bluuebunny/crossref_metadata_2025_split huggingface dataset:
Female rat sexual behavior is unaffected by perinatal fluoxetine exposure
Authors: Hegstad Jan , Huijgens Patty T. , Houwing Danielle J. , Olivier Jocelien D.A. , Heijkoop Roy , Snoeren Eelke M.S. 
Published: May 2020

AbstractSerotonin plays an important role in adult female sexual behavior, however little is known about the influence of serotonin during early development on sexual functioning in adulthood. During early development, serotonin acts as neurotrophic factor, while it functions as a modulatory neurotransmitter in adulthood. The occurrence of serotonin release, could thus have different effects on behavioral outcomes, depending on the developmental period in which serotonin is released. Because serotonin is involved in the development of the HPG axis which is required for puberty establishment, serotonin could also alter expression patterns of for instance the estrogen receptor α (ERα).The aim of our study was to investigate the effects of increased serotonin levels during early development on adult female rat sexual behavior during the full behavioral estrus in a seminatural environment. To do so, rats were perinatally exposed with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10 mg/kg FLX) and sexual performance was tested during adulthood. All facets of female sexual behavior between the first and last lordosis (behavioral estrus), and within each copulation bout of the behavioral estrus were analyzed. Besides the length and onset of the behavioral estrus and the sexual behaviors patterns, other social and conflict behavior were also investigated. In addition, we studied the effects of perinatal FLX exposure on ERα expression patterns in the medial preoptic nucleus, ventromedial nucleus of the hypothalamus, medial amygdala, bed nucleus of the stria terminalis, and the dorsal raphé nucleus.The results showed that perinatal fluoxetine exposure has no effect on adult female sexual behavior. The behavioral estrus of FLX-females had the same length and pattern as CTR-females. In addition, FLX- and CTR-females showed the same amount of paracopulatory behavior and lordosis, both during the full behavioral estrus and the “most active bout”. Furthermore, no differences were found in the display of social and conflict behaviors, nor in ERα expression patterns in the brain. We conclude that increases in serotonin levels during early development do not have long-term consequences for female sexual behavior in adulthood.
Implantable Electrical Connector for Reconnecting Injured Neurons, Approach and Design
Authors: Hashemi Soheil , Abdolali Ali 
Published: May 2020

AbstractIn contrast to normal injuries, damages of the nervous system are very difficult to repair. In this paper, a connector is designed to reconnect injured nerve to healthy cells. This cord was designed and tested by the full wave and three dimensional electromagnetic modeling. The connector is comprised of three parts, including the conductor, dielectric coating, and second coating with high conductivity. Electromagnetic characteristics need to be unique to work fine, each part is obtained with regard to the distance between two neurons. The combination of materials with conductivity lower than 100 S/m and relative permittivity lower than 8 creates the connection of two neurons up to 35 cm. The connector is realizable by biocompatible polymers.
Divergent cancer etiologies drive distinct B cell signatures and tertiary lymphoid structures
Authors: Ruffin Ayana T , Cillo Anthony R , Tabib Tracy , Liu Angen , Onkar Sayali , Kunning Sheryl , Lampenfeld Caleb , Abecassis Irina , Qi Zengbiao , Soose Ryan , Duvvuri Umamaheswar , Kim Seungwon , Oesterrich Steffi , Lafyatis Robert , Ferris Robert L , Vignali Dario AA , Bruno Tullia C 
Published: May 2020

