bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel mouse model of cerebral adrenoleukodystrophy highlights NLRP3 activity in lesion pathogenesis
Authors: Hashemi Ezzat , Srivastava Isha Narain , Aguirre Alejandro , Yoseph Ezra Tilahan , Kaushal Esha , Awani Avni , Ryu Jae Kyu. , Akassoglou Katerina , Talebian Shahrzad , Chu Pauline , Pisani Laura , Musolino Patricia , Steinman Lawrence , Doyle Kristian , Robinson William H , Sharpe Orr , Cayrol Romain , Orchard Paul , Lund Troy , Vogel Hannes , Lenail Max , Han May Htwe , Bonkowsky Joshua Leith , Van Haren Keith P. 
Published: November 2023

AbstractObjectiveWe sought to create and characterize a mouse model of the inflammatory, cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD) that would facilitate the study of disease pathogenesis and therapy development. We also sought to cross-validate potential therapeutic targets such as fibrin, oxidative stress, and the NLRP3 inflammasome, in post-mortem human and murine brain tissues.BackgroundALD is caused by mutations in the geneABCD1encoding a peroxisomal transporter. More than half of males with anABCD1mutation develop the cerebral phenotype (cALD). Incomplete penetrance and absence of a genotype-phenotype correlation imply a role for environmental triggers. Mechanistic studies have been limited by the absence of a cALD phenotype in theAbcd1-null mouse.MethodsWe generated a cALD phenotype in 8-week-old, maleAbcd1-null mice by deploying a two-hit method that combines cuprizone (CPZ) and experimental autoimmune encephalomyelitis (EAE) models. We employedin vivoMRI and post-mortem immunohistochemistry to evaluate myelin loss, astrogliosis, blood-brain barrier (BBB) disruption, immune cell infiltration, fibrin deposition, oxidative stress, and Nlrp3 inflammasome activation in mice. We used bead-based immunoassay and immunohistochemistry to evaluate IL-18 in CSF and post-mortem human cALD brain tissue.ResultsMRI studies revealed T2 hyperintensities and post-gadolinium enhancement in the medial corpus callosum of cALD mice, similar to human cALD lesions. Both human and mouse cALD lesions shared common histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls,Abcd1-null mice had more severe cerebral inflammation, demyelination, fibrin deposition, oxidative stress, and IL-18 activation. IL-18 immunoreactivity co-localized with macrophages/microglia in the perivascular region of both human and mouse brain tissue.InterpretationThis novel mouse model of cALD suggests loss ofAbcd1function predisposes to more severe cerebral inflammation, oxidative stress, fibrin deposition, and Nlrp3 pathway activation, which parallels the findings seen in humans with cALD. We expect this model to enable long-sought investigations into cALD mechanisms and accelerate development of candidate therapies for lesion prevention, cessation, and remyelination.Graphical Abstract
Women with breast implants have a higher rate of cardiac catheterization but a lower rate of percutaneous coronary intervention suggesting breast implant interference leads to higher false positive rates of cardiac stress imaging
Authors: Movahed Mohammad Reza , Irannejad Kyvan , Venard Emma , Keating Luke , Hashemzadeh Mehrnoosh , Hashemzadeh Mehrtash 
Published: November 2023

AbstractBackgroundBreast implants cause attenuation during myocardial perfusion imaging (SPECT) and interfere with echocardiographic acoustic windows, which may cause false positive results. We hypothesized that false positive cardiac testing would lead to a lower rate of percutaneous intervention (PCI) in patients with breast implants who underwent cardiac catheterization.MethodsUsing ICD 10 codes for breast implants, cardiac catheterization, and percutaneous coronary interventions, we evaluated any association between these cardiac procedures and older adult women with breast implants.ResultsA total of 1,681,135 women 50 or older underwent cardiac catheterization and 792,760 of them underwent PCI. The total number of patients with breast implants who underwent cardiac catheterization was 1,980 (1.99%). The rate of cardiac catheterization was similar (2.99% vs 3.30%, p= 0.06). However, after multivariate adjustment, women with breast implants had a significantly higher rate of cardiac catheterization (OR: 1.12, CI: 1.00-1.25, P=0.05). Furthermore, women after undergoing cardiac catheterization had a lower unadjusted and adjusted rate of PCI (36.93% vs 47.08%, <0.001, unadjusted OR: 0.66, CI: 0.54-0.80, adjusted OR:0.79, CI: 0.64-0.97, p=0.02). Sensitivity analyses using different age cutoffs showed a similar pattern of findings.ConclusionsWomen with breast implants who underwent cardiac catheterization had significantly lower adjusted rates for PCI consistent with our hypothesis that breast implants may lead to higher false positive rates during cardiac ischemia testing. Therefore, women who consider breast implants should be informed about interference with cardiac diagnostic procedures.
Altered hippocampal activation in seizure-proneCACNA2D2knockout mice
Authors: Danis Alyssa , Gallagher Ashlynn A. , Anderson Ashley N. , Isakharov Arielle , Beeson Kathleen A. , Schnell Eric 
Published: November 2023

