bluuebunny/crossref_metadata_2025_split huggingface dataset:
GABAergic neurons in the olfactory cortex projecting to the lateral hypothalamus in mice
Authors: Murata Koshi , Kinoshita Tomoki , Fukazawa Yugo , Kobayashi Kenta , Kobayashi Kazuto , Miyamichi Kazunari , Okuno Hiroyuki , Bito Haruhiko , Sakurai Yoshio , Yamaguchi Masahiro , Mori Kensaku , Manabe Hiroyuki 
Published: September 2018

AbstractOlfaction guides goal-directed behaviours including feeding. To investigate how central olfactory neural circuits control feeding behaviour in mice, we performed retrograde tracing from the lateral hypothalamus (LH), an important feeding centre. We observed a cluster of retrogradely labelled cells distributed in the posteroventral region of the olfactory peduncle. Histochemical analyses revealed that a majority of these retrogradely labelled projection neurons expressed glutamic acid decarboxylase 65/67 (GAD65/67), but not vesicular glutamate transporter 1 (VGluT1). We named this region with GABAergic projection neurons the ventral olfactory nucleus (VON) to discriminate it from the conventional olfactory peduncle. VON neurons were less immunoreactive for DARPP-32, a striatal neuron marker, in comparison to those in the olfactory tubercle and nucleus accumbens, which distinguished the VON from the ventral striatum. Fluorescent labelling confirmed synaptic contacts between VON neurons and olfactory bulb projection neurons. Rabies-virus-mediated trans-synaptic labelling revealed that VON neurons received synaptic inputs from the olfactory bulb, other olfactory cortices, horizontal limb of the diagonal band, and prefrontal cortex. Collectively, these results identified novel GABAergic projection neurons in the olfactory cortex that can integrate olfactory sensory and top-down inputs and send inhibitory output to the LH, which may contribute to forming odour-guided LH-related behaviours.
Role of PML-Nuclear Bodies in Human Herpesvirus 6A and 6B Genome Integration
Authors: Collin Vanessa , Gravel Annie , Kaufer Benedikt B. , Flamand Louis 
Published: September 2018

AbstractHuman herpesviruses 6A and 6B (HHV-6A/B) are two betaherpesviruses that readily integrate their genomes into the telomeres of human chromosomes. To date, the cellular or viral proteins that facilitate HHV-6A/B integration remain elusive. In the present study, we demonstrate that the immediate early protein 1 (IE1) of HHV-6A/B colocalizes with telomeres during infection. Moreover, IE1 associates with PML-NBs, a nuclear complex that regulates multiples cellular mechanism including DNA repair and antiviral responses. Furthermore, we could demonstrate that IE1 targets all PML isoforms and that both proteins colocalize at telomeres. To determine the role of PML in HHV-6A/B integration, we generated PML knockout cell lines using CRISPR/Cas9. Intriguingly, in the absence of PML, the IE1 protein could still localize to telomeres albeit less frequently. More importantly, HHV-6A/B integration was impaired in the absence of PML, indicating that it plays a role in the integration process. Taken together, we identified the first cellular protein that aids in the integration of HHV-6A/B and shed light on this targeted integration mechanism.Author summaryHuman herpesviruses type 6A and 6B are relatively common viruses whose infections can be life threatening in patients with a compromised immune system. A rather unique feature of these viruses is their ability to integrate their genome in human chromosomes. Integration takes place is a specialized region of the chromosomes known as telomeres, a region that controls cellular lifespan. To date, the mechanisms leading to HHV-6A and HHV-6B integration remain elusive. Our laboratory has identified that the IE1 protein of HHV-6A and HHV-6B target the telomeres. Moreover, we have shown that IE1 associates with a cellular protein, PML, that is responsible for the regulation of important cellular mechanisms such as the life span of cells and DNA repair. Hence, we studied the role of PML in HHV-6 integration. Our study demonstrates that in absence of PML, the HHV-6A and HHV-6B integrate 50-70% less frequently. Thus, our study unveils the first cellular protein involved in HHV-6A and HHV-6 chromosomal integration.
When one phenotype is not enough – divergent evolutionary trajectories govern venom variation in a widespread rattlesnake species
Authors: Zancolli Giulia , Calvete Juan J. , Cardwell Michael D. , Greene Harry W. , Hayes William K. , Hegarty Matthew J. , Herrmann Hans-Werner , Holycross Andrew T. , Lannutti Dominic I. , Mulley John F. , Sanz Libia , Travis Zachary D. , Whorley Joshua R. , Wüster Catharine E. , Wüster Wolfgang 
Published: September 2018

