bluuebunny/crossref_metadata_2025_split huggingface dataset:
RyR1 protein content is reduced in inflammatory and mitochondrial myopathies and induces ER stress
Authors: Vidal Jeremy , Fernandez Eric , Wohlwend Martin , Laurila Pirkka-Pekka , Mejia Andrea Lopez , Ochala Julien , Lopez Mejia Isabel Christina , Lobrinus Johannes Alexandre , Kayser Bengt , Place Nicolas , Zanou Nadège 
Published: February 2023

AbstractDecreased ryanodine receptor type 1 (RyR1) protein is a hallmark of recessiveRYR1-related myopathies (RyR1-RM), which are caused by recessive mutations in theRYR1gene. It is not clear how the decrease in the RyR1 protein triggers muscular disorders. Furthermore, it is a hot topic whether a decrease in RyR1 protein levels can also occur during non-RYR1-related myopathies. In this study, we first show that reducedRYR1transcripts are associated with various human myopathies, and that RyR1 protein levels are significantly decreased in muscle samples analysed in inflammatory myopathies (IM) and mitochondrial myopathies (MM), both of which are non-RYR1-RM. Secondly, proteomic data show that exclusive depletion of RyR1 proteinin vitrorecapitulates the common altered molecular pathways observed during myopathies. RyR1 protein depletion impairs ER-mitochondria tethering and Ca2+transfer to mitochondria, decreases mitophagy genes and induces an accumulation of dysfunctional mitochondria. This phenomenon is also associated with altered lipid homeostasis with an increase in deleterious sphingolipid species. Finally, decreased RyR1 protein levels lead to an increase in the ER stress markers GRP78-Bip and CHOP in muscle cellin vitro, and in mouse and human muscles. Overall, our results indicate an important role of RyR1 protein depletion and ER stress in the pathogenesis of myopathies.
Relationship between sexting and self-esteem, depression, anxiety, and stress among young people
Authors: Galanis Petros , Katsiroumpa Zoe , Katsiroumpa Aglaia , Tsakalaki Anastasia , Vasilopoulos Stefanos 
Published: February 2023

AbstractIntroductionThe huge spread of the internet and especially of social media has led to new ways of communication, even erotic communication, especially among young people, replacing, in many cases, activities that until now required the face-to-face meeting of individuals.AimTo investigate the relationship between sexting and self-esteem, depression, anxiety, and stress among young people. Also, we investigated the impact of demographic characteristics on sexting.MethodsA cross-sectional study was conducted with 368 young people aged 18-30 years old. We created an anonymous form of the study questionnaire with Google forms and we disseminated it through social media. Thus, we obtained a convenience sample. We used valid scales to measure sexting, self-esteem, depression, anxiety and stress among young people. All scales in our study had very good Cronbach ‘s alpha.ResultsMean age of the participants was 23.7 years, while 82.3% was females. Mean every day time that participants spent on social media/platforms/applications was 4.7 hours. Participants used more often to communicate with others Instagram (86.8%) and Facebook (62.8%), and then Viber (29.9%), TikTok (9.8%), Snapchat (6%) and WhatsApp (5.1%). Frequency of texting was low among participants, while self-esteem level was average. Moreover, participants had higher levels of stress than depression and anxiety. We found that increased sexting was associated with decreased self-esteem (r=-0.3, p=0.02), increased depression (r=0.4, p=0.001), increased anxiety (r=0.3, p=0.005), and increased stress (r=0.4, p<0.001). Multivariable linear regression analysis identified that increased number of accounts on social media/platforms/applications (coefficient beta=0.07, 95% confidence interval=0.01 to 0.13, p-value=0.023) and increased age (coefficient beta=0.08, 95% confidence interval=0.01 to 0.13, p-value=0.003) was associated with increased sexting.ConclusionsUnderstanding the relationship between sexting and self-esteem, depression, anxiety, and stress in young people will give policy makers the opportunity to develop appropriate health education programmes to reduce risky sexual behaviors.
HPVsim: An agent-based model of HPV transmission and cervical cancer
Authors: Stuart Robyn M. , Cohen Jamie A. , Kerr Cliff C. , Mathur Prashant ,   National Disease Modeling Consortium of India, Abeysuriya Romesh G. , Zimmermann Marita , Rao Darcy W. , Boudreau Mariah C. , Lee Serin , Yang Luojun , Klein Daniel J. 
Published: February 2023

