Impact of body size on efficacy of high-dose dual therapy for Helicobacter pylori eradication.

BACKGROUND: High-dose dual therapy (HDDT) is an emerging and promising therapeutic regime for Helicobacter pylori (H. pylori) eradication. However, the pharmacokinetics of the components of HDDT, amoxicillin and proton pump inhibitor, are likely to be affected by body size. In this study, we aimed to find out the impact of body size on the efficacy of HDDT. METHODS: We collected the medical data of 385 treatment-naive patients infected with H. pylori who received HDDT (esomeprazole 20 mg and amoxicillin 750 mg four times daily) for 14 days from July 2020 to December 2021. The associations among the eradication efficacy, adverse events, and variables (sex, age, height, body weight, body mass index (BMI), body surface area (BSA), smoking, drinking, etc.) were analyzed respectively in our study. Among these factors, continuous variables were classified into categorical variables using the cut-off values which were calculated by receiver operating characteristic analysis. RESULTS: The eradication rate of HDDT was 89.9%. There were 55 (14.3%) patients who occurred adverse events during the treatment. Patients with height <170.5 cm, body weight <60.5 kg, BMI <20.55 kg/m2 , BSA <1.69 m2 had a higher eradication rate (92.1% vs. 84.0%, 93.1% vs. 86.8%, 96.0% vs. 87.8%, 93.4% vs. 84.8%, all p < .05). The multivariate analysis showed that BSA ≥1.69 m2 (OR 2.53, 95% CI: 1.28-4.99, p = .007) was the only independent predictor of eradication failure. CONCLUSION: HDDT could achieve better eradication efficacy in patients with small BSA. Clinicians should be aware of the impact of BSA on the H. pylori eradication rate and pay more attention to patients with large BSA.

Construction, Characterization, and Application of an Ammonium Transporter (AmtB) Deletion Mutant of the Nitrogen-Fixing Bacterium Kosakonia radicincitans GXGL-4A in Cucumis sativus L. Seedlings.

Nitrogen is an important factor affecting crop yield, but excessive use of chemical nitrogen fertilizer has caused decline in nitrogen utilization and soil and water pollution. Reducing the utilization of chemical nitrogen fertilizers by biological nitrogen fixation (BNF) is feasible for green production of crops. However, there are few reports on how to have more ammonium produced by nitrogen-fixing bacteria (NFB) flow outside the cell. In the present study, the amtB gene encoding an ammonium transporter (AmtB) in the genome of NFB strain Kosakonia radicincitans GXGL-4A was deleted and the △amtB mutant was characterized. The results showed that deletion of the amtB gene had no influence on the growth of bacterial cells. The extracellular ammonium nitrogen (NH4+) content of the △amtB mutant under nitrogen-free culture conditions was significantly higher than that of the wild-type strain GXGL-4A (WT-GXGL-4A), suggesting disruption of NH4+ transport. Meanwhile, the plant growth-promoting effect in cucumber seedlings was visualized after fertilization using cells of the △amtB mutant. NFB fertilization continuously increased the cucumber rhizosphere soil pH. The nitrate nitrogen (NO3-) content in soil in the △amtB treatment group was significantly higher than that in the WT-GXGL-4A treatment group in the short term but there was no difference in soil NH4+ contents between groups. Soil enzymatic activities varied during a 45-day assessment period, indicating that △amtB fertilization influenced soil nitrogen cycling in the cucumber rhizosphere. The results will provide a solid foundation for developing the NFB GXGL-4A into an efficient biofertilizer agent.

Prognostic value and immune infiltration of the gasdermin family in lung adenocarcinoma.

Background: The GSDM family includes six members, GSDMA, GSDMB, GSDMC, GSDMD, GSDME (DFNA5), and PJVK (Pejvakin, DFNB59), which can induce pyroptosis, thereby regulating the tumorigenesis of various cancers. However, the clinical characteristics and role of the GSDM family in LUAD are not well understood. Methods: In this study, several important bioinformatics databases were used to integrate the analysis of the expression, prognostic value, and immune infiltration of GSDMs in LUAD. These databases include UALCAN, DiseaseMeth, GEPIA, THPA, cBioPortal, TIMER, WebGestalt, STRING database, and Cytoscape. Results: The findings from the UALCAN database revealed that the expression of all six GSDMs based on the tumor stage in LUAD was increased (particularly GSDMD). Our IHC results verified it. Additionally, the DiseaseMeth database showed that the methylation levels of GSDMA, GSDMB, GSDMC, and GSDMD were decreased. The expression of six GSDMs was related to shorter overall survival in patients with LUAD, according to the GEPIA database. The cBioPortal database was further used to explore the alteration rate and correlated genes in LUAD. Subsequently, these genes were subjected to functional enrichment and protein-protein interaction network analyses. We identified that the GSDM family regulate several signaling pathways, including immune-associated signaling pathways. According to tumor-infiltrating immune cell analysis from the TIMER database, GSDM family members are associated with the infiltration of important immune cells and their signature markers. Conclusions: GSDM family may be prognostic markers and novel strategies for the treatment of LUAD.

