bluuebunny/crossref_metadata_2025_split huggingface dataset:
Medical relevance of common protein-altering variants in GPCR genes across 337,205 individuals in the UK Biobank
Authors: DeBoever Christopher , Venkatakrishnan AJ , Paggi Joseph M , Heydenreich Franziska M. , Laurin Suli-Anne , Masureel Matthieu , Tanigawa Yosuke , Venkataraman Guhan , Bouvier Michel , Dror Ron O. , Rivas Manuel A. 
Published: December 2019

AbstractG protein-coupled receptors (GPCRs) drive an array of critical physiological functions and are an important class of drug targets, though a map of which GPCR genetic variants are associated with phenotypic variation is lacking. We performed a phenome-wide association analysis for 269 common protein-altering variants in 156 GPCRs and 275 phenotypes, including disease outcomes and diverse quantitative measurements, using 337,205 UK Biobank participants and identified 138 associations. We discovered novel associations between GPCR variants and migraine risk, hypothyroidism, and dietary consumption. We also demonstrated experimentally that variants in the β2adrenergic receptor (ADRB2) associated with immune cell counts and pulmonary function and variants in the gastric inhibitory polypeptide receptor (GIPR) associated with food intake and body size affect downstream signaling pathways. Overall, this study provides a map of genetic associations for GPCR coding variants across a wide variety of phenotypes, which can inform future drug discovery efforts targeting GPCRs.
BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression
Authors: Cohen Batya , Tempelhof Hanoch , Raz Tal , Oren Roni , Nicenboim Julian , Bochner Filip , Even Ron , Jelinski Adam , Eilam Raya , Ben-Dor Shifra , Adaddi Yoseph , Golani Ofra , Lazar Shlomi , Yaniv Karina , Neeman Michal 
Published: December 2019

AbstractAngiogenesis and lymphangiogenesis are key processes during embryogenesis as well as under physiological and pathological conditions. Vascular endothelial growth factor C (VEGFC), the ligand for both VEGFR2 and VEGFR3, is a central lymphangiogenic regulator that also drives angiogenesis. Here we report that members of the highly conserved BACH (BTB and CNC homology) family of transcription factors regulate VEGFC expression, through direct binding to its promoter. Accordingly, downregulation ofbach2ahinders blood-vessel formation and impairs lymphatic sprouting in avegfc-dependent manner during zebrafish embryonic development. In contrast, BACH1-overexpression enhances intratumoral blood-vessel density and peritumoral lymphatic vessel diameter in ovarian and lung mouse tumor models. The effects on the vascular compartment correlate spatially and temporally with BACH1 transcriptional regulation ofVEGFCexpression. Altogether, our results uncover a novel role for the BACH/VEGFC signaling axis in lymphatic formation during embryogenesis and cancer, providing a novel potential target for therapeutic interventions.
Model-based Clustering using Automatic Differentiation: Confronting Misspecification and High-Dimensional Data
Authors: Kasa Siva Rajesh , Rajan Vaibhav 
Published: December 2019

AbstractWe study two practically important cases of model based clustering using Gaussian Mixture Models: (1) when there is misspecification and (2) on high dimensional data, in the light of recent advances in Gradient Descent (GD) based optimization using Automatic Differentiation (AD). Our simulation studies show that EM has better clustering performance, measured by Adjusted Rand Index, compared to GD in cases of misspecification, whereas on high dimensional data GD outperforms EM. We observe that both with EM and GD there are many solutions with high likelihood but poor cluster interpretation. To address this problem we design a new penalty term for the likelihood based on the Kullback Leibler divergence between pairs of fitted components. Closed form expressions for the gradients of this penalized likelihood are difficult to derive but AD can be done effortlessly, illustrating the advantage of AD-based optimization. Extensions of this penalty for high dimensional data and for model selection are discussed. Numerical experiments on synthetic and real datasets demonstrate the efficacy of clustering using the proposed penalized likelihood approach.
Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation
Authors: Nishana Mayilaadumveettil , Ha Caryn , Rodriguez-Hernaez Javier , Ranjbaran Ali , Chio Erica , Nora Elphege P. , Badri Sana B. , Kloetgen Andreas , Bruneau Benoit G. , Tsirigos Aristotelis , Skok Jane A. 
Published: December 2019

