bluuebunny/crossref_metadata_2025_split huggingface dataset:
AAV-mediated gene therapy for Sialidosis
Authors: van de Vlekkert Diantha , Hu Huimin , Fremuth Leigh E. , Brown Scott A. , Weesner Jason A. , Gomero Elida , Campos Yvan , d’Azzo Alessandra 
Published: November 2023

AbstractSialidosis is a glycoprotein storage disease caused by deficiency of the lysosomal sialidase NEU1, which leads to pathogenic accumulation of sialylated glycoproteins and oligosaccharides in tissues and body fluids. The disease belongs to the group of orphan disorders with no therapy currently available. Here, we have tested the therapeutic potential of AAV-mediated gene therapy for the treatment of sialidosis in a mouse model of the disease. One-month-oldNeu1−/−mice were co-injected with two scAAV2/8 vectors, expressing NEU1 and its chaperone PPCA, and sacrificed at 3 months post-injection. Treated mice were phenotypically indistinguishable from their WT controls. Histopathologically, they showed diminished or absent vacuolization in cells of visceral organs, including the kidney, as well as the choroid plexus and other areas of the brain. This was accompanied by restoration of NEU1 activity in most tissues, reversal of sialyl-oligosacchariduria, and normalization of lysosomal exocytosis in the CSF and serum of treated mice. AAV injection prevented the occurrence of generalized fibrosis, which is a prominent contributor of disease pathogenesis inNeu1−/−mice and likely in patients. Overall, this therapeutic strategy holds promise for the treatment of sialidosis and may be applicable to adult forms of human idiopathic fibrosis with low NEU1 expression.
The effects of mutation and recombination rate heterogeneity on the inference of demography and the distribution of fitness effects
Authors: Soni Vivak , Pfeifer Susanne P. , Jensen Jeffrey D. 
Published: November 2023

AbstractDisentangling the effects of demography and selection has remained a focal point of population genetic analysis. Knowledge about mutation and recombination is essential in this endeavour; however, despite clear evidence that both mutation and recombination rates vary across genomes, it is common practice to model both rates as fixed. In this study, we quantify how this unaccounted for rate heterogeneity may impact inference using common approaches for inferring selection (DFE-alpha, Grapes, and polyDFE) and/or demography (fastsimcoal2 andδaδi). We demonstrate that, if not properly modelled, this heterogeneity can increase uncertainty in the estimation of demographic and selective parameters and in some scenarios may result in mis-leading inference. These results highlight the importance of quantifying the fundamental evolutionary parameters of mutation and recombination prior to utilizing population genomic data to quantify the effects of genetic drift (i.e., as modulated by demographic history) and selection; or, at the least, that the effects of uncertainty in these parameters can and should be directly modelled in downstream inference.Significance StatementDespite evidence from numerous species that mutation and recombination rates vary along the genome, both rates tend to be modelled as fixed when performing population genetic inference. The impact of failing to account for this rate heterogeneity on the estimation of demographic and selective parameters has yet to be well quantified; thus, we here study this effect by comparing inference under both fixed and variable rate scenarios. Our results demonstrate that unaccounted for rate heterogeneity can increase uncertainty and lead to mis-inference in certain scenarios. We highlight the importance of utilizing mutation and recombination rate maps where possible, and of modelling the uncertainty underlying these estimates.
A non-adaptive explanation for macroevolutionary patterns in the evolution of complex multicellularity
Authors: Bingham Emma P. , Ratcliff William C. 
Published: November 2023

