bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation
Authors: Zeppillo Tommaso , Ali Heba , Wenger Sally , Lopez Murcia Francisco J. , Gideons Erinn , Signorelli Janetti , Schmeisser Michael J. , Wiltfang Jens , Rhee JeongSeop , Brose Nils , Taschenberger Holger , Krueger-Burg Dilja 
Published: August 2022

AbstractThe function of GABAergic synapses is critically shaped by cell adhesion proteins that recruit GABAARs to synapses and mediate transsynaptic signalling, but the synapse-type-specific function of such synaptic adhesion proteins and their mutual interaction remain incompletely understood. A ubiquitous cell adhesion protein at GABAergic synapses is Neuroligin-2 (Nlgn2), which recruits synaptic GABAARs by promoting the assembly of the postsynaptic gephyrin scaffold. While Nlgn2 is present at virtually all GABAergic synapses throughout the forebrain, its loss affects different GABAergic synapse subtypes with different severity, indicating that synapse-specific interactors and synapse-organizer-redundancies define the function of Nlgn2 for a given synapse type. Here we investigated how Nlgn2 function at GABAergic synapses in mouse hippocampal area CA1 is modulated by two recently identified interaction partners, MDGA1 and MDGA2. We show that Nlgn2 and MDGA1 colocalize most prominently in the stratum radiatum (S.R.) of area CA1, and that combined Nlgn2 and MDGA1 deletion causes a layer-specific exacerbation of the loss of gephyrin puncta in layer S.R. seen following Nlgn2 deletion. Intriguingly, combined Nlgn2 and MDGA1 deletion concurrently ameliorates the abnormal cytosolic gephyrin aggregation, the reduction in inhibitory synaptic transmission and the exacerbated anxiety-related behavior seen in Nlgn2 knockout (KO) mice. In contrast, heterozygous deletion of MDGA2 in Nlgn2 KO mice has only minor effects on gephyrin and GABAAR puncta and does not normalize cytosolic gephyrin aggregates, inhibitory synaptic transmission or anxiety-related behavior. Our data indicate that MDGA1, but not MDGA2, modulates Nlgn2 function, primarily by regulating the formation of cytosolic gephyrin aggregates. Given that both Nlgn2 and the MDGA family of proteins have been linked to psychiatric disorders, such as autism and schizophrenia, our data lead to the notion that abnormal gephyrin aggregation may contribute to the pathophysiology of these disorders, and that intervention with gephyrin aggregation could present a novel therapeutic strategy.
Emergence of Erythromycin Resistant Invasive Group A Streptococcus in West Virginia, United States
Authors: Powell Lillie , Choi Soo Jeon , Chipman Chloe , Grund Megan , LaSala P. Rocco , Lukomski Slawomir 
Published: August 2022

ABSTRACTCombination therapy with penicillin and clindamycin has been a mainstay for treatment of invasive group A Streptococcus (iGAS) infections yet increasing macrolide resistance may limit such treatment for strains displaying MLSB phenotypes. The CDC recently reported erythromycin and clindamycin resistance rates for iGAS exceeding 20% in 2017. Here, we investigated 76 iGAS isolates from 66 patients identified at J.W. Ruby Memorial Hospital in West Virginia from 2020-2021. emm typing was performed using the CDC protocol and database. Resistance genes were detected by PCR and sequencing, whereas antimicrobial susceptibility testing was performed in clinical and research laboratories with standard techniques. Median patient age was 42 years (23-86 range). 76% (n=50) of isolates were simultaneously resistant to erythromycin and clindamycin, which included both inducible (n=40) and constitutive (n=9) resistance. All emm92 (n=35) and emm11 (n=8) isolates were erythromycin resistant, while the remaining 11% (n=7) of resistant isolates comprised 5 emm types. Susceptible isolates primarily included emm89 (n=6) iGAS. Macrolide resistance was conferred by the plasmid-borne ermT gene in all emm92 isolates and by chromosomally-encoded ermA (n=7), ermB (n=7), and mefA (n=1) in other emm types. Macrolide-resistant iGAS were typically resistant to tetracycline and aminoglycoside antibiotics. Here, we characterized iGAS infections affecting non-pediatric residents across West Virginia. We showed a shift in emm-type distribution compared to historical and national reports, and dominance of macrolide-resistant isolates which raises concern for emerging resistance to commonly-prescribed antibiotics used in treatment of iGAS infections.
Common and rare variants in SLCO1B1 are associated with statin intolerance
Authors: Bigossi Margherita , Maroteau Cyrielle , Dawed Adem Y , Taylor Alasdair , Srinivasan Sundararajan , Melhem Alaa’ Lufti , Pearson Ewan R , Pola Roberto , Palmer Colin N A , Siddiqui Moneeza K 
Published: August 2022

