bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo18F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation
Authors: Morley Victoria , Singh Dolt Karamjit , Alcaide-Corral Carlos J. , Walton Tashfeen , Lucatelli Christophe , Mashimo Tomoji , Tavares Adriana A. S. , Kunath Tilo 
Published: November 2022

AbstractParkinson’s disease (PD) is a neurodegenerative condition with several major hallmarks, including loss ofsubstantia nigraneurons, reduction in striatal dopaminergic function, and formation of α-synuclein-rich Lewy bodies. Mutations inSNCA, encoding for α-synuclein, are a known cause of familial PD, and the G51D mutation causes a particularly aggressive form of the condition. CRISPR/Cas9 technology was used to introduce the G51D mutation into the endogenous ratSNCAgene.SNCAG51D/+andSNCAG51D/G51Drats were born in Mendelian ratios and did not exhibit any severe behavourial defects.L-3,4-dihydroxy-6-18F-fluorophenylalanine (18F-DOPA) positron emission tomography (PET) imaging was used to investigate this novel rat model. Wild-type (WT),SNCAG51D/+andSNCAG51D/G51Drats were characterised over the course of ageing (5, 11, and 16 months old) using18F-DOPA PET imaging and kinetic modelling. We measured the influx rate constant (Ki) and effective distribution volume ratio (EDVR) of18F-DOPA in the striatum relative to the cerebellum in WT,SNCAG51D/+andSNCAG51D/G51Drats. A significant reduction inEDVRwas observed inSNCAG51D/G51Drats at 16 months of age indicative of increased dopamine turnover. Furthermore, we observed a significant asymmetry in EDVR between the left and right striatum in agedSNCAG51D/G51Drats. The increased and asymmetric dopamine turnover observed in the striatum of agedSNCAG51D/G51Drats is similar to prodromal PD, which suggests the presence of compensatory mechanisms.SNCAG51Drats represent a novel genetic model of PD, and kinetic modelling of18F-DOPA PET data has identified a highly relevant early disease phenotype.
Isolation and characterization of bacteriophages against IMP-6-producingKlebsiella pneumoniaeisolated from clinical settings in Japan
Authors: Kondo Kohei , Nakano Satoshi , Hisatsune Junzo , Sugawara Yo , Kataoka Michiyo , Kayama Shizuo , Sugai Motoyuki , Kawano Mitsuoki 
Published: November 2022

AbstractCarbapenemase-producingEnterobacteriaceae(CPE) are one of the most detrimental species of antibiotic-resistant bacteria worldwide. Phage therapy has emerged as an effective strategy for the treatment of infections caused by CPE pathogens. In west Japan, the increasing occurrence ofKlebsiella pneumoniaeharboring the pKPI-6 plasmid, which encodesblaIMP-6, is a growing concern. To manage such major antimicrobial-resistant pathogens, we isolated 29 novel phages from sewage in Japan, targeting 31 strains ofK. pneumoniaeand one strain ofEscherichia coliharboring the pKPI-6 plasmid. Electron microscopy analysis indicated that of the 29 isolated phages, 21 (72.4%), 5 (17.2%), and 3 (10.3%) belonged toMyoviridae, Siphoviridae, andPodoviridae, respectively. Host range analysis revealed that 20Myoviridaemembers in isolated phages infected 25–26 strains ofK. pneumoniae, indicating that most of the isolated phages have a broad host range. TheK. pneumoniaeKp21 can only be infected by phage øKp_21, while Kp22 can be infected by more than 20 phages. We applied a phage cocktail, which consists of 10 phages, against Kp21 and Kp22 and found that the phage cocktail delayed the emergence of phage-resistant bacteria for Kp21 strain but not for the Kp22 strain. Furthermore, phage-resistant Kp21 (Kp21r) became prone to be infected from other bacteriophages as a “trade-off” of resistance to phage øKp_21. Our proposed phage set has an adequate number of phages to combat theK. pneumoniaestrain isolated in Japan. Notably, our work demonstrates how a suitable phage cocktail diminishes the occurrence of phage-resistant bacteria.ImportanceKlebsiella pneumoniaeharboring the plasmid carryingblaIMP-6is becoming an increasingly hazardous species in Japan. We collected and characterized 29 novel bacteriophages that infectK. pneumoniaecarrying the pKPI-6 plasmid, isolated in clinical settings of west Japan. Our phages showed broad host ranges. We applied a phage cocktail treatment constructed from 10 phages against two host strains, Kp21 and Kp22, which show different phage susceptibility patterns each other. Although the phage cocktail delayed phage-resistant Kp21 emergence, the emergence of phage-resistant Kp22 could not be delayed. Moreover, phage-resistant Kp21 became sensitive to other phages, which did not originally infect wild-type Kp21. Our study demonstrates how a suitable phage cocktail can diminish the occurrence of phage-resistant bacteria.
Musical expertise enhances neural alignment-to-young in sensorimotor regions that predicts older adults’ audiovisual speech-in-noise perception
Authors: Zhang Lei , Wang Xiuyi , Du Yi 
Published: November 2022

