bluuebunny/crossref_metadata_2025_split huggingface dataset:
Greater neurodegeneration and behavioral deficits after single closed head traumatic brain injury in adolescent vs adult mice
Authors: Guilhaume-Correa Fernanda , Cansler Shelby M. , Shalosky Emily M. , Goodman Michael D. , Evanson Nathan K. 
Published: March 2019

AbstractIntroductionTraumatic brain injury (TBI) is a major public health concern affecting 2.8 million people per year, of which about 1 million are children under 19 years old. Animal models of TBI have been developed and used in multiple ages of animals, but direct comparisons of adult and adolescent populations are rare. The current studies were undertaken to directly compare outcomes between adult and adolescent mice, using a closed head, single impact model of TBI.MethodsSix-week-old adolescent and 9-week-old adult male mice were subjected to TBI using a closed head weight drop model. Histological measures for neurodegeneration, gliosis, and microglial neuroinflammation, and behavioral tests of locomotion and memory were performed.ResultsAdolescent TBI mice have increased mortality (X2= 20.72, p < 0.001) compared to adults. There is also evidence of hippocampal neurodegeneration in adolescents, but not adults. Presence of hippocampal neurodegeneration correlates with histologic activation of microglia, but not with increased markers of astrogliosis. Adults and adolescents have similar locomotion deficits after TBI that recover by 16 days post-injury. Adolescents have memory deficits as evidenced by impaired novel object recognition performance 3 and 16 days post injury (F1,26 = 5.23, p = 0.031) while adults do not.ConclusionsAdults and adolescents within a close age range (6-9 weeks) respond to TBI differently. Adolescents are more severely affected by mortality, neurodegeneration, and inflammation in the hippocampus compared to adults. Adolescents, but not adults, have worse memory performance after TBI that lasts up to 16 days post injury.
Is evolution predictable? Quantitative genetics under complex genotype-phenotype maps
Authors: Milocco Lisandro , Salazar-Ciudad Isaac 
Published: March 2019

AbstractA fundamental aim of post-genomic 21st century biology is to understand the genotype-phenotype map (GPM) or how specific genetic variation relates to specific phenotypic variation (1). Quantitative genetics approximates such maps using linear models, and has developed methods to predict the response to selection in a population (2, 3). The other major field of research concerned with the GPM, developmental evolutionary biology or evo-devo (1, 4–6), has found the GPM to be highly nonlinear and complex (4, 7). Here we quantify how the predictions of quantitative genetics are affected by the complex, nonlinear maps found in developmental biology. We combine a realistic development-based GPM model and a population genetics model of recombination, mutation and natural selection. Each individual in the population consists of a genotype and a multi-trait phenotype that arises through the development model. We simulate evolution by applying natural selection on multiple traits per individual. In addition, we estimate the quantitative genetics parameters required to predict the response to selection. We found that the disagreements between predicted and observed responses to selection are common, roughly in a third of generations, and are highly dependent on the traits being selected. These disagreements are systematic and related to the nonlinear nature of the genotype-phenotype map. Our results are a step towards integrating the fields studying the GPM.
Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors
Authors: Felix Jan , Weinhäupl Katharina , Chipot Christophe , Dehez François , Hessel Audrey , Gauto Diego F. , Morlot Cecile , Abian Olga , Gutsche Irina , Velazquez-Campoy Adrian , Schanda Paul , Fraga Hugo 
Published: March 2019

AbstractCoordinated conformational transitions in oligomeric enzymatic complexes modulate function in response to substrates and play a crucial role in enzyme inhibition and activation. ClpP protease is a tetradecameric complex that has emerged as a drug target against multiple pathogenic bacteria. During drug development efforts, the activation of different ClpPs by inhibitors was independently reported, but so far, no rationale for inhibitor-induced activation has been proposed. Using an integrated approach that included X-ray crystallography, solid-and solution-state NMR, MD simulations and ITC we show that the proteasome-inhibitor bortezomib binds to the ClpP active site serine mimicking a peptide substrate and induces the concerted allosteric activation of the complex. The bortezomib activated conformation also displays a higher affinity for its cognate unfoldase ClpX. We propose a universal allosteric mechanism where substrate binding to a single subunit locks ClpP into an active conformation optimized for chaperone association as well as protein processive degradation.
Reward boosts neural coding of task rules to optimise cognitive flexibility
Authors: Hall-McMaster S. , Muhle-Karbe P.S. , Myers N.E. , Stokes M.G. 
Published: March 2019