AbstractThe voltage-gated calcium channel subunit α2δ-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To determine whether mice without α2δ-2 demonstrate hippocampal activation or histopathological changes associated with seizure activity, we measured expression of the activity-dependent genec-fosand various histopathological correlates of temporal lobe epilepsy in hippocampal tissue from wildtype (WT) and α2δ-2 knockout (CACNA2D2KO) mice using immunohistochemical staining and confocal microscopy. Both genotypes demonstrated similarly sparsec-fosexpression within the hippocampal dentate granule cell layer (GCL) at baseline, consistent with no difference in basal activity of granule cells between genotypes. Surprisingly, when mice were assayed 1 hour after handling-associated convulsions, KO mice had fewer c-fos-positive cells in the dentate gyrus, indicating that activity in the dentate gyrus actually decreased. However, the dentate was significantly more active in KO mice compared to WT after administration of a subthreshold pentylenetetrazole dose, consistent with increased susceptibility to proconvulsant stimuli. Other histopathological markers of temporal lobe epilepsy in these mice, including markers of neurogenesis, glial activation, and mossy fiber sprouting, were similar in WT and KO mice, apart from a small but significant increase in hilar mossy cell density, opposite to what is typically found in mice with temporal lobe epilepsy. This suggests that the differences in seizure-associated hippocampal function in the absence of α2δ-2 protein are likely due to altered functional properties of the network without associated structural changes in the hippocampus at the typical age of seizure onset.Significance StatementCalcium channel α2δ subunits play important roles in controlling neuronal circuit structure and function, and mutation of the α2δ-2 isoform of this protein is associated with spontaneous seizures. In this study, we find that seizures in α2δ-2 mutant mice involve altered hippocampal activation without substantial histopathological changes in hippocampal structure. This suggests that the differences in seizure-associated hippocampal function are likely due to altered functional properties of the network as well as to the contribution of additional brain regions to seizures in mice lacking this protein.
Phylogeographic analysis ofBegomoviruscoat and replication-associated proteins
Authors: Crespo-Bellido Alvin , Hoyer J. Steen , Burgos-Amengual Yeissette , Duffy Siobain 
Published: November 2023

ABSTRACTBegomoviruses are globally distributed plant pathogens that significantly limit crop production. These viruses are traditionally described according to phylogeographic distribution and categorized into two groups: begomoviruses from the Africa, Asia, Europe, and Oceania (AAEO) region and begomoviruses from the Americas. Monopartite begomoviruses are more common in the AAEO region while bipartite viruses predominate in the Americas, where the begomoviruses lack the V2/AV2 gene involved in inter-cellular movement and RNA silencing suppression found in AAEO begomoviruses. While these features are generally accepted as lineage-defining, the number of known species has doubled due to sequence-based discovery since 2010. To reevaluate the geographic groupings after the rapid expansion of the genus, we conducted phylogenetic analyses for begomovirus species representatives of the two longest and most conserved begomovirus proteins: the coat and replication-associated proteins. Both proteins still largely support the broad AAEO and Americas begomovirus groupings, except for sweetpotato-infecting begomoviruses that form an independent, well-supported clade for their coat protein regardless of the region they were isolated from. Our analyses do not support more fine-scaled phylogeographic groupings. Monopartite and bipartite genome organizations are broadly interchanged throughout the phylogenies and the absence of the V2/AV2 gene is highly reflective of the split between Americas and AAEO begomoviruses. We observe significant evidence of recombination within the Americas and within the AAEO region, but rarely between the regions. We speculate that increased globalization of agricultural trade, the invasion of polyphagous whitefly vector biotypes and recombination will blur begomovirus phylogeographic delineations in the future.
Robust detection of SARS-CoV-2 exposure in the population using T-cell repertoire profiling
Authors: Vlasova Elizaveta K. , Nekrasova Alexandra I. , Komkov Alexander Y , Izraelson Mark , Snigir Ekaterina A. , Mitrofanov Sergey I. , Yudin Vladimir S. , Makarov Valentin V. , Keskinov Anton A. , Korneeva Darya , Pivnyuk Anastasia , Shelyakin Pavel V , Mamedov Ilgar Z , Rebrikov Denis V , Chudakov Dmitry M , Yudin Sergey M. , Skvortsova Veronika I. , Britanova Olga V , Shugay Mikhail A. 
Published: November 2023