AbstractMusical training can offset age-related decline in speech-in-noise perception. However, how lifelong musical expertise affects the functional reorganization of older brain in speech-in-noise perception has not yet been systematically investigated. Here, we address this issue by analyzing fMRI responses of older musicians, older non-musicians and, young non-musicians identifying noise-masked audiovisual syllables. First, we confirmed that older musicians outperformed older non-musicians and even equaled young non-musicians. Then, we showed that both older groups showed decreased auditory activation and increased visual activation compared to young non-musicians, while older musicians showed higher activation in speech motor regions and greater deactivation of default mode network (DMN) regions than older non-musicians. Next, we revealed that musical expertise counteracted the age-related neural dedifferentiation of speech representation, making older musicians exhibit higher neural alignment-to-young in bilateral sensorimotor areas. Finally, we disentangled that greater activation in speech motor areas and stronger deactivation in DMN regions were correlated with higher neural alignment in sensorimotor areas, which strongly predicted better performance in older adults. Together, long-term musical expertise mitigates age-related deficits in audiovisual speech-in-noise processing through enhanced compensatory scaffolding that reserves youth-like representation in sensorimotor areas. Our findings provide a comprehensive perspective on understanding age- and experience-related brain reorganization during speech perception.
Exploring the genome and protein space of viruses
Authors: Lu Congyu , Wu Yifan , Zhang Zheng , Mao Longfei , Ge Xingyi , Wu Aiping , Sun Fengzhu , Jiang Yongqiang , Peng Yousong 
Published: November 2022

AbstractRecent metagenomic studies have identified a vast number of viruses. However, the systematic assessment of the true genetic diversity of the whole virus community on our planet remains to be investigated. Here, we explored the genome and protein space of viruses by simulating the process of virus discovery in viral metagenomic studies. Among multiple functions, the power function was found to best fit the increasing trends of virus diversity and was therefore used to predict the genetic space of viruses. The estimate suggests that there are at least 8.23e+08 viral Operational Taxonomic Units (vOTUs) and 1.62e+09 viral protein clusters on Earth when assuming the saturation of the virus genetic space, taking into account the balance of costs and the identification of novel viruses. It’s noteworthy that less than 3% of the viral genetic diversity has been uncovered thus far, emphasizing the vastness of the unexplored viral landscape. To saturate the genetic space, a total of 3.08e+08 samples would be required. Analysis of viral genetic diversity by ecosystem yielded estimates consistent with those mentioned above. Furthermore, the estimate of the virus genetic space remained robust when accounting for the redundancy of sampling, sampling time, sequencing platform, and parameters used for protein clustering. This study provides a guide for future sequencing efforts in virus discovery and contributes to a better understanding of viral diversity in nature.
Establishment and characterisation of oviductal organoids from farm and companion animals
Authors: Lawson Edwina F. , Ghosh Arnab , Blanch Victoria , Grupen Christopher G. , Aitken R John , Lim Rebecca , Drury Hannah R. , Baker Mark A. , Gibb Zamira , Tanwar Pradeep S. 
Published: November 2022

