bluuebunny/crossref_metadata_2025_split huggingface dataset:
JAK Inhibitors Suppress Colon Cancer Cachexia-Associated Anorexia and Adipose Wasting in Mice
Authors: Arora Gurpreet , Gupta Arun , Guo Tong , Gandhi Aakash , Laine Aaron , Ahn Chul , Williams Dorothy , Iyengar Puneeth , Infante Rodney 
Published: January 2020

ABSTRACTBackgroundCachexia (CX), a syndrome of muscle atrophy, adipose loss, and anorexia, is associated with reduced survival in cancer patients. The colon adenocarcinoma C26c20 cell line secretes the cytokine leukemia inhibitor factor (LIF) which induces CX. We characterized how LIF promotes CX-associated weight loss and anorexia in mice through JAK-dependent changes in adipose and hypothalamic tissues.MethodsCX was inducedin vivowith C26c20 colon adenocarcinoma cells or recombinant LIF administration in the absence or presence of JAK inhibitors. Blood, adipose, and hypothalamic tissues were collected and processed for cyto/adipokine ELISAs, immunoblot analysis, and quantitative RT-PCR. CX was inducedin vitroby stimulating differentiated adipocytes with recombinant LIF or IL-6 in the absence or presence of lipase or JAK inhibitors. These activated adipocytes were processed for lipolysis, immunoblot analysis, and RT-PCR.ResultsTumor-secreted LIF induced changes in adipose tissue expression and serum levels of IL-6 and leptin in a JAK-dependent manner influencing CX-associated adipose wasting and anorexia. We identified two JAK inhibitors that block cytokine-mediated adipocyte lipolysis and IL-6 induction using anin vitroCX lipolysis assay. JAK inhibitors administered toin vivocolon cancer CX mouse models led to 1) a decrease in STAT3 phosphorylation in hypothalamic and adipose tissues, 2) a reverse in the CX serum cyto/adipokine signature, 3) a delay in colon cancer CX-associated anorexia and adipose loss, and 4) an improvement in overall survival.ConclusionsJAK inhibitors suppress cytokine-associated adipose loss and anorexia in multiplein vitroandin vivomodels of cancer CX.
A peptidergic amygdala microcircuit modulates sexually dimorphic contextual fear
Authors: Rajbhandari AK , Octeau JC , Gonzalez S , Pennington ZT , Trott J , Chavez J , Ngyuen E , Keces N , Hong WZ , Neve RL , Waschek J , Khakh BS , Fanselow MS 
Published: January 2020

AbstractTrauma can cause dysfunctional fear regulation leading some to develop disorders like post-traumatic stress disorder (PTSD). The amygdala regulates fear, and, PACAP and PAC1 receptors are linked to PTSD symptom severity at genetic/epigenetic levels, with a strong link in females with PTSD. We discovered a PACAPergic projection from the basomedial amygdala (BMA) to the medial intercalated cells (mICCs). In vivo optogenetic stimulation of this pathway increased cfos expression in mICCs, decreased fear retention and increased fear extinction. Selective deletion of PAC1 receptors from the mICCs in females reduced fear acquisition, but enhanced fear generalization and reduced fear extinction in males. Optogenetic stimulation of the BMA-mICCs PACAPergic pathway produced excitatory postsynaptic currents (EPSCs) in mICCs neurons, which was enhanced by PAC1 receptor antagonist, PACAP 6-38. Our findings show that mICCs modulate contextual fear in a dynamic and sex-dependent manner via the microcircuit containing the BMA and mICCs, dependent on behavioral state.
Genome-wide mapping and prediction of plant architecture in a sorghum nested association mapping population
Authors: Olatoye Marcus O. , Hu Zhenbin , Morris Geoffrey P. 
Published: January 2020