AbstractCurrent immunotherapy paradigms aim to reinvigorate CD8+T cells, but the contribution of humoral immunity to antitumor immunity remains understudied1,2. Head and neck squamous cell carcinoma (HNSCC) is caused by either human papillomavirus (HPV+) or environmental carcinogens (i.e. tobacco and alcohol; HPV–)3,4. Here, we demonstrate that HPV+ HNSCC patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with GC-like tertiary lymphoid structures (TLS), both of which correlate with favorable outcomes in HNSCC patients. Further, our single-cell RNAseq data also indicate that GC TIL-Bs are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. High-dimensional spectral flow cytometry permitted in depth characterization of activated, memory and GC TIL-Bs. Further, single cell RNAseq analysis and subsequent protein validation identified a role for semaphorin 4a (Sema4a) in the differentiation of GC TIL-Bs and indicated that expression of Sema4a was enhanced on GC TIL-Bs and within GC-like TLS in the TME. Thus, in contrast to some reports on the detrimental role of TIL-Bs in human tumors, our findings suggest that TIL-Bs play an instrumental role in antitumor immunity5,6. Novel therapeutics to enhance TIL-B responses in HNSCC should be prioritized as a compliment to current T-cell mediated immunotherapies.
Direct reprogramming of adult hepatocytes to generate LGR5+ endodermal progenitor
Authors: Chaker Diana , Desterke Christophe , Moniaux Nicolas , Ernault Tony , Oudrhiri Noufissa , Faivre Jamila , Turhan Ali G , Bennaceur-Griscelli Annelise , Griscelli Frank 
Published: May 2020

AbstractWe successfully converted hepatocytes isolated from adult mice into expandable and stable leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5)-positive endodermal progenitor cells (EndoPCs). This was accomplishedin vitrothrough transient exposure to four transcriptional factors (OCT3/4, SOX2, KLF4, and cMYC) and STAT3 activators. EndoPCs were generated by a process that involved an epithelial-mesenchymal transition (EMT) without the use of any components of the canonical WNT/β-catenin or LGR5/R-spondin signaling pathways. We showed that the proliferation and capacity for self-renewal of EndoPCs in 2D long-term culture were controlled by three interrelated signaling pathways: gp130/JAK/STAT3, LGR5/R-spondin, and WNT/β-catenin. After long-term maintenance in two- and three-dimensional culture systems, EndoPCs were able to differentiate into liver-restricted lineages such as hepatocyte-like cells and bile duct-like structuresin vitroandin vivo. After intra-muscular injection, EndoPCs generated macroscopically visible and well-vascularized liver-like tissue, which contained Alb+liver parenchyma-like structures and substantial, KRT7/KRT19+bile duct-like cell organizations.ConclusionWe have developed an efficient method for producing LGR5+adult endodermal stem cells. These cells will be useful for thein vitrostudy of the molecular mechanisms of liver development and have important potential for therapeutic strategies, including approaches based on bioengineered liver tissue. These cells also open up new avenues for experiments focused on disease modeling, toxicology studies, and regenerative medicine applications.
The effect of resource limitation on the temperature-dependence of mosquito population fitness
Authors: Huxley Paul J. , Murray Kris A. , Pawar Samraat , Cator Lauren J. 
Published: May 2020

ABSTRACTLaboratory-derived temperature dependencies of life history traits are increasingly being used to make mechanistic predictions for how climatic warming will affect vector-borne disease dynamics, partially by affecting abundance dynamics of the vector population. These temperature-trait relationships are typically estimated from populations reared on optimal resource supply, even though natural populations of vectors are expected to experience variation in resource supply, including intermittent resource limitation. Using laboratory experiments on the mosquitoAedes aegypti, a principal arbovirus vector, combined with stage-structured population modelling, we show that low-resource supply significantly depresses the vector’s maximal population growth rate across the entire temperature range (22-32°C) and causes it to peak at a lower temperature than at high-resource supply. This effect is primarily driven by an increase in juvenile mortality and development time, combined with an exaggerated decrease in adult size with temperature at low-resource supply. Our study suggests that projections of vector abundance and disease transmission based on laboratory studies are likely to substantially underestimate how resource supply can modulate the temperature-dependency of population-level fitness through its influence on juvenile survival and development time. Our results provide compelling evidence for future studies to consider resource supply when predicting the effects of climate and habitat change on disease vectors and transmission.
Non-REM sleep facilitates consolidation of contextual fear memory through temporal coding among hippocampal neurons
Authors: Skilling Quinton M. , Clawson Brittany C. , Eniwaye Bolaji , Shaver James , Ognjanovski Nicolette , Aton Sara J. , Zochowski Michal 
Published: May 2020

