bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diverse states and stimuli tune olfactory receptor expression levels to modulate food-seeking behavior
Authors: McLachlan Ian G. , Kramer Talya S. , Dua Malvika , DiLoreto Elizabeth M. , Dag Ugur , Srinivasan Jagan , Flavell Steven W. 
Published: April 2022

ABSTRACTAnimals must weigh competing needs and states to generate adaptive behavioral responses to the environment. Sensorimotor circuits are thus tasked with integrating diverse external and internal cues relevant to these needs to generate context-appropriate behaviors. However, the mechanisms that underlie this integration are largely unknown. Here, we show that a wide range of states and stimuli converge upon a single C. elegans olfactory neuron to modulate food-seeking behavior. Using an unbiased ribotagging approach, we find that the expression of olfactory receptor genes in the AWA olfactory neuron is influenced by a wide array of states and stimuli, including feeding state, physiological stress, and recent sensory cues. We identify odorants that activate these state-dependent olfactory receptors and show that altered expression of these receptors influences food-seeking and foraging. Further, we dissect the molecular and neural circuit pathways through which these diverse cues are integrated by AWA. This reveals a modular organization in which state-related signals arising from different cell types in the body converge on AWA and independently control chemoreceptor expression. The synthesis of these signals by AWA allows animals to generate sensorimotor responses that reflect the animal’s overall state. Our findings suggest a general model in which state-dependent transcriptional changes at the sensory periphery modulate animals’ sensorimotor responses to meet their ongoing needs and states.
Characterization of the cluster MabR prophages of Mycobacterium abscessus and Mycobacterium chelonae
Authors: Cote Jacob , Welch Colin , Kimble Madeline , Archambault Dakota , Ross John Curtis , Orellana Hector , Amero Katelyn , Bourett Claire , Daigle Andre , Hutchison Keith W. , Molloy Sally D. 
Published: April 2022

AbstractMycobacterium abscessus is an emerging pathogen of concern in cystic fibrosis and immunocompromised patients and is considered one of the most drug-resistant mycobacteria. The majority of clinical M. abscessus isolates carry one or more prophages that are hypothesized to contribute to virulence and bacterial fitness. The prophage McProf was identified in the genome of the Bergey strain of M. chelonae, and is distinct from previously described prophages of M. abscessus. The McProf genome increases intrinsic antibiotic resistance of M. chelonae and drives expression of the intrinsic antibiotic resistance gene, whiB7, when superinfected by a second phage. The prevalence of McProf-like genomes was determined in sequenced mycobacterial genomes. Related prophage genomes were identified in the genomes of 25 clinical isolates of M. abscessus and assigned to the novel cluster, MabR. The MabR genomes share less than 10% gene content with previously described prophages; however, share features typical of prophages, including polymorphic toxin immunity (PT-Imm) systems.
Diversity and abundance of archaeal amoA genes in the permanent and temporary oxygen minimum zones of Indian Ocean
Authors: Chinnamani Prasannakumar , Elamaran Anandjothi 
Published: April 2022

AbstractOxygen minimum zones are results of oxygen consumption exceeding the oxygen availability in stratified water columns of the marine environment. We compared the ammonia monooxygenase subunit A (amoA) gene abundance and the diversity of ammonia-oxidising archaea (AOA) in the Arabian Sea (AS) with those of the Bay of Bengal (BoB). Three primer pairs targeting amoA genes of water column A (WCA), water column B (WCB) and total AOA (amoAt) captured different densities of gene copy numbers in both marginal seas. Water column A (WCA) ecotypes were more abundant in the AS than in the BoB. Core-OMZ depths of the BoB contained 10 times lower amoA copy numbers than those of the AS. Along with sampling depth, concentration of ammonia shapes the WCA/WCB ecotypes in AS/BoB. Among the total AOA populations, WCB ecotypes were more abundant. The amoA gene sequences were either of Nitrosopumilales or Ca. Nitrosotaleales members and belonged to NP-γ, NP-δ, NS-β, NS-γ and NS-ε sub-clades. Pairwise distance and nucleotide diversity index analysis reveals that BoB nurtures two times more diverse amoA sequences than the AS. The core OMZ region of the BoB contains a two-fold higher diversity of amoA gene sequences compared to the AS, whereas the AS contains 13 times more abundant amoA copies than the BoB.
AnkG-Neurofascin complex structure reveals binding mechanisms required for integrity of the AIS
Authors: He Liping , Jiang Wenli , Li Jianchao , Wang Chao 
Published: April 2022