Abstract“Complex multicellularity”, conventionally defined as large organisms with many specialized cell types, has evolved five times independently in eukaryotes, but never within prokaryotes. A number hypotheses have been proposed to explain this phenomenon, most of which posit that eukaryotes evolved key traits (e.g., dynamic cytoskeletons, alternative mechanisms of gene regulation, or subcellular compartments) which were a necessary prerequisite for the evolution of complex multicellularity. Here we propose an alternative, non-adaptive hypothesis for this broad macroevolutionary pattern. By binning cells into groups with finite genetic bottlenecks between generations, the evolution of multicellularity greatly reduces the effective population size (Ne) of cellular populations, increasing the role of genetic drift in evolutionary change. While both prokaryotes and eukaryotes experience this phenomenon, they have opposite responses to drift: mutational biases in eukaryotes tend to drive genomic expansion, providing additional raw genetic material for subsequent multicellular innovation, while prokaryotes generally face genomic erosion. These effects become more severe as organisms evolve larger size and more stringent genetic bottlenecks between generations— both of which are hallmarks of complex multicellularity. Taken together, we hypothesize that it is these idiosyncratic lineagespecific mutational biases, rather than cell-biological innovations within eukaryotes, that underpins the long-term divergent evolution of complex multicellularity across the tree of life.
Xanthomonas rydalmerenesissp. nov., a novel plant bacteria isolated fromFragaria x ananassa
Authors: McKnight Daniel J E , Wong Johanna , Okoh Efenaide B , Snijders Fridtjof , Lidbetter Fiona , Webster John , Haughton Mathew , Darling Aaron E , Djordjevic Steven P , Bogema Daniel R , Chapman Toni 
Published: November 2023

ABSTRACTWe describe five bacterial isolates that were isolated fromFragaria x ananassain 1976 in Rydalmere, Australia, during routine biosecurity surveillance. Initially, biochemical characterisation identified these isolates as members of theXanthomonasgenus. To determine their species, we conducted further analysis using both phenotypic and genotypic approaches. Phenotypic analysis involved using MALDI-TOF MS and BIOLOG GEN III microplates, which confirmed that the isolates belonged to theXanthomonasgenus but could not classify species. Genome relatedness indices and extensive phylogenetic analysis confirmed that the isolates belonged to theXanthomonasgenus and represented a new species. Based on the absence of virulence factors typically found inXanthomonasspp. genomes, we suggest that these isolates are non-pathogenic. This conclusion was supported by a pathogenicity assay. Based on these findings, we propose the nameXanthomonas rydalmerenesis, with DAR34855 = ICMP24941 as the type strain.
The mitochondrial deoxyguanosine kinase is required for female fertility in mice
Authors: Gao Yake , Dong Rui , Yan Jiacong , Chen Huicheng , Sang Lei , Yao Xinyi , Fan Die , Wang Xin , Zuo Xiaoyuan , Zhang Xu , Yang Shengyu , Wu Ze , Sun Jianwei 
Published: November 2023

AbstractMitochondrial homeostasis plays a pivotal role in oocyte maturation and embryonic development. Deoxyguanosine kinase (DGUOK) is a nucleoside kinase that salvages purine nucleoside in the mitochondria and is critical for mitochondrial DNA replication and homeostasis in non-proliferating cells.Dguokloss-of-function mutations and deletions lead to hepatocerebral mitochondrial DNA deletion syndrome. However, its potential role in reproduction remains largely unknown. We found thatDguokknockout results in female infertility. Mechanistically, the deficiency of DGUOK hinders ovarian development and oocyte maturation. Moreover,Dguokdeficiency in oocytes caused a significant reduction in mitochondrial DNA and abnormal mitochondrial dynamics, and impaired germinal vesicle breakdown. Only few DGUOK-deficient oocytes were able to extrude the first polar body duringin vitromaturation, and these oocytes showed irregular chromosome arrangement and different spindle lengths. In addition,Dguokdeficiency elevated reactive oxygen species and accelerated apoptosis in oocytes. Our findings reveal novel physiological roles for the mitochondrial nucleoside salvage pathway in oocyte maturation and implicate that DGUOK is a potential marker for the diagnosis of female infertility.
Exercise intervention for the management of chemotherapy-induced peripheral neuropathy: A systematic review and network meta-analysis
Authors: Nakagawa Natsuki , Yamamoto Sena , Hanai Akiko , Oiwa Ayano , Arao Harue 
Published: November 2023

