bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the Links between Specific Depression Symptoms and Brain Structure: A Network Study
Authors: Hilland Eva , Landrø Nils Inge , Kraft Brage , Tamnes Christian K. , Fried Eiko I. , Maglanoc Luigi A. , Jonassen Rune 
Published: September 2019

AbstractThe network approach to psychopathology has recently received considerable attention, and is as a novel way of conceptualizing mental disorders as causally interacting symptoms. In this study, we modeled a joint network of depression symptoms and depression-related brain structures, using 21 symptoms and five regional brain measures. We used a mixed sample of 268 individuals previously treated for one or more major depressive episodes and never depressed individuals. The network revealed associations between brain structure and unique depressive symptoms, which may clarify relationships regarding symptomatic and biological heterogeneity in depression.
Dendritic GABAB receptors control nonlinear information transfer along the dendro-somatic axis in layer 5 pyramidal neurons
Authors: Schulz Jan M. , Larkum Matthew E. 
Published: September 2019

SummaryDendritic GABAB receptors (GABABRs) mediate a slow form of interhemispheric inhibition. Surprisingly, this inhibition has no detectable effect on the somatic membrane potential of layer 5 pyramidal neurons, whereas the action potential (AP) output is robustly decreased even when the input is proximal to the cell body. To elucidate the underlying mechanisms, we systematically mapped the AP frequency-current (F-I) relationship during dual patch-clamp recordings from soma and apical dendrite. The AP output function was governed by the synergistic interaction between dendritic and somatic compartments as the local input and transfer resistance from dendrite to soma (Kds) depended on the dendritic membrane potential. Thus, Kds doubled at an estimated rate of once per 28.7 mV depolarization due to HCN channel deactivation. In addition, dendritic L-type Ca2+ channels converted individual APs into dendritic Ca2+ spikes causing high-frequency bursts of APs (HFB) during large dendritic depolarization. Activation of dendritic GABABRs greatly reduced both nonlinear mechanisms. While direct block of L-type Ca2+ channels reduced the number of HFBs, K+ channel activation decreased voltage-dependent input and transfer resistances and decreased the AP rate under all conditions. These results highlight the powerful modulation of the input integration in pyramidal neurons by metabotropic receptor-activated K+ channels.
Timing and duration of phenological subsidies: toward a mechanistic understanding of impacts on community structure and ecosystem processes in stream food chains
Authors: Takimoto Gaku , Sato Takuya 
Published: September 2019

ABSTRACTPhenological resources are common across many ecological communities, and can strongly affect community dynamics. Recent field manipulation experiments in stream food chains found that seasonal timing and duration of terrestrial prey inputs affected the feeding behavior, growth, and maturation of fish predators, caused predator-mediated indirect effects on aquatic prey, and modified trophic-cascading effects on litter processing. These experiments described impacts of resource phenological changes over a few month period, and long-term impacts of continued changes in resource phenology are unknown. Here we develop a mathematical model to extrapolate long-term predictions about the effects of changes in resource phenology from the results of field manipulation experiments. The model predicts that advanced timing generally decreases aquatic prey and litter processing and prolonged duration will either increase or decrease aquatic prey and litter processing depending on the total amount and pre-disturbed timing and duration of terrestrial prey inputs. Importantly, our modeling approach clarifies the mechanisms by which stage-specific responses of life history processes in fish, such as growth, maturation, and reproduction, respond to phenological changes in terrestrial prey inputs and mediate indirect effects on aquatic prey and litter processing. Stage-specific responses of life history processes are an integral part of the mechanisms with which to predict the consequences of phenological species interactions at the community and ecosystem levels.
Vaginal microbiota of adolescents and their mothers: A preliminary study of vertical transmission and persistence
Authors: Bassis Christine M. , Bullock Kaylie A. , Sack Daniel E. , Saund Katie , Pirani Ali , Snitkin Evan S. , Alaniz Veronica I. , Quint Elisabeth H. , Young Vincent B. , Bell Jason D. 
Published: September 2019