Evaluation of the potential of ultrasound-mediated drug delivery for the treatment of ovarian cancer through preclinical studies.

Ovarian cancer (OC) has the greatest mortality rate among gynecological cancers, with a five-year survival rate of <50%. Contemporary adjuvant chemotherapy mostly fails in the case of OCs that are refractory, metastatic, recurrent, and drug-resistant. Emerging ultrasound (US)-mediated technologies show remarkable promise in overcoming these challenges. Absorption of US waves by the tissue results in the generation of heat due to its thermal effect causing increased diffusion of drugs from the carriers and triggering sonoporation by increasing the permeability of the cancer cells. Certain frequencies of US waves could also produce a cavitation effect on drug-filled microbubbles (MBs, phospholipid bilayers) thereby generating shear force and acoustic streaming that could assist drug release from the MBs, and promote the permeability of the cell membrane. A new class of nanoparticles that carry therapeutic agents and are guided by US contrast agents for precision delivery to the site of the ovarian tumor has been developed. Phase-shifting of nanoparticles by US sonication has also been engineered to enhance the drug delivery to the ovarian tumor site. These technologies have been used for targeting the ovarian cancer stem cells and protein moieties that are particularly elevated in OCs including luteinizing hormone-releasing hormone, folic acid receptor, and vascular endothelial growth factor. When compared to healthy ovarian tissue, the homeostatic parameters at the tissue microenvironment including pH, oxygen levels, and glucose metabolism differ significantly in ovarian tumors. US-based technologies have been developed to take advantage of these tumor-specific alterations for precision drug delivery. Preclinical efficacy of US-based targeting of currently used clinical chemotherapies presented in this review has the potential for rapid human translation, especially for formulations that use all substances that are deemed to be generally safe by the U.S. Food and Drug Administration.

Optimized dual therapy for treatment-naive patients of Helicobacter pylori infection: A large-scale prospective, multicenter, open-label, randomized controlled study.

BACKGROUND: The efficacy and safety of high-dose amoxicillin (AMX) and proton pump inhibitors (PPI) dual therapy raises much more attention in recent years. Comparative studies among the dual therapies are required to explore more suitable regimens. This study compared the efficacy, adverse events, and patient compliance of three different high-dose dual regimens in treatment-naive patients of Helicobacter pylori (H. pylori) infection. MATERIALS AND METHODS: The study was a prospective, multicenter, open-label, randomized controlled trial, including H. pylori-infected treatment-naive patients at 12 tertiary hospitals in China. The eligible subjects received high-dose AMX and esomeprazole (ESO) dual therapy of different regimens. They were randomly assigned to group A (ESO 20 mg plus AMX 750 mg, Qid for 14 days), group B (ESO 40 mg Bid plus AMX 1 g Tid for 14 days), or group C (ESO 20 mg plus AMX 1 g, Tid for 14 days). The eradication rates, adverse events, and patient compliance of the three groups were compared. RESULTS: Between April 2021 and January 2022, a total of 1080 subjects were screened and 945 were randomized. The eradication rates in groups A, B, and C were 88.6% (95% CI 84.5%-91.9%), 84.4% (95% CI 80.0%-88.3%), and 86.7% (95% CI 82.4%-90.2%; p = .315), respectively, based on intention-to-treat analysis; 90.3% (95% CI 86.4%-93.3%), 85.5% (95% CI 81.1%-89.2%), and 87.8% (95% CI 83.6%-91.2%; p = .197), respectively, according to modified intention-to-treat analysis; and 90.4% (95% CI 86.5%-93.5%), 85.8% (95% CI 81.4%-89.5%), and 88.3% (95% CI 84.1%-91.7%; p = .202) in per-protocol analysis. History of antibiotics use in 2 years reduced eradication effect in group B (ESO 40 mg Bid, AMX 1 g Tid). The modified intention-to-treat eradication rates were 81.4% vs 90.0% among those with or without a history of antibiotics use in group B (p = .031). The adverse event rates were 13.7%, 12.7%, and 12.1% in groups A, B, and C, respectively (p = .834). Patient compliance of the three groups was similar. CONCLUSIONS: Two optimized AMX and PPI dual regimens (ESO 40 mg Bid or 20 mg Tid plus AMX 1 g Tid for 14 days) had similar efficacy, safety and compliance as compared with classical dual regimen (ESO 20 mg plus AMX 750 mg Qid for 14 days) in H. pylori-infected treatment-naive patients.

