bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unraveling the Link between CNVs, General Cognition, and Individual Neuroimaging Deviation Scores from a Reference Cohort
Authors: Fraza Charlotte , Sønderby Ida E. , Boen Rune , Shi Yingjie , Beckmann Christian F. , Marquand Andre F. 
Published: November 2023

AbstractCopy number variations (CNVs) are genetic variants that can have a substantial influence on neurodevelopment, neuropsychiatric traits, and morphometric brain changes, yet their impact at the individual level remains unknown. Common case-control approaches for analyzing CNVs suffer from limitations: they are unable to inform on individual variation between carriers and preclude the study of rarer variants, due to their limited sample size. This cross-sectional study aims to map individualized brain deviation scores in individuals with pathogenic CNVs. We used normative modeling to map neuroimaging features from several large neuroimaging datasets and applied these models to understand the neurobiological profile of CNV carriers in the UK Biobank. We highlight the 1q21.1 distal deletion and duplication, as an example of our individual-level normative modeling-CNV approach. Next, we counted the number of extreme deviations for each participant from the mean and centiles of variation from population reference norms, giving us a combined risk score per participant per imaging modality. We show a high degree of heterogeneity between pathogenic CNV carriers in their implicated brain regions. For example, the cerebellum, brainstem, and pallidum show large negative deviations for specific 1q21.1 duplication carriers. For certain 1q21.1 deletion CNV carriers the caudate and accumbens show notable positive deviations. Finally, we show that negative deviations from these models are correlated to cognitive function. This study marks a starting point in understanding the impact of pathogenic CNVs on brain phenotypes, underscoring the intricacies of these genetic variations at the individual level and providing a means to study the effects of rare CNVs in carrier individuals.
Primary exposure to Zika virus increases risk of symptomatic dengue virus infection with serotypes 2, 3, and 4 but not serotype 1
Authors: Zambrana Jose Victor , Hasund Chloe M. , Aogo Rosemary A. , Bos Sandra , Arguello Sonia , Gonzalez Karla , Collado Damaris , Miranda Tatiana , Kuan Guillermina , Gordon Aubree , Balmaseda Angel , Katzelnick Leah , Harris Eva 
Published: November 2023

ABSTRACTInfection with any of the four dengue virus serotypes (DENV1-4) can protect against or enhance subsequent dengue depending on pre-existing antibodies and the subsequent infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) has been shown to increase DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by all four serotypes in a pediatric Nicaraguan cohort. Of 3,412 participants in 2022, 10.6% experienced symptomatic DENV infections caused by DENV1 (n=139), DENV4 (n=133), DENV3 (n=54), DENV2 (n=9), or an undetermined serotype (n=39). Longitudinal clinical and serological data were used to define infection histories, and generalized linear and additive models adjusted for age, sex, time since the last infection, cohort year, and repeat measurements were used to predict disease risk. Compared to flavivirus-naïve participants, primary ZIKV infection increased disease risk of DENV4 (relative risk = 2.62, 95% confidence interval: 1.48-4.63) and DENV3 (2.90, 1.34-6.27) but not DENV1 (1.20, 0.72-1.99). Primary DENV infection or a DENV followed by ZIKV infection also increased DENV4 risk. We re-analyzed 19 years of cohort data and demonstrated that prior flavivirus-immunity and pre- existing antibody titer differentially affected disease risk for incoming serotypes, increasing risk of DENV2 and DENV4, protecting against DENV1, and protecting at high titers but enhancing at low titers against DENV3. We thus find that prior ZIKV infection, like prior DENV infection, increases risk of certain DENV serotypes. Cross-reactivity among flaviviruses should be carefully considered when assessing vaccine safety and efficacy.One-Sentence SummaryDengue disease risk is differentially modulated depending on pre- existing immunity to dengue and Zika virus infections and the secondary infecting serotype.
A systematic review of Flotation-Restricted Environmental Stimulation Therapy (REST)
Authors: Lashgari Elnaz , Chen Emma , Gregory Jackson , Maoz Uri 
Published: November 2023

