bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recent genetic and functional insights in autism spectrum disorder
Authors: Nakanishi Moe , Anderson Matthew P. , Takumi Toru 
Published: May 2019

Purpose of review
Recent advances in genetic technologies allowed researchers to identify large numbers of candidate risk genes associated with autism spectrum disorder (ASD). Both strongly penetrant rare variants and the accumulation of common variants with much weaker penetrance contribute to the cause of ASD. To identify the highly confident candidate genes, software and resources have been applied, and functional evaluation of the variants has provided further insights for ASD pathophysiology. These studies ultimately identify the molecular and circuit alteration underlying the behavioral abnormalities in ASD. In this review, we introduce the recent genetic and genomic findings and functional approaches for ASD variants providing a deeper understanding of the etiology of ASD.

Recent findings
Integrated meta-analysis that recruited a larger number of ASD cases has helped to prioritize ASD candidate genes or genetic loci into highly confidence candidate genes for further investigation. Not only coding but also noncoding variants have been recently implicated to confer the risk of ASD. Functional approaches of genes or variants revealed the disruption of specific molecular pathways. Further studies combining ASD genetics and genomics with recent techniques in engineered mouse models show molecular and circuit mechanisms underlying the behavioral deficits in ASD.

Summary
Advances in ASD genetics and the following functional studies provide significant insights into ASD pathophysiology at molecular and circuit levels.
Dynamical decoration of stabilized-microtubules by tau-proteins
Authors: Hervy Jordan , Bicout Dominique J. 
Published: May 2019

AbstractTau is a microtubule-associated protein that regulates axonal transport, stabilizes and spatially organizes microtubules in parallel networks. The Tau-microtubule pair is crucial for maintaining the architecture and integrity of axons. Therefore, it is essential to understand how these two entities interact to ensure and modulate the normal axonal functions. Based on evidence from several published experiments, we have developed a two-dimensional model that describes the interaction between a population of Tau proteins and a stabilized microtubule at the scale of the tubulin dimers (binding sites) as an adsorption-desorption dynamical process in which Tau can bind on the microtubule outer surface via two distinct modes: a longitudinal (along a protofilament) and lateral (across adjacent protofilaments) modes. Such a process yields a dynamical distribution of Tau molecules on the microtubule surface referred to asmicrotubule decorationthat we have characterized at the equilibrium using two observables: the total microtubule coverage (density of the Taus on the microtubule surface) and the nearest neighbor distribution of Tau. Using both analytical and numerical approaches, we have derived expressions and computed these observables as a function of key parameters controlling the binding reaction: the stoichiometries of the Taus in the two binding modes, the binding equilibrium constants and the ratio of the Tau concentration to that of microtubule tubulin dimers.
Time elapsed between choices in a probabilistic task correlates with repeating the same decision
Authors: Jabłońska Judyta , Szumiec Łukasz , Zieliński Piotr , Parkitna Jan Rodriguez 
Published: May 2019

AbstractReinforcement learning causes an action that yields a positive outcome more likely to be taken in the future. Here, we investigate how the time elapsed from an action affects subsequent decisions. Groups of C57BL6/J mice were housed in IntelliCages with access to water and chowad libitum; they also had access to bottles with a reward: saccharin solution, alcohol or a mixture of the two. The probability of receiving a reward in two of the cage corners changed between 0.9 and 0.3 every 48 h over a period of ~33 days. As expected, in most animals, the odds of repeating a corner choice were increased if that choice was previously rewarded. Interestingly, the time elapsed from the previous choice also influenced the probability of repeating the choice, and this effect was independent of previous outcome. Behavioral data were fitted to a series of reinforcement learning models. Best fits were achieved when the reward prediction update was coupled with separate learning rates from positive and negative outcomes and additionally a “fictitious” update of the expected value of the nonselected choice. Additional inclusion of a time-dependent decay of the expected values improved the fit marginally in some cases.
Three-dimensional connectivity and chromatin environment mediate the activation efficiency of mammalian DNA replication origins
Authors: Jodkowska Karolina , Pancaldi Vera , Almeida Ricardo , Rigau Maria , Graña-Castro Osvaldo , Fernández-Justel José M. , Rodríguez-Acebes Sara , Rubio-Camarillo Miriam , Carrillo-de Santa Pau Enrique , Pisano David , Al-Shahrour Fátima , Valencia Alfonso , Gómez María , Méndez Juan 
Published: May 2019