AbstractBackgroundFactors that influence vaginal microbiota composition, including its source, are not well understood. To determine if vaginal microbiota transmission from mother to daughter at birth influences the human vaginal microbiota composition in adolescence, we investigated the relationship between the vaginal microbiota of 13 mother/daughter pairs and the daughter’s birth mode.ResultsBased on analysis of bacterial 16S rRNA gene sequences, the vaginal microbiotas of mother/daughter pairs were more similar to each other if the daughter was born by vaginal delivery rather than by C-section. Additionally, genome sequences from an important member of the vaginal microbiota, Lactobacillus crispatus, isolated from one mother/daughter pair in which the daughter was born by vaginal delivery, were highly similar.ConclusionsBoth community-level analysis and isolate genome sequence analysis are consistent with birth-mode dependent transmission and persistence of at least some members of the vaginal microbiota.ImportanceThe composition of the human vaginal microbiota is related to many aspects of health from infection susceptibility to preterm birth. Our study provides evidence that transmission of vaginal bacteria from mother to daughter at birth may be an important factor influencing vaginal microbiota composition into adolescence.
Bacteria control cell volume by coupling cell-surface expansion to dry-mass growth
Authors: Oldewurtel Enno R. , Kitahara Yuki , Cordier Baptiste , Özbaykal Gizem , van Teeffelen Sven 
Published: September 2019

AbstractCells exhibit a high degree of intracellular crowding. To control the level of crowding during growth cells must increase their volumes in response to the accumulation of biomass. UsingEscherichia colias a model organism, we found that cells control cell volume indirectly, by increasing cell-surface area in proportion to biomass growth. Thus, dry-mass density, a readout of intracellular crowding, varies in proportion to the surface-to-volume ratio, both during the cell cycle and during perturbations such as nutrient shifts. On long time scales after shifts, initial dry-mass density is nearly restored by slow variations of the surface-to-mass ratio. Contrary to a long-standing paradigm, cell-envelope expansion is controlled independently of cell-wall synthesis but responds to the activity of cell-wall cleaving hydrolases. Finally, we observed rapid changes of Turgor pressure after nutrient shifts, which were likely responsible for initial changes of cell diameter and dry-mass-density. Together, our experiments reveal important regulatory relationships for cell volume and shape.
Methylthioadenosine is Not Dramatically Elevated inMTAP-Homozygous Deleted Primary Glioblastomas
Authors: Barekatain Yasaman , Yan Victoria C. , Ackroyd Jeffrey J. , Poral Anton H. , Tran Theresa , Georgiou Dimitra K. , Arthur Kenisha , Lin Yu-Hsi , Satani Nikunj , Ballato Elliot S. , deCarvalho Ana , Verhaak Roel , de Groot John , Huse Jason T. , Asara John M. , Muller Florian L. 
Published: September 2019

In BriefThe co-deletion ofMTAPin theCDKN2Alocus is a frequent event in diverse cancers including glioblastoma. Recent publications report that significant accumulations of the MTAP substrate, methylthioadenosine (MTA), can sensitizeMTAP-deleted cancer cells to novel inhibitors of PRMT5 and MAT2A for targeted therapy against tumors with this particular genetic alteration. In this work, using comprehensive metabolomic profiling, we show that MTA is primarily secreted, resulting in exceedingly high levels of extracellular MTAin vitro. We further show that primary human glioblastoma tumors minimally accumulate MTAin vivo, which is likely explained by the metabolism of MTA byMTAP-competent stromal cells. Together, these data challenge whether the metabolic conditions required for therapies to exploit vulnerabilities associatedMTAPdeletions are present in primary human tumors, questioning their translational efficacy in the clinic.HighlightsMethylthioadenosine (MTA) is elevated inMTAP-deleted cancer cellsin vitro, which provides a selective vulnerability to PRMT5 and MAT2A inhibitorsAccumulation of MTA inMTAP-deleted cancer cells is predominately extracellular, suggesting active secretion of MTA.MTAP-deleted primary human glioblastoma tumors show minimal intratumoral elevations of MTA, which is likely explained by secretion and metabolism byMTAP-competent stromal cells.SUMMARYHomozygous deletion of theCDK2NAlocus frequently results in co-deletion of methylthioadenosine phosphorylase (MTAP) in many fatal cancers such as glioblastoma multiforme (GBM), resulting in elevations of the substrate metabolite, methylthioadenosine (MTA). To capitalize on such accumulations, therapeutic targeting of protein arginine methyltransferase 5 (PRMT5) and methionine adenosyl transferase (MAT2A) are ongoing. While extensively corroboratedin vitro, the clinical efficacy of these strategies ultimately relies on equally significant accumulations of MTA in human tumors. Here, we show thatin vitroaccumulation of MTA is a predominately extracellular phenomenon, indicating secretion of MTA fromMTAP-deleted cells. In primary human GBMs, we find that MTA levels are not significantly higher inMTAP-deleted compared toMTAP-intact tumors or normal brain tissue. Together, these findings highlight the metabolic discrepancies betweenin vitromodels and primary human tumors and should thus be carefully considered in the development of the precision therapies targetingMTAP-homozygous deleted GBM.
An Open Source Unsupervised Algorithm for Identification and Fast Prediction of Behaviors
Authors: Hsu Alexander I. , Yttri Eric A. 
Published: September 2019