ABSTRACTOrganoid technology has provided us with a unique opportunity to study early human development and decipher various steps involved in the pathogenesis of human diseases. The technology is already used in clinics to improve human patient outcomes. However, limited knowledge of the methodologies required to establish organoid culture systems in domestic animals has slowed the advancement and application of organoid technology in veterinary medicine. Here, we have developed a platform to grow organoids from animal tissue samples and characterized oviductal organoids from five domestic animal species. Organoids were grown progressively from single cells derived from the enzymatic digestion of freshly collected equine, bovine, feline, canine, and porcine oviducts. The addition of WNT, TGFB, BMP, Rock, and Notch signalling pathway activators or inhibitors in the culture medium suggested remarkable conservation of the molecular signals involved in oviductal epithelial development and differentiation across species. The gross morphology of organoids from all the domestic species was initially similar. However, some differences in size, complexity, and growth rate were observed and described. Well-defined and synchronised motile ciliated cells were observed in differentiated organoids in mature populations. Histopathologically, oviductal organoids mimicked their respective native tissue. In summary, we have developed a detailed cross-species comparison of oviductal organoid models, which will be valuable for advancing assisted reproductive technologies and fertility studies in these animal species in the future.Summary sentenceOrganoids can be derived from the oviductal epithelium of cow, cat, dog, horse, and pig to advance assisted reproductive technologies in animals.
Xist ribonucleoproteins promote female sex-biased autoimmunity
Authors: Dou Diana R. , Zhao Yanding , Belk Julia A. , Zhao Yang , Casey Kerriann M. , Chen Derek C. , Li Rui , Yu Bingfei , Srinivasan Suhas , Abe Brian T. , Kraft Katerina , Hellström Ceke , Sjöberg Ronald , Chang Sarah , Feng Allan , Goldman Daniel W. , Shah Ami A. , Petri Michelle , Chung Lorinda S. , Fiorentino David F. , Lundberg Emma K. , Wutz Anton , Utz Paul J. , Chang Howard Y. 
Published: November 2022

SUMMARYAutoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long noncoding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex, comprised of numerous autoantigenic components, is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form ofXistin male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multiorgan pathology in pristane-induced model of lupus than wild-type males. Xist expression in males reprogrammed T and B cell population and chromatin states to more resemble wild type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.HIGHLIGHTSTransgenic mouse models inducibly express Xist in male animals.Xist expression in males induce autoantibodies and autoimmune pathology.Xist in males reprograms T and B cell populations to female-like patterns.Autoantibodies to Xist RNP characterize female-biased autoimmune diseases.
Microprism-based two-photon imaging of the mouse inferior colliculus reveals novel organizational principles of the auditory midbrain
Authors: Ibrahim Baher A. , Shinagawa Yoshitaka , Douglas Austin , Xiao Gang , Asilador Alexander R. , Llano Daniel A. 
Published: November 2022

AbstractTo navigate real-world listening conditions, the auditory system relies on the integration of multiple sources of information. However, to avoid inappropriate cross-talk between inputs, highly connected neural systems need to strike a balance between integration and segregation. Here, we develop a novel approach to examine how repeated neurochemical modules in the mouse inferior colliculus lateral cortex (LC) allow controlled integration of its multimodal inputs. The LC had been impossible to study via imaging because it is buried in a sulcus. Therefore we coupled two-photon microscopy with the use of a microprism to reveal the first-ever sagittal views of the LC to examine neuronal responses with respect to its neurochemical motifs under anesthetized and awake conditions. This approach revealed marked differences in the acoustic response properties of LC and neighboring nonlemniscal portions of the inferior colliculus. In addition, we observed that the module and matrix cellular motifs of the LC displayed distinct somatosensory and auditory responses. Specifically, neurons in modules demonstrated primarily offset responses to acoustic stimuli with enhancement in responses to bimodal stimuli, whereas matrix neurons showed onset response to acoustic stimuli and suppressed responses to bimodal stimulation. Thus, this new approach revealed that the repeated structural motifs of the LC permit functional integration of multimodal inputs while retaining distinct response properties.
Transcriptional control of motor pool formation and motor circuit connectivity by the LIM-HD protein Isl2
Authors: Lee Yunjeong , Yeo In Seo , Kim Namhee , Lee Dong-Keun , Kim Kyung-Tai , Yoon Jiyoung , Hong Young Bin , Choi Byung-Ok , Kosodo Yoichi , Kim Daesoo , Park Jihwan , Song Mi-Ryoung 
Published: November 2022