AbstractModifying plant architecture is often necessary for yield improvement and climate adaptation, but we lack understanding of the genotype-phenotype map for plant morphology in sorghum. Here, we use a nested association mapping (NAM) population that captures global allelic diversity of sorghum to characterize the genetics of leaf erectness, leaf width (at two stages), and stem diameter. Recombinant inbred lines (n = 2200) were phenotyped in multiple environments (35,200 observations) and joint linkage mapping was performed with ∼93,000 markers. Fifty-four QTL of small to large effect were identified for trait BLUPs (9–16 per trait) each explaining 0.4–4% of variation across the NAM population. While some of these QTL colocalize with sorghum homologs of grass genes [e.g. involved in hormone synthesis (maizespi1), floral transition (SbCN8), and transcriptional regulation of development (riceIdeal plant architecture1)], most QTL did not colocalize with ana prioricandidate gene (82%). Genomic prediction accuracy was generally high in five-fold cross-validation (0.65–0.83), and varied from low to high in leave-one-family-out cross-validation (0.04–0.61). The findings provide a foundation to identify the molecular basis of architecture variation in sorghum and establish genomic-enabled breeding for improved plant architecture.Core ideasUnderstanding the genetics of plant architecture could facilitate the development of crop ideotypes for yield and adaptationThe genetics of plant architecture traits was characterized in sorghum using multi-environment phenotyping in a global nested association mapping populationFifty-five quantitative trait loci were identified; some colocalize with homologs of known developmental regulators but most do notGenomic prediction accuracy was consistently high in five-fold cross-validation, but accuracy varied considerably in leave-one-family-out predictions
Off-target glycans encountered along the synthetic biology route towards humanized N-glycans inPichia pastoris
Authors: Laukens Bram , Jacobs Pieter P. , Geysens Katelijne , Martins Jose , De Wachter Charlot , Ameloot Paul , Morelle Willy , Haustraete Jurgen , Renauld Jean-Christophe , Samyn Bart , Contreras Roland , Devos Simon , Callewaert Nico 
Published: January 2020

ABSTRACTBackgroundThe glycosylation pathways of several eukaryotic protein expression hosts are being engineered to enable the production of therapeutic glycoproteins with humanized application-customized glycan structures. In several expression hosts, this has been quite successful, but one caveat is that the new N-glycan structures inadvertently might be substrates for one or more of the multitude of endogenous glycosyltransferases in such heterologous background. This then results in the formation of novel, undesired glycan structures, which often remain insufficiently characterized.ResultsWhen expressing mouse interleukin-22 (mIL-22) in aPichia pastoris(syn.Komagataella phaffi) GlycoSwitchM5 strain which had been optimized to produce Man5GlcNAc2N-glycans, glycan profiling revealed two major species: Man5GlcNAc2and an unexpected, partially α-mannosidase-resistant structure. A detailed structural analysis using exoglycosidase sequencing, mass spectrometry, linkage analysis and NMR, revealed that this novel glycan was Man5GlcNAc2modified with a Glcα-1,2-Manβ-1,2-Manβ-1,3-Glcα-1,3-R tetra-saccharide. Also the biosynthetic intermediates of this off-target modification were detected. Expression of a Golgi-targeted GlcNAc Transferase-I strongly inhibited the formation of this novel modification, resulting in more homogeneous modification with the targeted GlcNAcMan5GlcNAc2structure. We have also observed the off-target glycan on other glycoproteins produced in the GlycoSwitchM5 strain. This illustrates the intricacies of Golgi glycosylation pathways and cautions that the use of glyco-engineered expression host cells should always be accompanied by detailed glycan analysis of the particular therapeutic proteins being produced.ConclusionsOur findings reinforce accumulating evidence that robustly customizing the N-glycosylation pathway inPichia pastoristo produce particular human-type structures is still an incompletely solved synthetic biology challenge, which will require further innovation to enable safe glycoprotein pharmaceutical production.
Diverse cell stimulation kinetics identify predictive signal transduction models
Authors: Jashnsaz Hossein , Fox Zachary R , Hughes Jason , Li Guoliang , Munsky Brian , Neuert Gregor 
Published: January 2020

