bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amplification of potential thermogenetic mechanisms in cetacean brains
Authors: Manger Paul R. , Patzke Nina , Spocter Muhammad A. , Bhagwandin Adhil , Karlsson Karl Æ. , Bertelsen Mads F. , Alagaili Abdulaziz N. , Bennett Nigel C. , Mohammed Osama B. , Herculano-Houzel Suzana , Hof Patrick R. , Fuxe Kjell 
Published: October 2020

AbstractTo elucidate causality underlying the evolution of large brains in cetaceans, we examined the brains of 16 cetartiodactyl species for evidence of non-shivering thermogenesis. In comparison to the artiodactyl brain, the cetacean brain exhibits an expanded expression of uncoupling protein 1 (UCP1, UCPs being mitochondrial inner membrane proteins that dissipate the proton gradient to generate heat) in cortical neurons, localization of UCP4 within a substantial proportion of glia throughout the brain, and an increased density of noradrenergic axonal boutons (noradrenaline functioning to control concentrations of and activate UCPs). Thus, cetacean brains possess multiple characteristics indicative of intensified thermogenetic functionality that can be related to their current and historical obligatory aquatic niche. These findings necessitate reassessment of our concepts regarding the reasons for large brain evolution and associated functional capacities in cetaceans.
Neural Mechanism of Hunger-gated Food-seeking and Evaluating
Authors: Lee Young Hee , Kim You Bin , Kim Kyu Sik , Song Ha Young , Jang Mirae , Ha Dong-Soo , Park Joon Seok , Jung Sang-Ho , Lee Jaegeon , Kim Kyung Min , Cheon Deok-Hyeon , Baek Inhyeok , Shin Min-Gi , Lee Eun Jeong , Kim Sang Jeong , Choi Hyung Jin 
Published: October 2020

AbstractThe physiological need for energy evokes motivated feeding behaviours that help to ensure survival. However, the neural mechanisms underlying the generation of food motivation remain poorly understood. We investigated these mechanisms by subdividing feeding-related motivated behaviours into food-seeking, evaluating, and swallowing. Micro-endoscopic results indicated that neurons containing leptin receptors (LepRs) in the lateral hypothalamus (LH) are the major food-specific subpopulation of LHGABAneurons. Optogenetic manipulation of LHLepRneurons bidirectionally regulated both food-seeking and evaluating. Furthermore, micro-endoscope data revealed that distinct LHLepRneurons encode seeking and evaluating. Computational modelling analysis demonstrated that LHLepRneurons encode motivation, whereas neurons containing agouti-related peptide and neuropeptide Y (AgRP/NPY) encode the need for food. Additionally, slice studies revealed that NPY decreases inhibitory input to LHLepRneurons via LHGABAinterneurons. This mechanism explains the permissive gate role of hunger (food need) in seeking/evaluating motivation. Together, the present study provides a comprehensive neural mechanism of how physiological needs drive distinct motivated behaviours.
Retrograde suppression of post-tetanic potentiation at the mossy fiber-CA3 pyramidal cell synapse
Authors: Makani Sachin , Lutzu Stefano , Lituma Pablo J. , Hunt David L. , Castillo Pablo E. 
Published: October 2020

ABSTRACTIn the hippocampus, the excitatory synapse between dentate granule cell axons – or mossy fibers (MF) – and CA3 pyramidal cells (MF-CA3) expresses robust forms of short-term plasticity, such as frequency facilitation and post-tetanic potentiation (PTP). These forms of plasticity are due to increases in neurotransmitter release, and can be engaged when dentate granule cells fire in bursts (e.g. during exploratory behaviors) and bring CA3 pyramidal neurons above threshold. While frequency facilitation at this synapse is limited by endogenous activation of presynaptic metabotropic glutamate receptors, whether MF-PTP can be regulated in an activity-dependent manner is unknown. Here, using physiologically relevant patterns of mossy fiber stimulation in acute mouse hippocampal slices, we found that disrupting postsynaptic Ca2+dynamics increases MF-PTP, strongly suggesting a form of Ca2+-dependent retrograde suppression of this form of plasticity. PTP suppression requires a few seconds of MF bursting activity and Ca2+release from internal stores. Our findings raise the possibility that the powerful MF-CA3 synapse can negatively regulate its own strength not only during PTP-inducing activity typical of normal exploratory behaviors, but also during epileptic activity.SIGNIFICANCE STATEMENTThe powerful mossy fiber-CA3 synapse exhibits strong forms of plasticity that are engaged during location-specific exploration, when dentate granule cells fire in bursts. While this synapse is well-known for its presynaptically-expressed LTP and LTD, much less is known about the robust changes that occur on a shorter time scale. How such short-term plasticity is regulated, in particular, remains poorly understood. Unexpectedly, anin vivo-like pattern of presynaptic activity induced robust post-tetanic potentiation (PTP) only when the postsynaptic cell was loaded with a high concentration of Ca2+buffer, indicating a form of Ca2+–dependent retrograde suppression of PTP. Such suppression may have profound implications for how environmental cues are encoded into neural assemblies, and for limiting network hyperexcitability during seizures.
Mitochondrial ATP Synthase Trafficking along Microtubules to Cell Surface Depends on KIF5B and DRP1
Authors: Chang Yi-Wen , Yang T. Tony , Chen Min-Chun , Liaw Y-geh , Yin Chieh-Fan , Huang Ting-Yu , Hou Jen-Tzu , Hung Yi-Hsuan , Hsu Chia-Lang , Huang Hsuan-Cheng , Juan Hsueh-Fen 
Published: October 2020