ABSTRACTIn mammalian cells, chromosomal replication starts at thousands of origins at which replisomes are assembled and bidirectional DNA synthesis is established. The slowdown of DNA polymerases at endogenous or exogenous obstacles triggers the activation of additional ‘dormant’ origins whose genomic positions and regulation are not well understood. Here we report a comparative study of origin activity in mouse embryonic stem cells growing in control conditions or in the presence of mild replication stress. While stress-responsive origins can be identified, we find that the majority of them are also active, albeit with lower frequency, in the control population. To gain insights into the molecular and structural determinants of origin efficiency, we have analyzed the genetic and epigenetic features of origins stratified according to their frequency of activation. We have also integrated the linear origin maps into three-dimensional (3D) chromatin interaction networks, revealing a hierarchical organization in which clusters of connected origins are brought together by longer-range chromatin contacts. Origin efficiency is proportional to the number of connections established with other origin-containing fragments. Interacting origins tend to be activated with similar efficiency and share their timing of replication even when located in different topologically associated domains. Our results are consistent with a model in which clusters of origins are arranged in 3D in replication factories. Within each factory, ‘main’ and ‘dormant’ origins are functionally defined by a combination of chromatin environment and 3D connectivity.
Emergence of an invariant representation of texture in primate somatosensory cortex
Authors: Lieber Justin D. , Bensmaia Sliman J. 
Published: May 2019

ABSTRACTA major function of sensory processing is to achieve neural representations of objects that are stable across changes in context and perspective. Small changes in exploratory behavior can lead to large changes in signals at the sensory periphery, thus resulting in ambiguous neural representations of objects. Overcoming this ambiguity is a hallmark of human object recognition across sensory modalities. Here, we investigate how the perception of tactile texture remains stable across exploratory movements of the hand, including changes in scanning speed, despite the concomitant changes in afferent responses. To this end, we scanned a wide range of everyday textures across the fingertips of Rhesus macaques at multiple speeds and recorded the responses evoked in tactile nerve fibers and somatosensory cortical neurons. We found that individual cortical neurons exhibit a wider range of speed-sensitivities than do nerve fibers. The resulting representations of speed and texture in cortex are more independent than are their counterparts in the nerve and account for speed-invariant perception of texture. We demonstrate that this separation of speed and texture information is a natural consequence of previously described cortical computations.
Epigenetic regulation underlying Plasmodium berghei gene expression during its developmental transition from host to vector
Authors: Witmer Kathrin , Fraschka Sabine AK , Vlachou Dina , Bártfai Richárd , Christophides George K 
Published: May 2019

ABSTRACTEpigenetic regulation of gene expression is an important attribute in the survival and adaptation of the malaria parasite Plasmodium in its human host. Our understanding of epigenetic regulation of gene expression in Plasmodium developmental stages beyond asexual replication in the mammalian host is sparse. We used chromatin immune-precipitation (ChIP) and RNA sequencing to create an epigenetic and transcriptomic map of the murine parasite Plasmodium berghei development from asexual blood stages to male and female gametocytes, and finally, to ookinetes. We show that heterochromatin 1 (HP1) almost exclusively associates with variantly expressed gene families at subtelomeric regions and remains stable across stages and various parasite lines. Variant expression based on heterochromatic silencing is observed only in very few genes. In contrast, the active histone mark histone 3 Lysine 9 acetylation (H3K9ac) is found between heterochromatin boundaries and occurs as a sharp peak around the start codon for ribosomal protein genes. H3K9ac occupancy positively correlates with gene transcripts in asexual blood stages, male gametocytes and ookinetes. Interestingly, H3K9ac occupancy does not correlate with transcript abundance in female gametocytes. Finally, we identify novel DNA motifs upstream of ookinete-specific genes thought to be involved in transcriptional activation upon fertilization.
Frontal eye field inactivation alters the readout of superior colliculus activity for saccade generation in a task-dependent manner
Authors: Peel Tyler R. , Dash Suryadeep , Lomber Stephen G. , Corneil Brian D. 
Published: May 2019