AbstractThe COVID-19 pandemic offers a powerful opportunity to develop methods for monitoring the spread of infectious diseases based on their signatures in population immunity. Adaptive immune receptor repertoire sequencing (AIRR-seq) has become the method of choice for identifying T cell receptor (TCR) biomarkers encoding pathogen specificity and immunological memory. AIRR-seq can detect imprints of past and ongoing infections and facilitate the study of individual responses to SARS-CoV-2, as shown in many recent studies. Here, we have applied a machine learning approach to two large AIRR-seq datasets with more than 1,200 high-quality repertoires from healthy and COVID-19-convalescent donors to infer TCR repertoire features that were induced by SARS-CoV-2 exposure. The new batch effect correction method allowed us to use data from different batches together, as well as combine the analysis for data obtained using different protocols. Proper standardization of AIRR-seq batches, access to human leukocyte antigen (HLA) typing, and the use of both α- and β-chain sequences of TCRs resulted in a high-quality biomarker database and a robust and highly accurate classifier for COVID-19 exposure. This classifier is applicable to individual TCR repertoires obtained using different protocols, paving the way to AIRR-seq-based immune status assessment in large cohorts of donors.
Bacterial community complexity in the phyllosphere penalises specialists over generalists
Authors: Schlechter Rudolf O. , Remus-Emsermann Mitja N. P. 
Published: November 2023

AbstractThe leaf surface, i.e. the phylloplane, is an oligotrophic and heterogeneous environment due to its topography and uneven distribution of resources. Despite being a limiting environment, leaves host bacteria that are abundant and establish spatially-structured communities. However, factors that drive spatial distribution patterns are not well understood. Since leaf-associated bacteria can have beneficial effects to their host, understanding the rules of the community assembly can lead to novel strategies for crop protection. To investigate changes in population density and spatial distribution of bacteria in synthetic communities, we examined the behaviour of two prevalent bacterial groups in theArabidopsis thalianaleaf microbiota:Methylobacteriumspp. (specialists) andSphingomonasspp. (generalists). We designed synthetic communities composed of two (S2) or three strains (S3) in a full factorial design and tested whether density and spatial structure of communities in S3 can be explained by pairwise comparisons in S2. Our results showed that specialists are more susceptible to changes in population densities and spatial distribution patterns than generalists, with lower densities and aggregation patterns when a specialist is in S3 than in S2. Additionally, pairwise comparisons were not sufficient to explain the observed patterns in S3, suggesting that higher-order interactions play a role in the resulting structure of complex communities at the micrometre scale.
Comparison oftet(X4)-containing contigs from metagenomic sequencing data with plasmid sequences of isolates from a cohort of healthy subjects
Authors: Ding Yichen , Er Shuan , Tan Abel , Gounot Jean-Sebastien , Saw Woei-Yuh , Lin Tan Linda Wei , Teo Yik Ying , Nagarajan Niranjan , Seedorf Henning 
Published: November 2023