SUMMARYUnderstanding the relationship between genome, phenotypic variation, and the ecological pressures that act to maintain that variation, represents a fundamental challenge in evolutionary biology. Functional polymorphisms typically segregate in spatially isolated populations [1, 2] and/or discrete ecological conditions [3-5], whereas dissecting the evolutionary processes involved in adaptive geographic variation across a continuous spatial distribution is much more challenging [6]. Additionally, pleiotropic interactions between genes and phenotype often complicate the identification of specific genotype-phenotype links [7-8], and thus of the selective pressures acting on them. Animal venoms are ideal systems to overcome these constraints: they are complex and variable, yet easily quantifiable molecular phenotypes with a clear function and a direct link to both genome and fitness [9]. Here, we use dense and widespread population-level sampling of the Mohave rattlesnake, Crotalus scutulatus, and show that genomic structural variation at multiple loci underlies extreme geographic variation in venom composition, which is maintained despite extensive gene flow. Unexpectedly, selection for diet does not explain venom variation, contrary to the dominant paradigm of venom evolution, and neither does neutral population structure caused by past vicariance. Instead, different toxin genes correlate with distinct environmental factors, suggesting that divergent selective pressures can act on individual loci independently of their genomic proximity or co-expression patterns. Local-scale spatial heterogeneity thus appears to maintain a remarkably ancient complex of molecular phenotypes, which have been retained in populations that diverged more than 1.5-2 MYA, representing an exceptional case of long-term structural polymorphism. These results emphasize how the interplay between genomic architecture and spatial heterogeneity in selective pressures may facilitate the retention of functional polymorphisms of an adaptive phenotype.
Hormonal regulation of social ascent and temporal patterns of behavior in an African cichlid
Authors: Alward Beau A. , Hilliard Austin T. , York Ryan A. , Fernald Russell D. 
Published: September 2018

AbstractFor many species, social rank determines which individuals perform certain social behaviors and when. Higher ranking or dominant (DOM) individuals maintain status through aggressive interactions and perform courtship behaviors while non-dominant (ND) individuals do not. In some species ND individuals ascend (ASC) in social rank when the opportunity arises. Many important questions related to the mechanistic basis of social ascent remain to be answered. We probed whether androgen signaling regulates social ascent in male Astatotilapia burtoni, an African cichlid whose social hierarchy can be readily controlled in the laboratory. As expected, androgen receptor (AR) antagonism abolished reproductive behavior during social ascent. However, we discovered multiple AR-dependent—and AR-independent—temporal behavioral patterns that typify social ascent and dominance. AR antagonism in ASC males reduced the speed of behavioral performance compared to DOM males. Socially ascending males, independent of AR activation, were more likely than DOM males to follow aggressive displays with another aggressive display. Further analyses revealed differences in the sequencing of aggressive and courtship behaviors, wherein DOM males were more likely than ASC males to follow male-directed aggression with courtship displays. Strikingly, this difference was driven mostly by ASC males taking longer to transition from aggression to courtship, suggesting ASC males can perform certain DOM-typical temporal behavioral patterns. Our results indicate androgen signaling drives social ascent, but hormonal signaling and social experience shape the full suite of DOM-typical behavioral patterns.
Accurate error control in high dimensional association testing using conditional false discovery rates
Authors: Liley James , Wallace Chris 
Published: September 2018

AbstractHigh-dimensional hypothesis testing is ubiquitous in the biomedical sciences, and informative covariates may be employed to improve power. The conditional false discovery rate (cFDR) is widely-used approach suited to the setting where the covariate is a set of p-values for the equivalent hypotheses for a second trait. Although related to the Benjamini-Hochberg procedure, it does not permit any easy control of type-1 error rate, and existing methods are over-conservative. We propose a new method for type-1 error rate control based on identifying mappings from the unit square to the unit interval defined by the estimated cFDR, and splitting observations so that each map is independent of the observations it is used to test. We also propose an adjustment to the existing cFDR estimator which further improves power. We show by simulation that the new method more than doubles potential improvement in power over unconditional analyses compared to existing methods. We demonstrate our method on transcriptome-wide association studies, and show that the method can be used in an iterative way, enabling the use of multiple covariates successively. Our methods substantially improve the power and applicability of cFDR analysis.
Contribution of FEF to attentional periodicity during visual search: a TMS study
Authors: Dugué Laura , Beck Alexy Asaf , Marque Philippe , VanRullen Rufin 
Published: September 2018