AbstractThe fidelity of motor control requires the precise positional arrangement of motor pools and the establishment of synaptic connections between these pools. In the developing spinal cord, motor nerves project to specific target muscles and receive proprioceptive input from the muscles via the sensorimotor circuit. LIM-homeodomain transcription factors are known to successively restrict specific motor neuronal fates during neural development; however, it remains unclear to what extent they contribute to limb-based motor pools and locomotor circuits. Here, we showed in mice that deletion ofIsl2resulted in scattered motor pools, primarily in the median motor column and lateral LMC (LMCl) populations, and lacked Pea3 expression in the hindlimb motor pools, accompanied by reduced terminal axon branching and disorganized neuromuscular junctions. Transcriptomic analysis ofIsl2- deficient spinal cords revealed that a variety of genes involved in motor neuron differentiation, axon development, and synapse organization were downregulated in hindlimb motor pools. Moreover, the loss ofIsl2impaired sensorimotor connectivity and hindlimb locomotion. Together, our studies indicate thatIsl2plays a critical role in organizing motor pool position and sensorimotor circuits in hindlimb motor pools.
Normalized Semi-Covariance Co-Efficiency Analysis of Spike Proteins from SARS-CoV-2 variant Omicron and Other Coronaviruses for their Infectivity and Virulence
Authors: Xu Tong , Zhou Shanyue , Huang Jun Steed , Zhang Wandong 
Published: November 2022

AbstractSpectrum-based Mass-Charge modeling is increasingly used in biological analysis. To explain statistical phenomenon with positive and negative fluctuations of amino acid charges in spike protein sequences from Omicron and other coronaviruses, we propose calculation-based Mass-Charge modeling, a normalized derivation algorithm with exact Excel and MATLAB tool involving separate quadrant extension to normalized covariance, which is still compatible with Pearson covariance co-efficiency. The number of amino acids, molecular weight, isoelectric point, amino acid composition, charged residues, mass-charge ratio, hydropathicity of the proteins were taken into consideration in the analyses, and the relative peak and dip of the average with spike protein sequences based on hydrophobic mass to isoelectric charges of amino acids were also examined. The analyses with the algorithm provide more clear insights leading to revealing underline evolving trends of the viral proteins. Spike proteins from SARS-CoV-2 variants, seasonal and murine coronaviruses were taken as representative examples in this study. The analyses demonstrate that the Mass-Charge covariance co-efficiency can distinguish subtle differences between biological properties of spike proteins and correlate well with viral infectivity and virulence.
COMPUTATIONAL EVIDENCE FOR MULTI-LAYER CROSSTALK BETWEEN THE CADHERIN-11 AND PDGFR PATHWAYS
Authors: Karagöz Zeynep , Passanha Fiona R. , Robeerst Lars , van Griensven Martijn , LaPointe Vanessa L. S. , Carlier Aurélie 
Published: November 2022

