A role for tunneling nanotubes in virus spread

Tunneling nanotubes (TNTs) are actin-rich intercellular conduits that mediate distant cell-to-cell communication and enable the transfer of various cargos, including proteins, organelles, and virions. They play vital roles in both physiological and pathological processes. In this review, we focus on TNTs in different types of viruses, including retroviruses such as HIV, HTLV, influenza A, herpesvirus, paramyxovirus, alphavirus and SARS-CoV-2. We summarize the viral proteins responsible for inducing TNT formation and explore how these virus-induced TNTs facilitate intercellular communication, thereby promoting viral spread. Furthermore, we highlight other virus infections that can induce TNT-like structures, facilitating the dissemination of viruses. Moreover, TNTs promote intercellular spread of certain viruses even in the presence of neutralizing antibodies and antiviral drugs, posing significant challenges in combating viral infections. Understanding the mechanisms underlying viral spread via TNTs provides valuable insights into potential drug targets and contributes to the development of effective therapies for viral infections

Interlayer and interfacial stress transfer in hBN nanosheets

From IOP Publishing via Jisc Publications RouterHistory: received 2021-03-18, revised 2021-06-03, accepted 2021-06-16, oa-requested 2021-06-17, epub 2021-06-30, open-access 2021-06-30, ppub 2021-07Publication status: PublishedFunder: Henry Royce Institute; doi: http://dx.doi.org/10.13039/100016128Funder: China Scholarship Council; doi: http://dx.doi.org/10.13039/501100004543Abstract: Stress transfer has been investigated for exfoliated hexagonal boron nitride (hBN) nanosheets (BNNSs) through the use of Raman spectroscopy. Single BNNSs of different thicknesses of up to 100 nm (300 layers) were deposited upon a poly(methyl methacrylate) (PMMA) substrate and deformed in unixial tension. The Raman spectra from the BNNSs were relatively weak compared to graphene, but the in-plane E2g Raman mode (the G band) could be distinguished from the spectrum of the PMMA substrate. It was found that G band down-shifted during tensile deformation and that the rate of band shift per unit strain decreased as the thickness of the BNNSs increased, as is found for multi-layer graphene. The efficiency of internal stress transfer between the different hBN layers was found to be of the order of 99% compared to 60%–80% for graphene, as a result of the stronger bonding between the hBN layers in the BNNSs. The reduction in bandshift rate can be related to the effective Young’s modulus of the 2D material in a nanocomposites and the findings show that it would be expected that even 100 layer BNNSs should have a Young’s modulus of more than half that of hBN monolayer. Interfacial stress transfer between a single hBN nanosheet and the PMMA substrate has been evaluated using shear lag theory. It is found that the interfacial shear stress between the BNNS and the substrate is of the order of 10 MPa, a factor of around 4 higher than that for a graphene monolayer. These findings imply that BNNSs should give better mechanical reinforcement than graphene in polymer-based nanocomposites as a result of good internal interlayer stress transfer within the nanosheets and better interfacial stress transfer to the polymer matrix

Identification of hub genes significantly linked to tuberous sclerosis related-epilepsy and lipid metabolism via bioinformatics analysis

BackgroundTuberous sclerosis complex (TSC) is one of the most common genetic causes of epilepsy. Identifying differentially expressed lipid metabolism related genes (DELMRGs) is crucial for guiding treatment decisions.MethodsWe acquired tuberous sclerosis related epilepsy (TSE) datasets, GSE16969 and GSE62019. Differential expression analysis identified 1,421 differentially expressed genes (DEGs). Intersecting these with lipid metabolism related genes (LMRGs) yielded 103 DELMRGs. DELMRGs underwent enrichment analyses, biomarker selection, disease classification modeling, immune infiltration analysis, weighted gene co-expression network analysis (WGCNA) and AUCell analysis.ResultsIn TSE datasets, 103 DELMRGs were identified. Four diagnostic biomarkers (ALOX12B, CBS, CPT1C, and DAGLB) showed high accuracy for epilepsy diagnosis, with an AUC value of 0.9592. Significant differences (p < 0.05) in Plasma cells, T cells regulatory (Tregs), and Macrophages M2 were observed between diagnostic groups. Microglia cells were highly correlated with lipid metabolism functions.ConclusionsOur research unveiled potential DELMRGs (ALOX12B, CBS, CPT1C and DAGLB) in TSE, which may provide new ideas for studying the psathogenesis of epilepsy