AbstractEctopic adenosine triphosphate (eATP) synthase, located on the cell surface instead of the mitochondrial inner membrane, has been discovered to be a novel target for the treatment of various types of cancer. However, the mechanism of eATP synthase trafficking toward the cell surface remains unclear. In this study, we used an integrative approach incorporating multiomics, super-resolution imaging, real-time live-cell tracing, and various functional analyses to derive a transport model of eATP synthase from the mitochondria to the plasma membrane in cancer cells. We determined that the ATP synthase complex is first assembled in the mitochondria and subsequently delivered to the cell surface through the microtubule-mediated mitochondrial transport pathway. We also found that dynamin-related protein 1 (DRP1) enhances mitochondrial fission and subsequently associates with microtubule motor protein kinesin family member 5B (KIF5B) to promote the subcellular transportation of eATP synthase. Consequently, our work provides a blueprint for eATP synthase trafficking from the mitochondria toward the cell surface.
Corticostriatal Projections of Macaque Area 44
Authors: Korponay Cole , Choi Eun Young , Haber Suzanne N. 
Published: October 2020

ABSTRACTVentrolateral frontal area 44 is implicated in inhibitory motor functions and facilitating prefrontal control over vocalization. Yet, the corticostriatal circuitry that may contribute to area 44 functions is not clear, as prior investigation of area 44 corticostriatal projections is limited. Here, we used anterograde and retrograde tracing in macaques to map the innervation zone of area 44 corticostriatal projections, quantify their strengths, and evaluate their convergence with corticostriatal projections from non-motor and motor-related frontal regions. First, terminal fields from a rostral area 44 injection site were found primarily in the central caudate nucleus, whereas those from a caudal area 44 injection site were found primarily in the ventrolateral putamen. Second, amongst sampled striatal retrograde injection sites, area 44 input as a percentage of total frontal cortical input was highest in the ventral putamen at the level of the anterior commissure. Third, area 44 projections converged with both orofacial premotor area 6VR and other motor related projections (in the putamen), and with non-motor prefrontal projections (in the caudate nucleus). These findings support the role of area 44 as an interface between motor and non-motor functional domains, possibly facilitated by rostral and caudal area 44 subregions with distinct corticostriatal connectivity profiles.
Transcriptomics-based drug repositioning pipeline identifies therapeutic candidates for COVID-19
Authors: Le Brian L. , Andreoletti Gaia , Oskotsky Tomiko , Vallejo-Gracia Albert , Rosales Romel , Yu Katharine , Kosti Idit , Leon Kristoffer E. , Bunis Daniel G. , Li Christine , Kumar G. Renuka , White Kris M. , García-Sastre Adolfo , Ott Melanie , Sirota Marina 
Published: October 2020