AbstractThe axon initial segment (AIS) has characteristically clustering of voltage-gated sodium channels (Nav), cell adhesion molecule Neurofascin (Nfasc), and neuronal scaffold protein Ankyrin-G (AnkG) in neurons, which facilitate generation of action potential and maintenance of axonal polarity. However, the mechanisms underlying AIS assembly and maintenance remain poorly understood. Here we report the high-resolution crystal structure of the AnkG in complex with a fragment from Nfasc cytoplasmic tail that shows, in conjunction with binding affinity assays, the molecular basis of AnkG-Nfasc binding. We confirm AnkG interacts with the FIGQY motif in Nfasc, and identify another region required for their high affinity binding. Structural analysis revealed that ANK repeats form four hydrophobic or hydrophilic layers in the AnkG inner groove that coordinate interactions with Nfasc. Moreover, disruption of the AnkG-Nfasc complex abolishes Nfasc enrichment at the AIS in hippocampal neurons. Finally, structural and biochemical analysis indicated that L1 syndrome-associated mutations in L1CAM compromise binding with ankyrins. These results define the mechanisms underlying AnkG-Nfasc complex formation and show that AnkG-dependent clustering of Nfasc is required for AIS integrity.
Parkinson mutations in DNAJC6 cause lipid defects and neurodegeneration that are rescued by Synj1
Authors: Jacquemyn Julie , Kuenen Sabine , Swerts Jef , Pavie Benjamin , Vijayan Vinoy , Kilic Ayse , Chabot Dries , Wang Yu-Chun , Schoovaerts Nils , Verstreken Patrik 
Published: April 2022

ABSTRACTRecent evidence links dysfunctional lipid metabolism to the pathogenesis of Parkinson’s disease, but the mechanisms are not resolved. Here, we created a new Drosophila knock-in model of DNAJC6/Auxilin and find that the pathogenic mutation causes synaptic dysfunction, neurological defects and neurodegeneration, as well as specific lipid metabolism alterations. In these mutants membrane lipids containing long-chain polyunsaturated fatty acids, including phosphatidylinositol lipid species that are key for synaptic vesicle recycling and organelle function are reduced. Overexpression of another protein mutated in Parkinson’s disease, Synaptojanin-1, known to bind and synthesize specific phosphoinositides, strongly rescues the DNAJC6/Auxilin neuronal defects and neurodegeneration. Our work reveals a functional relation between two proteins mutated in Parkinson’s disease and implicates deregulated phosphoinositide metabolism in the maintenance of neuronal integrity and neuronal survival in Parkinsonism.
Equilibrative Nucleoside Transporter 3 is an IFN-stimulated Gene that Facilitates Viral Genome Release
Authors: Hsieh Yu-Ting , Tsai Tsung-Lin , Tu Chia-Chun , Huang Shen-Yan , Heng Jian-Wen , Tsai Pei-Yuan , Chao Tai-Ling , Tsai Ya-Min , Chang Pei-Ching , Lee Chien-Kuo , Yu Guann-Yi , Chang Sui-Yuan , Dzhagalov Ivan L. , Hsu Chia-Lin 
Published: April 2022

AbstractAn increasing body of evidence emphasizes the role of metabolic reprogramming in immune cells to fight off infections. However, little is known about the regulation of metabolite transporters that facilitate and support metabolic demands. In this study, we found that equilibrative nucleoside transporter 3 (ENT3) expression is part of the innate immune response, and is rapidly upregulated upon bacterial and viral infection. The transcription of ENT3 is directly under the regulation of IFN-induced signaling, positioning this metabolite transporter as an Interferon-stimulated gene (ISG). Moreover, we unveil that several viruses, including SARS-CoV2, require ENT3 to facilitate their entry into the cytoplasm. The removal or suppression of ENT3 expression is sufficient to significantly decrease viral replication in vitro and in vivo.
Cortical magnification eliminates differences in contrast sensitivity across but not around the visual field
Authors: Jigo Michael , Tavdy Daniel , Himmelberg Marc M. , Carrasco Marisa 
Published: April 2022