AbstractCognitive flexibility is critical for intelligent behaviour. However, its execution is effortful and often suboptimal. Recent work indicates that flexible behaviour can be improved by the prospect of reward, which suggests that rewards optimise flexible control processes. Here we investigated how different reward prospects influence neural encoding of task rule information to optimise cognitive flexibility. We applied representational similarity analysis (RSA) to human electroencephalograms, recorded while female and male participants performed a rule-guided decision-making task. During the task, the prospect of reward varied from trial to trial. Participants made faster, more accurate judgements on high reward trials. Critically, high reward boosted neural coding of the active task rule and the extent of this increase was associated with improvements in task performance. Additionally, the effect of high reward on task rule coding was most pronounced on switch trials, where rules were updated relative to the previous trial. These results suggest that reward prospect can promote cognitive performance by strengthening neural coding of task rule information, helping to improve cognitive flexibility during complex behaviour.Significance StatementThe importance of motivation is evident in the ubiquity with which reward prospect guides adaptive behaviour and the striking number of neurological conditions associated with motivational impairments. In this study, we investigated how dynamic changes in motivation, as manipulated through reward, shape neural coding for task rules during a flexible decision-making task. The results of this work suggest that motivation to obtain reward modulates encoding of task rules needed for flexible behaviour. The extent to which reward increased task rule coding also tracked improvements in behavioural performance under high reward conditions. These findings help inform how motivation shapes neural processing in the healthy human brain.
Kindlin-3 Mutation in Mesenchymal Stem Cells Results in Enhanced Chondrogenesis
Authors: Kerr Bethany A. , Shi Lihong , Jinnah Alexander H. , Willey Jeffrey S. , Lennon Donald P. , Caplan Arnold I. , Byzova Tatiana V. 
Published: March 2019

ABSTRACTIdentifying patient mutations driving skeletal development disorders has driven our understanding of bone development. Integrin adhesion deficiency disease is caused by a Kindlin-3 (fermitin family member 3) mutation and its inactivation results in bleeding disorders and osteopenia. In this study, we uncover a role for Kindlin-3 in the differentiation of bone marrow mesenchymal stem cells (BMSCs) down the chondrogenic lineage. Kindlin-3 expression increased with chondrogenic differentiation similar to RUNX2. BMSCs isolated from a Kindlin-3 deficient patient expressed chondrocyte markers including SOX9 under basal conditions, which were further enhanced with chondrogenic differentiation. Rescue of integrin activation by a constitutively activated β3 integrin construct increased adhesion to multiple extracellular matrices and reduced SOX9 expression to basal levels. Growth plates from mice expressing a mutated Kindlin-3 with the integrin binding site ablated demonstrated alterations in chondrocyte maturation similar to that seen with the human Kindlin-3 deficient BMSCs. These findings suggest that Kindlin-3 expression mirrors RUNX2 during chondrogenesis.SUMMARYThis study by Kerr et al. describes a new role for Kindlin-3 in controlling early chondrocyte differentiation from mesenchymal stem cells and later hypertrophic differentiation of chondrocytes.
Imaging the Electrical Activity Of Organelles in living cells
Authors: Matamala Ella , Castillo Cristian , Vivar Juan Pablo , Brauchi Sebastian 
Published: March 2019