AbstractBackground and AimsThe efficacy of statin therapy is hindered by adverse drug reactions, most frequently musculoskeletal symptoms. Variants in SLCO1B1, which encodes the hepatic transporter OATB1B1, influence statin pharmacokinetics, resulting in altered plasma concentration of the drug and its metabolites. While pharmacogenetic testing of the loss-of-function Val174Ala (rs4149056T>C) is recommended to reduce risk of statin intolerance, current guidelines acknowledge the potential role of gain-of-function variants. This study tests the hypothesis that accounting for gain-of-function variants in SLCO1B1, in addition to Val174Ala, will provide more reliable estimates of statin intolerance.Methods and ResultsHigh-risk haplotypes were derived from Val174Ala and three common gain-of-function SLCO1B1 variants and compared to low-risk haplotypes. In statin users from Tayside Scotland, UK, those with high-risk haplotypes had increased odds across three phenotypes of statin intolerance (general statin intolerance: ORGSI 2.42[95%CI:1.29, 4.31], p=0.003; statin-related myopathy ORSRM 2.51[95%CI:1.28, 4.53],p=0.004; statin-related suspected rhabdomyolysis: ORSRSR 2.85[95%CI:1.03, 6.65],p=0.02). In contrast, using the Val174Ala genotype alone produced weaker results. A meta-analysis with results from adjudicated cases of statin-induced myopathy in the PREDICTION-ADR Consortium confirmed these findings (ORVal174Ala 1.99 [95%CI:1.01, 3.95],p=0.048; ORrisk-haplotypes 1.76 [95%CI:1.16, 2.69],p=0.008). For those requiring high-dose statin therapy, high-risk haplotypes were more consistently associated with the time to onset of statin intolerance amongst the three phenotypes compared to Val174Ala (general statin intolerance: HRVal174Ala 2.49 [95%CI:1.09, 5.68],p=0.03; HRrisk-haplotypes 2.44 [95%CI:1.46, 4.08],p<0.001). Exome-sequenced rare variants were found to be associated with the risk of intolerance (p=0.02).ConclusionsWe demonstrate that accounting for gain-of-function variants in SLCO1B1, in addition to Val174Ala, provides more reliable estimates of statin intolerance.
Rigorous hepatitis B surface antigen analyses and identification of hepatitis B chronicity amongst South Africans attending public health facilities over a five-year period: 2015 to 2019
Authors: Moonsamy Shelina , Pillay Pavitra , Prabdial-Sing Nishi 
Published: August 2022

AbstractHepatitis B, a potentially life-threatening viral infection of the liver, remains a global public health concern despite the availability of effective vaccines for over three decades. Given that most HBsAg studies targeted distinct cohorts, we aimed to provide HBsAg data nationally in the public health sector of South Africa.We conducted a cross-sectional study on HBsAg tests obtained from the National Health Laboratory Service Central Data Warehouse for tests performed nationally during the period 2015 to 2019. Annual data were cleaned and appended prior to data interrogation to determine and analyse the total number of cases who tested positive for HBsAg and the number of chronic HBV infections.We identified 176,530 cases who tested positive for HBsAg at least once during the 5-year period, with a test positivity rate of 9%. Chronic infections were identified in 6.4% of HBsAg positive cases. Clearance of HBsAg was observed in 5,571 cases, inclusive of clearance in 135 chronic cases. Significantly more males tested positive for HBsAg and were chronically infected (p < 0.0001). Amongst individuals who were vaccine-eligible as infants (0 to 19 years old), 4,980 tested HBsAg positive, of which 22.7% (1,131) were under 5 years old, with a HBsAg population positivity rate of 0.02% and test positivity rate of 4.83%.HBsAg positivity amongst vaccine-eligible individuals is likely due to suboptimal vaccine coverage rates reported for South Africa. Without a birth dose of the HBV vaccine and lack of routine HBsAg screening at antenatal care, it is likely that the majority of HBsAg positive cases under 5 years old were vertically infected. Optimal HBV vaccine coverage, inclusive of a birth dose, is key to eliminating horizontal and vertical transmission of HBV. Early identification of HBV chronicity is fundamental in reducing the risk of liver cirrhosis and hepatocellular carcinoma.
Abrupt permafrost thaw triggers microbial bloom and grazer succession
Authors: Scheel Maria , Zervas Athanasios , Rijkers Ruud , Tveit Alexander Tøsdal , Ekelund Flemming , Jiménez Francisco Campuzano , Jacobsen Carsten Suhr , Christensen Torben Røjle 
Published: August 2022