AbstractBackgroundRestricted Environmental Stimulation Therapy (REST) is a therapeutic technique that involves immersing an individual in an environment with minimal sensory input or stimulation. The goal of REST is to induce a state of relaxation that is deeper than what can be achieved through other forms of relaxation techniques. Research suggests that REST can help reduce anxiety, alleviate chronic pain, improve sleep, and enhance creativity and cognitive function. Flotation-REST is a popular type of REST that utilizes an enclosed tank filled with buoyant saltwater to facilitate relaxation. This study aimed to synthesize the evidence on studies that investigate the effects of flotation-REST.MethodsWe used PRISMA to survey the flotation-REST literature from 1960 to 2023. This search was conducted on 29 January 2023 within the Google Scholar and PubMed databases. Journal and conference papers, as well as electronic preprints, that used flotation-REST in their methods, were written in English, and were published in or after 1960 were included; non-original research papers (e.g., review papers, book chapters, and papers solely on types of REST other than flotation-REST (e.g., chamber-REST) were excluded. From each eligible paper, we extracted information regarding the participant sample, application of flotation-REST, experimental design, treatment delivery method, questionnaires and tools, and study results.ResultsIn total, we found 60 studies that included 1,838 participants. We propose that the application of flotation-REST can be divided into nine main categories: pain, athletic performance, physiology, stress, consciousness, psychology, creativity, clinical anxiety, sleep, smoking cessation, and other miscellaneous applications. In general, flotation-REST was found to bring about positive effects on pain, athletic performance, stress, mental well-being, and clinical anxiety, while having limited to no effect on sleep-related disorders and smoking cessation.ConclusionThis paper provides a comprehensive overview of the current research on flotation-REST, highlights ongoing limitations in the literature, and outlines potential areas for future research. While flotation-REST appears to induce various benefits for physical and mental well-being, particularly when it comes to managing states like pain and stress, more research is needed to better understand the mechanisms underlying these effects and to identify optimal treatment protocols for different populations. A limitation of this paper is the relatively small number of studies available for review, which limits the generalizability of certain findings and highlights the need for additional research in this area.
Abundance of human T-cell epitopes in microbial proteomes
Authors: Kovaleva Vasilisa A. , Zvyagin Ivan V. 
Published: November 2023

AbstractMolecular mimicry, the structural similarity between self and foreign antigens, is considered as a key factor in post-infectious autoimmunity. While certain examples of molecular mimicry are well studied, a comprehensive analysis of its prevalence and impact on the type of T cell response to such self is absent. In this work, we comprehensively studied the frequency of molecular mimicry between human and microbial T-cell epitopes. We performed anin silicoanalysis of the occurrence of T-cell epitopes originating from different sets of proteins: normal self epitopes, proteins involved in autoimmunity, and cancer neoantigens, in the proteomes of commensal and pathogenic microbiota. We show a significant overlap between repertoires of human T-cell epitopes and predicted epitopes from proteins of both commensal and pathogenic microbiota: the counterparts for over 90% of human HLA-I and 5% of HLA-II ligands were found in the microbial proteomes. HLA-II epitopes derived from the proteins involved in autoimmunity were more frequent in microbiota compared to normal self, suggesting a potential deleterious effect of molecular mimicry, while we did not observe this effect for HLA-I epitopes. Cancer epitopes were less frequent in microbiota compared to normal self of epitopes, implicating potential cancer escape from cross-reactive T cells specific to microbial antigens. Together, our results show that molecular mimicry might have a general pro-inflammatory effect on similar self epitopes, though much in this field remains to be explored.
Glycodiversification of gentamicins throughin vivoglycosyltransferase swapping enabled the creation of novel hybrid aminoglycoside antibiotics with potent activity and low ototoxicity
Authors: Jian Xinyun , Wang Cheng , Wu Shijuan , Sun Guo , Huang Chuan , Qiu Chengbing , Liu Yuanzheng , Leadlay Peter F. , Liu Dong , Deng Zixin , Zhou Fuling , Sun Yuhui 
Published: November 2023