Meta-analysis of the association between toll-like receptor gene polymorphisms and hepatitis C virus infection

ObjectiveThe objective of this study is to investigate the association between toll-like receptor (TLR) 3/7 gene polymorphisms and the infection by hepatitis C virus (HCV).MethodsPubMed, Embase, Web of Science, Scopus, CNKI, Wanfang Data, and SinoMed were searched to identify studies focusing on the association between the TLR3 rs3775290 or the TLR7 rs179008 single nucleotide polymorphisms (SNPs) and the HCV infection. All the related articles were collected from the inception of each database to 15 January 2023. Our meta-analysis was conducted using the allelic model, the dominant model, and the recessive model. Outcomes were presented by odds ratio (ORs) and 95% confidence interval (95%CI). The heterogeneity across studies was assessed by the I2 test. A subgroup analysis was performed to explore the source of heterogeneity. Funnel plots were drawn to assess the risk of publication bias. Review Manager 5.4 was used for statistical analysis.ResultsTen articles were finally included, among which six studies were analyzed for rs3775290 and five studies were analyzed for rs179008. Studies relating to rs3775290 included 801 patients and 1,045 controls, whereas studies relating to rs179008 included 924 patients and 784 controls. The results of the meta-analysis showed that there is no significant association between rs3775290 gene polymorphism and HCV infection (T vs. C: OR = 1.12, 95%CI 0.97–1.30; TT+CT vs. CC: OR = 1.20, 95%CI 0.73–1.96; TT vs. CT+CC: OR = 1.13, 95%CI 0.68–1.89). The recessive model showed that rs179008-T allele homozygotes had an 89% increased risk of infection by HCV compared with rs179008-A allele carriers (TT vs. AT+AA: OR = 1.89, 95%CI 1.13–3.16). The results of the subgroup analysis demonstrated that the characteristics of the control population may serve as an important source of heterogeneity. In the African populations, individuals with homozygous rs179008-T alleles had a higher risk of infection by HCV than rs179008-A allele carriers (OR = 2.14, 95%CI 1.18–3.87). We did not find that this difference existed in the European populations (OR = 1.24, 95%CI 0.43–3.56).ConclusionThere is no significant association between rs3775290 single nucleotide polymorphism and the infection by HCV. Individuals with homozygous rs179008-T alleles have a higher risk of an infection by HCV than rs179008-A allele carriers, which is statistically significant in the African populations

High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways

Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology

Bayesian approach to support vector machines

Ph.DDOCTOR OF PHILOSOPH

Predicting In Vivo Anti-Hepatofibrotic Drug Efficacy Based on In Vitro High-Content Analysis

Background/Aims Many anti-fibrotic drugs with high in vitro efficacies fail to produce significant effects in vivo. The aim of this work is to use a statistical approach to design a numerical predictor that correlates better with in vivo outcomes. Methods High-content analysis (HCA) was performed with 49 drugs on hepatic stellate cells (HSCs) LX-2 stained with 10 fibrotic markers. ~0.3 billion feature values from all cells in >150,000 images were quantified to reflect the drug effects. A systematic literature search on the in vivo effects of all 49 drugs on hepatofibrotic rats yields 28 papers with histological scores. The in vivo and in vitro datasets were used to compute a single efficacy predictor (Epredict). Results We used in vivo data from one context (CCl4 rats with drug treatments) to optimize the computation of Epredict. This optimized relationship was independently validated using in vivo data from two different contexts (treatment of DMN rats and prevention of CCl4 induction). A linear in vitro-in vivo correlation was consistently observed in all the three contexts. We used Epredict values to cluster drugs according to efficacy; and found that high-efficacy drugs tended to target proliferation, apoptosis and contractility of HSCs. Conclusions The Epredict statistic, based on a prioritized combination of in vitro features, provides a better correlation between in vitro and in vivo drug response than any of the traditional in vitro markers considered.Institute of Bioengineering and Nanotechnology (Singapore)Singapore. Biomedical Research CouncilSingapore. Agency for Science, Technology and ResearchSingapore-MIT Alliance for Research and Technology Center (C-185-000-033-531)Janssen Cilag (R-185-000-182-592)Singapore-MIT Alliance Computational and Systems Biology Flagship Project (C-382-641-001-091)Mechanobiology Institute, Singapore (R-714-001-003-271