ABSTRACTThe drive to understand cell signaling responses to environmental, chemical and genetic perturbations has produced outstanding fits of computational models to increasingly intricate experiments, yet predicting quantitative responses for new biological conditions remains challenging. Overcoming this challenge depends not only on good models and detailed experimental data but perhaps more so on how well the two are integrated. Our quantitative, live single-cell fluorescence imaging datasets and computational framework to model generic signaling networks show how different changing environments (hereafter ‘kinetic stimulations’) probe and result in distinct pathway activation dynamics. Utilizing multiple diverse kinetic stimulations better constrains model parameters and enables predictions of signaling dynamics that would be impossible using traditional step-change stimulations. To demonstrate our approach’s generality, we use identified models to predict signaling dynamics in normal, mutated, and drug-treated conditions upon multitudes of kinetic stimulations and quantify which proteins and reaction rates are most sensitive to which extracellular stimulations.
Chloe: Flexible, Efficient Data Provenance and Management
Authors: Kazic Toni 
Published: January 2020

1AbstractReproducible and sharable research requires robust data provenance during and after the experimental process. Each laboratory and experiment has its own goals and methods, and these change frequently. Planning, managing, and collecting data from research crops are particularly labor-intensive tasks, given the tightly compressed time schedule and the operating environments. Moving from a lab’s present record-keeping approach to an electronic ecosystem that improves provenance is an additional burden for groups without dedicated, consistent computational support to make that transition and then to adapt the system as needed. This high barrier to entry and the press of field work makes it easy to postpone “computerizing”.I have developedChloeto reduce manual effort during experiments and maintain data provenance. A flexible, modular system,Chloeintegrates simple equipment, data collection strategies, and software into workflows. The design lets one use parts without deploying the whole. This reduces the barriers to entry while still improving workflow efficiency and makingChloeaccessible to a wide range of users. I offer guidance on ways to adaptChloeto one’s own experimental situation.Chloehas been tested and refined with many changes of students, hardware, and experimental goals over the last fourteen years. Though originally designed for maize genetics and computational experiments,Chloecan accommodate other types of experiments, wetbench work, and other crops.
Peripheral Myelin Protein 22 Preferentially Partitions into Ordered Phase Membrane Domains
Authors: Marinko Justin T. , Li Geoffrey C. , Kenworthy Anne K. , Sanders Charles R. 
Published: January 2020

AbstractThe ordered environment of membrane rafts is thought to exclude many transmembrane proteins. Nevertheless, some multi-pass transmembrane proteins have been proposed to partition into ordered domains. Here, giant plasma membrane vesicles (GPMVs) were employed to quantitatively show that the tetraspan peripheral myelin protein 22 (PMP22) exhibits a pronounced preference for, promotes the formation of, and stabilizes ordered membrane domains. Neither S-palmitoylation of PMP22 nor its putative cholesterol binding motifs are required for partitioning to ordered domains. In contrast, disruption of its unusual first transmembrane helix (TM1) reduced ordered phase preference. Charcot-Marie-Tooth disease-causing mutations that destabilize PMP22 also reduced or eliminated this preference in favor of the disordered phase. These studies demonstrate PMP22’s ordered phase preference derives both from the distinctive properties of TM1 and global structural features associated with its transmembrane domain, providing a first glimpse at the structural factors that promote raft partitioning for multi-pass proteins.Significance StatementThe preferential partitioning of single span membrane proteins for the ordered phase of ordered/disordered phase-separated membranes is now reasonably well understood, but little is known about this phase preferences of multi-pass membrane proteins. Here, it is shown that the disease-linked tetraspan integral membrane protein, PMP22, displays a pronounced preference to partition into the ordered phase, a preference that is reversed by disease mutations. This phase preference may be related to the role of PMP22 in cholesterol homeostasis in myelinating Schwann cells, a role that is also known to be disrupted under conditions of CMTD peripheral neuropathy caused bypmp22mutations.
Neural Circuit Dynamics for Sensory Detection
Authors: Mallik Sruti , Nizampatnam Srinath , Nandi Anirban , Saha Debajit , Raman Baranidharan , Ching ShiNung 
Published: January 2020

