bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individual, but not population asymmetries, are modulated by social environment and genotype inDrosophila melanogaster
Authors: Versace Elisabetta , Caffini Matteo , Werkhoven Zach , de Bivort Benjamin L. 
Published: July 2019

AbstractTheory predicts that social interactions can induce an alignment of behavioral asymmetries between individuals (i.e., population-level lateralization), but evidence for this effect is mixed. To understand how interaction with other individuals affects behavioral asymmetries, we systematically manipulated the social environment ofDrosophila melanogaster, testing individual flies and dyads (female-male, female-female and male-male pairs). In these social contexts we measured individual and population asymmetries in individual behaviors (circling asymmetry, wing use) and dyadic behaviors (relative position and orientation between two flies) in five different genotypes. We reasoned that if coordination between individuals drives alignment of behavioral asymmetries, greater alignment at the population-level should be observed in social contexts compared to solitary individuals. We observed that the presence of other individuals influenced the behavior and position of flies but had unexpected effects with respect to individual and population asymmetries: individual-level asymmetries were strong and modulated by the social context but population-level asymmetries were mild or absent. Moreover, the strength of individual-level asymmetries differed between strains, but this was not the case for population-level asymmetries. These findings suggest that the degree of social interaction found in Drosophila is insufficient to drive population-level behavioral asymmetries.
Decoding WW Domain Tandem-mediated Target Recognitions in Tissue Growth and Cell Polarity
Authors: Lin Zhijie , Yang Zhou , Xie Ruiling , Ji Zeyang , Guan Kunliang , Zhang Mingjie 
Published: July 2019

SummaryWW domain tandem-containing proteins such as KIBRA, YAP, and MAGI play critical roles in cell growth and polarity via binding to and positioning target proteins in specific subcellular regions. An immense disparity exists between promiscuity of WW domain-mediated target bindings and specific roles of WW domain scaffold proteins in cell growth regulation. Here, we discovered that WW domain tandems of KIBRA and MAGI, but not YAP, bind to specific target proteins with extremely high affinity and exquisite specificity. Via systematic structural biology and biochemistry approaches, we decoded the target binding rules of WW domain tandems from cell growth regulatory proteins and uncovered a list of previously unknown WW tandem binding proteins such as β-Dystroglycan, JCAD, and PTPN21. The WW tandem-mediated target recognition mechanisms elucidated here can guide functional studies of WW domain proteins in cell growth and polarity as well as in other cellular processes including neuronal synaptic signaling.
Oxytocin increases after affiliative interactions in male Barbary macaques
Authors: Rincon Alan V. , Deschner Tobias , Schülke Oliver , Ostner Julia 
Published: July 2019

AbstractMammals living in stable social groups often mitigate the costs of group living through the formation of social bonds and cooperative relationships. The neuropeptide hormone oxytocin (OT) has been proposed to promote both bonding and cooperation although only a limited number of studies have investigated this under natural conditions. Our aim was to assess the role of OT in bonding and cooperation in male Barbary macaques (Macaca sylvanus). First we tested for an effect of affiliation - grooming and triadic male-infant-male interactions - with bond and non-bond partners on urinary OT levels. Secondly we aimed to test whether grooming interactions (and thus increased OT levels) increase a male’s general propensity to cooperate in polyadic conflicts. We collected behavioral data via full-day focal animal protocols on 14 adult males and measured endogenous OT levels from 139 urine samples collected after affiliation and non-social control periods. Urinary OT levels were higher after grooming with any partner. By contrast, OT levels after male-infant-male interactions with any partner or with bond partners were not different from controls but were higher after interactions with non-bond partners. Previous grooming did not increase the likelihood of males to support others in conflicts. Collectively, our results support research indicating that OT is involved in the regulation of adult social bonds, including in non-reproductive contexts. However, our male-infant-male interaction results go against previous studies suggesting that it is affiliation with bond rather than non-bond partners that trigger the release of OT. Alternatively, OT levels may have been elevated prior to male-infant-male interactions thus facilitating interaction between non-bond partners. The lack of an association of grooming (and by extension increased OT levels) and subsequent support speaks against an OT linked increase in the general propensity to cooperate, yet further studies are needed for a more direct test including the possibility of partner-specific contingent cooperation.
Targeted cancer cell killing by highly selective miRNA-triggered activation of a prokaryotic toxin-antitoxin system
Authors: Turnbull Alice , Bermejo-Rodríguez Camino , Preston Mark A. , Garrido-Barros María , Pimentel Belén , de la Cueva-Méndez Guillermo 
Published: July 2019