AbstractPermafrost soils store a substantial part of the global soil carbon and nitrogen. However global warming causes abrupt erosion and gradual thaw, which make these stocks vulnerable to microbial decomposition into greenhouse gases. Here, we investigated the microbial response to abruptin situpermafrost thaw. We sequenced the total RNA of a 1 m deep soil core consisting of up to 26’500-year-old permafrost material from an active abrupt erosion site. We analysed the microbial community in the active layer soil, the recently thawed, and the intact permafrost and found maximum RNA:DNA ratios indicating a microbial bloom in recently thawed permafrost. Several fast-growing prokaryotic taxa dominated thawed permafrost, including Sphingobacteriales, Burkholderiales, and Nitrosomonadales. Overall, the thaw state and soil moisture consistently explained changes in community composition, with especially the permafrost community being significantly distinct from thawed soils. Predation correlated with changes in prokaryotic composition. Bacterial grazers were dominated by Myxococcales and abundant in the active layer. In contrast, protozoa, especially Cercozoa and Ciliophora, doubled in relative abundance in thawed layers. Our findings highlight the ecological importance of a rapid development of microbial blooms as well as the successive predation as biological control mechanism in abruptly thawing permafrost.One sentence summaryUsing total RNA from an up to 26’500-year-old abruptly eroding permafrost site in Greenland, we described a microbial bloom and its controls, including bacterial and microeukaryotic predators.Abstract Figure
The asthma gut microbiota influences lung inflammation in gnotobiotic mice
Authors: Wilson Naomi G. , Hernandez-Leyva Ariel , Rosen Anne L. , Jaeger Natalia , McDonough Ryan T. , Santiago-Borges Jesus , Lint Michael A. , Rosen Thomas R. , Tomera Christopher P. , Bacharier Leonard B. , Swamidass S. Joshua , Kau Andrew L. 
Published: August 2022

AbstractThe composition of the gut microbiota in early childhood is linked to asthma risk but the role of the gut microbiota in older patients with established asthma is less clear. Here, we used a cohort of 38 school-aged children (19 with asthma) and 57 adults (17 with asthma) to develop a model that aids in the design of mechanistic experiments in gnotobiotic mice. These experiments show that enterotoxigenic Bacteroides fragilis (ETBF) is associated with increased gut permeability, oxidative stress, and markers of Th17-mediated inflammation in the lungs of mice following ovalbumin sensitization and challenge (OSC). Further, ETBF is enriched in a human population with asthma compared to healthy controls. Our results provide evidence that ETBF has the potential to alter the phenotype of airway inflammation in a subset of patients with asthma outside of early childhood which suggests that therapies targeting the gut microbiota may be helpful tools for asthma control.
Dystroglycan N-terminal domain enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy
Authors: Okuma Hidehiko , Hord Jeffrey M. , Chandel Ishita , Venzke David , Anderson Mary E. , Walimbe Ameya S. , Joseph Soumya , Gastel Zeita , Hara Yuji , Saito Fumiaki , Matsumura Kiichiro , Campbell Kevin P. 
Published: August 2022

AbstractDystroglycan (DG) requires extensive post-translational processing to function as a receptor for extracellular matrix proteins containing laminin-G-like (LG) domains. Matriglycan is an elongated polysaccharide of alternating xylose and glucuronic acid that is uniquely synthesized on α-dystroglycan (α-DG) by like-acetylglucosaminyltransferase-1 (LARGE1) and binds with high affinity to matrix proteins like laminin. Defects in the post-translational processing of α-DG that result in a shorter form of matriglycan reduce the size of α-DG and decrease laminin binding, leading to various forms of muscular dystrophy. However, little is known regarding mechanisms that generate full-length matriglycan on α-DG (~150-250 kDa). Here, we show that LARGE1 can only synthesize a short, non-elongated form of matriglycan in mouse skeletal muscle that lacks the DG N-terminus (α-DGN), resulting in a ~100-125 kDa α-DG. This smaller form of α-DG binds laminin and maintains specific force but does not prevent muscle pathophysiology, including reduced force induced by eccentric contractions and abnormalities in neuromuscular junctions. Collectively, our study demonstrates that α-DGN is required for LARGE1 to extend matriglycan to its full mature length on α-DG and thus prevent muscle pathophysiology.
Ex vivomidgut cultures ofAedes aegyptiare efficiently infected by mosquito-borne alpha- and flaviviruses
Authors: Rosales Rosas Ana Lucia , Wang Lanjiao , Goossens Sara , Cuvry Arno , Li Li-Hsin , Santos-Ferreira Nanci , Soto Alina , Dallmeier Kai , Rocha-Pereira Joana , Delang Leen 
Published: August 2022