AbstractWe consider the question of how sensory networks enable the detection of sensory stimuli in a combinatorial coding space. We are specifically interested in the olfactory system, wherein recent experimental studies have reported the existence of rich, enigmatic response patterns associated with stimulus onset and offset. This study aims to identify the functional relevance of such response patterns, i.e., what benefits does such neural activity provide in the context of detecting stimuli in a natural environment. We study this problem through the lens of normative, optimization-based modeling. Here, we define the notion of a low dimensional latent representation of stimulus identity, which is generated through action of the sensory network. The objective of our optimization framework is to ensure high fidelity tracking of a nominal representation in this latent space in an energy efficient manner. It turns out that the optimal motifs emerging from this framework possess morphological similarity with prototypical onset and offset responses observedin vivo. Furthermore, this objective can be exactly achieved by a network with reciprocal excitatory-inhibitory competitive dynamics, similar to interactions between principal neurons (PNs) and local neurons (LNs) in the early olfactory system of insects. The derived model also makes several predictions regarding maintenance of robust latent representations in the presence of confounding background information and tradeoffs between the energy of sensory activity and resultant behavioral measures such as speed and accuracy of stimulus detection.Significance StatementA key area of study in olfactory coding involves understanding the transformation from high-dimensional sensory stimulus to low-dimensional decoded representation. Here, we treat not only the dimensionality reduction of this mapping but also its temporal dynamics, with specific focus on stimuli that are temporally continuous. We examine through optimization-based synthesis how sensory networks can track representations without prior assumption of discrete trial structure. We show that such tracking can be achieved by canonical network architectures and dynamics, and that the resulting responses resemble observations from neurons in the insect olfactory system. Thus, our results provide hypotheses regarding the functional role of olfactory circuit activity at both single neuronal and population scales.
Purkinje cell neurotransmission patterns cerebellar basket cells into zonal modules that are defined by distinct pinceau sizes
Authors: Zhou Joy , Brown Amanda M. , Lackey Elizabeth P. , Arancillo Marife , Lin Tao , Sillitoe Roy V. 
Published: January 2020

AbstractRamón y Cajal proclaimed the neuron doctrine based on circuit features he exemplified using cerebellar basket cell projections. Basket cells form dense inhibitory plexuses that wrap Purkinje cell somata and terminate as pinceaux at the initial segment of axons. Here, we demonstrate that HCN1, Kv1.1, PSD95 and GAD67 unexpectedly mark patterns of basket cell pinceaux that map onto Purkinje cell functional zones. Using cell-specific genetic tracing with anAscl1CreERT2mouse conditional allele, we reveal that basket cell zones comprise different sizes of pinceaux. We tested whether Purkinje cells instruct the assembly of inhibitory projections into zones, as they do for excitatory afferents. Genetically silencing Purkinje cell neurotransmission blocks the formation of sharp Purkinje cell zones and disrupts excitatory axon patterning. The distribution of pinceaux into size-specific zones is eliminated without Purkinje cell output. Our data uncover the cellular and molecular diversity of a foundational synapse that revolutionized neuroscience.
Hilbert space filling curves for interpretable point mutation effects on peptide conformational dynamics
Authors: Rath Siddharth S. , Hennig Tatum G. , Jorgenson Tyler D. , Fischer-Marques Pedro , Kumar Nitya Krishna , Starkebaum David , Ustundag Burak Berk , Sarikaya Mehmet 
Published: January 2020