AbstractStudying naturalistic behavior remains a prohibitively difficult objective. Recent machine learning advances have enabled limb localization. Extracting behaviors, however, requires ascertaining the spatiotemporal patterns of these positions. To provide the missing bridge from poses to actions and their kinematics, we developed B-SOiD - an open-source, unsupervised algorithm that identifies behavior without user bias. By training a machine classifier on pose pattern statistics clustered using new methods, our approach achieves greatly improved processing speed and the ability to generalize across subjects or labs. Using a frameshift alignment paradigm, B-SOiD overcomes previous temporal resolution barriers that prevent the use of other algorithms with electrophysiological recordings. Using only a single, off-the-shelf camera, B-SOiD provides categories of sub-action for trained behaviors and kinematic measures of individual limb trajectories in an animal model. These behavioral and kinematic measures are difficult but critical to obtain, particularly in the study of pain, OCD, and movement disorders.
Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective
Authors: Oliynyk Roman Teo 
Published: September 2019

AbstractWith the accumulation of scientific knowledge of the genetic causes of common diseases and continuous advancement of gene-editing technologies, gene therapies to prevent polygenic diseases may soon become possible. This study endeavored to assess population genetics consequences of such therapies. Computer simulations were used to evaluate the heterogeneity in causal alleles for polygenic diseases that could exist among geographically distinct populations. The results show that although heterogeneity would not be easily detectable by epidemiological studies following population admixture, even significant heterogeneity would not impede the outcomes of preventive gene therapies. Preventive gene therapies designed to correct causal alleles to a naturally-occurring neutral state of nucleotides would lower the prevalence of polygenic early- to middle-age-onset diseases in proportion to the decreased population relative risk attributable to the edited alleles. The outcome would manifest differently for late-onset diseases, for which the therapies would result in a delayed disease onset and decreased lifetime risk, however the lifetime risk would increase again with prolonging population life expectancy, which is a likely consequence of such therapies. If gene therapies that prevent heritable diseases were to be applied on a large scale, the decreasing frequency of risk alleles in populations would reduce the disease risk or delay the age of onset, even with a fraction of the population receiving such therapies. With ongoing population admixture, all groups would benefit over generations.
A noble TGFβ biogenesis inhibitor exhibits both potent anti-fibrotic and anti-inflammatory capabilities
Authors: Kim Han-Soo , Meang Moon Kee , Kim Saesbyeol , Lee Ji Yong , Seong Baik L. , Kim Ik-Hwan , Youn Byung-Soo 
Published: September 2019