AbstractAedes aegyptimosquitoes can transmit several arboviruses, including chikungunya virus (CHIKV), dengue virus (DENV), and Zika virus (ZIKV). When blood-feeding on a virus-infected human, the mosquito ingests the virus into the midgut (stomach), where it replicates and must overcome the midgut barrier to disseminate to other organs and ultimately be transmitted via the saliva. Current tools to study mosquito-borne viruses (MBVs) include 2D-cell culture systems andin vivomosquito infection models, which offer great advantages, yet have some limitations.Here, we describe a long-termex vivoculture ofAe. aegyptimidguts. Cultured midguts were metabolically active for 7 days in a 96-well plate at 28°C and were permissive to ZIKV, DENV, Ross River virus (RRV) and CHIKV.Ex vivomidguts fromCulex pipiensmosquitoes were found to be permissive to Usutu virus (USUV). Immunofluorescence staining confirmed viral protein synthesis in CHIKV-infected midguts ofAe. aegypti. Furthermore, fluorescence microscopy revealed replication and spread of a reporter DENV in specific regions of the midgut. In addition, two known antiviral molecules, β-D-N4-hydroxycytidine (NHC) and 7-deaza-2’-C-methyladenosine (7DMA), were able to inhibit CHIKV and ZIKV replication, respectively, in theex vivomodel.Together, our results show thatex vivomidguts can be efficiently infected with mosquito-borne alpha- and flaviviruses and employed to evaluate antiviral drugs. Furthermore, the setup can be extended to other mosquito species.Ex vivomidgut cultures could thus be a new model to study MBVs, offering the advantage of reduced biosafety measures compared to infecting living mosquitoes.ImportanceMosquito-borne viruses (MBVs) are a significant global health threat since they can cause severe diseases in humans, such as hemorrhagic fever, encephalitis, and chronic arthritis. MBVs rely on the mosquito vector to infect new hosts and perpetuate virus transmission. No therapeutics are currently available. The study of arbovirus infection in the mosquito vector can greatly contribute to elucidating strategies for controlling arbovirus transmission. This work investigated the infection of midguts fromAedes aegyptimosquitoes in anex vivoplatform. We found several MBVs capable of replicating in the midgut tissue, including viruses of major health importance, such as dengue, chikungunya, and Zika viruses. Additionally, antiviral compounds reduced arbovirus infection in the cultured midgut tissue. Overall, the midgut model emerges as a useful tool for diverse applications such as studying tissue-specific responses to virus infection and screening potential anti-arboviral molecules.
Disabling of ARC1 through CRISPR/CAS9 leads to a complete breakdown of self-incompatibility responses in Brassica napus
Authors: Abhinandan Kumar , Hickerson Neil M.N. , Lan Xingguo , Samuel Marcus A. 
Published: August 2022

AbstractSelf-incompatibility (SI) is a genetic mechanism utilized by many flowering plants to promote outcrossing by recognizing and rejecting self-pollen. While the molecular mechanisms controlling SI can differ in various families, plants in the Brassicaceae family have been found to regulate SI through a S-haplotype-specific receptor-ligand interaction. The recognition of self-pollen leads to the activation of ARMADILLO-REPEAT-CONTAINING1 (ARC1), an E3 ligase which is thought to degrade the compatibility factors required for pollen germination, thus resulting in SI. However, the role of ARC1 in SI in the Brassicaceae family has been disputed within the scientific community. While various studies demonstrate that the manipulation of ARC1 and its downstream targets can break-down the SI response, others show that the SI phenotype can be imparted to self-compatible cultivars without the ARC1 gene. This study investigated the involvement of ARC1 in SI through the generation of loss-of-function ARC1 mutants using CRISPR-Cas9 in B. napus. Loss of ARC1 resulted in complete breakdown of SI in two different S-haplotypes providing strong evidence for the essential nature of ARC1 for mounting a successful SI response.
Semi-Self-Supervised Learning for Semantic Segmentation in Images with Dense Patterns
Authors: Najafian Keyhan , Ghanbari Alireza , Kish Mahdi Sabet , Eramian Mark , Shirdel Gholam Hassan , Stavness Ian , Jin Lingling , Maleki Farhad 
Published: August 2022

