrier is expected to physically restrict parasite colonization of this niche, resulting in a selection bottleneck. Using libraries of barcodedT. gondiiwe evaluate shifts in the population structure from acute to chronic infection of mice. Contrary to expectation, most barcodes were present in the brain one-month post-intraperitoneal infection in both inbred CBA/J and outbred Swiss mice. Although parasite cyst number and barcode diversity declined over time, barcodes that represented a minor fraction of the inoculum could become a dominant population in the brain by three months post-infection. Together, these data establish the first, robust molecular barcoding approach for protozoa and evidence that the blood-brain barrier does not represent a major bottleneck to colonization byT. gondii.
Expression of ACE2, TMPRSS2 and CTSL in human airway epithelial cells under physiological and pathological conditions: Implications for SARS-CoV-2 infection
Authors: Yin Junping , Kasper Brigitte , Petersen Frank , Yu Xinhua 
Published: August 2020

AbstractSARS-CoV-2 enters into human airway epithelial cells via membrane fusion or endocytosis, and this process is dependent on ACE2, TMPRSS2, and cathepsin L. In this study, we examined the expression profiles of the three SARS-CoV-2 entry-related genes in primary human airway epithelial cells isolated from donors with different physiological and pathological backgrounds such as smoking, COPD, asthma, lung cancer, allergic rhinitis, cystic fibrosis, or viral infections. By reanalyzing 54 GEO datasets comprising transcriptomic data of 3428 samples, this study revealed that i) smoking is associated with an increased expression of ACE2 and TMPRSS2 and a decreased expression of cathepsin L; ii) infection of rhinovirus as well as poly(I:C) stimulation leads to high expression of all three SARS-CoV-2 entry-related genes; iii) expression of ACE2 and cathepsin L in nasal epithelial cells are decreased in patients with asthma and allergic rhinitis. In conclusion, this study implicates that infection of respiratory viruses, cigarette smoking and allergic respiratory diseases might affect the susceptibility to and the development of COVID-19.
Near-infrared Spectroscopy evaluations for rapid differentiation of carbapenem resistant Enterobacteriaceae from susceptible strains
Authors: Alharbi Bushra , Sikulu-Lord Maggy T. , Lord Anton , Zowawi Hosam M , Trembizki Ella 
Published: August 2020

AbstractAntimicrobial resistance (AMR) caused by Carbapenem-Resistant Enterobacteriaceae (CRE) is a global threat. Accurate identification of these bacterial species with associated AMR is critical for their management. While highly accurate methods to detect CRE are available, they are costly, timely and require expert skills making their application infeasible in low-resource settings. Here, we investigated the potential of Near-infrared Spectroscopy (NIRS) for a range of applications; i) the detection and differentiation of isolates of two pathogenic Enterobacteriaceae species,Klebsiella pneumoniaeandEscherichia coliand, ii) the differentiation of carbapenem resistant and susceptibleK. pneumoniae. NIRS has successfully differentiated betweenK. pneumoniaeandE. coliisolates with a predictive accuracy of 89.04% (95% CI; 88.7-89.4%).K. pneumoniaeisolates harbouring carbapenem resistance determinants were differentiated from susceptibleK. pneumoniaestrains with an accuracy of 85% (95% CI; 84.2-86.1%). To our knowledge, this is the largest demonstration of a proof of concept for the utility and feasibility of NIRS for rapidly differentiating betweenK. pneumoniaefromE.colias well as from carbapenem resistantK. pneumoniaefrom susceptible strains.
Systematic comparison of developmental GRNs explains how novelty is incorporated in early development
Authors: Cary Gregory A. , McCauley Brenna S. , Zueva Olga , Pattinato Joseph , Longabaugh William , Hinman Veronica F. 
Published: August 2020