1AbstractAlthough exercise is recommended for cancer survivors with chemotherapy-induced peripheral neuropathy (CIPN), the effective types of exercise for preventing and treating CIPN remain unclear. This systematic review and network meta-analysis (NMA) aimed to evaluate the comparative effects of exercise on CIPN. We included relevant randomized controlled trials (RCTs) identified in a 2019 systematic review that evaluated the effects of exercise on CIPN and conducted an additional search for RCTs published until 2023. We evaluated the risk of bias for each RCT; the comparative effectiveness of exercise on patient-reported quality of life (QOL) through an NMA; and the effectiveness of exercise on QOL scores, patient-reported CIPN symptoms, and pain through additional meta-analyses.Twelve studies (exercise, n=540; control, n=527) comparing 8 exercise interventions were included in the analysis. All studies were determined to have a high risk of bias. The meta-analyses showed significantly improved QOL (standard mean differences [SMD] 0.45; 95% confidence interval [CI] = 0.12 to 0.78) and CIPN symptoms (SMD 0.46; 95% CI = 0.11 to 0.82). No severe adverse events were reported. Pain tended to improve with exercise (SMD 0.84; 95% CI = −0.11 to 1.80). An NMA suggested that the interventions of combination of balance and strength training showed the significant improvement in QOL scores compared to the control. Exercise interventions are safe and effective in improving QOL. For exercise categories, the combination of balance and strength training would be the promising program. Patients with CIPN will benefit from frequent exercise focusing on the declined symptoms.
Genetic analyses of inflammatory polyneuropathy and chronic inflammatory demyelinating polyradiculoneuropathy identified candidate genes
Authors: Du Zhaohui , Lessard Samuel , Iyyanki Tejaswi , Chao Michael ,   FinnGen, Hammond Timothy , Ofengeim Dimitry , Klinger Katherine , de Rinaldis Emanuele , Shameer Khader , Chatelain Clément 
Published: November 2023

AbstractObjectiveChronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, immune-mediated disorder in which an aberrant immune response causes demyelination and axonal damage of the peripheral nerves. Genetic contribution to CIDP is unclear and no genome-wide association study (GWAS) has been reported so far. In this study, we aimed to identify CIDP-related riskloci, genes and pathways.MethodsTo increase power, we first included all patients with a diagnosis of inflammatory polyneuropathy (IP) as cases. We performed a GWAS study using FinnGen R10 individual data and combined the results with GWAS from UK biobank (UKBB) using a fixed-effect meta-analysis. A total of 1,261 IP cases and 823,730 controls were included in the analysis. The second GWAS focused on CIDP patients and a total of 516 CIDP cases and 403,545 controls were included in the analysis. Stratified analyses by gender were also performed for both IP and CIDP. We performed gene-level analyses using transcriptome-wide mendelian randomization (TWMR) analysis, colocalization analysis, transcriptome-wide association study (TWAS) using S-PrediXcan and MAGMA to identify genes associated with IP and CIDP. Gene-set analyses were conducted using MAGMA to identify pathways that are related to IP and CIDP.ResultsIn GWAS study, we identified one genome-wide significant loci at 20q13.33 for CIDP risk among women; the top variant located at the intron region of geneCDH4. TWMR, colocalization and S-PrediXcan analyses identifiedDGKQ, GLDC, IDUA, SLAMF9andTMEM175as candidate pathogenic genes for IP; genesDIRAS1, GNG7, andSLC39A3for CIDP; genesDIRAS1, DCTN1, andME1for IP among males; and genes DIRAS1 andME1for IP among women. MAGMA gene-set analyses identified a total of 18 pathways related to IP or CIDP.ConclusionOur study identified suggestive risk genes and pathways for IP and CIDP. Functional analysis should be conducted to further confirm these associations.
Automated quantitative evaluation of thymic involution and hyperplasia on plain chest CT
Authors: Okamura Yuki T. , Endo Katsuhiro , Toriihara Akira , Fukuda Issei , Isogai Jun , Sato Yasunori , Yasuoka Kenji , Kagami Shin-Ichiro 
Published: November 2023