AbstractThe novel SARS-CoV-2 virus emerged in December 2019 and has few effective treatments. We applied a computational drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available data. We utilized three independent published studies to acquire or generate lists of differentially expressed genes between control and SARS-CoV-2-infected samples. Using a rank-based pattern matching strategy based on the Kolmogorov-Smirnov Statistic, the signatures were queried against drug profiles from Connectivity Map (CMap). We validated sixteen of our top predicted hits in live SARS-CoV-2 antiviral assays in either Calu-3 or 293T-ACE2 cells. Validation experiments in human cell lines showed that 11 of the 16 compounds tested to date (including clofazimine, haloperidol and others) had measurable antiviral activity against SARS-CoV-2. These initial results are encouraging as we continue to work towards a further analysis of these predicted drugs as potential therapeutics for the treatment of COVID-19.
Biomolecular models of EPI-X4 binding to CXCR4 allow the rational optimization of peptides with therapeutic potential
Authors: Sokkar Pandian , Harms Mirja , Stürzel Christina , Gilg Andrea , Kizilsavas Gönül , Raasholm Martina , Preising Nico , Wagner Manfred , Ständker Ludger , Weidinger Gilbert , Münch Jan , Sanchez-Garcia Elsa 
Published: October 2020

ABSTRACTThe Endogenous Peptide Inhibitor of CXCR4 (EPI-X4) is a body-own fragment of albumin and specific antagonist of the CXC-motif-chemokine receptor 4 (CXCR4). CXCR4 signaling is induced by its sole chemokine ligand CXCL12 and is involved in a plethora of functions including cell homing, differentiation, survival and angiogenesis. Consequently, dysregulation of CXCR4 is involved in a variety of disorders, such as cancer or inflammatory diseases, making CXCR4 an attractive drug target. EPI-X4 and derivatives with increased CXCR4 binding affinities represent promising leads as CXCR4 antagonists and have shown therapeutic activity in mouse models of inflammatory diseases. However, it is currently unclear how EPI-X4 and its derivatives interact with CXCR4. Here, by combining biomolecular simulations with experimental mutagenesis and activity studies we investigated the binding behavior of EPI-X4 to CXCR4 at the molecular level. Our work allowed us to show that the EPI-X4 peptide interacts primarily in the minor pocket of CXCR4 through its N-terminal residues. The biomolecular interactions highlighted by the computational studies are in good agreement with the experimental mutagenesis data. Moreover, we found that the N-terminal seven amino-acids of EPI-X4 (a 16-mer) and its improved derivatives (12-mers) are sufficient for CXCR4 binding, which led to the development of shorter leads with optimized CXCR4 antagonizing properties. Collectively, we here established how EPI-X4 binds to its receptor and used this knowledge for rational drug design. The new peptide variants developed by us are more potent in terms of inhibiting CXCR4-downstream signaling and cancer cell migration, without toxic effects.
Chemoprophylaxis vaccination with aPlasmodiumliver stage autophagy mutant affords enhanced and long-lasting protection
Authors: Sahu Tejram , Gehrke Ella J. , Flores-Garcia Yevel , Mlambo Godfree , Romano Julia D. , Coppens Isabelle 
Published: October 2020

AbstractGenetically-attenuated sporozoite vaccines can elicit long-lasting protection against malaria but pose risks of breakthrough infection. Chemoprophylaxis vaccination (CVac) has proven to be the most effective vaccine strategy against malaria. Though CVac with WT sporozoites confers better immunity, the overhanging threat of drug resistance limits its use as a vaccine. Here, we demonstrate that a liver stage-specific mutant ofPlasmodium bergheiwhen used as a vaccine under a CVac regimen provides superior long-lasting protection, in both inbred and outbred mice, as compared to WT-CVac. Uniquely, the protection elicited by this mutant is predominantly dependent on a CD8+T-cell response through an IFN-γ-independent mechanism and is associated with a stable population of antigen-experienced CD8+T cells. Jointly, our findings support the benefit of liver stage mutants as vaccines over WT, under a CVac protocol. This vaccination strategy is also a powerful model to study the mechanisms of protective immunity and discover new protective antigens.
Differences in the gut microbiomes of distinct ethnicities within the same geographic area are linked to host metabolic health
Authors: Ang Qi Yan , Alba Diana L. , Upadhyay Vaibhav , Bisanz Jordan E. , Cai Jingwei , Lee Ho Lim , Barajas Eliseo , Wei Grace , Noecker Cecilia , Patterson Andrew D. , Koliwad Suneil K. , Turnbaugh Peter J. 
Published: October 2020