SUMMARYThe impressive array of morphological diversity among animal taxa represents the product of millions of years of evolution. Morphology is the output of development, therefore phenotypic evolution arises from changes to the topology of the gene regulatory networks (GRNs) that control the highly coordinated process of embryogenesis1. While genetic variation can arise anywhere in the genome and affect any part of an individual GRN, the need to form a viable embryo provides a constraint on the types of variation that pass the filter of selection. A particular challenge in understanding the origins of animal diversity lies in determining how GRNs incorporate novelty while preserving the overall stability of the network, and hence, embryonic viability. Here we assemble a comprehensive GRN, consisting of 42 genes (nodes) and 84 interactions (edges), for the model of endomesoderm specification in the sea star from zygote through gastrulation that corresponds to the GRN for sea urchin development of equivalent territories and stages2. Using these detailed models we make the first systems-level comparison of early development and examine how novelty is incorporated into GRNs. We show how the GRN is resilient to the introduction of a transcription factor,pmar1, the inclusion of which leads to a switch between two stable modes of Delta-Notch signaling. Signaling pathways can function in multiple modes and we propose that GRN changes that lead to switches between modes may be a common evolutionary mechanism for changes in embryogenesis. Our data additionally proposes a model in which evolutionarily conserved network motifs, or kernels, may function throughout development to stabilize these signaling transitions.
Nerve fibers in the Tumor Microenvironment are co-localized with Tertiary Lymphoid Structures
Authors: Heij Lara R. , Tan Xiuxiang , Kather Jakob N. , Niehues Jan M. , Sivakumar Shivan , Heussen Nicole , van der Kroft Gregory , Olde Damink Steven W.M. , Lang Sven , Bednarsch Jan , Aberle Merel R. , Luedde Tom , Gaisa Nadine T. , Liu Drolaiz H.W. , Cleutjens Jack P.M. , Modest Dominik P. , Wiltberger Georg J. , Neumann Ulf P. 
Published: August 2020

ABSTRACTBackgroundB cells and tertiary lymphoid structures (TLS) are reported to be important in the improvement of survival of cancer patients. These secondary lymphoid organs have been associated with the generation of an anti-tumor response. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types and the stromal architecture shapes the intratumoral heterogeneity. The stroma of PDAC is a complex system in which crosstalk takes place between cancer-associated fibroblasts, immune cells, endothelial cells and the cancer cells. Besides immune cells and fibroblasts, there is some limited data about the influence of nerve fibers on cancer progression.Patients and methodsNerve Fiber Density (NFD) was analysed in our cohort of 188 patients with Pancreatic Ductal Adenocarcinoma who underwent pancreatic surgery. We used immunohistochemistry and multiplex imaging to phenotype the immune cell infiltrate. The cell detection classifier measured distance from immune cell to cancer gland and with a heat map we could count TLS. By using Machine learning we were able to define the spatial distribution and counting Tertiary Lymphoid Structures.ResultsHigh NFD is significantly associated with prolonged overall survival (HR 1.676 (95%CI 1.126,2.495) for low vs. high NFD, p-value 0.0109). The immune cells surrounding the nerve fibers were phenotyped in B cells, T cells and dendritic follicular cells, matching a TLS. Here we show that small nerve fibers are located at the TLS in Pancreatic Cancer and a high Nerve Fiber Density combined with more than 5 TLS is associated with a better survival (HR 0.388 (95%CI 0.218, 0.689).ConclusionThe co-localization of small nerve fibers with TLS is a new finding which has not been described before. However the precise roles of these TLS and nerve fibers remains unknown. These findings unravel future pathways and has the potential to reach new directions into already existing targeted therapy.
Reliability assessment of temporal discounting measures in virtual reality environments
Authors: Bruder Luca R. , Scharer Lisa , Peters Jan 
Published: August 2020