AbstractAlthough not evolved to function in eukaryotes, prokaryotic toxin Kid induces apoptosis in human cells, and this is avoided by co-expression of its neutralizing antitoxin, Kis. Inspired by the way Kid becomes active in bacterial cells we had previously engineered a synthetic toxin-antitoxin system bearing a Kis protein variant that is selectively degraded in cells expressing viral oncoprotein E6, thus achieving highly selective killing of cancer cells transformed by human papillomavirus. Here we aimed to broaden the type of oncogenic insults, and therefore of cancer cells, that can be targeted using this approach. We show that appropriate linkage of the kis gene to a single, fully complementary, target site for an oncogenic human microRNA enables the construction of a synthetic toxin-antitoxin pair that selectively kills cancer cells overexpressing that particular microRNA. Importantly, the resulting system spares non-targeted cells from collateral damage, even when they overexpress highly homologous, though non-targeted, microRNAs.
Nestin selectively facilitates the phosphorylation of the Lissencephaly-linked protein doublecortin (DCX) by cdk5/p35 to regulate growth cone morphology and Sema3a sensitivity in developing neurons
Authors: Bott Christopher J. , McMahon Lloyd P. , Keil Jason M. , Yap Chan Choo , Kwan Kenneth Y. , Winckler Bettina 
Published: July 2019

AbstractNestin, an intermediate filament protein widely used as a marker of neural progenitors, was recently found to be expressed transiently in developing cortical neurons in culture and in developing mouse cortex. In young cortical cultures, nestin regulates axonal growth cone morphology. In addition, nestin, which is known to bind the neuronal cdk5/p35 kinase, affects responses to axon guidance cues upstream of cdk5, specifically, to Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, and changes in microtubules and actin filaments are well studied. In contrast, the roles of intermediate filament proteins in this process are poorly understood, even in cultured neurons. Here, we investigate the molecular mechanism by which nestin affects growth cone morphology and Sema3a sensitivity. We find that nestin selectively facilitates the phosphorylation of the lissencephaly-linked protein doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected by nestin. We uncover that this substrate selectivity is based on the ability of nestin to interact with DCX, but not with other cdk5 substrates. Nestin thus creates a selective scaffold for DCX with activated cdk5/p35. Lastly, we use cortical cultures derived from DCX knockout mice to show that the effects of nestin on growth cone morphology and on Sema3a sensitivity are DCX-dependent, thus suggesting a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating the intracellular kinase signaling environment in developing neurons. The sex of animal subjects is unknown.Significance StatementNestin, an intermediate filament protein highly expressed in neural progenitors, was recently identified in developing neurons where it regulates growth cone morphology and responsiveness to the guidance cue Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, but the roles of intermediate filaments in this process are poorly understood. We now report that nestin selectively facilitates phosphorylation of the lissencephaly-linked doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected. This substrate selectivity is based on preferential scaffolding of DCX, cdk5, and p35 by nestin. Additionally, we demonstrate a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating intracellular kinase signaling in developing neurons.
Integrative genomics approach identifies conserved transcriptomic networks in Alzheimer’s disease
Authors: Morabito Samuel , Miyoshi Emily , Michael Neethu , Swarup Vivek 
Published: July 2019

AbstractAlzheimer’s disease (AD) is a devastating neurological disorder characterized by changes in cell-type proportions and consequently marked alterations of the transcriptome. Here we use a data-driven systems biology approach across multiple cohorts of human AD, encompassing different brain regions, and integrate with multi-scale datasets comprising of DNA methylation, histone acetylation, transcriptome- and genome-wide association studies as well as quantitative trait loci to define the genetic architecture of AD. We perform co-expression network analysis across more than twelve hundred human brain samples, identifying robust AD-associated dysregulation of the transcriptome, unaltered in normal human aging. We further integrate co-expression modules with single-cell transcriptome generated from 27,321 nuclei from postmortem human brain to identify AD-specific transcriptional changes and assess cell-type proportion changes in the human AD brain. We also show that genetic variants of AD are enriched in a glial AD-associated module and identify key transcription factors regulating co-expressed modules. Additionally, we validate our results in multiple published human AD datasets which are easily accessible using our online resource (https://swaruplab.bio.uci.edu/consensusAD).
EEG power spectra and subcortical pathology in chronic disorders of consciousness
Authors: Lutkenhoff Evan S. , Nigri Anna , Sebastiano Davide Rossi , Sattin Davide , Visani Elisa , Rosazza Cristina , D’Incerti Ludovico , Bruzzone Maria Grazia , Franceschetti Silvana , Leonardi Matilde , Ferraro Stefania , Monti Martin M. 
Published: July 2019