ABSTRACTVarious cell surface receptors play an important role in the differentiation and self-renewal of human mesenchymal stem cells (hMSCs). One example of such receptors are the cadherins, which maintain cell–cell adhesion and mechanically couple cells together. Recently, cadherin-11, which is a member of the type II classical cadherin family, has been shown to be involved in the fate commitment of hMSCs. Interestingly, cadherin-11 has no known intrinsic signaling activity and is thought to affect cell behavior via interactions with other cell surface receptors. Members of the platelet-derived growth factor receptor (PDGFR) family are hypothesized to be one of the interaction partners of cadherin-11. Experiments confirmed that PDGFR-α binding to extracellular cadherin-11 regions increases the PDGFR-α activity, whereas the interaction between PDGFR-β and cadherin-11 suppresses the activity of the growth factor receptor. Cadherin-11 knockdown experiments also decreased cell proliferation. These interactions between cadherin-11 and PDGFRs indicate a crosstalk between these receptors and their downstream signaling activities but the nature of this crosstalk is not entirely known. In this study, we used a computational model to represent the experimentally proven interactions between cadherin-11 and the two PDGFRs and we inspected whether the crosstalk also exists downstream of the signaling initiated by the two receptor families. The computational framework allowed us to monitor the relative activity levels of each protein in the network. We performed model simulations to mimic the conditions of previous cadherin-11 knockdown experiments and to predict the effect of crosstalk on cell proliferation. Overall, our predictions suggest the existence of another layer of crosstalk, namely between β-catenin (downstream to cadherin-11) and an ERK inhibitor protein (e.g. DUSP1), different than the crosstalk at the receptor level between cadherin-11 and PDGFR-α and -β. By investigating the multi-level crosstalk between cadherin and PDGFRs computationally, this study contributes to an improved understanding of the effect of cell surface receptors on hMSCs proliferation.
Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection
Authors: Milighetti Martina , Peng Yanchun , Tan Cedric , Mark Michal , Nageswaran Gayathri , Byrne Suzanne , Ronel Tahel , Peacock Tom , Mayer Andreas , Chandran Aneesh , Rosenheim Joshua , Whelan Matthew , Yao Xuan , Liu Guihai , Felce Suet Ling , Dong Tao , Mentzer Alexander J. , Knight Julian C. , Balloux Francois , Greenstein Erez , Reich-Zeliger Shlomit , Pade Corrina , Gibbons Joseph M. , Semper Amanda , Brooks Tim , Otter Ashley , Altmann Daniel M , Boyton Rosemary J , Maini Mala K , McKnight Aine , Manisty Charlotte , Treibel Thomas A. , Moon James C. ,   COVIDsortium Investigators, Noursadeghi Mahdad , Chain Benny 
Published: November 2022

AbstractWe analyzed the dynamics of the earliest T cell response to SARS-COV-2. A wave of TCRs strongly but transiently expand during infection, frequently peaking the same week as the first positive PCR test. These expanding TCR CDR3s were enriched for sequences functionally annotated as SARS-COV-2 specific. Most epitopes recognized by the expanding TCRs were highly conserved between SARS-COV-2 strains, but not with circulating human coronaviruses. Many expanding CDR3s were also present at high precursor frequency in pre-pandemic TCR repertoires. A similar set of early response TCRs specific for lymphocytic choriomeningitis virus epitopes were also found at high frequency in the pre-infection naïve repertoire. High frequency naïve precursors may allow the T cell response to respond rapidly during the crucial early phases of acute viral infection.One-Sentence SummaryHigh frequency naïve precursors underly the rapid T cell response during the crucial early phases of acute viral infection.
What drives chorismate mutase to top performance? Insights from a combinedin silicoandin vitrostudy
Authors: Thorbjørnsrud Helen V. , Bressan Luca , Khatanbaatar Tamjidmaa , Carrer Manuel , Würth-Roderer Kathrin , Cordara Gabriele , Kast Peter , Cascella Michele , Krengel Ute 
Published: November 2022

ABSTRACTUnlike typical chorismate mutases, the enzyme fromMycobacterium tuberculosis(MtCM) has only low activity on its own. Remarkably, its catalytic efficiencykcat/Kmcan be boosted more than 100-fold by complex formation with a partner enzyme. Recently, an autonomously fully active MtCM variant was generated using directed evolution, and its structure solved by X-ray crystallography. However, key residues were involved in crystal contacts, challenging the functional interpretation of the structural changes. Here, we address these challenges by microsecond molecular dynamics simulations, followed up by additional kinetic and structural analyses of selected sets of specifically engineered enzyme variants. A comparison of wild-type MtCM with naturally and artificially activated MtCMs revealed the overall dynamic profiles of these enzymes as well as key interactions between the C-terminus and the active site loop. In the artificially evolved variant of this model enzyme, this loop is pre-organized and stabilized by Pro52 and Asp55, two highly conserved residues in typical, highly active chorismate mutases. Asp55 stretches across the active site and helps to appropriately position active site residues Arg18 and Arg46 for catalysis. The role of Asp55 can be taken over by another acidic residue, if introduced at position 88 close to the C-terminus of MtCM, as suggested by MD simulations and confirmed by kinetic investigations of engineered variants.