AbstractIn 2020, the WHO launched its first Global Strategy to Accelerate the Elimination of Cervical Cancer, outlining an ambitious set of targets for countries to achieve over the next decade. At the same time, new tools, technologies, and strategies are in the pipeline that may improve screening performance, expand the reach of prophylactic vaccines, and prevent the acquisition, persistence and progression of oncogenic HPV. Detailed mechanistic modeling can help identify the combinations of current and future strategies to combat cervical cancer. Open-source modeling tools are needed to shift the capacity for such evaluations in-country. Here, we introduce the Human papillomavirus simulator (HPVsim), a new open-source software package for creating flexible agent-based models parameterized with country-specific vital dynamics, structured sexual networks, and co-transmitting HPV genotypes. HPVsim includes a novel methodology for modeling cervical disease progression, designed to be readily adaptable to new forms of screening. The software itself is implemented in Python, has built-in tools for simulating commonly-used interventions, includes a comprehensive set of tests and documentation, and runs quickly (seconds to minutes) on a laptop. Performance is greatly enhanced by HPVsim’s multi-scale modeling functionality. HPVsim is open source under the MIT License and available via both the Python Package Index (via pip install) and GitHub (hpvsim.org).
Co-chaperone BAG3 directly target autophagic degradation via its LC3-interacting regions
Authors: Körschgen Hagen , Baeken Marius , Schmitt Daniel , Nagel Heike , Behl Christian 
Published: February 2023

AbstractThe co-chaperone BAG3 is a hub for a variety of cellular pathways via its multiple domains and its interaction with HSP70 and HSPB8. Under aging and cellular stress conditions in particular, together with molecular chaperones, BAG3 ensures the sequestration of aggregated or aggregation prone ubiquitinated proteins to the autophagic-lysosomal system via ubiquitin receptors. There are emerging indications that BAG3-mediated selective macroautophagy also copes with non-ubiquitinated cargo. Phylogenetically, BAG3 comprises several highly conserved predicted LIRs, LC3-interacting regions, which might directly target BAG3 including its cargo to ATG8 proteins and directly drive their autophagic degradation. Based on pull-down experiments, peptide arrays and proximity ligation assays, our results provide evidence of an interaction of BAG3 with ATG8 proteins. In addition, we could demonstrate that mutations within the LIRs impair co-localization with ATG8 proteins in immunofluorescence. A BAG3 variant mutated in all LIRs results in a substantial decrease of BAG3 levels within purified native autophagic vesicles compared to wild-type BAG3. These results strongly suggest LC3-mediated sequestration of BAG3. Therefore, we conclude that in addition of being a key co-chaperone to HSP70, BAG3 may also act as cargo receptor for client proteins, which would significantly extend the role of BAG3 in selective macroautophagy and protein quality control.SynopsisBAG3 ensures sequestration of aggregated ubiquitinated proteins to the autophagic-lysosomal degradation. Based on emerging indications this BAG3-mediated macroautophagy may also cope with non-ubiquitinated clients and comprises conserved predicted LC3 interacting regions, we analyzed the interaction with LC3 proteins. We evidenced an interaction of BAG3 with LC3 proteins by various measures including pull-down experiments, peptide arrays, proximity ligation assays, co-localization and native autophagic vesicles analysis. These results suggest BAG3 may additionally act as cargo receptor for client proteins.Abstract Figure
Deep Learning-based Identification of Intraocular Pressure-Associated Genes Influencing Trabecular Meshwork Cell and Organelle Morphology
Authors: Greatbatch Connor J , Lu Qinyi , Hung Sandy , Tran Son N , Wing Kristof , Liang Helena , Han Xikun , Zhou Tiger , Siggs Owen M , Mackey David A , Liu Guei-Sheung , Cook Anthony L , Powell Joseph E , Craig Jamie E , MacGregor Stuart , Hewitt Alex W 
Published: February 2023