Urgent Endoscopy in Nonvariceal Upper Gastrointestinal Hemorrhage: A Retrospective Analysis.

OBJECTIVE: The role of urgent endoscopy in nonvariceal upper gastrointestinal hemorrhage (NVUGIH) remains controversial. We designed a retrospective study to compare the outcomes between urgent endoscopy (within 12 h) and non-urgent endoscopy for patients with NVUGIH. METHODS: A total of 540 hospitalized patients with NVUGIH were included in our study. Patients who received endoscopy within 12 h or after 12 h were divided into two groups, the urgent and non-urgent endoscopy groups, respectively. The clinical outcomes including rebleeding, mortality, endoscopic re-intervention, need for emergency surgery and interventional radiotherapy were compared between the groups. Patients with Glasgow-Blatchford scores (GBS) <12 and ≥12 were defined as the lower- and high-risk groups, respectively, and the predictors of rebleeding and mortality in both groups were analyzed individually. RESULTS: Patients with NVUGIH in the urgent endoscopy group had a higher rate of rebleeding (27.6% vs. 16.9%, P=0.003) and blood transfusion (73.2% vs. 55.5%, P<0.001) than those in the non-urgent endoscopy group, while the mortality and the length of hospitalization were not significantly different between the groups (P>0.05). For lower-risk patients, urgent endoscopy was independently associated with a higher likelihood of rebleeding (adjusted OR: 1.73, 95% CI: 1.03-2.88), while it was not associated with in-hospital mortality. However, the urgent need for endoscopy was not associated with rebleeding and inhospital mortality in high-risk patients. CONCLUSION: Endoscopy within 12 h did not provide any advantage in the outcomes of patients with NVUGIH, and may even lead to an increased rebleeding rate in lower-risk patients.

Does off-hours endoscopic hemostasis affect outcomes of nonvariceal upper gastrointestinal bleeding?

Aim: Different researches showed controversial results about the 'off-hours effect' in nonvariceal upper gastrointestinal bleeding (NVUGIB). Materials & methods: A total of 301 patients with NVUGIB were divided into regular-hours group and off-hours group based on when they received endoscopic hemostasis, and the relationship of the clinical outcomes with off-hours endoscopic hemostasis was evaluated. Results: Patients who received off-hours endoscopy were sicker and more likely to experience worse clinical outcomes. Off-hours endoscopic hemostasis was a significant predictor of the composite outcome in higher-risk patients (adjusted OR: 4.63; 95% CI: 1.35-15.90). However, it did not associate with the outcomes in lower-risk patients. Conclusion: Off-hours effect may affect outcomes of higher-risk NVUGIB patients receiving endoscopic hemostasis (GBS ≥12).

Bromodomain-containing protein 9 promotes hepatocellular carcinoma progression via activating the Wnt/ß-catenin signaling pathway.

BACKGROUND: Epigenetic dysregulation participates in the initiation and progression of hepatocellular carcinoma (HCC). Bromodomain-containing protein 9 (BRD9) can identify acetylated lysine residues, contributing to several cancers. The function and molecular mechanism of BRD9 in HCC remain poorly understood. METHODS: BRD9 levels in tissues and cells of HCC and normal liver were evaluated using bioinformatic analysis, real-time PCR, and western blot. BRD9's association with clinical outcomes was investigated via survival analyses. Biological behaviors and pathways related to BRD9 were predicted using gene set enrichment analysis. BRD9's role in proliferation was verified via cell counting kit 8, colony formation, and 5-Ethynyl-2'-deoxyuridine assays. Its role in the cell cycle and apoptosis was assessed using flow cytometry. The role of BRD9 in vivo was investigated using xenograft tumor models. A rescue assay was performed to investigate the molecular mechanism of BRD9. RESULTS: BRD9 was markedly upregulated in HCC and higher BRD9 expression was associated with higher grade, advanced stage, greater tumor size, and poorer prognosis. BRD9 overexpression enhanced cell proliferation, cell cycle progress, but impeded cell apoptosis. BRD9 downregulation had the opposite effects. In vivo, BRD9 promoted xenograft tumor growth. Mechanistically, BRD9 activated Wnt/ß-catenin signaling, obstruction of which abrogated BRD9-mediated tumorigenesis. CONCLUSION: Increased BRD9 in HCC correlated with poor prognosis, which functioned via activating Wnt/ß-catenin signaling. Thus, BRD9 might be a promising biomarker and therapeutic target for patients with HCC.