AbstractObjectiveTo determine (i) the association between long-term impairment of consciousness after severe brain injury, spontaneous brain oscillations, and underlying subcortical damage, and (ii) whether such data can be used to aid patient diagnosis, a process known to be susceptible to high error rates.MethodsCross-sectional observational sample of 116 patients with a disorder of consciousness secondary to brain injury, collected prospectively at a tertiary center between 2011 and 2013. Multimodal analyses relating clinical measures of impairment, electroencephalographic measures of spontaneous brain activity, and magnetic resonance imaging data of subcortical atrophy were conducted in 2018.ResultsIn the final analyzed sample of 61 patients, systematic associations were found between electroencephalographic power spectra and subcortical damage. Specifically, the ratio of beta-to-delta relative power was negatively associated with greater atrophy in regions of the bilateral thalamus and globus pallidus (both left > right) previously shown to be preferentially atrophied in chronic disorders of consciousness. Power spectrum total density was also negatively associated with widespread atrophy in regions of the left globus pallidus, right caudate, and in brainstem. Furthermore, we showed that the combination of demographics, encephalographic, and imaging data in an analytic framework can be employed to aid behavioral diagnosis.ConclusionsThese results ground, for the first time, electroencephalographic presentation detected with routine clinical techniques in the underlying brain pathology of disorders of consciousness and demonstrate how multimodal combination of clinical, electroencephalographic, and imaging data can be employed in potentially mitigating the high rates of misdiagnosis typical of this patient cohort.Search termsdisorders of consciousness, subcortical pathology, EEG, MRI.
Temporal regularity and stimulus control in multiple fixed interval schedules
Authors: Nepomoceno Estela B. , Cravo André M. , Reyes Marcelo B. , Caetano Marcelo S. 
Published: July 2019

AbstractIn multiple fixed interval schedules of reinforcement, different time intervals are signaled by different environmental stimuli which acquire control over behavior. Previous work has shown that temporal performance is controlled not only by external stimuli but also by temporal aspects of the task, depending on the order in which the different intervals are trained – intermixed across trials or in blocks of several trials. The aim of this study was to further describe the training conditions under which the stimuli acquire control over temporal performance. We manipulated the number of consecutive trials of each fixed interval (FI) per training block (Experiment I) and the number of FIs trained (Experiment II). The results suggest that when trained in blocks of several consecutive trials of the same FI, temporal performance is controlled by temporal regularities across trials and not by the visual stimuli that signal the FIs. One possible account for those data is that the temporal cues overshadow the visual stimuli for the control of temporal performance. Similar results have also been observed with humans, which suggest that temporal regularity overcomes the stimuli in the control of behavior in temporal tasks across species.
Structural determinants of protocadherin-15 elasticity and function in inner-ear mechanotransduction
Authors: Choudhary Deepanshu , Narui Yoshie , Neel Brandon L. , Wimalasena Lahiru N. , Klanseck Carissa F. , De-la-Torre Pedro , Chen Conghui , Araya-Secchi Raul , Tamilselvan Elakkiya , Sotomayor Marcos 
Published: July 2019

AbstractProtocadherin-15 (PCDH15), an atypical member of the cadherin superfamily, is essential for vertebrate hearing and its dysfunction has been associated with deafness and progressive blindness. The PCDH15 ectodomain, made of eleven extracellular cadherin (EC1-11) repeats and a membrane adjacent domain (MAD12), assembles as a parallel homodimer that interacts with cadherin-23 (CDH23) to form the tip link, a fine filament necessary for inner-ear mechanotransduction. Here we report X-ray crystal structures of a PCDH15 + CDH23 heterotetrameric complex and ten PCDH15 fragments that were used to build complete high-resolution models of the monomeric PCDH15 ectodomain. Using molecular dynamics (MD) simulations and validated crystal contacts we propose models for complete PCDH15 parallel homodimers and the tip-link bond. Steered MD simulations of these models predict their strength and suggest conditions in which a multimodal PCDH15 ectodomain can act as a stiff or soft gating spring. These results provide a detailed view of the first molecular steps in inner-ear sensory transduction.
Measuring the host-seeking ability of Aedes aegypti destined for field release
Authors: Lau Meng-Jia , Endersby-Harshman Nancy M. , Axford Jason K. , Ritchie Scott A. , Hoffmann Ary A. , Ross Perran A. 
Published: July 2019