SummarySleep plays a critical role in memory consolidation, although the exact mechanisms mediating this process are unknown. Combining computational andin vivoexperimental approaches, we test the hypothesis that reduced cholinergic input to the hippocampus during non-rapid eye movement (NREM) sleep generates stable spike timing relationships between neurons. We find that the order of firing among neurons during a period of NREM sleep reflects their relative firing rates during prior wake, and changes as a function of prior learning. We show that learning-dependent pattern formation (e.g. “replay”) in the hippocampus during NREM, together with spike timing dependent plasticity (STDP), restructures network activity in a manner similar to that observed in brain circuits across periods of sleep. This suggests that sleep actively promotes memory consolidation by switching the network from rate-based to firing phase-based information encoding.
Mathematical modelling of megakaryopoiesis in Mpl-deficient and continuously thrombopoietin-stimulated mice points to an unknown control mechanism
Authors: Diebner Hans H. , Gottschalk Andrea , Baldow Christoph , Klose Markus , Glauche Ingmar 
Published: May 2020

ABSTRACTThrombopoietin (TPO) is the ligand of the Mpl receptor and the key regulator of megakaryopoiesis and platelet production. A loss or gain of the TPO-receptor function affects haematopoiesis and results in severe diseases in humans. Appropriate mouse strains are available to mimic both myeloproliferative neoplasm (MPN) and congenital amegakaryocytic thrombocytopenia (CAMT) resulting from TPO overexpression or knockout of TPO receptor Mpl on megakaryocytes and platelets, respectively. However, at a quantitative level it is not understood, how the known regulations can establish the impaired but stable disease phenotypes.Starting out from an established mathematical model for megakaryopoiesis, we aim to adapt it to both the healthy situation and to distinct diseased phenotypes mimicking MPN. We thereby identify, that some of the model parameters are invariant with respect to the mouse strain while others have to be estimated in a strain-dependent manner. A systematic process of parameter identification provides strong evidence that the well-known excess production of megakaryocytes and early progenitors in MPN is either directly contingent on Mpl expression of platelets and megakaryocytes or, alternatively, that the knockout of Mpl is not as precisely restricted to megakaryocytes and platelets but may also effect their progenitors.In conclusion, our analysis hints towards an opaque control mechanism rendering megakaryopoiesis at a yet unknown level, and awaiting further experimental evaluation.
Integrating multimodal data through interpretable heterogeneous ensembles
Authors: Li Yan Chak , Wang Linhua , Law Jeffrey N. , Murali T. M. , Pandey Gaurav 
Published: May 2020

AbstractMotivationIntegrating multimodal data represents an effective approach to predicting biomedical characteristics, such as protein functions and disease outcomes. However, existing data integration approaches do not sufficiently address the heterogeneous semantics of multimodal data. In particular, early and intermediate approaches that rely on a uniform integrated representation reinforce the consensus among the modalities, but may lose exclusive local information. The alternative late integration approach that can address this challenge has not been systematically studied for biomedical problems.ResultsWe propose Ensemble Integration (EI) as a novel systematic implementation of the late integration approach. EI infers local predictive models from the individual data modalities using appropriate algorithms, and uses effective heterogeneous ensemble algorithms to integrate these local models into a global predictive model. We also propose a novel interpretation method for EI models. We tested EI on the problems of predicting protein function from multimodal STRING data, and mortality due to COVID-19 from multimodal data in electronic health records. We found that EI accomplished its goal of producing significantly more accurate predictions than each individual modality. It also performed better than several established early integration methods for each of these problems. The interpretation of a representative EI model for COVID-19 mortality prediction identified several disease-relevant features, such as laboratory test (blood urea nitrogen (BUN) and calcium) and vital sign measurements (minimum oxygen saturation) and demographics (age). These results demonstrated the effectiveness of the EI framework for biomedical data integration and predictive modeling.AvailabilityCode and data are available athttps://github.com/GauravPandeyLab/ensemble_integration.Contactgaurav.pandey@mssm.edu
Development of a Tet-On inducible expression system for the anhydrobiotic cell line, Pv11
Authors: Tokumoto Shoko , Miyata Yugo , Usui Kengo , Deviatiiarov Ruslan , Ohkawa Takahiro , Kondratieva Sabina , Shagimardanova Elena , Gusev Oleg , Cornette Richard , Itoh Masayoshi , Hayashizaki Yoshihide , Kikawada Takahiro 
Published: May 2020