AbstractAminoglycosides (AGs) are a class of potent antibiotics with a broad spectrum of activity. However, their use is limited by safety concerns associated with nephrotoxicity and ototoxicity, as well as drug resistance. To address these issues, semi-synthetic approaches for modifying natural AGs have successfully generated new generations of AGs, however, with limited types of modification due to significant challenges in synthesis. This study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid AGs, installing extensive natural modifications from gentamicins onto kanamycins. This was achieved by glycodiversification of gentamicins via swapping the glycosyltransferase (GT) in their producer with the GT from kanamycins biosynthetic pathway and resulted in the creation of a series of novel AGs with combined structural features of two, therefore referred to as genkamicins (GKs). The manipulation of the hybrid metabolic pathway enabled the target accumulation of different GK species and the successful isolation and characterization of six GK components. These compounds display retained antimicrobial activity against a panel of World Health Organization (WHO) critical priority pathogens, and GK-C2a, in particular, demonstrates low ototoxicity compared to clinical drugs in zebrafish embryos. This study provides a new strategy for diversifying the structure of AGs and a potential avenue for developing less toxic AG drugs to combat infectious diseases.
Validation of a heat-inducibleIxodes scapularisHSP70 promoter and developing a tick-specific 3xP3 promoter sequence in ISE6 cells
Authors: Pham Michael , Hoffmann Hans-Heinrich , Kurtti Timothy J. , Chana Randeep , Garcia-Cruz Omar , Aliabadi Simindokht , Gulia-Nuss Monika 
Published: November 2023

ABSTRACTIxodes scapularisis an important vector of many pathogens, including the causative agent of Lyme disease, tick-borne encephalitis, and anaplasmosis. The study of gene function inI. scapularisand other ticks has been hampered by the lack of genetic tools, such as an inducible promoter to permit temporal control over transgenes encoding protein or double-stranded RNA expression. Studies of vector-pathogen relationships would also benefit from the capability to activate anti-pathogen genes at different times during pathogen infection and dissemination. We have characterized an intergenic sequence upstream of the heat shock protein 70 (HSP70) gene that can driveRenillaluciferase expression and mCherry fluorescence in theI. scapulariscell line ISE6. In another construct, we replaced theDrosophila melanogasterminimal HSP70 promoter in the synthetic 3xP3 promoter with a minimal portion of theI. scapularisHSP70 promoter and generated anI. scapularisspecific 3xP3 (Is3xP3) promoter. Both promoter constructs, IsHSP70 and Is3xP3, allow for heat-inducible expression of mCherry fluorescence in ISE6 cells with an approximately 10-fold increase in the percentage of fluorescent positive cells upon exposure to a 2 h heat shock. These promoters described here will be valuable tools for gene function studies and temporal control of gene expression, including anti-pathogen genes.Graphical abstract
P. aeruginosacontrols bothC. elegansattraction and pathogenesis by regulating nitrogen assimilation
Authors: Marogi Jacob G. , Murphy Coleen T. , Myhrvold Cameron , Gitai Zemer 
Published: November 2023

AbstractDetecting chemical signals is important for identifying food sources and avoiding harmful agents. Like most animals,C. elegansuse olfaction to chemotax towards their main food source, bacteria. However, little is known about the bacterial compounds governingC. elegansattraction to bacteria and the physiological importance of these compounds to bacteria. Here, we address these questions by investigating the function of a small RNA, P11, in the pathogen,Pseudomonas aeruginosa,that was previously shown to mediate learned pathogen avoidance. We discovered that this RNA also affects the attraction of untrainedC. eleganstoP. aeruginosaand does so by controlling production of ammonia, a volatile odorant produced during nitrogen assimilation. We untangle the complex regulation ofP. aeruginosanitrogen assimilation, which is mediated by a partner-switching mechanism involving environmental nitrates, sensor proteins, and P11. In addition to mediatingC. elegansattraction, nitrogen assimilation is important for bacterial fitness and pathogenesis duringC. elegansinfection byP. aeruginosa. These studies define ammonia as a major mediator of trans-kingdom signaling, reveal the physiological importance of nitrogen assimilation for both bacteria and host organisms, and highlight how a bacterial metabolic pathway can either benefit or harm a host in different contexts.
Use of TSAR, Thermal Shift Analysis in R, to identify Folic Acid as a Molecule that Interacts with HIV-1 Capsid
Authors: Gao X. , McFadden W. M. , Wen X. , Emanuelli A. , Lorson Z. C. , Zheng H. , Kirby K. A. , Sarafianos S. G. 
Published: November 2023