ABSTRACTPURPOSEThe exact pathogenesis of primary open-angle glaucoma (POAG) is poorly understood. Genome-wide association studies (GWAS) have recently uncovered many loci associated with variation in intraocular pressure (IOP); a crucial risk factor for POAG. Artificial intelligence (AI) can be used to interrogate the effect of specific genetic knockouts on the morphology of trabecular meshwork cells (TMCs), the regulatory cells of IOP.METHODSSixty-two genes at fifty-five loci associated with IOP variation were knocked out in primary TMC lines. All cells underwent high-throughput microscopy imaging after being stained with a five-channel fluorescent cell staining protocol. A convolutional neural network (CNN) was trained to distinguish between gene knockout and normal control cell images. The area under the receiver operator curve (AUC) metric was used to quantify morphological variation in gene knockouts to identify potential pathological perturbations.RESULTSCells whereRALGPS1had been perturbed demonstrated the greatest morphological variation from normal TMCs (AUC 0.851, SD 0.030), followed byLTBP2(AUC 0.846, SD 0.029) andBCAS3(AUC 0.845, SD 0.020). Of seven multi-gene loci, five had statistically significant differences in AUC (p<0.05) between genes, allowing for pathological gene prioritisation. The mitochondrial channel most frequently showed the greatest degree of morphological variation (33.9% of cell lines).CONCLUSIONSWe demonstrate a robust method for functionally interrogating genome-wide association signals using high-throughput microscopy and AI. Genetic variations inducing marked morphological variation can be readily identified, allowing for the gene-based dissection of loci associated with complex traits.
Comparison of commercial DNA extraction kits for whole metagenome sequencing of human oral, vaginal, and rectal microbiome samples
Authors: Wright Michelle L. , Podnar Jessica , Longoria Kayla D. , Nguyen Tien C. , Lim Sungju , Garcia Sarina , Wylie Dennis 
Published: February 2023

AbstractIntroductionAdvancements in DNA extraction and sequencing technologies have been fundamental in deciphering the significance of the microbiome related to human health and pathology. Whole metagenome shotgun sequencing (WMS) is gaining popularity in use compared to its predecessor (i.e., amplicon-based approaches). However, like amplicon-based approaches, WMS is subject to bias from DNA extraction methods that can compromise the integrity of sequencing and subsequent findings. The purpose of this study was to evaluate systematic differences among four commercially available DNA extraction kits frequently used for WMS analysis of the microbiome.MethodsOral, vaginal, and rectal swabs were collected in replicates of four by a healthcare provider from five participants and randomized to one of four DNA extraction kits. Two extraction blanks and three replicate mock community samples were also extracted using each extraction kit. WMS was completed with NovaSeq 6000 for all samples. Sequencing and microbial communities were analyzed using nonmetric multidimensional scaling and compositional bias analysis.ResultsExtraction kits differentially biased the percentage of reads attributed to microbial taxa across samples and body sites. The PowerSoil Pro kit performed best in approximating expected proportions of mock communities. While HostZERO was biased against gram-negative bacteria, the kit outperformed other kits in extracting fungal DNA. In clinical samples, HostZERO yielded a smaller fraction of reads assigned toHomo sapiensacross sites and had a higher fraction of reads assigned to bacterial taxa compared to other kits. However, HostZERO appears to bias representation of microbial communities and demonstrated the most dispersion by site, particularly for vaginal and rectal samples.ConclusionsSystematic differences exist among four frequently referenced DNA extraction kits when used for WMS analysis of the human microbiome. Consideration of such differences in study design and data interpretation is imperative to safeguard the integrity of microbiome research and reproducibility of results.
Genome sequence ofOphryocystis elektroscirrha, an apicomplexan parasite of monarch butterflies: cryptic diversity and response to host-sequestered plant chemicals
Authors: Mongue Andrew J. , Martin Simon H. , Manweiler Rachel E. V. , Scullion Helena , Koehn Jordyn L. , de Roode Jacobus C. , Walters James R. 
Published: February 2023