Positive and Negative Regulation of Gli Activity by Kif7 in the Zebrafish Embryo

Loss of function mutations of Kif7, the vertebrate orthologue of the Drosophila Hh pathway component Costal2, cause defects in the limbs and neural tubes of mice, attributable to ectopic expression of Hh target genes. While this implies a functional conservation of Cos2 and Kif7 between flies and vertebrates, the association of Kif7 with the primary cilium, an organelle absent from most Drosophila cells, suggests their mechanisms of action may have diverged. Here, using mutant alleles induced by Zinc Finger Nuclease-mediated targeted mutagenesis, we show that in zebrafish, Kif7 acts principally to suppress the activity of the Gli1 transcription factor. Notably, we find that endogenous Kif7 protein accumulates not only in the primary cilium, as previously observed in mammalian cells, but also in cytoplasmic puncta that disperse in response to Hh pathway activation. Moreover, we show that Drosophila Costal2 can substitute for Kif7, suggesting a conserved mode of action of the two proteins. We show that Kif7 interacts with both Gli1 and Gli2a and suggest that it functions to sequester Gli proteins in the cytoplasm, in a manner analogous to the regulation of Ci by Cos2 in Drosophila. We also show that zebrafish Kif7 potentiates Gli2a activity by promoting its dissociation from the Suppressor of Fused (Sufu) protein and present evidence that it mediates a Smo dependent modification of the full length form of Gli2a. Surprisingly, the function of Kif7 in the zebrafish embryo appears restricted principally to mesodermal derivatives, its inactivation having little effect on neural tube patterning, even when Sufu protein levels are depleted. Remarkably, zebrafish lacking all Kif7 function are viable, in contrast to the peri-natal lethality of mouse kif7 mutants but similar to some Acrocallosal or Joubert syndrome patients who are homozygous for loss of function KIF7 alleles

Costs-effectiveness Analysis of Elective Cesarean Section Compared with Vaginal Delivery: a prospective cohort study in a hospital in León, Nicaragua

Background There is an increasing rate of cesarean section globally. Both low and high cesarean section rates are associated with maternal and neonatal mortality and morbidities. In Nicaragua, the rate of cesarean section is beyond the WHO recommendation of 10% to 15%. Aim The aim of this study was to evaluate the costs-effectiveness of elective caesarean section when compared with vaginal delivery in hospital in Nicaragua, a lower-middle income setting. Methods A 3 months prospective cohort study was conducted in a hospital in León, Nicaragua, from 1st May 2010 to 31st July 2010. Two questionnaires were used to obtain data, one on costs and maternal complications after delivery, and the other on postpartum complications. A descriptive analysis regarding maternal and neonatal outcomes, and a cost-effectiveness analysis were conducted comparing elective cesarean section with vaginal delivery, followed by a sensitivity analysis regarding change on rates of elective cesarean section. Results The cesarean section rate was 37.9%, and the elective cesarean section rate was 21%. The percentage of live births was 99.6% in elective cesarean section group and 98.9% in vaginal delivery group. Cesarean section had both positive and negative influences on maternal complications and postpartum complications. The costs of elective cesarean section was higher than vaginal delivery ($66 compared to$39.36). For one more live birth, 3805.71 US dollars were needed. Conclusion The maternal outcomes of cesarean section need to be improved. With the increasing cesarean section rates, more medical resources are needed in the future