AbstractsIdiopathy pulmonary fibrosis (IPF) is an intractable and fatal human disorder. Our previous study showed that eupatilin exerted a potent anti-fibrotic effect on both in vitro fibrogenesis and bleomycin-induced lung fibrosis model (BLM). Subsequently, an analog called ONG41008 had been identified as a more potent anti-fibrotic than eupatilin and also showed a potent anti-inflammatory capability. Orally administered ONG41008 significantly improved onset of BLM in both prophylactic and therapeutic model and its therapeutic efficacy was similarly compared to or better than pirfenidone by measuring production of collagen and hydroxyproline. Staining collagen or αSMA corroborated these results.As in vitro fibrogenesis models, DHLF (Diseased Human Lung Fibroblasts from IPF patients) and HSC (hepatic stellate cells) were used for direct effects of ONG41008 on pivotal cellular and molecular functions associated with pathogenic myofibroblasts; ONG41008 dismantled latent TGFb complex (LTC), generating inactive forms of TGFβ, likely limiting TGFβ to TGFβ receptor via depolymerization of F-actin and this blunted SMAD2/SMAD3 phosphorylation, thereby reprogramming EMT. A set of cell imaging studies and transcriptomic analysis were conducted to explore how ONG41008 elicited both anti-fibrotic and anti-inflammatory capabilities. Elastin (ELN) seemed to be a pioneering pharmacodynamic marker. It was also found that NOX4 played an important role in anti- fibrosis because it was functionally connected to major central nod proteins such as lysyl- oxidase (LOX) and numerous collagen family members in an ONG41008-specific fibrogenic interactome. Human NOX4 was significantly induced by TGFβ and completely knocked down by ONG41008. It has been shown that production of reactive oxygen species (ROS) led to activation of inflammasome. ONG41008 may be likely related to anti-inflammation, leading to a key protective effect on fibrogenesis. Concomitant with downregulation of NOX4, expression of macrophages homing chemokines, CCL2 and CCL7 were significantly attenuated by ONG41008. In vitro anti-inflammatory activities of ONG41008 were investigated in RAW264.7 cells, a mouse monocytic cell line stimulated with LPS. ONG41008 substantially attenuated TNFα, CXCL10, CCL2 and CCL7, which are proinflammatory cytokine and important chemokines influencing T cells or macrophages. TNFα was situated at the central nod in LPS-treated macrophages via an ONG41008-specific interactome analysis.Taken together, ONG41008 is a TGFβ biogenesis inhibitor, being a potent drug for a broad range of fibrotic diseases and could antagonize inflammatory diseases as well.
The Tolman-Eichenbaum Machine: Unifying space and relational memory through generalisation in the hippocampal formation
Authors: Whittington James CR , Muller Timothy H , Mark Shirley , Chen Guifen , Barry Caswell , Burgess Neil , Behrens Timothy EJ 
Published: September 2019

The hippocampal-entorhinal system is important for spatial and relational memory tasks. We formally link these domains; provide a mechanistic understanding of the hippocampal role in generalisation; and offer unifying principles underlying many entorhinal and hippocampal cell-types. We propose medial entorhinal cells form a basis describing structural knowledge, and hippocampal cells link this basis with sensory representations. Adopting these principles, we introduce the Tolman-Eichenbaum machine (TEM). After learning, TEM entorhinal cells include grid, band, border and object-vector cells. Hippocampal cells include place and landmark cells, remapping between environments. Crucially, TEM also predicts empirically recorded representations in complex non-spatial tasks. TEM predicts hippocampal remapping is not random as previously believed. Rather structural knowledge is preserved across environments. We confirm this in simultaneously recorded place and grid cells.One Sentence SummarySimple principles of representation and generalisation unify spatial and non-spatial accounts of hippocampus and explain many cell representations.
A primitive type of renin-expressing lymphocyte protects the organism against infections
Authors: Belyea Brian C. , Santiago Araceli E. , Vasconez Wilson A. , Nagalakshmi Vidya K. , Mehalic Theodore C. , Sequeira-Lopez Maria Luisa S. , Ariel Gomez R. 
Published: September 2019

ABSTRACTThe hormone renin plays a crucial role in the regulation of blood pressure and fluid-electrolyte homeostasis. Normally, renin is synthesized by juxtaglomerular (JG) cells, a specialized group of myoepithelial cells located near the entrance to the kidney glomeruli. In response to low blood pressure and/or a decrease in extracellular fluid volume (as it occurs during dehydration, hypotension, or septic shock) JG cells respond by releasing renin to the circulation to reestablish homeostasis. Interestingly, renin-expressing cells also exist outside of the kidney, where their function has remained a mystery. We discovered a unique type of renin-expressing B-1 lymphocytes that may have unrecognized roles in defending the organism against infections. These cells synthesize and release renin, entrap and phagocyte bacteria and control bacterial growth. The ability of renin-bearing lymphocytes to control infections – which is enhanced by the presence of renin – adds a novel, previously unsuspected dimension to the defense role of renin-expressing cells, linking the endocrine control of circulatory homeostasis with the immune control of infections to ensure survival.
Non-enzymatic primer extension with strand displacement
Authors: Zhou Lijun , Kim Seohyun Chris , Ho Katherine H. , O’Flaherty Derek K. , Giurgiu Constantin , Wright Tom H. , Szostak Jack W. 
Published: September 2019