AbstractThermal shift assay (TSA) is a versatile biophysical technique for studying protein interactions. Here, we report a free, open-source software tool TSAR (Thermal Shift Analysis in R) to expedite and automate the analysis of thermal shift data derived either from individual experiments or large screens of chemical libraries. The TSAR package incorporates multiple, dynamic workflows to facilitate the analysis of TSA data and returns publication-ready graphics or processed results. Further, the package includes a graphic user interface (GUI) that enables easy use by non-programmers, aiming to simplify TSA analysis while diversifying visualization. To exemplify the utility of TSAR we screened a chemical library of vitamins to identify molecules that interact with the capsid protein (CA) of human immunodeficiency virus type 1 (HIV-1). Our data show that hexameric CA interacts with folic acidin vitro.
Predicting the similarity of two mass spectrometry runs using only MS1 data
Authors: Shouaib Abdullah , Lin Andy 
Published: November 2023

AbstractBackgroundTraditionally researchers can compare the similarity between a pair of mass spectrometry-based proteomics samples by comparing the lists of detected peptides that result from database searching or spectral library searching. Unfortunately, this strategy requires having substantial knowledge of the sample and parameterization of the peptide detection step. Therefore, new methods are needed that can rapidly compare proteomics samples against each other without extensive knowledge of the sample.ResultsWe present a set of neural network architectures that predict the proportion of confidently detected peptides in common between two proteomics runs using solely MS1 information as input. Specifically, when compared to several baseline models, we found that the convolutional and siamese neural networks obtained the best performance. In addition, we demonstrate that unsupervised clustering techniques can leverage the predicted output from our method to perform sample-level characterizations. Our methodology allows for the rapid comparison and characterization of proteomics samples sourced from various different acquisition methods, organisms, and instrument types.ConclusionsWe find that machine learning models, using only MS1 information, can be used to predict the similarity between liquid chromatography-tandem mass spectrometry proteomics runs.
Multi-Omic blood analysis reveals differences in innate inflammatory sensitivity between species
Authors: Gregory David J. , Han Feifei , Li Peng , Gritsenko Marina , Kyle Jennifer , Riley Frank E. , Chavez Deborah , Yotova Vania , Sindeaux Renata H.M. , Hawash Mohamed B. F. , Xu Fengyun , Hung Li-Yuan , Hayden Douglas L. , Tompkins Ron G. , Lanford Robert E. , Kobzik Lester , Hellman Judith , Jacobs Jonathan M. , Barreiro Luis B. , Xiao Wenzhong , Warren H. Shaw 
Published: November 2023

AbstractVertebrates differ greatly in responses to pro-inflammatory agonists such as bacterial lipopolysaccharide (LPS), complicating use of animal models to study human sepsis or inflammatory disorders. We compared transcriptomes of resting and LPS-exposed blood from six LPS-sensitive species (rabbit, pig, sheep, cow, chimpanzee, human) and four LPS-resilient species (mice, rats, baboon, rhesus), as well as plasma proteomes and lipidomes. Unexpectedly, at baseline, sensitive species already had enhanced expression of LPS-responsive genes relative to resilient species. After LPS stimulation, maximally different genes in resilient species included genes that detoxify LPS, diminish bacterial growth, discriminate sepsis from SIRS, and play roles in autophagy and apoptosis. The findings reveal the molecular landscape of species differences in inflammation, and may inform better selection of species for pre-clinical models.One-Sentence SummaryFundamental differences are present in blood of humans, mice and other species that differ in sensitivity to inflammation.
Glucosylceramide depletion disrupts endolysosomal function in GBA-linked Parkinson’s fibroblasts?
Authors: Bhardwaj M , Kula Z , Weng Y , te Vruchte D , Breda C , Sillence D.J. 
Published: November 2023