BackgroundUbiquitously expressed CTCF is involved in numerous cellular functions, such as organizing chromatin into TAD structures. In contrast, its paralog, CTCFL is normally only present in testis. However, it is also aberrantly expressed in many cancers. While it is known that shared and unique zinc finger sequences in CTCF and CTCFL enable CTCFL to bind competitively to a subset of CTCF binding sites as well as its own unique locations, the impact of CTCFL on chromosome organization and gene expression has not been comprehensively analyzed in the context of CTCF function. Using an inducible complementation system, we analyze the impact of expressing CTCFL and CTCF-CTCFL chimeric proteins in the presence or absence of endogenous CTCF to clarify the relative and combined contribution of CTCF and CTCFL to chromosome organization and transcription.ResultsWe demonstrate that the N terminus of CTCF interacts with cohesin which explains the requirement for convergent CTCF binding sites in loop formation. By analyzing CTCF and CTCFL binding in tandem we identify phenotypically distinct sites with respect to motifs, targeting to promoter/intronic intergenic regions and chromatin folding. Finally, we reveal that the N, C and zinc finger terminal domains play unique roles in targeting each paralog to distinct binding sites, to regulate transcription, chromatin looping and insulation.ConclusionThis study clarifies the unique and combined contribution of CTCF and CTCFL to chromosome organization and transcription, with direct implications for understanding how their co-expression deregulates transcription in cancer.
Serotonin, norepinephrine and acetylcholine differentially affect astrocytic potassium clearance to modulate somatosensory signaling in male mice
Authors: Wotton Caitlin A. , Cross Cassidy D. , Bekar Lane K. 
Published: December 2019

AbstractChanges in extracellular potassium ([K+]e) modulate neuronal networks via changes in membrane potential, voltage-gated channel activity and alteration of transmission at the synapse. Given the limited extracellular space in the CNS, potassium clearance is crucial. As activity-induced potassium transients are rapidly managed by astrocytic Kir4.1 and astrocyte-specific Na+/K+-ATPase (NKA), any neurotransmitter/neuromodulator that can regulate their function may have indirect influence on network activity. Neuromodulators differentially affect cortical/thalamic networks to align sensory processing with differing behavioral states. Given serotonin (5HT), norepinephrine (NE), and acetylcholine (ACh) differentially affect spike frequency adaptation and signal fidelity (“signal-to-noise”) in somatosensory cortex, we hypothesize that [K+]emay be differentially regulated by the different neuromodulators to exert their individual effects on network function. This study aimed to compare effects of individually applied 5HT, NE, and ACh on regulating [K+]ein connection to effects on cortical evoked response amplitude and adaptation in male mice. Using extracellular field and K+ion-selective recordings of somatosensory stimulation, we found that differential effects of 5HT, NE, and ACh on [K+]eregulation mirrored differential effects on amplitude and adaptation. 5HT effects on transient K+recovery, adaptation and field post-synaptic potential amplitude were disrupted by barium (200 µM), whereas NE and ACh effects were disrupted by ouabain (1 µM) or iodoacetate (100 µM). Considering the impact [K+]ecan have on many network functions; it seems highly efficient that neuromodulators regulate [K+]eto exert their many effects. This study provides functional significance for astrocyte-mediated buffering of [K+]ein neuromodulator-mediated shaping of cortical network activity.Significance statementWe demonstrate that the neuromodulators serotonin, norepinephrine, and acetylcholine all have distinct effects on astrocyte-mediated extracellular potassium regulation and that these differential actions are associated with the different effects of the neuromodulators on cortical networks. By affecting astrocytic potassium regulation, long-range neuromodulatory networks can rapidly and efficiently affect broad areas of the brain. Given that neuromodulatory networks are at the core of our behavioral state and determine how we interact with our environment, these studies highlight the importance of basic astrocyte function in general cognition and psychiatric disorders.
Novel pelagiphages prevail in the ocean
Authors: Zhang Zefeng , Qin Fang , Chen Feng , Chu Xiao , Luo Haiwei , Zhang Rui , Du Sen , Tian Zhen , Zhao Yanlin 
Published: December 2019