AbstractSaccades require a spatiotemporal transformation of activity between the intermediate layers of the superior colliculus (iSC) and downstream brainstem burst generator. The dynamic linear ensemble-coding model (Goossens and Van Opstal, 2006) proposes that each iSC spike contributes a fixed mini-vector to saccade displacement. Although biologically-plausible, this model assumes cortical areas like the frontal eye fields (FEF) simply provide the saccadic goal to be executed by the iSC and brainstem burst generator. However, the FEF and iSC operate in unison during saccades, and a pathway from the FEF to the brainstem burst generator that bypasses the iSC exists. Here, we investigate the impact of large yet reversible inactivation of the FEF on iSC activity in the context of the model across four saccade tasks. We exploit the overlap of saccade vectors generated when the FEF is inactivated or not, comparing the number of iSC spikes for metrically-matched saccades. We found that the iSC emits fewer spikes for metrically-matched saccades during FEF inactivation. The decrease in spike count is task-dependent, with a greater decrease accompanying more cognitively-demanding saccades. Our results show that FEF integrity influences the readout of iSC activity in a task-dependent manner. We propose that the dynamic linear ensemble-coding model be modified so that FEF inactivation increases the gain of a readout parameter, effectively increasing the influence of a single iSC spike. We speculate that this modification could be instantiated by a direct pathway from the FEF to the omnipause region that modulates the excitability of the brainstem burst generator.Significance statementOne of the enduring puzzles in the oculomotor system is how it achieves the spatiotemporal transformation, converting spatial activity within the intermediate layers of the superior colliculus (iSC) into a rate code within the brainstem burst generator. The spatiotemporal transformation has traditionally been viewed as the purview of the oculomotor brainstem. Here, within the context of testing a biologically-plausible model of the spatiotemporal transformation, we show that reversible inactivation of the frontal eye fields (FEF) decreases the number of spikes issued by the iSC for metrically-matched saccades, with greater decreases accompanying more cognitively-demanding tasks. These results show that signals from the FEF influence the spatiotemporal transformation.
Age-dependent sexual dimorphism in the adult human gut microbiota
Authors: Zhang Xiuying , Zhong Huanzi , Li Yufeng , Shi Zhun , Zhang Zhe , Zhou Xianghai , Ren Huahui , Tang Shanmei , Han Xueyao , Lin Yuxiang , Wang Dan , Yang Fangming , Fang Chao , Fu Zuodi , Wang Lianying , Zhu Shida , Hou Yong , Xu Xun , Yang Huanming , Wang Jian , Kristiansen Karsten , Li Junhua , Ji Linong 
Published: May 2019

AbstractA decade of studies has established the importance of the gut microbiome in human health. In spite of sex differences in the physiology, lifespan, and prevalence of many age-associated diseases, sex and age disparities in the gut microbiota have been little studied. Here we show age-related sex differences in the adult gut microbial composition and functionality in two community-based cohorts from Northern China and the Netherlands. Consistently, women harbour a more diverse and stable microbial community across broad age ranges, whereas men exhibit a more variable gut microbiota strongly correlated with age. Reflecting the sex-biased age-gut microbiota interaction patterns, sex differences observed in younger adults are considerably reduced in the elderly population. Our findings highlight the age- and sex-biased differences in the adult gut microbiota across two ethnic population and emphasize the need for considering age and sex in studies of the human gut microbiota.
Behaviour, biology, and evolution of vocal learning in bats
Authors: Vernes Sonja C. , Wilkinson Gerald S. 
Published: May 2019