AbstractIn recent years the emergence of high-performance virtual reality (VR) technology has opened up new possibilities for the examination of context effects in psychological studies. The opportunity to create ecologically valid stimulation in a highly controlled lab environment is especially relevant for studies of psychiatric disorders, where it can be problematic to confront participants with certain stimuli in real life. However, before VR can be confidently applied widely it is important to establish that commonly used behavioral tasks generate reliable data within a VR surrounding. One field of research that could benefit greatly from VR-applications are studies assessing the reactivity to addiction related cues (cue-reactivity) in participants suffering from gambling disorder. Here we tested the reliability of a commonly used temporal discounting task in a novel VR set-up designed for the concurrent assessment of behavioral and psychophysiological cue-reactivity in gambling disorder. On two days, thirty-four healthy non-gambling participants explored two rich and navigable VR-environments (neutral: café vs. gambling-related: casino and sports-betting facility), while their electrodermal activity was measured using remote sensors. In addition, participants completed the temporal discounting task implemented in each VR environment. On a third day, participants performed the task in a standard lab testing context. We then used comprehensive computational modeling using both standard softmax and drift diffusion model (DDM) choice rules to assess the reliability of discounting model parameters assessed in VR. Test-retest reliability estimates were good to excellent for the discount rate log(k), whereas they were poor to moderate for additional DDM parameters. Differences in model parameters between standard lab testing and VR, reflecting reactivity to the different environments, were mostly numerically small and of inconclusive directionality. Finally, while exposure to VR generally increased tonic skin conductance, this effect was not modulated by the neutral vs. gambling-related VR-environment. Taken together this proof-of- concept study in non-gambling participants demonstrates that temporal discounting measures obtained in VR are reliable, suggesting that VR is a promising tool for applications in computational psychiatry, including studies on cue-reactivity in addiction.
Machine learning prediction and experimental validation of antigenic drift in H3 influenza A viruses in swine
Authors: Zeller Michael A. , Gauger Phillip C. , Arendsee Zebulun W. , Souza Carine K. , Vincent Amy L. , Anderson Tavis K. 
Published: August 2020

ABSTRACTThe antigenic diversity of influenza A virus (IAV) circulating in swine challenges the development of effective vaccines, increasing zoonotic threat and pandemic potential. High throughput sequencing technologies are able to quantify IAV genetic diversity, but there are no accurate approaches to adequately describe antigenic phenotypes. This study evaluated an ensemble of non-linear regression models to estimate virus phenotype from genotype. Regression models were trained with a phenotypic dataset of pairwise hemagglutination inhibition (HI) assays, using genetic sequence identity and pairwise amino acid mutations as predictor features. The model identified amino acid identity, ranked the relative importance of mutations in the hemagglutinin (HA) protein, and demonstrated good prediction accuracy. Four previously untested IAV strains were selected to experimentally validate model predictions by HI assays. Error between predicted and measured distances of uncharacterized strains were 0.34, 0.70, 2.19, and 0.17 antigenic units. These empirically trained regression models can be used to estimate antigenic distances between different strains of IAV in swine using sequence data. By ranking the importance of mutations in the HA, we provide criteria for identifying antigenically advanced IAV strains that may not be controlled by existing vaccines and can inform strain updates to vaccines to better control this pathogen.
PELP1/SRC-3-dependent regulation of metabolic kinases drives therapy resistant ER+ breast cancer
Authors: Truong Thu H. , Benner Elizabeth A. , Hagen Kyla M. , Temiz Nuri A. , Kerkvliet Carlos Perez , Wang Ying , Cortes-Sanchez Emilio , Yang Chieh-Hsiang , Pengo Thomas , Guillen Katrin P. , Welm Bryan E. , Telang Sucheta , Lange Carol A. , Ostrander Julie H. 
Published: August 2020

ABSTRACTRecurrence of metastatic breast cancer stemming from acquired endocrine and chemotherapy resistance remains a health burden for women with luminal (ER+) breast cancer. Disseminated ER+ tumor cells can remain viable but quiescent for years to decades. Contributing factors to metastatic spread include the maintenance and expansion of breast cancer stem cells (CSCs). Breast CSCs frequently exist as a minority population in therapy resistant tumors. In this study, we show that cytoplasmic complexes composed of steroid receptor (SR) co-activators, PELP1 and SRC-3, modulate breast CSC expansion through upregulation of the HIF-activated metabolic target genesPFKFB3andPFKFB4. Seahorse metabolic assays demonstrated that cytoplasmic PELP1 influences cellular metabolism by increasing both glycolysis and mitochondrial respiration. PELP1 interacts with PFKFB3 and PFKFB4 proteins, and inhibition of PFKFB3 and PFKFB4 kinase activity blocks PELP1-induced tumorspheres and protein-protein interactions with SRC-3. PFKFB4 knockdown inhibitedin vivoemergence of circulating tumor cell (CTC) populations in mammary intraductal (MIND) models. Application of PFKFB inhibitors in combination with ER targeted therapies blocked tumorsphere formation in multiple models of advanced breast cancer, including tamoxifen (TamR) and paclitaxel (TaxR) resistant models and ER+ patient-derived organoids (PDxO). Together, our data suggest that PELP1, SRC-3, and PFKFBs cooperate to drive ER+ tumor cell populations that include CSCs and CTCs.SignificanceIdentifying non-ER pharmacological targets offers a useful approach to blocking metastatic escape from standard of care ER/estrogen (E2)-targeted strategies to overcome endocrine and chemotherapy resistance.
Adipose tissue developmental growth constraints uncouple fat distribution from glucose metabolism in two mouse models of obesity
Authors: Sebo Zachary L. , Church Christopher , Berry Ryan , Rodeheffer Matthew S. 
Published: August 2020