AbstractSpontaneous self-organization of solid-binding peptides on single-layer atomic materials offers enormous potential in employing these systems for practical technological and medical applications. Molecular self-organization of peptides depends highly on their sequences which, in turn, affect their conformational behavior under aqueous conditions. Traditional ways of computationally studying the effect of mutations on the conformation states involves dimension reduction on cosine and sine transformed torsion angles, often represented as Ramachandran plots. Although these studies successfully cluster conformation states, they fail to intuitively characterize the effect of the point mutation(s) directly, necessitating further data analysis. Here, we apply Hilbert Space-Filling-Curve (HSFC) on the torsion angles and demonstrate intuitive visualization for the effect of point mutations on conformation states and secondary structure dynamics along a reaction coordinate. We perform molecular dynamics (MD) simulation on wild-type graphene binding peptide (WT-GrBP5). The 12-amino acid long peptide was selected by directed evolution and known to self-organize on atomically flat surface of graphene only under low-neutral pH at room temperature. A charge neutral mutant, M9-GrBP5, on the other hand, assembles at a broader range of pH’s at room temperature, as expected. The HSFC shows clearly that the mutated amino acids in M9 do not correlate with the reaction coordinate of pH change, unlike that of WT, confirming heuristic knowledge. Understanding the effect of specific amino acid φ-ψ pairs that contribute most to the changes in the conformational space of the peptide with changing conditions, will help in analyzing effects of point mutations in peptide sequences. The knowledge of the conformational behavior of solid binding peptides, in general, and its effect on their self-organization propensities on solid surfaces would lead to the rational design of sequences that form soft bio/nano hybrid interfaces in the future towards robust strategies for surface biofunctionalization, in general, and bioelectronics and biosensors, in particular.
CD44 regulates blood-brain barrier integrity in response to fluid shear stress
Authors: DeOre Brandon J. , Partyka Paul P. , Fan Fan , Galie Peter A. 
Published: January 2020

AbstractFluid shear stress is an important mediator of vascular permeability, yet the molecular mechanisms underlying the response of the blood-brain barrier to shear have yet to be studied in cerebral vasculature despite its importance for brain homeostasis. The goal of this study is to probe components of shear mechanotransduction within the blood-brain barrier to gain a better understanding of pathologies associated with changes in cerebral blood flow including ischemic stroke. Interrogating the effects of shear stress in vivo is complicated by the complexity of factors in the brain parenchyma and the difficulty associated with modulating blood flow regimes. Recent advances in the ability to mimic the in vivo microenvironment using three-dimensional in vitro models provide a controlled setting to study the response of the blood-brain barrier to shear stress. The in vitro model used in this study is compatible with real-time measurement of barrier function using transendothelial electrical resistance as well as immunocytochemistry and dextran permeability assays. These experiments reveal that there is a threshold level of shear stress required for barrier formation and that the composition of the extracellular matrix, specifically the presence of hyaluronan, dictates the flow response. Gene editing to modulate the expression of CD44, a receptor for hyaluronan that previous studies have identified to be mechanosensitive, demonstrates that the receptor is required for the endothelial response to shear stress. Manipulation of small GTPase activity reveals CD44 activates Rac1 while inhibiting RhoA activation. Additionally, adducin-γ localizes to tight junctions in response to shear stress and RhoA inhibition and is required to maintain the barrier. This study identifies specific components of the mechanosensing complex associated with the blood-brain barrier response to fluid shear stress, and therefore illuminates potential targets for barrier manipulation in vivo.
Identifying spawning activity in aquatic species based on environmental DNA spikes
Authors: Tsuji Satsuki , Shibata Naoki 
Published: January 2020

AbstractAn understanding of the reproductive biology of aquatic organisms is crucial for the efficient conservation and management of species and/or populations. Nevertheless, conventional spawning surveys such as visual- and capture-based monitoring generally require laborious, time-consuming work and are subject to monitoring biases such as observer bias, as well as miscounts due to false spawning. In addition, direct capture often damages eggs or individuals. Thus, an efficient non-invasive approach for monitoring spawning activity on aquatic species would be a valuable tool to understand their reproductive biology and conserving biodiversity. Here, we proposed an environmental DNA (eDNA)-based approach for monitoring and understanding spawning activity by observing spikes in eDNA concentration after spawning activity. We found in cross experiments using two medaka species (Oryzias latipesandO. sakaizumii, 1:1 individual per tank) that an eDNA spike occurred in only male species after spawning activity. In addition, the magnitude of the eDNA spike was dependent on the number of spawning activities with egg and sperm release. In the field survey during the reproductive season, eDNA concentration after spawning were 3–25 times higher than before spawning. On the other hand, there was no increase in eDNA concentration during the non-reproductive season. Therefore, our results demonstrated that spikes in the eDNA concentration are mainly caused by the release of sperm during spawning activity, and it can be used as evidence of spawning in field survey. The presented approach could be a practical tool for studying reproductive biology and provides an opportunity to design effective conservation and environmental management actions.