AbstractVisual search, looking for a target embedded among distractors, has long been used to study attention. Current theories postulate a two-stage process in which early visual areas perform feature extraction, while higher-order regions perform attentional selection. Such a model implies iterative communication between low- and high-level regions to sequentially select candidate targets in the array, focus attention on these elements, and eventually permit target recognition. This leads to two predictions: (1) high-level, attentional regions and (2) early visual regions should both be iteratively (periodically) involved during the search. Here, we used Transcranial Magnetic Stimulation (TMS) applied over the Frontal-Eye Field (FEF), known to be involved in attentional selection, at various delays while observers performed a difficult, attentional search task. We observed a periodic pattern of interference at 7 Hz (theta) suggesting that the FEF is periodically involved during this difficult search task. We further compared this result with two previous studies (Dugué et al., 2011; 2015a) in which a similar TMS procedure was applied over the early visual cortex (V1) while observers performed the same task. This analysis revealed, for both studies, the same pattern of interference, i.e. V1 is periodically involved during this difficult search task, at the theta frequency. Together, these converging findings confirm our predictions that difficult search is supported by the periodic involvement of both low- and high-level regions, at the theta frequency.Significant statementAttention models postulate a two-stage process during visual search in which early visual regions perform feature extraction, while higher-order regions perform attentional selection, these two levels iteratively (periodically) communicating until target recognition. Using TMS, we tested whether there is a causal link between both attentional and early visual regions, and attentional search performance. We showed that a difficult, attentional search is supported by the periodic involvement of both V1 and the FEF, at the theta frequency (∼6-7 Hz). This finding support the idea that visual search tasks are processed by a hierarchical system involving periodic, iterative connections between low- and high-level regions allowing successful attentional exploration.
Oxidative stress, telomere length, and frailty in an old age population
Authors: Martínez-Ezquerro José Darío , Rodriguez-Castañeda Aleida , Ortiz-Ramirez Mauricio , Sanchez-Garcia Sergio , Rosas-Vargas Haydee , Sanchez-Arenas Rosalinda , Garcia-delaTorre Paola 
Published: September 2018

AbstractBackgroundA global aging population requires focusing on the risk factors for unhealthy aging, preventive medicine, and chronic disease management. The identification of adverse health outcomes in older adults has been addressed by the characterization of frailty as a biological syndrome. On the other hand, oxidative stress and telomere length have been suggested as biomarkers of aging.ObjectiveTo study the association of oxidative stress, telomere length, and frailty in an old age population.MethodsThis was a cross-sectional study based on 2015 data from 202 members from a cohort of older adults (n=202; gender F/M ratio: 133/69; mean age: 69.89 ± 7.39 years). Reactive oxygen species (ROS) were measured by dichlorofluorescin diacetate, and lipid peroxidation by malondialdehyde. Telomere length was determined using qPCR with SYBR Green Master Mix.ResultsStatistical analysis showed an association between telomere length and frailty but no association between oxidative stress on telomere length or frailty.ConclusionsTelomere length could eventually be used as a marker to discriminate between healthy and unhealthy aging as expressed by frailty phenotype. However, oxidative stress seems as just a biological process of aging.
Biological variation in the sizes, shapes and locations of visual cortical areas in the mouse
Authors: Waters Jack , Lee Eric , Gaudreault Nathalie , Griffin Fiona , Lecoq Jerome , Slaughterbeck Cliff , Sullivan David , Farrell Colin , Perkins Jed , Reid David , Feng David , Graddis Nile , Garrett Marina , Li Yang , Long Fuhui , Mochizuki Chris , Roll Kate , Zhuang Jun , Thompson Carol 
Published: September 2018