AbstractObjectiveTo establish an automatic method to quantify thymic involution and hyperplasia based on plain chest computed tomography (CT).MethodsWe defined the thymic region for quantification (TRQ) as the target region. We manually segmented the TRQ in 135 CT studies, followed by construction of segmentation neural network (NN) models based on the data. We developed the estimator of thymic volume (ETV), a measure of the thymic tissue volume in the segmented TRQ. The Hounsfield unit (HU) value and volume of the TRQ were measured, and the ETV was calculated in each CT study from 853 healthy subjects. We investigated how these measures were related to the age and sex using quantile additive regression models. We defined the ETV z-score, an age- and sex-adjusted version of ETV, to distinguish between subjects with thymic hyperplasia (18 cases) and healthy subjects. A receiver operating characteristic (ROC) curve analysis was conducted.ResultsA significant correlation between the NN-segmented and manually segmented TRQ was seen for both the HU value and volume of the TRQ (r= 0.996 andr= 0.986 respectively). The ETV could detect age-related decline in the thymic tissue volume (p< 0.001). No statistically significant difference was detected between male and female subjects (p= 0.19). The ETV was significantly higher in the thymic hyperplasia group as compared with that in the healthy control group (p< 0.001). The ETV z-score could distinguish between subjects with thymic hyperplasia and healthy subjects, with the ROC curve analysis revealing an area under the curve (AUC) of 0.88 (95% CI: 0.75-1.0).ConclusionOur method enabled robust quantification of thymic involution and hyperplasia. The results were consistent with the trends found in previous studies.Clinical Relevance StatementOur method allows reliable and automatic measurement of thymic involution and hyperplasia on CT images. This may aid in the early detection and monitoring of pathologies related to the thymus, including autoimmune diseases.Key Points-We defined the thymic region for quantification (TRQ) to fully automate the evaluation of thymic involution and hyperplasia. The neural networks could identify the TRQ with sufficient accuracy.-We developed the estimator of thymic volume (ETV) to quantify the thymic tissue in the TRQ. ETV captured age-related thymic involution and thymic hyperplasia.-The ETV could prove useful in the management of pathologies associated with involution or hyperplasia of the thymus.
Somatic RIT1 indels identified in arteriovenous malformations hyperactivate RAS-MAPK signaling and are amenable to MEK inhibition
Authors: Kapp Friedrich G. , Bazgir Farhad , Mahammadzade Nagi , Vassella Erik , Döring Yvonne , Holm Annegret , Karow Axel , Seebauer Caroline , Batista da Silva Natascha Platz , Wohlgemuth Walter A. , Kröning Pia , Niemeyer Charlotte M. , Schanze Denny , Zenker Martin , Eng Whitney , Ahmadian Mohammad R. , Baumgartner Iris , Rössler Jochen 
Published: November 2023

AbstractArteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. Treatment is often difficult and relapse after therapy is common. AVM are mainly caused by somatic mosaicism with pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep next generation sequencing we identified novel somaticRIT1indel variants in lesional tissue of three AVM patients.RIT1– not previously implicated in AVM development – encodes a RAS-like protein that can modulate RAS-MAPK signaling. For biochemical characterization, we expressedRIT1variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of theRIT1indels in zebrafish embryos induced AVM formation, highlighting the functional importance in vascular development. Both ERK1/2 hyperactivationin vitroand AVM formationin vivocould be suppressed by pharmacological MEK inhibition. Targeted treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings expand the genetic spectrum of AVM by identifyingRIT1as a novel gene involved in AVM formation and pave the way for targeted treatment and clinical trials in patients with AVM.
Genome-wide association study analysis of disease severity in Acne reveals novel biological insights
Authors: Du Zhaohui , Iyyanki Tejaswi , Lessard Samuel , Chao Michael ,   FinnGen, Asbrand Christian , Nassar Dany , Klinger Katherine , de Rinaldis Emanuele , Khader Shameer , Chatelain Clément 
Published: November 2023

AbstractAcne vulgaris is a common skin disease that affects >85% of teenage young adults among which >8% develop severe lesions that leaves permanent scars. Genetic heritability studies of acne in twin cohorts have estimated that the heritability for acne is 80%. Previous genome-wide association studies (GWAS) have identified 50 geneticlociassociated with increased risk of developing acne when compared to healthy individuals. However only a few studies have investigated genetic association with disease severity. GWAS of disease progression may provide a more effective approach to unveil potential disease modifying therapeutic targets.Here, we performed a multi-ethnic GWAS analysis to capture disease severity in acne patients by using individuals with normal acne as a control. Our cohort consists of a total of 2,956 participants, including 290 severe acne cases and 930 normal acne controls from FinnGen, and 522 cases and 1,214 controls from BioVU. We also performed mendelian randomization (MR), colocalization analyses and transcriptome-wide association study (TWAS) to identify putative causal genes. Lastly, we performed gene-set enrichment analysis using MAGMA to implicate biological pathways that drive disease severity in Acne.We identified two new loci associated with acne severity at the genome-wide significance level, six novel associated genes by MR, colocalization and TWAS analyses, including genesCDC7, SLC7A1, ADAM23, TTLL10, CDK20andDNAJA4, and 5 novel pathways by MAGMA analyses. Our study suggests that the etiologies of acne susceptibility and severity have limited overlap, with only 26% of known acne risk loci presenting nominal association with acne severity and none of the novel severity associated genes reported as associated with acne risk in previous GWAS.
Effect of Sinotubular Junction Size on TAVR Leaflet Thrombosis: A Fluid-structure Interaction Analysis
Authors: Oks David , Reza Symon , Vázquez Mariano , Houzeaux Guillaume , Kovarovic Brandon , Samaniego Cristóbal , Bluestein Danny 
Published: November 2023