AbstractHost-seeking is an essential process in mosquito reproduction. Field releases of modified mosquitoes for population transformation rely on successful host-seeking by female mosquitoes, but host-seeking ability is rarely tested in a realistic context. We tested the host-seeking ability of female Aedes aegypti mosquitoes using a semi-field system. Females with different Wolbachia infection types (wMel-, wAlbB-infected and uninfected) or from different origins (laboratory and field) were released at one end of a semi-field cage and recaptured as they landed on human experimenters fifteen meters away. Mosquitoes from each population were then identified with molecular tools or through marking with a consistent weight of fluorescent powder. Wolbachia-infected and uninfected populations had similar average durations to landing and overall recapture proportions, as did laboratory and field-sourced A. aegypti. These results suggest that the host-seeking ability of mosquitoes is not negatively affected by Wolbachia infection or long-term laboratory maintenance. This method provides an approach to study the host-seeking ability of mosquitoes across a long distance which will be useful when evaluating strains of mosquitoes that are planned for releases into the field to suppress arbovirus transmission. An adjustment of this method may also be useful in sterile insect release programs because male host-seeking and swarming around female feeding sites can also be investigated.
Synthetic Genetic Codes Designed to Hinder Evolution
Authors: Calles Jonathan , Justice Isaac , Brinkley Detravious , Garcia Alexa , Endy Drew 
Published: July 2019

ABSTRACTOne challenge in engineering organisms is guaranteeing system behavior over many generations. Spontaneous mutations that arise before or during use can impact heterologous genetic functions, disrupt system integration, or change organism phenotype. Here, we propose restructuring the genetic code itself such that all point mutations in protein-coding sequences are selected against. Synthetic genetic systems so-encoded should “fail safely” in response to many individual spontaneous mutations. We designed a family of such fail-safe codes and analyzed their expected effect on the evolution of engineered organisms via simulation. We predict that fail-safe codes supporting expression of 20 or 15 amino acids could slow the evolution of proteins in so-encoded organisms to 30% or 0% the rate of standard-code organisms, respectively. We also designed quadruplet-codon codes that should be capable of encoding at least 20 amino acids while ensuring all single point mutations in protein-coding sequences are selected against. We show by in vitro experiments that a reduced set of 21 tRNA is capable of expressing a protein whose coding sequence is recoded to use a fail-safe code, whereas a standard-code encoding is not expressed. Our work suggests that a rationally depleted but otherwise natural translation system should yield biological systems with intrinsically reduced evolutionary capacity, and that so-encoded hypoevolvable organisms might be less likely to invade new niches or outcompete native populations.
ORP5/8 AND MIB/MICOS LINK ER-MITOCHONDRIA AND INTRAMITOCHONDRIAL CONTACTS FOR NON-VESICULAR TRANSPORT OF PHOSPHATIDYLSERINE
Authors: Monteiro-Cardoso Vera F. , Rochin Leila , Arora Amita , Houcine Audrey , Jääskeläinen Eeva , Kivelä Annukka M. , Sauvanet Cécile , Bars Romain Le , Marien Eyra , Dehairs Jonas , Neveu Julie , Khallouki Naima El , Santonico Elena , Swinnen Johannes V. , Tareste David , Olkkonen Vesa M. , Giordano Francesca 
Published: July 2019

SUMMARYMitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mitochondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at sites of close organelle apposition called membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological localization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membranes (MAMs) subdomains, physically linked to the MIB/MICOS complexes that bridge the two mitochondrial membranes. We also show that ORP5/8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a novel physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochondrial membranes contacts maintained by the MIB/MICOS complexes.
Selective clearance of the inner nuclear membrane protein emerin by vesicular transport during ER stress
Authors: Buchwalter Abigail , Schulte Roberta , Tsai Hsiao , Capitanio Juliana , Hetzer Martin 
Published: July 2019

AbstractThe inner nuclear membrane (INM) is a subdomain of the endoplasmic reticulum (ER) that is gated by the nuclear pore complex. It is unknown whether proteins of the INM and ER are degraded through shared or distinct pathways in mammalian cells. We applied dynamic proteomics to profile protein half-lives and report that INM and ER residents turn over at similar rates, indicating that the INM’s unique topology is not a barrier to turnover. Using a microscopy approach, we observed that the proteasome can degrade INM proteins in situ. However, we also uncovered evidence for selective, vesicular transport-mediated turnover of a single INM protein, emerin, that is potentiated by ER stress. Emerin is rapidly cleared from the INM by a mechanism that requires emerin’s LEM domain to mediate vesicular trafficking to lysosomes. This work demonstrates that the INM can be dynamically remodeled in response to environmental inputs.