ABSTRACTVisual cortex is organized into discrete sub-regions or areas that are arranged into a hierarchy and serve different functions in the processing of visual information. In our previous work, we noted that retinotopic maps of cortical visual areas differed between mice, but did not quantify these differences or determine the relative contributions of biological variation and measurement noise. Here we quantify the biological variation in the size, shape and locations of 11 visual areas in the mouse. We find that there is substantial biological variation in the sizes of visual areas, with some visual areas varying in size by two-fold across the population of mice.
Stable Carbon Isotopes in Zea mays
Authors: Twohey Robert J. , Roberts Lucas M. , Studer Anthony J. 
Published: September 2018

SummaryThe increasing demand for food production and predicted climate change scenarios highlight the need for improvements in crop sustainability. The efficient use of water will become increasingly important for rainfed agricultural crops even in fertile regions that have historically received ample precipitation. Improvements in water-use efficiency in Zea mays have been limited, and warrants a renewed effort aided by molecular breeding approaches. Progress has been constrained by the difficulty of measuring water-use in a field environment. The stable carbon isotope composition (δ13C) of the leaf has been proposed as an integrated signature of carbon fixation with a link to stomatal conductance. However, additional factors affecting leaf δ13C exist, and a limited number of studies have explored this trait in Z. mays. Here we present an extensive characterization of leaf δ13C in Z. mays. Significant variation in leaf δ13C exists across diverse lines of Z. mays, which we show to be heritable across several environments.Furthermore, we examine temporal and spatial variation in leaf δ13C to determine the optimum sampling time to maximize the use of leaf δ13C as a trait. Finally, our results demonstrate the relationship between transpiration and leaf δ13C in the field and the greenhouse. Decreasing transpiration and soil moisture are associated with decreasing leaf δ13C. Taken together these results outline a strategy for using leaf δ13C and reveal its usefulness as a measure of transpiration efficiency under well-watered conditions rather than a predictor of performance under drought.Significance StatementThis study identifies sources of variation in stable carbon isotopes of maize leaves and establishes the framework for connecting leaf δ13C and transpiration efficiency.
Unsupervised Learning of Persistent and Sequential Activity
Authors: Pereira Ulises , Brunel Nicolas 
Published: September 2018

AbstractTwo strikingly distinct types of activity have been observed in various brain structures during delay periods of delayed response tasks: Persistent activity (PA), in which a sub-population of neurons maintains an elevated firing rate throughout an entire delay period; and Sequential activity (SA), in which sub-populations of neurons are activated sequentially in time. It has been hypothesized that both types of dynamics can be ‘learned’ by the relevant networks from the statistics of their inputs, thanks to mechanisms of synaptic plasticity. However, the necessary conditions for a synaptic plasticity rule and input statistics to learn these two types of dynamics in a stable fashion are still unclear. In particular, it is unclear whether a single learning rule is able to learn both types of activity patterns, depending on the statistics of the inputs driving the network. Here, we first characterize the complete bifurcation diagram of a firing rate model of multiple excitatory populations with an inhibitory mechanism, as a function of the parameters characterizing its connectivity. We then investigate how an unsupervised temporally asymmetric Hebbian plasticity rule shapes the dynamics of the network. Consistent with previous studies, we find that for stable learning of PA and SA, an additional stabilization mechanism, such as multiplicative homeostatic plasticity, is necessary. Using the bifurcation diagram derived for fixed connectivity, we study analytically the temporal evolution and the steady state of the learned recurrent architecture as a function of parameters characterizing the external inputs. Slow changing stimuli lead to PA, while fast changing stimuli lead to SA. Our network model shows how a network with plastic synapses can stably and flexibly learn PA and SA in an unsupervised manner.
Fate Before Function: Specification of the Hair Follicle Niche Occurs Prior to its Formation and Is Progenitor Dependent
Authors: Mok Ka-Wai , Saxena Nivedita , Heitman Nicholas , Grisanti Laura , Srivastava Devika , Muraro Mauro , Jacob Tina , Sennett Rachel , Wang Zichen , Su Yutao , Yang Lu M. , Ma’ayan Avi , Ornitz David M. , Kasper Maria , Rendl Michael 
Published: September 2018