AbstractIn Gaucher and Niemann-Pick C diseases, the glucosylceramide (GlcCer) depletion hypothesis states that depletion of non-lysosomal sphingolipid pools can lead to dysfunction in the secretory and lysosomal system. The hypothesis suggests: 1) lysosomal dysfunction can be separated from lysosomal storage, 2) Lysosomal/secretory dysfunction/vATPase activity is corrected by increasing non-lysosomal GlcCer pools, and 3) Changes in higher glycosphingolipid synthesis due to changes in Golgi pH and/or GlcCer non-vesicular transport. Evidence for this mechanism includes 1) Successful treatment of cells and animals by imino sugar inhibition of the non-lysosomal neutral pH GlcCer hydrolase GBA2, 2) Increasing ER/cytosol GlcCer increases in vATPase regulatory V0a1 subunit expression.Heterozygous mutations in GBA1, a lysosomal glucocerebrosidase (GCase), cause GCase misfolding and mislocalisation in the ER/cytoplasm which is linked to Parkinson’s disease (GBA-PD). Unexpectedly, similar to previous results in storing fibroblasts, N370S and L444P fibroblasts revealed increased endolysosomal pH and size despite the absence of glucolipid storage. Induction of storage by reducing residual lysosomal GCase activity in the N370S/L444P fibroblasts by the addition conduritol B-epoxide had no further effect on lysosomal function. In contrast, the addition of a soluble GlcCer analogue (adaGlcCer) reverses increased endolysosomal pH and volume in N370S mutant fibroblasts. The results are consistent with ER/cytosolic glucolipid depletion in GBA-PD fibroblasts. We discuss the potential for toxic/ectopic GBA1 hydrolysis and disrupted vATPase activity may lead to defective dopamine packaging and synaptic vesicle endocytosis as a new hypothesis in GBA-PD.
TERRA ONTseq: a long read-based sequencing pipeline to study the human telomeric transcriptome
Authors: Rodrigues Joana , Alfieri Roberta , Bione Silvia , Azzalin Claus M. 
Published: November 2023

ABSTRACTThe long noncoding RNA TERRA is transcribed from telomeres in virtually all eukaryotes with linear chromosomes. In humans, TERRA transcription is driven in part by promoters comprising CpG dinucleotide-rich repeats of 29 base pairs (29 bp repeats), believed to be present in half of the subtelomeres. Thus far, TERRA expression has been analyzed mainly using molecular biology-based approaches that only generate partial and somehow biased results. Here, we present a novel experimental pipeline to study human TERRA based on long read sequencing (TERRA ONTseq). By applying TERRA ONTseq to different cell lines, we show that the vast majority of human telomeres produce TERRA and that the cellular levels of TERRA transcripts varies according to their chromosomes of origin. Using TERRA ONTseq, we also identified regions containing TERRA transcription start sites (TSSs) in more than half of human subtelomeres. TERRA TSS regions are generally found immediately downstream of 29 bp repeat-related sequences, which appear to be more widespread than previously estimated. Finally, we isolated a novel TERRA promoter from the highly expressed subtelomere of the long arm of chromosome 7. With the development of TERRA ONTseq, we provide a refined picture of human TERRA biogenesis and expression and we equip the scientific community with an invaluable tool for future studies.
The C-terminus of CFAP410 forms a tetrameric helical bundle that is essential for its localization to the basal body
Authors: Stadler Alexander , De Liz Laryssa , Gabriel Heloisa B. , Alonso-Gil Santiago , Crickley Robbie , Korbula Katharina , Žagrović Bojan , Vaughan Sue , Sunter Jack D. , Dong Gang 
Published: November 2023

AbstractCilia are antenna-like organelles protruding from the surface of many cell types in the human body. Defects in ciliary structure or function often lead to diseases that are collectively called ciliopathies. Cilia and flagella associated protein 410 (CFAP410) localizes at the basal body of cilia/flagella and plays essential roles in ciliogenesis, neuronal development, and DNA damage repair. It remains unknown how its specific basal body location is achieved. Multiple single amino acid mutations in CFAP410 have been identified in patients with various ciliopathies. One of the mutations, L224P, is located in the C-terminal domain (CTD) of human CFAP410 and causes severespondylometaphysealdysplasia,axial (SMDAX). However, the molecular mechanism for how the mutation causes the disorder remains unclear. Here, we report our structural studies on the CTD of CFAP410 from three distantly related organisms,Homo sapiens, Trypanosoma brucei, andChlamydomonas reinhardtii.The crystal structures reveal that the three proteins all adopt the same conformation as a tetrameric helical bundle. Our work further demonstrates that the tetrameric assembly of the CTD is essential for the correct localization of CFAP410 inT. brucei, as the L224P mutation that disassembles the tetramer disrupts its basal body localization. Taken together, our studies reveal that the basal body localization of CFAP410 is controlled by the CTD and provide a mechanistic explanation for how the mutation L224P in CFAP410 causes ciliopathies in humans.