AbstractDeep learning has shown potential in domains where large-scale annotated datasets are available. However, manual annotation is expensive, time-consuming, and tedious. Pixel-level annotations are particularly costly for semantic segmentation in images with dense irregular patterns of object instances, such as in plant images. In this work, we propose a method for developing high-performing deep learning models for semantic segmentation of wheat heads utilizing little manual annotation. We simulate a computationally-annotated dataset using a few annotated images, a short unannotated video clip of a wheat field, and several video clips from fields with no wheat. This dataset is then used to train a customized U-Net model for wheat head segmentation. Considering the distribution shift between the simulated and real data, we apply three domain adaptation steps to gradually bridge the domain gap. Only using two annotated images, we achieved a Dice score of 0.89 on the internal test set, i.e., images extracted from the wheat field video. The model trained using only two annotated images was evaluated on a diverse external dataset collected from 18 different domains across five countries and achieved a Dice score of 0.73. To further expose the model to images from different growth stages and environmental conditions, we incorporated two annotated images from each of the 18 domains and further fine-tuned the model. This resulted in improving the Dice score to 0.91. These promising results highlight the utility of the proposed approach in the absence of large-annotated datasets. Although the utility of the proposed method is shown on a wheat head dataset, it can be extended to other segmentation tasks with similar characteristics of irregularly repeating patterns of object instances.
Six states of Enterococcus hirae V-type ATPase reveals non-uniform rotor rotation during turnover
Authors: Burton-Smith Raymond N. , Song Chihong , Ueno Hiroshi , Murata Takeshi , Iino Ryota , Murata Kazuyoshi 
Published: August 2022

SummaryThe vacuolar-type ATPase from Enterococcus hirae (EhV-ATPase) is a thus-far unique adaptation of V-ATPases, as it performs Na+ transport and demonstrates an off-axis rotor assembly. Recent single molecular studies of the isolated V1 domain have indicated that there are subpauses within the three major states of the pseudo three-fold symmetric rotary enzyme. However, there was no structural evidence for these. Herein we activated the EhV-ATPase complex with ATP and identified multiple structures consisting of a total of six states of this complex by using cryo-electron microscopy. The orientations of the rotor complex during turnover, especially in the intermediates, were not as perfectly uniform as expected. The densities in the nucleotide binding pockets in the V1 domain indicated the different catalytic conditions for the six conformations. The off-axis rotor and its’ interactions with the stator a-subunit during rotation suggests that this non-uniform rotor rotation is performed through the entire complex.
Long-lasting impact of chito-oligosaccharide application on strigolactone biosynthesis and fungal accommodation promotes arbuscular mycorrhiza inMedicago truncatula
Authors: Volpe Veronica , Chialva Matteo , Mazzarella Teresa , Crosino Andrea , Capitanio Serena , Costamagna Lorenzo , Kohlen Wouter , Genre Andrea 
Published: August 2022

SummaryThe establishment of arbuscular mycorrhiza (AM) between plants and Glomeromycotina fungi is preceded by the exchange of chemical signals: fungal released Myc-factors, including chitoligosaccharides (CO) and lipo-chitooligosaccharides (LCO), activate plant symbiotic responses, while root exuded strigolactones stimulate hyphal branching and boost CO release.Furthermore, fungal signaling reinforcement through CO application was shown to promote AM development inMedicago truncatula, but the cellular and molecular bases of this effect remained unclear.Here we focused on long-termM. truncatularesponses to CO treatment, demonstrating its impact on the transcriptome of both mycorrhizal and non-mycorrhizal roots over several weeks and providing a novel insight into the mechanistic bases of the CO-dependent promotion of AM colonization.CO treatment caused the long-lasting regulation of strigolactone biosynthesis and fungal accommodation related genes. This was mirrored by an increase in root didehydro-orobanchol content, and the promotion of accommodation responses to AM fungi in root epidermal cells. Lastly, an advanced down-regulation of AM symbiosis marker genes was observed at the latest time point in CO-treated plants, in line with an increased number of senescent arbuscules.Overall, CO treatment triggered molecular, metabolic and cellular responses underpinning a protracted acceleration of AM development.