AbstractThe recently discovered tigecycline-inactivating enzyme Tet(X4) can confer high-level tigecycline resistance on its hosts, which makes it a public health concern. This study focused on detection, analysis, and characterization of Tet(X4)-positive Enterobacteriaceae from the gut microbiota of a healthy cohort of individuals in Singapore using cultivation-dependent and cultivation-independent approaches. Twelve Tet(X4)-positive Enterobacteriaceae strains that were previously obtained from the cohort were fully genome-sequenced and comparatively analysed. A metagenomic sequencing (MS) dataset of the same samples was mined for contigs that harboured thetet(X4) resistance gene. The sequences oftet(X4)-containing contigs and plasmids sequences were compared. The presence of the resistance genesfloRandcatD(also annotated asestT) was detected in the same cassette in 10 and 12 out of the 12tet(X4)-carrying plasmids, respectively. MS detectedtet(X4)-containing contigs in two out of 109 subjects, while cultivation-dependent analysis previously reported a prevalence of 10.1%. Contig sequences are relatively short (∼14-33 kb) but show high similarity to the respective plasmid sequences of the isolates. The frequent co-occurrence offlorRandcatDwithtet(X4) corroborates the hypothesis that the transmission oftet(X4) may have originated from the veterinary sector. Our findings show that MS can complement efforts in the surveillance of antibiotic resistance genes for clinical samples, while it has a lower sensitivity than a cultivation-based method when the target organism have a low abundance. Further optimisation is required if MS is to be utilised in antibiotic resistance surveillance.
Signal Transduction in an Enzymatic Photoreceptor Revealed by Cryo-Electron Microscopy
Authors: Malla Tek Narsingh , Hernandez Carolina , Menendez David , Bizhga Dorina , Mendez Joshua H. , Muniyappan Srinivasan , Schwander Peter , Stojković Emina A. , Schmidt Marius 
Published: November 2023

AbstractPhytochromes are essential photoreceptor proteins in plants with homologs in bacteria and fungi that regulate a variety of important environmental responses. They display a reversible photocycle between two distinct states, the red-light absorbing Pr and the far-red light absorbing Pfr, each with its own structure. The reversible Pr to Pfr photoconversion requires covalently bound bilin chromophore and regulates the activity of a C-terminal enzymatic domain, which is usually a histidine kinase (HK). In plants, phytochromes translocate to nucleus where the C-terminal effector domain interacts with protein interaction factors (PIFs) to induce gene expression. In bacteria, the HK phosphorylates a response-regulator (RR) protein triggering downstream gene expression through a two-component signaling pathway. Although plant and bacterial phytochromes share similar structural composition, they have contrasting activity in the presence of light with most BphPs being active in the dark. The molecular mechanism that explains bacterial and plant phytochrome signaling has not been well understood due to limited structures of full-length phytochromes with enzymatic domain resolved at or near atomic resolution in both Pr and Pfr states. Here, we report the first Cryo-EM structures of a wild-type bacterial phytochrome with a HK enzymatic domain, determined in both Pr and Pfr states, between 3.75 and 4.13 Å resolution, respectively. Furthermore, we capture a distinct Pr/Pfr heterodimer of the same protein as potential signal transduction intermediate at 3.75 Å resolution. Our three Cryo-EM structures of the distinct signaling states of BphPs are further reinforced by Cryo-EM structures of the truncated PCM of the same protein determined for the Pr/Pfr heterodimer as well as Pfr state. These structures provide insight into the different light-signaling mechanisms that could explain how bacteria and plants see the light.
Genetic modification ofCandida maltosa, a nonpathogenic CTG species, revealsEFG1function
Authors: Chávez-Tinoco Marco , García-Ortega Luis F. , Mancera Eugenio 
Published: November 2023