AbstractViruses play a key role in biogeochemical cycling and host mortality, metabolism, physiology and evolution in the ocean. Viruses that infect the globally abundant marine SAR11 bacteria (pelagiphages) were reported to be an important component of the marine viral community. In this study, ten pelagiphages that infect three differentPelagibacterstrains were isolated from various geographical locations and were genomically characterized. All ten pelagiphages are novel, representing four new lineages of thePodoviridaefamily. Although they share limited homology with cultured phage isolates, they are all closely related to some environmental viral fragments. Two HTVC023P-type pelagiphages are shown to be related to the abundant VC_6 and VC_8 viral populations of the Global Oceans Viromes (GOV) datasets. Interestingly, HTVC103P-type pelagiphages contain a structural module similar to that in SAR116 phage HMO-2011. Three HTVC111P-type pelagiphages and HTVC106P are also novel and related to GOV VC_41 and VC_67 viral populations, respectively. Remarkably, these pelagiphage represented phage groups are all globally distributed and predominant. Half of the top ten most abundant known marine phage groups are represented by pelagiphages. The HTVC023P-type group is the most abundant known viral group, exceeding the abundance of HTVC010P-type and HMO-2011-type groups. Furthermore, the HTVC023P-type group is also abundant throughout the water column. Altogether, this study has greatly broadened our understanding of pelagiphages regarding their genetic diversity, phage-host interactions and the distribution pattern. Availability of these newly isolated pelagiphages and their genome sequences will allow us to further explore their phage-host interactions and ecological strategies.
Folding heterogeneity in the essential human telomerase RNA three-way junction
Authors: Palka Christina , Forino Nicholas M. , Hentschel Jendrik , Das Rhiju , Stone Michael D. 
Published: December 2019

AbstractTelomeres safeguard the genome by suppressing illicit DNA damage responses at chromosome termini. In order to compensate for incomplete DNA replication at telomeres, most continually dividing cells, including many cancers, express the telomerase ribonucleoprotein (RNP) complex. Telomerase maintains telomere length by catalyzing de novo synthesis of short DNA repeats using an internal telomerase RNA (TR) template. TRs from diverse species harbor structurally conserved domains that contribute to RNP biogenesis and function. In vertebrate TRs, the conserved regions 4 and 5 (CR4/5) fold into a three-way junction (3WJ) that binds directly to the telomerase catalytic protein subunit and is required for telomerase function. We have analyzed the structural properties of the human TR (hTR) CR4/5 domain using a combination of in vitro chemical mapping, endogenous RNP assembly assays, and single-molecule structural analysis. Our data suggest that a functionally essential stem loop within CR4/5 is not stably folded in the absence of the telomerase reverse transcriptase protein subunit in vitro. Rather, the hTR CR4/5 domain adopts a heterogeneous ensemble of conformations. RNA structural engineering intended to bias the folding landscape of the hTR CR4/5 demonstrates that a stably folded 3WJ motif is necessary but not sufficient to promote assembly of a functional RNP complex. Finally, single-molecule measurements on the hTR CR4/5 domain show that RNP assembly selects for a conformation that is not the major population in the heterogeneous free RNA ensemble, suggesting that non-canonical hTR folds may be required during telomerase biogenesis.
On anammox activity at low temperature: effect of ladderane composition, process conditions and dominant anammox population
Authors: Kouba V , Hurkova K , Navratilova K , Vejmelkova D , Benakova A , Laureni M , Vodickova P , Podzimek T , Lipovova P , van Niftrik L , Hajslova J , van Loosdrecht MCM , Weissbrodt DG , Bartacek J. 
Published: December 2019