AbstractThe Pv11 cell line established from an African chironomid,Polypedilum vanderplanki, is the only cell line tolerant to complete desiccation. In Pv11 cells, a constitutive expression system for Pv11 cells was previously exploited and several reporter genes were successfully expressed. Here we report the identification of an effective minimal promoter for Pv11 cells and its application to the Tet-On inducible expression system. First, using a luciferase reporter assay, we showed that a 202 bp deletion fragment derived from the constitutively active 121-promoter functions in Pv11 cells as an appropriate minimal promoter with the Tet-On inducible expression system. The AcGFP1 protein was also successfully expressed in Pv11 cells using the inducible system. In addition to these reporter genes, avian myeloblastosis virus reverse transcriptase α subunit (AMV RTα), which is one of the most widely commercially available RNA-dependent DNA polymerases, was successfully expressed through the inducible expression system and its catalytic activity was verified. These results demonstrate the establishment of an inducible expression system in cells that can be preserved in the dry state and highlight a possible application to the production of large and complex proteins.HighlightsA 202 bp-deletion fragment derived from a constitutively active promoter was identified as a minimal promoter in Pv11 cells.A Tet-On inducible expression system was developed for Pv11 cells using the minimal promoter.Typical reporter genes (GFP and luciferase) and an enzyme with complex structure, i.e. a viral reverse transcriptase, were successfully and inducibly expressed in Pv11 cells using the Tet-On system.
Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish
Authors: Hoeksma Jelmer , van der Zon Gerard C.M. , Dijke Peter ten , den Hertog Jeroen 
Published: May 2020

AbstractZebrafish models are well established tools for investigating underlying mechanisms of diseases. Here, we identified cercosporamide, a metabolite from the fungusAscochyta aquiliqiae, as a potent bone morphogenetic protein (BMP) type I receptor kinase inhibitor through a zebrafish embryo phenotypic screen. The developmental defects in zebrafish, including lack of the ventral fin induced by cercosporamide was strikingly similar as the phenotypes caused by renowned small molecule BMP type I receptor kinase inhibitors and inactivating mutations in zebrafish BMP receptors. In mammalian cell-based assays, cercosporamide blocked BMP/SMAD-dependent transcriptional reporter activity and BMP-induced SMAD1/5-phosphorylation. Biochemical assays with a panel of purified recombinant kinases demonstrated that cercosporamide directly inhibited kinase activity of BMP type I receptors (also called activin receptor-like kinases (ALKs)). In mammalian cells, cercosporamide selectively inhibited constitutively active BMP type I receptor-induced SMAD1/5 phosphorylation. Importantly, cercosporamide rescued the developmental defects caused by constitutively active Alk2 in zebrafish embryos. Taken together, we believe cercosporamide may be the first of a new class of molecules with potential to be developed further for clinical use against diseases that are causally linked to overactivation of BMP receptor signaling, including Fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma.
Multivalent lipid targeting by the calcium-independent C2A domain of Slp-4/granuphilin
Authors: Alnaas Aml A , Watson-Siriboe Abena , Tran Sherleen , Negussie Mikias , Henderson Jack A. , Osterberg J. Ryan , Chon Nara Lee , Oviedo Julianna , Lyakhova Tatyana , Michel Cole , Reisdorph Nichole , Reisdorph Richard , Shearn Colin T. , Lin Hai , Knight Jefferson D. 
Published: May 2020