ABSTRACTHuman visual performance changes dramatically both across (eccentricity) and around (polar angle) the visual field. Performance is better at the fovea, decreases with eccentricity, and is better along the horizontal than vertical meridian and along the lower than the upper vertical meridian. However, all neurophysiological and virtually all behavioral studies of cortical magnification have investigated eccentricity effects without considering polar angle. Most performance differences due to eccentricity are eliminated when stimulus size is cortically magnified (M-scaled) to equate the size of its cortical representation in primary visual cortex (V1). But does cortical magnification underlie performance differencesaroundthe visual field? Here, to assess contrast sensitivity, human adult observers performed an orientation discrimination task with constant stimulus size at different locations as well as when stimulus size was M-scaled according to stimulus eccentricity and polar angle location. We found that although M-scaling stimulus size eliminates differences across eccentricity, it does not eliminate differences around the polar angle. This finding indicates that limits in contrast sensitivity across eccentricity and around the visual field are mediated by different anatomical and computational constraints.
Inhibiting succinate release worsens cardiac reperfusion injury by enhancing mitochondrial reactive oxygen species generation
Authors: Milliken Alexander S. , Nadtochiy Sergiy M. , Brookes Paul S. 
Published: April 2022

ABSTRACTThe metabolite succinate accumulates during cardiac ischemia. Within 5 min. of reperfusion, succinate returns to baseline levels via both its release from cells and oxidation by mitochondrial complex II (Cx-II). The latter drives reactive oxygen species (ROS) generation and subsequent opening of the mitochondrial permeability transition (PT) pore, leading to cell death. Targeting succinate dynamics (accumulation/oxidation/release) may be therapeutically beneficial in cardiac ischemia-reperfusion (IR) injury. It has been proposed that blocking monocarboxylate transporter 1 (MCT-1) may be beneficial in IR, by preventing succinate release and subsequent engagement of downstream inflammatory signaling pathways. In contrast, herein we hypothesized that blocking MCT-1 would retain succinate in cells, exacerbating ROS generation and IR injury. Using the mitochondrial ROS probe mitoSOX, and a custom-built murine heart perfusion rig built into a spectrofluorometer, we measured ROS generation in-situ during the first moments of reperfusion, and found that acute MCT-1 inhibition enhanced mitochondrial ROS generation at reperfusion, and worsened IR injury (recovery of function and infarct size). Both these effects were abrogated by tandem inhibition of Cx-II, suggesting that succinate retention worsens IR due to driving more mitochondrial ROS generation. Furthermore, using the PT pore inhibitor cyclosporin A, along with monitoring of PT pore opening via the mitochondrial membrane potential indicator TMRE, we herein provide evidence that ROS generation during early reperfusion is upstream of the PT pore, not downstream as proposed by others. In addition, pore opening was exacerbated by MCT-1 inhibition. Together, these findings highlight the importance of succinate dynamics and mitochondrial ROS generation, as key determinants of PT pore opening and IR injury outcomes.
MYXOBACTERIA FROM VIETNAM: ISOLATION, PHYLOGENETIC ANALYSIS AND BIOPROSPECTION
Authors: Nguyen Yen Thi Ngoc , Duong Chung Dinh , Nguyen Hong Thi Kim , Nguyen Cham Phuong , Vo Nhan Thi , Dinh Linh Thi Lan , Nguyen Ngoc Le Bao , Nguyen Thai Minh , Nguyen Nga Dinh , Nguyen Anh Tu 
Published: April 2022

AbstractForty-three myxobacterial strains were isolated and identified from 20 soil samples collected in Vietnam. The information on morphological characteristics and 16S ribosomal gene sequencing showed that these strains were designated to seven genera belonging to Angiococcus, Archangium, Chondromyces, Corallococcus, Cystobacter, Melittangium, and Myxococcus, in suborder Cystobacterineae and Sorangiineae. The phylogenetic tree was constructed to clarify the genetic relationship between myxobacterial isolates. Myxobacteria were cultured, and crude extracts were obtained after 10-day fermentation in P-medium in the presence of the Amberlite XAD 16N adsorbent resin. Elution was carried out with acetone and methanol to obtain the crude extracts. Evaluation of antioxidant activity used the DPPH and ABTS assay, the minimum inhibitory concentration values were determined by the microdilution method. The total extract from CT21 had the highest total antioxidant activity (IC50 = 52.34 ± 1.47 µg/mL, 30.28 ± 0.74 µg/mL for DPPH and ABTS assays, respectively). The other potential strain was TG131 and GL41 that IC50 values were 40.28 ± 1.13 and 57.24 ± 1.52 µg/mL, respectively (by the DPPH method), and 48.35 ± 0.58 and 42.76 ± 0.50 µg/mL, respectively (by the ABTS method). Interestingly, 100% isolated myxobacterial strains show inhibitory activity against at least one of the tested microorganisms. The potential antimicrobial strain was GL41, which inhibited all tested microorganisms, and the MIC values were 1 µg/mL against MRSA, MSSA, S. faecalis, C. albicans, and A. niger. The highest active strains were members of Myxococcus sp. genus.
Persistence andin vivoevolution of vaginal bacterial strains over a multi-year time period
Authors: France Michael , Ma Bing , Ravel Jacques 
Published: April 2022