AbstractThe application of partial nitritation-anammox (PN/A) under mainstream conditions can enable substantial cost savings at wastewater treatment plants (WWTPs), but how process conditions and cell physiology affect anammox performance at psychrophilic temperatures below 15 °C remains poorly understood. We tested 14 anammox communities, including 8 from globally-installed PN/A processes, for (i) specific activity at 10-30 °C (batch assays), (ii) composition of membrane lipids (U-HPLC-HRMS/MS), and (iii) microbial community structure (16S rRNA gene amplicon sequencing). Crucially, the key parameters impacting anammox activity were the membrane lipid composition and cultivation temperature. The size of ladderane lipids and the content of bacteriohopanoids were key physiological drivers of anammox performance at low temperatures. Higher contents of (i) short C18 [3]-ladderane alkyl and (ii) large phosphatidylcholine headgroup were determined in anammox more active at 15-30 °C and 10-15 °C, respectively. At below 15 °C, the activation energies of most mesophilic cultures severely increased while those of the psychrophilic cultures remained stable; this indicates that the adaptation of mesophilic cultures to psychrophilic regime necessitates months, but in some cases can take up to 5 years. Interestingly, biomass enriched in the marine genus “CandidatusScalindua” displayed exceptionally highest activity at 10-20 °C (0.50 kg-N.kg-VSS−1.d−1at 10 °C, Ea10-30 °C = 51±16 kJ.mol−1), indicating outstanding potential for nitrogen removal from cold streams. Collectively, our comprehensive study provides essential knowledge of cold adaptation mechanism, will enable more accurate modelling and suggests highly promising target anammox genera for inoculation and set-up of anammox reactors, in particular for mainstream WWTPs.HighlightsLadderane size and cold exposure affected anammox activation energy (Ea).Ea improved with more C18 [3]-ladderanes over C20 and larger polar headgroup.Long-term cold exposure reduced Ea at 10-15 °C, not activityper se.Marine “Ca. Scalindua” was exceptionally suitable for cold streams.Anammox Ea at 15-30 °C was 79±18 kJ.mol−1.Graphical abstract
MAVS regulates the quality of the antibody response to West-Nile Virus
Authors: O’Ketch Marvin , Larson Cameron , Williams Spencer , Uhrlaub Jennifer L. , Wong Rachel , Deshpande Neha R. , Schenten Dominik 
Published: December 2019

AbstractA key difference that distinguishes viral infections from protein immunizations is the recognition of viral nucleic acids by cytosolic pattern recognition receptors (PRRs) such as RNA-sensing Rig-I-like receptors (RLRs). Insights into the specific functions of cytosolic PRRs in the instruction of adaptive immunity are therefore critical for the understanding of protective immunity to infections. West Nile virus (WNV) infection of mice deficent of MAVS, the essential RLR signaling adaptor, results in a defective adaptive immune response. While this finding suggests a role for RLRs in the instruction of adaptive immunity to WNV, it is difficult to interpret due to the high WNV viremia, associated exessive antigen loads, and pathology in the absence of a MAVS-dependent innate immune response. To overcome these limitations, we have infected MAVS-deficient mice with a single-round-of-infection mutant of WNV called RepliVAX (RWN). RWN-infected MAVS-deficient (MAVSKO) mice failed to produce an effective neutralizing antibody response to WNV despite normal titers of antibodies targeting the viral WNV-E protein. This defect occurred indepedently of antigen loads or overt pathology. The specificity of the antibody response in RWN-infected MAVSKOmice remained unchanged and was still dominated by antibodies that bound the neutralizing lateral ridge (LR) epitope in the DIII domain of WNV-E. Instead, MAVSKOmice produced IgM antibodies, the dominant isotype controlling primary WNV infection, with lower affinity for the DIII domain. Our findings suggest that RLR-dependent signals are important for the quality of the humoral immune response to WNV.
Properties and effect of Ittar in mice behavior and neurological functions
Authors: Al Asmari AbdulRahman , Kunnathodi Faisal , Anvarbatcha Riyasdeen , Tanwir Athar Mohammed , Khan Abdul Quaiyoom , Sigmani Dhayasankar , Idris Mohammed M 
Published: December 2019