SummaryThe comparative approach can provide insight into the evolution of human speech, language, and social communication by studying relevant traits in animal systems. Bats are emerging as a model system with great potential to shed light on these processes given their learned vocalisations, close social interactions, and mammalian brains and physiology. A recent framework outlined the multiple levels of investigation needed to understand vocal learning across a broad range of non-human species including cetaceans, pinnipeds, elephants, birds and bats. Herein we apply this framework to the current state of the art in bat research. This encompasses our understanding of the abilities bats have displayed for vocal learning, what is known about the timing and social structure needed for such learning, and current knowledge about the prevalence of the trait across the order. It also addresses the biology (vocal tract morphology, neurobiology, and genetics) and phylogenetics of this trait. We conclude by highlighting some key questions that should be answered to advance our understanding of the biological encoding and evolution of speech and spoken communication.
Microclimatic effects on alpine plant and flower visitor communities and their interactions
Authors: Ohler Lisa-Maria , Lechleitner Martin , Junker Robert R. 
Published: May 2019

AbstractHigh-alpine ecosystems are commonly assumed to be particularly endangered by climate warming. Recent research, however, suggests that the heterogeneous topography of alpine landscapes provide microclimatic niches for alpine plants, which may buffer negative effects. Whether the microclimatic heterogeneity also affects higher trophic levels remains unknown. This study shows that the variation in mean seasonal soil temperature within a single alpine pasture is within the same range as in plots differing in nearly 500 m in elevation. This pronounced heterogeneity affected the spatial distribution of plant cover, richness of flowering plant species and plant species composition. These microclimatic effects on plant communities also affected richness of flower visiting insects and the frequency and structure of plant-insect interactions suggesting an effect of microclimate also on higher trophic levels. Our results may stimulate a re-evaluation of the consequences of climate warming on ecosystems that may compensate warming by microclimatic refuges.
Phasic Dopamine Release Magnitude Tracks Individual Differences in Sensitization of Locomotor Response following a History of Nicotine Exposure
Authors: Fennell Ashley M. , Pitts Elizabeth G. , Sexton Lacey L. , Ferris Mark J. 
Published: May 2019

AbstractSmoking remains the primary cause of preventable death in the United States and smoking related illness costs more than $300 billion annually. Nicotine (the primary reinforcer in cigarettes) causes changes in behavior and neurochemistry that lead to increased probability of relapse. Given the role of mesolimbic dopamine projections in motivation, substance use disorder, and drug relapse, we examined the effect of repeated nicotine on rapid dopamine signals in the nucleus accumbens (NAc) of rats. Adult, male Sprague-Dawley rats were exposed to nicotine (0.2 or 0.4 mg/kg, subcutaneous) once daily for 7 days. On day 8, dopamine release and uptake dynamics, and their modulation by nicotinic receptor agonists and antagonists, were assessed using fast scan cyclic voltammetry in the NAc core. Nicotine exposure decreased electrically-stimulated dopamine release across a range of stimulation frequencies and decreased α6β2-containing nicotinic receptor control over dopamine release. Additionally, nicotine locomotor sensitization correlated with accumbal dopamine modulation by nicotine and mecamylamine. Taken together, our study suggests that repeated exposure to nicotine blunts dopamine release in the NAc core through changes in α6β2 modulation of dopamine release and individual differences in the sensitivity to this outcome may predict variation in behavioral models of vulnerability to substance use disorder.
Does the margin of stability measure predict stability of gait with a constrained base of support?
Authors: Gill Lakshdeep , Huntley Andrew H. , Mansfield Avril 
Published: May 2019