ABSTRACTBackgroundThe human gut microbiota exhibits marked variation around the world, which has been attributed to dietary intake and other environmental factors. However, the degree to which ethnicity-associated differences in gut microbial community structure and function are maintained following immigration or in the context of metabolic disease is poorly understood.ResultsWe conducted a multi-omic study of 46 lean and obese East Asian and White participants living in the San Francisco Bay Area. 16S rRNA gene sequencing revealed significant differences between ethnic groups in bacterial richness and community structure. White individuals were enriched for the mucin-degradingAkkermansia muciniphila.East Asian participants had increased levels of multiple bacterial phyla, fermentative pathways detected by metagenomics, and the short-chain fatty acid end products acetate, propionate, and isobutyrate. Differences in the gut microbiota between the East Asian and White groups could not be explained by reported dietary intake, were more pronounced in lean individuals, and were associated with current geographical location. Microbiome transplantations into germ-free mice confirmed that the differences in the gut microbiota of the East Asian and White individuals we analyzed are independent of diet and that they differentially impact host body weight and adiposity in genetically identical mouse recipients.ConclusionsThe reported findings emphasize the utility of studying diverse ethnic groups within a defined geographical location and provide a starting point for dissecting the mechanisms contributing to the complex interactions between the gut microbiome and ethnicity-associated lifestyle, demographic, metabolic, and genetic factors.
Viral mimicry of p65/RelA transactivation domain to inhibit NF-κB activation
Authors: Albarnaz Jonas D. , Ren Hongwei , Torres Alice A. , Shmeleva Evgeniya V. , Melo Carlos A. , Bannister Andrew J. , Brember Matthew P. , Chung Betty Y.-W. , Smith Geoffrey L. 
Published: October 2020

ABSTRACTSensing of virus infection activates NF-κB to induce the expression of interferons, cytokines and chemokines to initiate the antiviral response. Viruses antagonise these antiviral defences by interfering with immune sensing and blocking the actions of antiviral and inflammatory molecules. Here, we show that a viral protein mimics the transactivation domain of the p65 subunit of NF-κB. The C terminus of vaccinia virus (VACV) protein F14 (residues 51-73) activates transcription when fused to a DNA-binding domain-containing protein and F14 associates with NF-κB co-activator CBP, disrupting p65-CBP interaction. Consequently, F14 diminishes CBP-mediated acetylation of p65 and the downstream recruitment of the transcriptional regulator BRD4 to the promoter of the NF-κB-responsive genesCXCL10andCCL2, hence inhibiting their expression. Conversely, the recruitment of BRD4 to the promoters ofNFKBIA, which encodes the inhibitor of NF-κB (IκBα), andCXCL8remains unaffected in the presence of either F14 or JQ1, a competitive inhibitor of BRD4 bromodomains, indicating its recruitment is acetylation-independent. Therefore, unlike other viral NF-κB antagonists, F14 is a selective inhibitor of NF-κB-dependent gene expression. A VACV strain lacking F14 showed that it contributes to virulence in an intradermal model of infection. Our results uncover a mechanism by which viruses disarm the antiviral defences through molecular mimicry of a conserved host protein and provide insight into the regulation of NF-κB-dependent gene expression by BRD4.
Identification bioactive compounds from marine microorganism and exploration of structure–activity relationships (SARs)
Authors: Dinarvand Mojdeh , Spain Malcolm P. 
Published: October 2020

ABSTRACTMarine natural products (MNPs) have become new strong leads for antimicrobial drug discovery and an effective alternative to control drug resistant infections. Herein we report the bioassay guided fractionation of marine extracts from spongesLendenfeldia, IrciniaandDysideathat led us to identify novel compounds with antimicrobial properties. Tertiary amines or quaternary amine salts: anilines1, benzylamines2, tertiary amines3and4, and quaternary amine salt5, along with three known compounds (6-8) were isolated from a crude extract and MeOH eluent marine extracts. The absolute configurations of the new compounds were assigned based on tandem mass spectrometry (MS) analysis. Several of the compounds exhibited potentin-vitroantibacterial activity, especially againstMethicillin-resistant Staphylococcus aureus(MRSA) (MICs from 15.6 to 62.5 micro g/mL). Herein, we also, report structure activity relationships of a diverse range of commercial structurally similar compounds. The structure activity relationships (SARs) results clearly demonstrate that modification of the amines through linear chain length, and inclusion of aromatic rings, modifies the observed antimicrobial activity towards different biological activity. Several commercially available compounds, which are structurally related to the molecules we discovered showed broad spectrum antimicrobial activity against different test pathogens with an MIC50 range of 50 to 0.01 microM. The results of cross-referencing antimicrobial activity and cytotoxicity establish that these compounds are promising potential lead molecules, with a favourable therapeutic index for antimicrobial drug development. Additionally, the SAR studies show that simplified analogues of the isolated compounds with increased bioactivity
Isolation and characterization of a novel phage SaGU1 that infectsStaphylococcus aureusclinical isolates from patients with atopic dermatitis
Authors: Shimamori Yuzuki , Pramono Ajeng K. , Kitao Tomoe , Suzuki Tohru , Aizawa Shin-ichi , Kubori Tomoko , Nagai Hiroki , Takeda Shigeki , Ando Hiroki 
Published: October 2020