AbstractFragrances are generally synthetic, natural or a combination of both. Ittar or Attar is a natural fragrance material synthesized from plants which were majorly used by people worldwide as a matter of pride, deodorization and attractant. The effect and role of using Ittar on mammalian system is still not known at the behavioral and neurological level. This study was aimed to understand the constituents and the effect of Ittar on mice by measuring their behavioral and neurological changes upon exposure to Ittar. Batches of animals were exposed to ten different types of Ittar for 1, 2 and 3 weeks respectively. Behavior of the animals exposed to the Ittar perfumes were analyzed against the control animals behavior for physiological activities. Also, the expression level of neurotransmitter such as Dopamine, 5-HIAA, HVA and Serotonin were evaluated based on HPLC analysis. Based on this study it was found that all the ten Ittars were different for its different constituents with some basic overlapping molecules among them. The neurotransmitter such as DOPA, 5-HT, Homovanillic Acid and Serotonin were found non-significantly increased in the total brain after a three week long continuous exposures of Ittar to the animal. Histological analysis of the ittar exposed mice skin showed mild to massive changes in both epidermal and dermal layers characterized with intense infiltration of inflammatory cells, hyperplasia, hyperchromasia and edema formation against control animals in few of the Ittars. From this study it is evident that Ittar increases mood of the animal through the up-regulation of various neurotransmitter but subtle effect on the skin because of the presence of various chemical constituents of the Ittar. Based on this study it is evident that use of Ittar as fragrance might be beneficial at the molecular level and it will be appropriate to apply without direct exposure to skin.
Organophosphorus diisopropylfluorophosphate (DFP) intoxication in zebrafish larvae causes behavioral defects, neuronal hyperexcitation and neuronal death
Authors: Brenet Alexandre , Somkhit Julie , Hassan-Abdi Rahma , Yanicostas Constantin , Romain Christiane , Bar Olivier , Igert Alexandre , Saurat Dominique , Taudon Nicolas , Dal-Bo Gregory , Nachon Florian , Dupuis Nina , Soussi-Yanicostas Nadia 
Published: December 2019

AbstractWith millions of intoxications each year and over 200,000 deaths, organophosphorus (OP) compounds are an important public health issue worldwide. OP poisoning induces cholinergic syndrome, with muscle weakness, hypertension, and neuron damage that may lead to epileptic seizures and permanent psychomotor deficits. Existing countermeasures are lifesaving but do not prevent long-lasting neuronal comorbidities, emphasizing the urgent need for animal models to better understand OP neurotoxicity and identify novel antidotes. Here, using diisopropylfluorophosphate (DFP), a prototypic and moderately toxic OP, combined with zebrafish larvae, we first showed that DFP poisoning caused major acetylcholinesterase inhibition, resulting in paralysis and CNS neuron hyperactivation, as indicated by increased neuronal calcium transients and overexpression of the immediate early genesfosab, junBa, npas4b, andatf3. In addition to these epileptiform seizure-like events, DFP-exposed larvae showed increased neuronal apoptosis, which were both partially alleviated by diazepam treatment, suggesting a causal link between neuronal hyperexcitation and cell death. Last, DFP poisoning induced an altered balance of glutamatergic/GABAergic synaptic activity with increased NR2B-NMDA receptor accumulation combined with decreased GAD65/67 and gephyrin protein accumulation. The zebrafish DFP model presented here thus provides important novel insights into the pathophysiology of OP intoxication, making it a promising model to identify novel antidotes.
Complexity of frequency receptive fields predicts tonotopic variability across species
Authors: Gaucher Quentin , Panniello Mariangela , Ivanov Aleksandar Z , Dahmen Johannes C , King Andrew J , Walker Kerry M M 
Published: December 2019

AbstractPrimary cortical areas contain maps of sensory features, including sound frequency in primary auditory cortex (A1). Two-photon calcium imaging in mice has confirmed the presence of these large-scale maps, while uncovering an unexpected local variability in the stimulus preferences of individual neurons in A1 and other primary regions. Here we show that fractured tonotopy is not unique to rodents. Using two-photon imaging, we found that local variance in frequency preferences is equivalent in ferrets and mice. Much of this heterogeneity was due to neurons with complex frequency tuning, which are less spatially organized than those tuned to a single frequency. Finally, we show that microelectrode recordings may describe a smoother tonotopic arrangement due to a bias towards neurons with simple frequency tuning. These results show that local variability in the tonotopic map is not restricted to rodents and help explain inconsistencies in cortical topography across species and recording techniques.
A comprehensive pipeline for accurate annotation and quantification of circRNAs
Authors: Rabin Avigayel , Ashwal-Fluss Reut , Shenzis Shlomo , Apelblat Daniella , Kadener Sebastian 
Published: December 2019

ABSTRACTIdentification and quantification of circular RNAs (circRNAs) depends strongly on the utilized computational pipeline. Here we describe an integrative approach for accurate annotation and quantification of circRNAs. First, we utilize several circRNA-identification pipelines to annotate circRNAs in a given organism. Second, we build a short sequence index that is used to search the unaligned RNA-seq reads. Our approach allows full annotation of circRNAs with fewer false positives and negatives than any individual pipeline or combination of them. Moreover, our approach is more sensitive than any individual pipeline and allows more accurate quantification and larger number of differentially expressed circRNAs.