AbstractPurposeTAVR has emerged as a standard approach for treating severe aortic stenosis patients. However, it is associated with several clinical complications, including subclinical leaflet thrombosis characterized by Hypoattenuated Leaflet Thickening (HALT). A rigorous analysis of TAVR device thrombogenicity considering anatomical variations is essential for estimating this risk. Clinicians use the Sinotubular Junction (STJ) diameter for TAVR sizing, but there is a paucity of research on its influence on TAVR devices thrombogenicity.MethodsA Medtronic Evolut® TAVR device was deployed in three patient models with varying STJ diameters (26, 30, and 34mm) to evaluate its impact on post-deployment hemodynamics and thrombogenicity, employing a novel computational framework combining prosthesis deployment and fluid- structure interaction analysis.ResultsThe 30 mm STJ patient case exhibited the best hemodynamic performance: 5.94mmHgmean transvalvular pressure gradient (TPG), 2.64cm2mean geometric orifice area (GOA), and the lowest mean residence time (TR) - indicating a reduced thrombogenic risk; 26 mm STJ exhibited a 10 % reduction in GOA and a 35% increase in mean TPG compared to the 30 mm STJ; 34 mm STJ depicted hemodynamics comparable to the 30 mm STJ, but with a 6% increase in TRand elevated platelet stress accumulation.ConclusionA smaller STJ size impairs adequate expansion of the TAVR stent, which may lead to suboptimal hemodynamic performance. Conversely, a larger STJ size marginally enhances the hemodynamic performance but increases the risk of TAVR leaflet thrombosis. Such analysis can aid pre- procedural planning and minimize the risk of TAVR leaflet thrombosis.
Ability of calculated right adrenal vein aldosterone levels to identify the aldosterone-overproducing side in patients with primary aldosteronism undergoing adrenal venous sampling
Authors: Tuandam Lalita , Soonthornpun Supamai 
Published: November 2023

AbstractBackgroudAdrenal venous sampling (AVS) is a gold standard procedure to determine the dominant side of aldosterone secretion in patients with primary aldosteronism. Unsuccessful cannulation of right adrenal vein (RAV) is a common problem in performing AVS.ObjectiveTo use calculated aldosterone concentration in the RAV (cAldoRAV) for identifying the dominant side of aldosterone secretion.DesignRetrospective study, 2011-2023.MethodsBased on the assumption that cortisol production from both adrenal glands is equal, aldosterone concentration in the RAV was calculated by using the data from left adrenal vein (LAV) and inferior vena cava. The aldosterone concentration in the LAV (AldoLAV) compared to the cAldoRAV(AldoLAV:cAldoRAVratio) was then used to determine the dominant side of aldosterone secretion in patients with primary aldosteronism.ResultsOf 117 patients with successful AVS, 95 (81.2%) had concordant results between adrenal imaging and AVS study and were used as the gold standard for studying diagnostic performance. The AldoLAV:cAldoRAVratio with the cutoff values of ≥3 and ≤0.33 could identify unilateral diseases (left-sided and right-sided disease, respectively) with 93.8% sensitivity and 100% specificity. In 22 patients who had discordant results between adrenal imaging and standard AVS interpretation, 11 had concordant results when using the AldoLAV:cAldoRAVratio.ConclusionsThe AldoLAV:cAldoRAVratio can determine the dominant side of aldosterone secretion with high sensitivity and specificity. It can not only be used for patients with unsuccessful cannulation of RAV but also increase the concordance rate in those who have discordance between adrenal imaging and standard AVS interpretation.