AbstractEukaryotic cells are complex systems compartmentalized in membrane-bound organelles. Visualization of organellar electrical activity in living cells requires both a suitable reporter and non-invasive imaging at high spatiotemporal resolution. Here we present hVoSorg, an optical method to monitor changes in the membrane potential of subcellular membranes. This method takes advantage of a FRET pair consisting of a membrane-bound voltage-insensitive fluorescent donor and a colorless voltage-dependent acceptor that rapidly moves across the membrane in response to changes in polarity. Compared to the currently available techniques, hVoSorg has advantages including simple and precise subcellular targeting, the ability to record from individual organelles, and the potential for optical multiplexing.SummaryBy adapting a hybrid-FRET voltage sensor we report here the resting membrane potential of different organelles in living cells.
Evidence of decreased gap junction coupling between astrocytes and oligodendrocytes in the anterior cingulate cortex of depressed suicides
Authors: Tanti Arnaud , Lutz Pierre-Eric , Kim John , O’Leary Liam , Turecki Gustavo , Mechawar Naguib 
Published: March 2019

ABSTRACTGlial dysfunction is a major feature in the pathophysiology of mood disorders. While altered astrocyte (AS) and oligodendrocyte-lineage (OL) cell functions have been associated with depression, the crosstalk between these two major glial cell types has never been assessed in that context. AS are potent regulators of OL cells and myelination, in part through gap junction-mediated intercellular communication made possible by the heterotypic coupling of AS-specific (Cx30 and Cx43) and OL-specific (Cx32 and Cx47) connexins, allowing cytosolic transport and metabolic support to OL cells. Because changes in the expression of AS-specific connexins have been previously reported in the brain of depressed individuals, this study aimed at addressing the integrity of AS-OL coupling in the anterior cingulate cortex (ACC) of depressed suicides. Using immunofluorescence and confocal imaging, we characterized the distribution of the AS-specific Cx30 in the ACC, and mapped its expression onto oligodendrocyte somas and myelinated axons as well as brain vasculature in post-mortem brain samples from depressed suicides (N=48) and matched controls (N=23). The differential gene expression of key components of the gap junction nexus was also screened through RNA-sequencing dataset previously generated by our group, and validated by quantitative real-time PCR. Our results indicate that Cx30 expression mapping to OL cells is selectively decreased in depressed suicides, an effect that was associated with decreased expression of OL-specific connexins Cx32 and Cx47, as well as the downregulation of major connexin-interacting proteins essential for the scaffolding, trafficking and function of gap junction channels. These results provide a first evidence of impaired gap junction mediated communication between astrocytes and oligodendrocytes in the ACC of individuals with mood disorders. These changes in glial coupling are likely to have significant impact on brain function, and may contribute to the altered OL function previously reported in this brain region.
Blood cells of adultDrosophilado not expand, but control survival after bacterial infection by induction ofDrosocinaround their reservoir at the respiratory epithelia
Authors: Bosch Pablo Sanchez , Makhijani Kalpana , Herboso Leire , Gold Katrina S , Baginsky Rowan , Woodcock Katie J , Alexander Brandy , Kukar Katelyn , Corcoran Sean , Ouyang Debra , Wong Corinna , Ramond Elodie JV , Rhiner Christa , Moreno Eduardo , Lemaitre Bruno , Geissmann Frederic , Brückner Katja 
Published: March 2019

SummaryDrosophila melanogasterhas been an excellent model for innate immunity, but the role and regulation of adult blood cells and organismal immunity have remained incompletely understood. Here we address these questions in a comprehensive investigation of the blood cell system in adultDrosophila. As a central finding, we reveal the largest reservoir of blood cells (hemocytes) at the respiratory epithelia (tracheal air sacs) and fat body of the thorax and head. We show that most hemocytes of adultDrosophilaare phagocytic macrophages (plasmatocytes), derived by more than 60% from the embryonic lineage that parallels vertebrate tissue macrophages. Surprisingly, in contrast to hemocytes at the larval stage, we find no capacity of the adult blood cell system to expand. Instead, we demonstrate its central role in relaying an innate immune response to tissues surrounding the blood cell reservoir: Hemocytes, through Imd signaling and the Jak/Stat pathway ligand Upd3, act as sentinels of bacterial infection that induce expression of the antimicrobial peptide geneDrosocin in the respiratory epithelia and colocalizing domains of the fat body. We demonstrate that endogenousDrosocinexpression in these tissues promotes animal survival after bacterial infection. Our work identifies the first molecular step in a new relay of organismal immunity, establishing adultDrosophilaas model to dissect mechanisms of inter-organ immunity.
Robustness and timing of cellular differentiation through population-based symmetry breaking
Authors: Stanoev Angel , Schröter Christian , Koseska Aneta 
Published: March 2019