AbstractIt is not clear if the bacterial strains which comprise our microbiota are mostly long-term colonizers or transient residents. Studies have demonstrated decades long persistence of bacterial strains within the gut, but persistence at other body sites has yet to be determined. The vaginal microbiota (VMB) is often dominated byLactobacillus, although it is also commonly comprised of a more diverse set of other facultative and obligate anaerobes. Longitudinal studies have demonstrated that these communities can be stable over several menstrual cycles or can fluctuate temporally in species composition. We sought to determine whether the bacterial strains which comprise the VMB were capable of persisting over longer time-periods. We performed shotgun metagenomics on paired samples from 10 participants collected 1 and 2 years apart. The resulting sequences werede novoassembled and binned into high-quality metagenome assembled genomes. Persistent strains were identified based on the sequence similarity between the genomes present at the two timepoints and were found in the VMB of six of the participants, three of which had multiple. The VMB of the remaining four participants was similar in species composition at the two timepoints but was comprised of different strains. For the persistent strains, we were able to identify the mutations which fixed in the populations over the observed time period, giving insight into the evolution of these bacteria. These results indicate that bacterial strains can persist in the vagina for extended periods of time, providing an opportunity for them to evolve in the host microenvironment.ImportanceThe persistence of strains within the vaginal microbiota has not yet been characterized. Should these strains be capable of persisting for extended periods of time, they could evolve within their host in response to selective pressures exerted by the host or by other members of the community. Here, we present preliminary findings which demonstrate that bacterial strains can persist in the vagina for at least one year and evolve over time. In several cases, multiple strains persisted together in a community, indicating that co-evolution between bacterial strains could occur in the vagina. Our observations motivate future studies which collect samples from more participants, at more timepoints and over even longer periods of time. Understanding which strains persist, what factors drive their persistence, and what selective pressures they face will inform the development and delivery of rationally designed live biotherapeutics for the vagina.
Life stage-specific effects of genetic susceptibility to higher body size on body fat and lean mass: prospective cohort study
Authors: Waterfield Scott , Richardson Tom G. , Smith George Davey , O’Keeffe Linda M. , Bell Joshua A. 
Published: April 2022

AbstractBackground/ObjectivesSeparate genetic variants are associated with larger body size in childhood and adulthood. Whether these variants predominantly influence adiposity, and whether these truly differ by life stage is unknown. We examined how genetic variants influence total body fat and total lean mass trajectories from childhood to young adulthood.MethodsData were from the Avon Longitudinal Study of Parents and Children birth cohort. Sex-specific genetic risk scores (GRS) for childhood and adulthood body size were generated, and dual-energy X-ray absorptiometry scans were used to measure total body fat and lean mass 6 times between ages 9-25y. We used mutually-adjusted multilevel linear spline models to examine the independent sex-specific associations of childhood and adulthood body size GRSs with fat and lean mass trajectories from 9 -25y.ResultsIn males, the childhood and adulthood GRS were associated with similar differences in fat mass from 9 to 18y; 8.3% (95% confidence interval (CI): 5.1,11.6)) and 7.5% (95% CI: 4.3,10.8) higher fat mass at 18y per standard deviation (SD) higher childhood and adulthood GRS respectively. At 25y, childhood GRS associations with fat mass attenuated while adulthood GRS associations remained similar to those at 18y for males. Among females, associations for the childhood GRS were almost two-fold stronger than the adulthood GRS from 9 to 18y: 10.5% (95% CI: 8.5, 12.4) higher fat mass at 9y per SD higher childhood GRS compared with 5.1% (95% CI 3.2, 6.9) per SD higher adulthood GRS. At 25y, associations of the childhood and adulthood GRS with fat mass were similar; 5.0% (95% CI: 2.5, 7.5) and 5.8% (95% CI: 3.3, 8.3) higher fat mass per SD higher childhood and adulthood GRS respectively: Lean mass effect sizes were much smaller.ConclusionsGenetic variants for body size are more strongly associated with adiposity than lean mass from childhood to early adulthood; childhood variants are more strongly associated with adiposity in females until early adulthood whereas childhood and adulthood variants are similarly associated with adiposity across early life in males. Findings may inform selection of instruments for life stage-specific adiposity in future Mendelian randomization studies.
Phenotypic associations with the HMOX1 GT(n) promoter repeat in European populations
Authors: Hamilton Fergus , Mitchell Ruth , Ghazal Peter , Timpson Nic 
Published: April 2022