SUMMARYCell fate transitions are essential for specialization of stem cells and their niches, but the precise timing and sequence of molecular events during embryonic development are largely unknown. Here, we show that dermal condensates (DC), signaling niches for epithelial progenitors in hair placodes, are specified before niche formation and function. With 3D/4D microscopy we identify unclustered DC precursors. With population-based and single-cell transcriptomics we define a molecular time-lapse of dynamic niche signatures and the developmental trajectory as the DC lineage emerges from fibroblasts. Co-expression of downregulated fibroblast and upregulated DC genes in niche precursors reveals a transitory molecular state following a proliferation shutdown. Waves of transcription factor and signaling molecule expression then consolidate DC niche formation. Finally, ablation of epidermal Wnt signaling and placode-derived FGF20 demonstrates their requirement for DC-precursor specification. These findings uncover a progenitor-dependent niche precursor fate and the transitory molecular events controlling niche formation and function.Graphical AbstractHIGHLIGHTSPrecursors of the hair follicle niche are specified before niche cluster formationBulk/single cell RNA-seq defines early niche fate at molecular transitional stateSuccessive waves of transcription factor/signaling genes mark niche fate acquisitionNiche fate acquisition is not “pre-programmed” and requires FGF20 from progenitors
Bioinformatics workflows for genomic analysis of tumors from Patient Derived Xenografts (PDX): challenges and guidelines
Authors: Woo Xing Yi , Srivastava Anuj , Graber Joel H. , Yadav Vinod , Sarsani Vishal Kumar , Simons Al , Beane Glen , Grubb Stephen , Ananda Guruprasad , Liu Rangjiao , Stafford Grace , Chuang Jeffrey H. , Airhart Susan D. , Karuturi R. Krishna Murthy , George Joshy , Bult Carol J. 
Published: September 2018

AbstractBioinformatics workflows for analyzing genomic data obtained from xenografted tumor (e.g., human tumors engrafted in a mouse host) must address several challenges, including separating mouse and human sequence reads and accurate identification of somatic mutations and copy number aberrations when paired normal DNA from the patient is not available. We report here data analysis workflows that address these challenges and result in reliable identification of somatic mutations, copy number alterations, and transcriptomic profiles of tumors from patient derived xenograft models. We validated our analytical approaches using simulated data and by assessing concordance of the genomic properties of xenograft tumors with data from primary human tumors in The Cancer Genome Atlas (TCGA). The commands and parameters for the workflows are available at https://github.com/TheJacksonLaboratory/PDX-Analysis-Workflows.
A multidrug resistant clinical P. aeruginosa isolate in the MLST550 clonal complex: uncoupled quorum sensing modulates the interplay of virulence and resistance
Authors: Cao Huiluo , Xia Tingying , Li Yanran , Xu Zeling , Bougouffa Salim , Lo Yat Kei , Bajic Vladimir B. , Luo Haiwei , Woo Patrick C.Y. , Yan Aixin 
Published: September 2018

AbstractPseudomonas aeruginosa is a prevalent and pernicious pathogen equipped with both extraordinary capabilities to infect the host and to develop antimicrobials resistance (AMR). Monitoring the emergence of AMR high risk clones and understanding the interplay of their pathogenicity and antibiotic resistance is of paramount importance to avoid resistance dissemination and to control P. aeruginosa infections. In this study, we report the identification of a multidrug resistant (MDR) P. aeruginosa strain PA154197 isolated from a blood stream infection in Hong Kong. PA154197 belongs to a distinctive MLST550 clonal complex shared by two international P. aeruginosa isolates VW0289 and AUS544. Comparative genome and transcriptome analysis with the reference strain PAO1 led to the identification of a variety of genetic variations in antibiotic resistance genes and the hyper-expression of three multidrug efflux pumps MexAB-OprM, MexEF-OprN, and MexGHI-OpmD in PA154197. Unlike many resistant isolates displaying an attenuated virulence, PA154197 produces a significantly high level of the P. aeruginosa major virulence factor pyocyanin (PYO) and displays an uncompromised virulence compared to PAO1. Further analysis revealed that the secondary quorum sensing system Pqs which primarily controls the PYO production is hyper-active in PA154197 independent of the master QS systems Las and Rhl. Together, these investigations disclose a unique, uncoupled QS mediated pathoadaptation mechanism in clinical P. aeruginosa which may account for the high pathogenic potentials and antibiotics resistance in the MDR isolate PA154197.