AbstractDuring mammalian development, cell types expressing mutually exclusive genetic markers are differentiated from a multilineage primed state. These observations have invoked single-cell multistability view as the dynamical basis of differentiation. However, the robust regulative nature of mammalian development is not captured therein. Considering the well-established role of cell-cell communication in this process, we propose a fundamentally different dynamical treatment in which cellular identities emerge and are maintained on population level, as a novel unique solution of the coupled system. Subcritical system’s organization here enables symmetry-breaking to be triggered by cell number increase in a timed, self-organized manner. Robust cell type proportions are thereby an inherent feature of the resulting inhomogeneous solution. This framework is generic, as exemplified for early embryogenesis and neurogenesis cases. Distinct from mechanisms that rely on pre-existing asymmetries, we thus demonstrate that robustness and accuracy necessarily emerge from the cooperative behaviour of growing cell populations during development.
Gene Expression Mediated Antiproliferative Potential and Safety of Selected Medicinal Plants Against Cancerous and Normal Cells
Authors: Mbugua Regina Wachuka , Njagi Eliud Mwaniki , Ngule Chrispus Mutuku , Mwitari Peter 
Published: March 2019

AbstractGlobally, approximately 13% of all deaths annually are attributed to cancer. Surgery, radiation and chemotherapy are the current treatment techniques for cancer, however these methods are expensive, have high failure rates and have been associated with detrimental side effects. Plant derived products could be good candidates in alleviating challenges being experienced with these current methods. This study aimed at evaluating the phytochemistry, antiproliferation potential, and probable mechanism of action ofAlbizia gummifera,Rhamnus staddoandSenna didymobotryaplant extracts. Phytochemical screening was done as per standard procedures. The common 3– (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium (MTT) dye was used in the determination of the antiproliferative activity of the extracts. Extracts induction ofVEGF(angiogenesis) and p53 (apoptosis) genes’ expression was evaluated using Real Time Polymerase Chain Reaction. Phytochemical screening revealed presence of alkaloids, tannins, glycosides, flavonoids, terpenes, phenolics and saponins in the plants extracts.A. gummifera’sstem bark methanol: dichloromethane extract had the highest activity against the cancerous cell lines tested: HCC1395 (IC506.07±0.04μg/ml), DU145 (IC503.34±0.05μg/ml), CT26 (IC505.78±0.08μg/ml) and Hep2 (IC507.02±0.01μg/ml).R. staddoroot bark methanol: dichloromethane extract had an IC50value of 15.71±0.04μg/ml on HCC, 9.81±0.09μg/ml on Hep2 and 11.14±0.39μg/ml on CT26.S. didymobotryaroot bark methanol: dichloromethane extract inhibited HCC with an IC50of 65.06±0.07μg/ml, CT26 with an IC50of 15.71±0.04μg/ml and Hep2 with an IC50of 62.10±0.11μg/ml. From the results obtained, the plants exhibited selective toxicity to cancer cells while sparing the normal cells (SI ≥ 3).A. gummiferaandS. didymobotryaandR. staddoplant extracts upregulated p53 and down-regulatedVEGFgenes. In conclusion, this study confirms that these plant extracts could be potential candidates for development of drugs for the management of breast, prostrate, colorectal and throat cancer.
The Beacon Calculus: A formal method for the flexible and concise modelling of biological systems
Authors: Boemo Michael A. , Cardelli Luca , Nieduszynski Conrad A. 
Published: March 2019