AbstractNon-enzymatic RNA self-replication is integral to the ‘RNA World’ hypothesis. Despite considerable progress in non-enzymatic template copying, true replication remains challenging due to the difficulty of separating the strands of the product duplex. Here, we report a prebiotically plausible solution to this problem in which short ‘invader’ oligonucleotides unwind an RNA duplex through a toehold/branch migration mechanism, allowing non-enzymatic primer extension on a template that was previously occupied by its complementary strand. Kinetic studies of single-step reactions suggest that following invader binding, branch migration results in a 2:3 partition of the template between open and closed states. Finally, we demonstrate continued primer extension with strand displacement by employing activated 3′-aminonucleotides, a more reactive proxy for ribonucleotides. Our study suggests that complete cycles of non-enzymatic replication of the primordial genetic material may have been catalyzed by short RNA oligonucleotides.
Mechanical Roles of Vinculin/β-catenin interaction in Adherens Junction
Authors: Bertocchi Cristina , Ravasio Andrea , Ong Hui Ting , Toyama Yusuke , Kanchanawong Pakorn 
Published: September 2019

SummaryMechanical force transmission through the adherens junctions (AJs) are highly regulated processes essential for multicellular organization of tissues. AJ proteins such as E-cadherin, α-catenin, and vinculin have been shown to be sensing or bearing mechanical forces being transmitted between the actin cytoskeleton and the intercellular contacts. However, the molecular organization and connectivity of these components remains not well understood. Using a super-resolution microscopy approach, we report that vinculin, once activated, could form a direct structural connection with β-catenin, which can bypass α-catenin, one of the main mechanotransducers in AJs. Direct vinculin/β-catenin interaction is capable of supporting mechanical tension and contributes to the stabilization of the cadherin-catenin complexes. These findings suggest a multi-step model for the force-dependent reinforcement of AJs whereby α-catenin may serve as the initial catalytic activator of vinculin, followed by vinculin translocation to form a direct link between E-cadherin-bound β-catenin and the actin cytoskeleton.
Temporal complexity of fMRI is reproducible and correlates with higher order cognition
Authors: Omidvarnia Amir , Zalesky Andrew , Mansour Sina , Van De Ville Dimitri , Jackson Graeme D. , Pedersen Mangor 
Published: September 2019

AbstractIt has been hypothesized that resting state networks (RSNs) likely display unique temporal complexity fingerprints, quantified by their multi-scale entropy patterns [1]. This is a hypothesis with a potential capacity for developing digital biomarkers of normal brain function, as well as pathological brain dysfunction. Nevertheless, a limitation of [1] was that resting state functional magnetic resonance imaging (rsfMRI) data from only 20 healthy individuals was used for the analysis. To validate this hypothesis in a larger cohort, we used rsfMRI datasets of 1000 healthy young adults from the Human Connectome Project (HCP), aged 22-35, each with four 14.4-minute rsfMRI recordings and parcellated into 379 brain regions. We quantified multi-scale entropy of rsfMRI time series averaged at different cortical and sub-cortical regions. We performed effect-size analysis on the data in 8 RSNs. Given that the morphology of multi-scale entropy is affected by the choice of its tolerance parameter (r) and embedding dimension (m), we repeated the analyses at multiple values ofrandmincluding the values used in [1]. Our results reinforced high temporal complexity in the default mode and frontoparietal networks. Lowest temporal complexity was observed in the sub-cortical areas and limbic system. We investigated the effect of temporal resolution (determined by the repetition timeTR) after downsampling of rsfMRI time series at two rates. At a low temporal resolution, we observed increased entropy and variance across datasets. Test-retest analysis showed that findings were likely reproducible across individuals over four rsfMRI runs, especially when the tolerance parameterris equal to 0.5. A strong relationship was observed between temporal complexity of RSNs and fluid intelligence (people’s capacity to reason and think flexibly) through step-wise regression analysis suggesting that complex dynamics of the human brain is an important attribute of high-level brain function. Finally, the results confirmed that the relationship between functional brain connectivity strengths and rsfMRI temporal complexity changes over time scales, likely due to the regulation of neural synchrony at local and global network levels.