ABSTRACTThis study aimed to determine the validity of the centre of mass position (COM) position and extrapolated COM (XCOM), relative to the base of support, for predicting stability during a walking task where the base of support is constrained. Nine young healthy participants walked on a narrow beam. Three-dimensional motion capture was used to calculate the COM and XCOM relative to the base of support. Steps were classified as having either the COM or XCOM inside or outside the base of support, and were classified as successful (stable – foot placed on the beam) or failed (unstable – foot stepped off the beam). If the COM or XCOM are valid measures of stability, they should be within the base of support for successful steps and outside the base of support for failed steps. Classifying the COM and XCOM inside or outside the base of support correctly predicted successful or failed steps in 69% and 58% of cases, respectively. When the COM or XCOM were outside the base of support, walking faster seemed to help participants to maintain stability. The further the COM or XCOM were outside the base of support during a successful step, the more likely participants were to fail on a subsequent step. The results of this study suggest that both COM and XCOM are valid measures of stability during a beam walking task, but that classifying COM and XCOM as inside or outside the base of support may be over-simplistic.
Parallel and nonparallel genomic responses contribute to herbicide resistance inIpomoea purpurea, a common agricultural weed
Authors: Van Etten Megan , Lee Kristin M. , Chang Shu-Mei , Baucom Regina S. 
Published: May 2019

AbstractThe repeated evolution of herbicide resistance has been cited as an example of genetic parallelism, wherein separate species or genetic lineages utilize the same genetic solution in response to selection. However, most studies that investigate the genetic basis of herbicide resistance examine the potential for changes in the protein targeted by the herbicide rather than considering genome-wide changes. We used a population genomics screen and targeted exome re-sequencing to uncover the potential genetic basis of glyphosate resistance in the common morning glory,Ipomoea purpurea, and to determine if genetic parallelism underlies the repeated evolution of resistance across replicate resistant populations. We found no evidence for changes in 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), glyphosate’s target protein, that were associated with resistance, and instead identified five genomic regions that show evidence of selection. Within these regions, genes involved in herbicide detoxification--cytochrome P450s, ABC transporters, and glycosyltransferases--are enriched and exhibit signs of selective sweeps. One region under selection shows parallel changes across all assayed resistant populations whereas other regions exhibit signs of divergence. Thus, while it appears likely that the physiological mechanism of resistance in this species is likely the same among resistant populations, we find patterns of both similar and divergent selection across separate resistant populations at particular loci.
Modification of primary amines to higher order amines reduces in vivo hematological and immunotoxicity of cationic nanocarriers through TLR4 and complement pathways
Authors: Toy Randall , Pradhan Pallab , Ramesh Vijayeetha , Di Paolo Nelson C. , Lash Blake , Liu Jiaying , Blanchard Emmeline L. , Santangelo Philip J. , Shayakhmetov Dmitry M. , Roy Krishnendu 
Published: May 2019

ABSTRACTFor decades, cationic polymer nanoparticles have been investigated for nucleic acid delivery. Despite promising in vitro transfection results, most formulations have failed to translate into the clinic due to significantin vivotoxicity – especially when delivered intravenously. To address this significant problem, we investigated the detailed mechanisms that govern the complexin vivosystemic toxicity response to common polymeric nanoparticles. We determined that the toxicity response is material dependent. For branched polyethylenimine (bPEI) nanoparticles – toxicity is a function of multiple pathophysiological responses – triggering of innate immune sensors, induction of hepatic toxicity, and significant alteration of hematological properties. In contrast, for chitosan-based nanoparticles – systemic toxicity is primarily driven through innate immune activation. We further identified that modification of primary amines to secondary and tertiary amines using the small molecule imidazole-acetic-acid (IAA) amelioratesin vivotoxicity from both nanocarriers by different, material-specific mechanisms related to Toll-like receptor 4 activation (for bPEI) and complement activation driven neutrophil infiltration (for chitosan), respectively. Our results provide a detailed roadmap for evaluatingin vivotoxicity of nanocarriers and identifies potential opportunities to reduce toxicity for eventual clinical translation.Graphical Abstract