AbstractBiological systems are made up of components that change their actions (and interactions) over time and coordinate with other components nearby. Together with a large state space, the complexity of this behaviour can make it difficult to create concise mathematical models that can be easily extended or modified. This paper introduces the Beacon Calculus, a process algebra designed to simplify the task of modelling interacting biological components. Its breadth is demonstrated by creating models of DNA replication dynamics, the gene expression dynamics in response to DNA methylation damage, and a multisite phosphorylation switch. The flexibility of these models is shown by adapting the DNA replication model to further include two topics of interest from the literature: cooperative origin firing and replication fork barriers. The Beacon Calculus is supported with the open-source simulator bcs (https://github.com/MBoemo/bcs.git) to allow users to develop and simulate their own models.Author summarySimulating a model of a biological system can suggest ideas for future experiments and help ensure that conclusions about a mechanism are consistent with data. The Beacon Calculus is a new language that makes modelling simple by allowing users to simulate a biological system in only a few lines of code. This simplicity is critical as it allows users the freedom to come up with new ideas and rapidly test them. Models written in the Beacon Calculus are also easy to modify and extend, allowing users to add new features to the model or incorporate it into a larger biological system. We demonstrate the breadth of applications in this paper by applying the Beacon Calculus to DNA replication and DNA damage repair, both of which have implications for genome stability and cancer. We also apply it to multisite phosphorylation, which is important for cellular signalling. To enable users to create their own models, we created the open-source Beacon Calculus simulator bcs (https://github.com/MBoemo/bcs.git) which is easy to install and is well-supported by documentation and examples.
A draft genome sequence of the miniature parasitoid wasp, Megaphragma amalphitanum
Authors: Nedoluzhko Artem V. , Sharko Fedor S. , Lê Brandon M. , Tsygankova Svetlana V. , Boulygina Eugenia S. , Rastorguev Sergey M. , Sokolov Alexey S. , Rodriguez Fernando , Mazur Alexander M. , Polilov Alexey A. , Benton Richard , Evgen’ev Michael B. , Arkhipova Irina R. , Prokhortchouk Egor B. , Skryabin Konstantin G. 
Published: March 2019

ABSTRACTBody size reduction, also known as miniaturization, is an important evolutionary process that affects a number of physiological and phenotypic traits and helps animals to conquer new ecological niches. However, this process is poorly understood at the molecular level. Here, we report genomic and transcriptomic features of arguably the smallest known insect – the parasitoid wasp, Megaphragma amalphitanum (Hymenoptera: Trichogrammatidae). In contrast to expectations, we find that the genome and transcriptome sizes of this parasitoid wasp are comparable to other members of the Chalcidoidea superfamily. Moreover, the gene content of M. amalphitanum compared to other chalcid wasps is remarkably conserved. Among the very rare cases of apparent gene loss is centrosomin, which encodes an important centrosome component; the absence of this protein might be related to the large number of anucleate neurons in M. amalphitanum. Intriguingly, we also observed significant changes in M. amalphitanum transposable element dynamics over time, whereby an initial burst was followed by suppression of activity, possibly due to a recent reinforcement of the genome defense machinery. Thus, while the M. amalphitanum genomic data reveal certain features that may be linked to the unusual biological properties of this organism, miniaturization is not associated with a large decrease in genome complexity.
Estimation of Membrane Curvature for Cryo-Electron Tomography
Authors: Kalemanov Maria , Collado Javier F. , Baumeister Wolfgang , Fernández-Busnadiego Rubén , Martínez-Sánchez Antonio 
Published: March 2019

AbstractCurvature is an important morphological descriptor of cellular membranes. Cryo-electron tomography (cryo-ET) is particularly well-suited to visualize and analyze membrane morphology in a close-to-native state and high resolution. However, current curvature estimation methods cannot be applied directly to membrane segmentations in cryo-ET. Additionally, a reliable estimation requires to cope with quantization noise. Here, we developed and implemented a method for membrane curvature estimation from tomogram segmentations.From a membrane segmentation, a signed surface (triangle mesh) is first extracted. The triangle mesh is then represented by a graph (vertices and edges), which facilitates finding neighboring triangles and the calculation of geodesic distances necessary for local curvature estimation. Here, we present several approaches for accurate curvature estimation based on tensor voting. Beside curvatures, these methods also provide robust estimations of surface normals and principal directions.We tested the different methods on benchmark surfaces with known curvature, demonstrating the validity of these methods and their robustness to quantization noise. We also applied two of these approaches to biological cryo-ET data. The results allowed us to determine the best approach to estimate membrane curvature in cellular cryo-ET data.