AbstractApicomplexa are ancient and diverse organisms which have been poorly characterized by modern genomics. To better understand the evolution and diversity of these single-celled eukaryotes, we sequenced the genome ofOphryocystis elektroscirrha, a parasite of monarch butterflies,Danaus plexippus. The genome is miniscule, totaling only 9 million bases and containing fewer than 3,000 genes. We then compared this new sequence to the two other sequenced invertebrate-infecting apicomplexans,Porospora giganteaandGregarina niphandrodes, which have nearly twice the gene content and found thatO. elektroscirrhashares different orthologs with each sequenced relative, suggesting the true set of universally conserved apicomplexan genes is very small indeed. We investigated sequenced reads from other potential hosts to explore the viability ofin silicoinfection screening. We recovered a similarly sized parasite genome from another butterfly,Danaus chrysippus, that was highly diverged from theO. elektroscirrhareference, possibly representing a distinct species. Using these two new genomes, we investigated potential evolutionary response by parasites to toxic phytochemicals their hosts ingest and sequester. Monarch butterflies are well-known to tolerate toxic cardenolides thanks to changes in the sequence of their Type II ATPase sodium pumps. We show thatOphryocystiscompletely lacks Type II or Type 4 sodium pumps, and related proteins PMCA calcium pumps show extreme sequence divergence compared to other Apicomplexa, demonstrating new avenues of research opened by genome sequencing of non-model Apicomplexa.Author SummaryThere are many relatives ofPlasmodium, the single-celled parasites responsible for malaria, and they infect a wide range of animals, including insects. These parasites have received less attention however, leaving much unknown about them. We sequenced the genome of one such parasite,Ophryocystis elektroscirrha(OE), to compare it to better-studied parasites and shed light on OE’s interaction with its host, the monarch butterfly. We found that OE has a tiny genome with the fewest genes of any sequenced parasite in this group, lacking many genes found in its relatives. Using our new data, we also discovered evidence that infections of other butterfly species that have been attributed to OE may be caused by a previously undiscovered distinct parasite species. And finally, we explored the evolution of a family of genes that may be targeted by medicinal plant compounds in the monarch butterfly’s diet; OE has lost one of these genes and radically changed the sequence of another, setting a direction for future research.
Human Retinal Ganglion Cells Respond to Evolutionarily Conserved Chemotropic Cues for Intra Retinal Guidance and Regeneration
Authors: Subramani Murali , Hook Matthew Van , Rajamoorthy Mohanapriya , Qiu Fang , Ahmad Iqbal 
Published: February 2023

ABSTRACTRetinal ganglion cells (RGCs) connect the retina with the higher centers in the brain for visual perception. Their degeneration leads to irreversible vision loss in glaucoma patients. Since human RGCs (hRGCs) are born during fetal development and connections with the central targets are established before birth, the mechanism underlying their axon growth and guidance remains poorly understood. Here, using RGCs directly generated from human embryonic stem cells, we demonstrate that hRGCs express a battery of guidance receptors. These receptors allow hRGCs to read the spatially arrayed chemotropic cues in the developing rat retina for the centripetal orientation of axons toward the optic disc, suggesting that the mechanism of intra-retinal guidance is conserved in hRGCs. The centripetal orientation of hRGCs axons is not only in response to chemo-repulsion but also involves chemo-attraction, mediated by Netrin-1/DCC interactions. The spatially arrayed chemotropic cues differentially influence hRGCs physiological responses, suggesting that neural activity of hRGCs may facilitate axon growth during inter-retinal guidance. Additionally, we demonstrate that Netrin-1/DCC interactions, besides promoting axon growth, facilitate hRGCs axon regeneration by recruiting the mTOR signaling pathway. The diverse influence of Netrin-1/DCC interactions ranging from axon growth to regeneration may involve recruitment of multiple intracellular signaling pathways as revealed by transcriptome analysis of hRGCs. From the perspective ofex-vivostem cell approach to glaucomatous degeneration, our findings posit thatex-vivogenerated human RGCs are capable of reading the intra-retinal cues for guidance toward the optic disc, the first step toward connecting with the central target to restore vision.
Timing of antibiotic administration determines the spread of plasmid-encoded antibiotic resistance during microbial range expansion
Authors: Ma Yinyin , Ramoneda Josep , Johnson David R. 
Published: February 2023