AbstractSubcutaneous obesity is associated with better metabolic health than visceral obesity. Here, we leverage two mouse models with differing quantities of visceral and subcutaneous fat to assess the role of fat distribution in glucose homeostasis. Interestingly, we found genetic ablation of inguinal subcutaneous fat does not exacerbate obesity-associated impairments in glucose metabolism. Consistent with this observation, mutant mice that preferentially accrue subcutaneous fat display a similar metabolic profile to controls with equal fat mass. Importantly, the increased subcutaneous adiposity in these mice occurs downstream of androgen receptor deficiency and is not driven by elevated adiponectin activity. Rather, it is caused by diminished adipocyte precursor seeding in nascent visceral fat and proportionally greater growth of subcutaneous fat. Thus, the pattern of obesogenic fat mass expansion can be determined early in development without impacting glucose metabolism. This suggests that different mechanisms underlying biased fat accumulation exert different effects on glucometabolic health.
Egg size variation in the context of polyandry: a case study using long-term field data from snowy plovers
Authors: Eberhart-Hertel Luke Joseph , Falcão Rodrigues Lourenço , Krietsch Johannes , Eberhart-Hertel Anne G. , Cruz-López Medardo , Vázquez-Rojas Karina Alejandra , González-Medina Erick , Schroeder Julia , Küpper Clemens 
Published: August 2020

AbstractGamete size variationbetweenthe sexes is central to the concept of sex roles, however, to what extent gamete size variationwithinthe sexes relates to sex role variation remains unclear. Comparative and theoretical studies suggest that, when clutch size is invariable, polyandry is linked to a reduction of egg size, while increased female-female competition for mates favors early breeding when females cannot monopolize multiple males. To understand whether and how breeding phenology, egg size, and mating behavior are related at the individual level, we studied the reproductive histories of 424 snowy plover females observed in the wild over a 15-year period. Egg size, but not polyandry, were highly repeatable for individual females. Consistent with theoretical predictions, we found that polyandrous females were the earliest breeders and that early clutches contained smaller eggs than clutches initiated later. Neither egg size nor mating behavior showed clear signs of an age-related deterioration, on the contrary, prior experience acquired either through age or local recruitment enabled females to nest early. Taken together, these results suggest that gamete size variation is not linked to mating behavior at the individual level, and, consequently, the adaptive potential of such variation appears to be limited.Teaser TextComparative avian analyses have linked female polyandry and sex-role reversal to the production of smaller eggs: the notion being that smaller eggs allow polyandrous females to lay multiple sequential clutches quickly. Our research, however, has found that the notion is more complex at the individual level. We found that females who started breeding early in the season were more likely to be polyandrous and produce smaller eggs. Experience was also found to give older and locally-raised females a competitive advantage over younger and inexperienced females vying for early breeding opportunities. Despite this, we found limited evidence that egg size reduction gives a competitive advantage in the scramble for mates. Instead, seasonal variations in egg size can likely be attributed to other factors, such as the survival of early-hatching chicks, resource limitations during egg production, and individual differences. We found that senescence had little impact on egg size or mating behavior. Future research should also examine how seasonality, age, and mating behavior impact the reproductive fitness of males, who provide more parental care than females in many sex role reversed systems. By studying these effects in concert, we can gain a deeper understanding of sex roles in natural populations.