ABSTRACTCandida maltosais closely related to important pathogenicCandidaspecies, but it has been rarely isolated from humans. Therefore, through comparative studies, it could be a powerful model to understand the pathogenicity underpinnings ofCandidaspecies. To facilitate studyingC. maltosaat a molecular level, we built a cohesive genomic sequence composed of 45 scaffolds, a substantial improvement from the thousands of contigs of the available draft. Comparison withC. albicansandC. tropicalisrevealed a reduction in the total number of genes inC. maltosa. However, gene loss seems not to be associated to its avirulence given that most pathogenicity genes were also present inC. maltosa. To genetically editC. maltosawe generated triple auxotrophic strains so that gene deletions can be performed as has been routinely done in pathogenic species. As a proof of concept, we generated gene knockouts of Efg1, a transcription regulator involved in filamentation and biofilm formation in pathogenic species. Although inC. maltosaEfg1 also played a role in these processes, it seems to rather be a repressor of filamentation. The genome assembly and auxotrophic mutants developed are a key step to start usingC. maltosafor comparative studies at a molecular level.
The HIV-1 capsid serves as a nanoscale reaction vessel for reverse transcription
Authors: Jennings Jordan , Bracey Harrison , Nguyen Danny T. , Dasgupta Rishav , Rivera Alondra Vázquez , Sluis-Cremer Nicolas , Shi Jiong , Aiken Christopher 
Published: November 2023

AbstractThe viral capsid performs critical functions during HIV-1 infection and is a validated target for antiviral therapy. Previous studies have established that the proper structure and stability of the capsid are required for efficient HIV-1 reverse transcription in target cells. Moreover, it has recently been demonstrated that permeabilized virions and purified HIV-1 cores undergo efficient reverse transcription in vitro when the capsid is stabilized by addition of the host cell metabolite inositol hexakisphosphate (IP6). However, the molecular mechanism by which the capsid promotes reverse transcription is undefined. Here we show that wild type HIV-1 particles can undergo efficient reverse transcriptionin vitroin the absence of a membrane-permeabilizing agent. This activity, originally termed “natural endogenous reverse transcription” (NERT), depends on expression of the viral envelope glycoprotein during virus assembly and its incorporation into virions. Truncation of the gp41 cytoplasmic tail markedly reduced NERT activity, indicating that gp41 permits the entry of nucleotides into virions. Protease treatment of virions markedly reduced NERT suggesting the presence of a proteinaceous membrane channel. By contrast to reverse transcription in permeabilized virions, NERT required neither the addition of IP6 nor a mature capsid, indicating that an intact viral membrane can substitute for the function of the viral capsid during reverse transcriptionin vitro. Collectively, these results demonstrate that the viral capsid functions as a nanoscale container for reverse transcription during HIV-1 infection.
Empowering Healthcare Professionals in West Africa □ A Feasibility Study and Qualitative Assessment of a Dietary Screening Tool to Identify Adults at High Risk of Hypertension
Authors: Batubo Nimisoere P. , Nwanze Nnenna M. , Alikor Chizindu A. , Auma Carolyn I. , Moore J. Bernadette , Zulyniak Michael A. 
Published: November 2023

AbstractBackgroundDietary risks significantly contribute to hypertension in Nigeria. Food frequency questionnaires (FFQs) can provide valuable dietary assessment but require rigorous validation and careful design to facilitate usability. This study assessed the feasibility and potential effectiveness of implementing a clinical screening tool for identifying adults at high risk of hypertension in West Africa.Materials and methods58 consenting adult patients with hypertension and their caregivers and 35 healthcare professionals from a single-centre Nigerian hospital were recruited to complete a 27-item FFQ at two-time points and three 24-hour recalls for comparison in a mixed method study employing both quantitative questionnaires and qualitative techniques to elicit free form text. Data analyses were conducted using R software version 4.3.1 and NVivo version 14. The trial was registered withClinicalTrials.gov:NCT05973760.ResultsThe mean age of patients was 42.6 ± 11.9 years, with an average SBP of 140.3 ± 29.8 mmHg and a BMI of 29.5 ± 7.1 Kg/m2. The adherence rate was 87.9%, and the mean completion time was 7:37 minutes. 96.6% of patients found the FFQ easy to complete, comprehensive, and valuable. A minority reported difficulty (3.4%), discomfort (10.3%), and proposed additional foods (6.9%). Healthcare professionals considered the screening tool very important (82.9%) and expressed a willingness to adopt the tool, with some suggestions for clarification. Patients and healthcare professionals found the screening tool favourable for nutritional counselling in hypertension care.ConclusionThe tailored screening tool (FFQ) demonstrated promising feasibility for integration into clinical care as assessed by patients and healthcare professionals. Successful implementation may benefit from proactive time management and addressing training needs. This user-centred approach provided key insights to refine FFQ and set the foundation for ongoing validity testing and evaluation in clinical practice.