AbstractThe bacteriumStaphylococcus aureus, which grows on healthy human skin, may cause diseases such as atopic dermatitis (AD). Treatment for such AD cases involves antibiotic use; however, alternate treatments are preferred owing to the development of antimicrobial resistance. This study aimed to characterize the novel bacteriophage SaGU1 as a potential agent for phage therapy to treatS. aureusinfections. SaGU1 that infectsS. aureusstrains previously isolated from the skin of patients with AD was screened from sewage samples in Gifu, Japan. Its genome was sequenced and analyzed using bioinformatics tools, and the morphology, lytic activity, stability, and host range of the phage were determined. The SaGU1 genome consisted of 140,909 bp with an average GC content of 30.2%. The viral chromosome contained putative 225 protein-coding genes and four tRNA genes, carrying neither toxic nor antibiotic resistance genes. Electron microscopy analysis revealed that SaGU1 belongs to theMyoviridaefamily. Stability tests showed that SaGU1 was heat-stable under physiological and acidic conditions. Host-range testing revealed that SaGU1 could infect a broad range ofS. aureusclinical isolates present on the skin of patients with AD, whereas it did not kill strains ofStaphylococcus epidermidis, which are symbiotic bacteria in the human skin microbiota. Our data suggest that SaGU1 is a potential candidate for developing a phage therapy to treat AD caused by pathogenicS. aureus.
Can databases facilitate accountability? The case of Australian mercury accounting via the National Pollutant Inventory
Authors: Ullah Md. Hafij , Hazelton James , Nelson Peter F 
Published: October 2020

PurposeThis paper furthers research into the potential contribution of pollutant databases for corporate accountability. We evaluate the quality of corporate and government mercury reporting via the Australian National Pollutant Inventory (NPI), which underpins Australia's reporting under the Minamata Convention, a global agreement to reduce mercury pollution.Design/methodology/approachThe qualitative characteristics of accounting information are used as a theoretical frame to analyse ten interviews with thirteen interviewees as well as 54 submissions to the 2018 governmental enquiry into the NPI.FindingsWhile Australian mercury accounting using the NPI is likely sufficient to meet the expected Minamata reporting requirements (especially in comparison to developing countries), we find significant limitations in relation to comparability, accuracy, timeliness and completeness. These limitations primarily relate to government (as opposed to industry) deficiencies, caused by insufficient funding. The findings suggest that multiple factors are required to realise the potential of pollutant databases for corporate accountability, including appropriate rules, ideological commitment and resourcingPractical implicationsThe provision of additional funding would enable the NPI to be considerably improved (for mercury as well as other pollutants), particularly in relation to the measurement and reporting of emissions from diffuse sources.Originality/valueWhilst there have been prior reviews of the NPI, none have focused on mercury, whilst conversely prior studies which have discussed mercury information have not focused on the NPI. In addition, no prior NPI studies have utilised interviews nor have engaged directly with NPI regulators. There has been little prior engagement with pollutant databases in social and environmental accounting (SEA) research.
Influence of support on work engagement in nursing staff: the mediating role of possibilities for professional development
Authors: Contreras Francoise , Abid Ghulam , Govers Mark , Saman Elahi Natasha 
Published: October 2020

PurposeThe purpose of this study is to examine the effects of colleague and supervisor support on work engagement, examining the mediating role of possibilities for professional development in a healthcare setting.Design/methodology/approachA cross-sectional survey design was used. A sample of 253 Colombian nurses from a private hospital completed a series of questionnaires.FindingsAccording to the results, support from both colleagues and supervisors influences the work engagement of healthcare personnel. This research provides evidence about how to encourage work engagement in nursing staff through an adequate environment characterized by support and opportunities for career advancement.Research limitations/implicationsIn this study, a cross-sectional design was used; therefore, the generalization is limited, and it is not possible to infer causality.Originality/valueProviding certain conditions can promote not only work engagement with its desirable effects, but it may also mitigate the burden of a complex environment such as healthcare.