AbstractHO-1 is a key enzyme in the management of heme in humans. A GT(n) repeat length in the gene HMOX1, has previously been widely associated with a variety of phenotypes, including susceptibility and outcomes in diabetes, cancer, infections, and neonatal jaundice. However, studies are generally small and results inconsistent. In this study, we imputed the GT(n) repeat length in two European cohorts (UK Biobank, n = 463,005; and Avon Longitudinal Study of Parents and Children (ALSPAC n = 937), with the reliability of imputation tested in other cohorts (1000 Genomes, HGDP, and UK-PGP). Subsequently, we measured the relationship between repeat length and previously identified associations (diabetes, COPD, pneumonia and infection related mortality in UK Biobank; neonatal jaundice in ALSPAC) and performed a phenome-wide association study (PheWAS) in UK Biobank. Despite high quality imputation (correlation between true repeat length and imputed repeat length >0.9 in test cohorts), no clinical associations were identified in either the PheWAS or specific association studies. These findings were robust to definitions of repeat length and sensitivity analyses. Despite multiple smaller studies identifying associations across a variety of clinical settings; we could not replicate or identify any relevant phenotypic associations with the HMOX1 GT(n) repeat.
The 2’,3’ cyclic phosphatase Angel1 facilitates mRNA degradation during human ribosome-associated quality control
Authors: Nicholson-Shaw Tim , Ajaj Yasmeen , Perelis Mark , Fulzele Amit , Yeo Gene W. , Bennett Eric J. , Lykke-Andersen Jens 
Published: April 2022

SummaryThe Ribosome-associated Quality Control (RQC) pathway serves to resolve ribosomes stalled during the translation process and degrade the associated mRNA and nascent polypeptide. Here we identify the 2’,3’ cyclic phosphatase Angel1 as a rate-limiting factor for this process in human cells. Angel1 associates with proteins of the RQC pathway and with mRNA coding regions, consistent with a factor that monitors the translation process. Depletion of Angel1 causes stabilization of reporter mRNAs that are targeted for RQC by the absence of stop codons, but not an mRNA targeted for nonsense-mediated decay. Angel1 catalytic activity is critical for its function in RQC, as a catalytic inactivating mutation causes loss of RQC function. We also identify N4BP2 as the human RQC endonuclease. Given the biochemical activity of Angel1 as a 2’,3’ cyclic phosphatase, our findings suggest that a rate-limiting step in RQC-mediated mRNA decay is the resolution of a cyclic phosphate, possibly one generated upon N4BP2 cleavage.
Structural and functional characteristics of SARS-CoV-2 Omicron subvariant BA.2 spike
Authors: Zhang Jun , Tang Weichun , Gao Hailong , Lavine Christy L. , Shi Wei , Peng Hanqin , Zhu Haisun , Anand Krishna , Kosikova Matina , Kwon Hyung Joon , Tong Pei , Gautam Avneesh , Rits-Volloch Sophia , Wang Shaowei , Mayer Megan L. , Wesemann Duane R. , Seaman Michael S. , Lu Jianming , Xiao Tianshu , Xie Hang , Chen Bing 
Published: April 2022

AbstractThe Omicron subvariant BA.2 has become the dominant circulating strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in many countries. We have characterized structural, functional and antigenic properties of the full-length BA.2 spike (S) protein and compared replication of the authentic virus in cell culture and animal model with previously prevalent variants. BA.2 S can fuse membranes more efficiently than Omicron BA.1, mainly due to lack of a BA.1-specific mutation that may retard the receptor engagement, but still less efficiently than other variants. Both BA.1 and BA.2 viruses replicated substantially faster in animal lungs than the early G614 (B.1) strain in the absence of pre-existing immunity, possibly explaining the increased transmissibility despite their functionally compromised spikes. As in BA.1, mutations in the BA.2 S remodel its antigenic surfaces leading to strong resistance to neutralizing antibodies. These results suggest that both immune evasion and replicative advantage may contribute to the heightened transmissibility for the Omicron subvariants.