ABSTRACTSynaptotagmin-like protein 4 (Slp-4), also known as granuphilin, is a Rab effector responsible for docking secretory vesicles to the plasma membrane before exocytosis. Slp-4 binds vesicular Rab proteins via an N-terminal Slp homology (SHD) domain, interacts with plasma membrane SNARE complex proteins via a central linker region, and contains tandem C-terminal C2 domains (C2A and C2B) with affinity for phosphatidylinositol-(4,5)-bisphosphate (PIP2). The Slp-4 C2A domain binds with low nanomolar apparent affinity to PIP2in lipid vesicles that also contain background anionic lipids such as phosphatidylserine (PS), but much weaker when either the background anionic lipids or PIP2are removed. Through computational and experimental approaches, we show that this high affinity membrane interaction arises from concerted interaction at multiple sites on the C2A domain. In addition to a conserved PIP2-selective lysine cluster, there exists a larger cationic surface surrounding the cluster which contributes substantially to the affinity for physiologically relevant lipid compositions. While mutations at the PIP2-selective site decrease affinity for PIP2, multiple mutations are needed to decrease binding to physiologically relevant lipid compositions. Docking and molecular dynamics simulations indicate several conformationally flexible loops that contribute to the nonspecific cationic surface. We also identify and characterize a covalently modified variant in the bacterially expressed protein, which arises through reactivity of the PIP2-binding lysine cluster with endogenous bacterial compounds and has a low membrane affinity. Overall, multivalent lipid binding by the Slp-4 C2A domain provides selective recognition and high affinity docking of large dense-core secretory vesicles to the plasma membrane.
Role of matrix metalloproteinase-9 in neurodevelopmental disorders and experience-dependent plasticity in Xenopus tadpoles
Authors: Gore Sayali , James Eric J. , Huang Lin-Chien , Park Jenn J. , Berghella Andrea , Thompson Adrian , Cline Hollis T. , Aizenman Carlos D. 
Published: May 2020

AbstractMatrix metalloproteinase-9 (MMP-9) is a secreted endopeptidase targeting extracellular matrix proteins, creating permissive environments for neuronal development and plasticity. Developmental dysregulation of MMP-9 is also associated with neurodevelopmental disorders (ND). Here we test the hypothesis that chronically elevated MMP-9 activity during early neurodevelopment is responsible for neural circuit hyperconnectivity observed after early exposure to valproic acid (VPA), a known teratogen associated with autism spectrum disorder in humans. InXenopustadpoles, VPA exposure results in excess local synaptic connectivity, disrupted social behavior and increased seizure susceptibility. We found that overexpressing MMP-9 in the brain copies effects of VPA on synaptic connectivity, and blocking MMP-9 activity pharmacologically or genetically reverses effects of VPA on physiology and behavior. We further show that during normal neurodevelopment MMP-9 levels are tightly regulated by neuronal activity and required for structural plasticity. These studies show a critical role for MMP-9 in both normal and abnormal development.
Can’t decide how much to EAT? Effort variability for reward is associated with cognitive restraint
Authors: van den Hoek Ostende Mechteld M. , Neuser Monja P. , Teckentrup Vanessa , Svaldi Jennifer , Kroemer Nils B. 
Published: May 2020

AbstractFood intake is inherently variable and often characterized by episodical restraint or overeating (uncontrolled eating). Such heightened variability in intake has been associated with higher variability in the brain response to food reward, but it is an open issue whether comparable associations with elevated variability in reward seeking exist. Here, we assessed whether restraint and uncontrolled eating as markers of trait-like variability in eating are associated with higher intra-individual variability in reward seeking as captured by a cost-benefit paradigm. To test this hypothesis, 81 healthy, overnight-fasting participants (MBMI= 23.0 kg/m2± 2.95) completed an effort allocation task (EAT) twice. In the EAT, participants had to exert physical effort to earn monetary and food rewards and indicated levels of wanting through visual analog scales (VAS). As predicted, we found that greater trial-by-trial effort variability was associated with lower scores on cognitive restraint,rp(78) = −.28,p= .011 (controlled for average effort). In line with previous findings, higher wanting variability was associated with higher BMI,rp(78) = .25,p= .026 (controlled for average effort). Collectively, our results support the idea that higher variability in reward seeking is a potential risk factor for eating beyond homeostatic need. Since associations with variability measures of reward exceeded associations with average reward seeking, our findings may indicate that variability in the representation of the reward value could be a crucial aspect driving fluctuations in food intake.