AbstractThe spread of antibiotic resistance (AR) is a major threat to global health. Plasmid-mediated horizontal gene transfer is the main mechanism by which AR is transferred between cells lying within close spatial proximity to each other. In this study, we address a fundamental question regarding the spread of AR-encoding plasmids: Is there an optimal time to administer antibiotics to minimize plasmid spread within microbial communities? We addressed this question using microbial consortia consisting of twoPseudomonas stutzeristrains, where one is an AR-encoding plasmid donor and the other a potential recipient. We allowed the strains to co-expand across a nutrient-amended surface and administered antibiotics at different points in time. We found that the extents of plasmid transfer and transconjugant proliferation have unimodal relationships with the timing of antibiotic administration, where they reach maxima at intermediate administration times. Using an individual-based model, we found that these unimodal relationships result from an interplay between the probability to acquire plasmids from neighboring cells and the probability of plasmid loss upon cell division. Our study provides novel mechanistic insights into the transfer and proliferation of AR-encoding plasmids within microbial communities and identifies the timing of antibiotic administration as an important determinant of AR spread.
Capsicum chinenseJacq. derived glutaredoxin (CcGRXS12) alters phytohormonal pathways and redox status of the cells to confer resistance against pepper mild mottle virus (PMMoV-I)
Authors: Saravana Kumar R. M. , Ramesh S.V. , Sun Z. , Thankappan Sugitha , Binodh Asish Kanakaraj 
Published: February 2023

AbstractGlutaredoxins (Grxs) are small, ubiquitous, multi-functional proteins present in different compartments of plant cells. A chloroplast targeted class I GRX (CcGRXS12) gene was isolated fromCapsicum chinenseduring the pepper mild mottle virus (PMMoV) infection. Functional characterization of the gene was performed inN. benthamianatransgenic plants transformed with nativeC. chinense GRX(Nb:GRX),GRX-fused with GFP (Nb:GRX-GFP) andGRXtruncated for the chloroplast targeting sequences but fused with GFP (Nb:Δ2MGRX-GFP). Over-expression ofCcGRXS12inhibits the PMMoV-I accumulation at late stage of infection and is accompanied with the activation of SA- pathway pathogenesis related (PR) transcripts, and suppression of JA/ET- pathway transcripts. Further the reduced accumulation of auxin-induced Glutathione-S-Transferase (pCNT103) inCcGRXS12over expressing lines indicates that the protein could able to protect the plants from the oxidative stress caused by the virus. PMMoV-I infection increases accumulation of pyridine nucleotides (PNs) mainly due to the reduced form of PNs (NAD(P)H) and it was higher inNb:GRX-GFPlines compared to other lines where infection is limited. Apart from biotic stress,CcGRXS12protects the plants from abiotic stress conditions caused by H2O2and herbicide paraquat. CcGRXS12 exhibits GSH-disulphide oxidoreductase activityin vitrohowever devoid of complementary Fe-S cluster assembly mechanism in yeast.
Omicron’s Intrinsic Gene-Gene Interactions Jumped Away from Earlier SARS-CoV-2 Variants and Gene Homologs between Humans and Animals
Authors: Zhang Zhengjun 
Published: February 2023

SummaryOmicron and its subvariants have become the predominant SARS-CoV-2 variants worldwide. The Omicron’s basic reproduction number (R0) has been close to 20 or higher. However, it is not known what caused such an extremely high R0. This work aims to find an explanation for such high R0 Omicron infection. We found that Omicron’s intrinsic gene-gene interactions jumped away from earlier SARS-CoV-2 variants which can be fully described by a miniature set of genes reported in our earlier work. We found that the gene PTAFR (Platelet Activating Factor Receptor) is highly correlated with Omicron variants, and so is the gene CCNI (Cyclin I), which is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog. The combination of PTAFR and CCNI can lead to a 100% accuracy of differentiating Omicron COVID-19 infection and COVID-19 negative. We hypothesize that Omicron variants were potentially jumped from COVID-19-infected animals back to humans. In addition, there are also several other two-gene interactions that lead to 100% accuracy. Such observations can explain Omicron’s fast-spread reproduction capability as either of those two-gene interactions can lead to COVID-19 infection, i.e., multiplication of R0s leads to a much higher R0. At the genomic level, PTAFR, CCNI, and several other genes identified in this work rise to Omicron druggable targets and antiviral drugs besides the existing antiviral drugs.