Rutin pretreatment promotes microglial M1 to M2 phenotype polarization.

Microglial cells are important resident innate immune components in the central nervous system that are often activated during neuroinflammation. Activated microglia can display one of two phenotypes, M1 or M2, which each play distinct roles in neuroinflammation. Rutin, a dietary flavonoid, exhibits protective effects against neuroinflammation. However, whether rutin is able to influence the M1/M2 polarization of microglia remains unclear. In this study, in vitro BV-2 cell models of neuroinflammation were established using 100 ng/mL lipopolysaccharide to investigate the effects of 1-hour rutin pretreatment on microglial polarization. The results revealed that rutin pretreatment reduced the expression of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1ß, and interleukin-6 and increased the secretion of interleukin-10. Rutin pretreatment also downregulated the expression of the M1 microglial markers CD86 and inducible nitric oxide synthase and upregulated the expression of the M2 microglial markers arginase 1 and CD206. Rutin pretreatment inhibited the expression of Toll-like receptor 4 and myeloid differentiation factor 88 and blocked the phosphorylation of I kappa B kinase and nuclear factor-kappa B. These results showed that rutin pretreatment may promote the phenotypic switch of microglia M1 to M2 by inhibiting the Toll-like receptor 4/nuclear factor-kappa B signaling pathway to alleviate lipopolysaccharide-induced neuroinflammation.

Association of HMOX-1 with sporadic Alzheimer's disease in southern Han Chinese.

BACKGROUND AND PURPOSE: The aim of this study was to discover the associations between HMOX-1 and Alzheimer's disease (AD). METHODS: A total of 500 AD patients and 500 healthy controls were recruited in this study. Polymer chain reaction was used. RESULTS: There was a statistically significant difference between AD patients and controls in both the dominant and recessive models of HMOX-1 rs2071746 after adjustment for age, gender and education (dominant model: p = 0.047, odds ratio [OR] 1.34, 95% confidence interval [CI] 1.00-1.78, adjusted; recessive model: p = 0.049, OR 1.34, 95% CI 1.00-1.80, adjusted). There was also a trend for an association between the dominant model and late-onset AD after adjustment for age, gender and education (dominant model: p = 0.084, OR 1.37, 95% CI 0.96-1.95, adjusted). CONCLUSIONS: We found an association between the dominant and recessive models of HMOX1 rs2071746 and AD.

Triterpene saponins from tea seed pomace (Camellia oleifera Abel) and their cytotoxic activity on MCF-7 cells in vitro.

Triterpenoid saponins are the main active ingredients extracted from Camellia oleifera Abel. In this study, crude saponins (Tc) was extracted from tea seed pomace and purified to obtain total saponins (T0). We used a COSMOSIL C18-OPN to separate T0 into three fractions-highly polar saponins (T1), moderately polar saponins (T2), and weakly polar saponins (T3). HPLC-ESI-MS analysis revealed that T2 were mainly composed of components with m/z ([M-H]-) of 1201.5617, 1187.5822, 1245.5862, and 1215.5779. Cell cycle analysis showed that both T0 and T2 inhibited proliferation and induced S phase arrest of MCF-7 cells. Further cell invasion assays demonstrated T0 and T2 also significantly reduced the invasive potential of MCF-7 cells. So T2 extracted from tea seed pomace (Camellia oleifera) may have effective antitumor activity.

The Joubert Syndrome Gene arl13b is Critical for Early Cerebellar Development in Zebrafish.

Joubert syndrome is characterized by unique malformation of the cerebellar vermis. More than thirty Joubert syndrome genes have been identified, including ARL13B. However, its role in cerebellar development remains unexplored. We found that knockdown or knockout of arl13b impaired balance and locomotion in zebrafish larvae. Granule cells were selectively reduced in the corpus cerebelli, a structure homologous to the mammalian vermis. Purkinje cell progenitors were also selectively disturbed dorsomedially. The expression of atoh1 and ptf1, proneural genes of granule and Purkinje cells, respectively, were selectively down-regulated along the dorsal midline of the cerebellum. Moreover, wnt1, which is transiently expressed early in cerebellar development, was selectively reduced. Intriguingly, activating Wnt signaling partially rescued the granule cell defects in arl13b mutants. These findings suggested that Arl13b is necessary for the early development of cerebellar granule and Purkinje cells. The arl13b-deficient zebrafish can serve as a model organism for studying Joubert syndrome.

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The typhoon outbreaks of 1986 caused many gaps in the cold temperate coniferous forest and Betula errmanii forest on the western and southern slopes in the Changbai Mountain. In 2017, a research area at the 1600-1800 m altitude in Changbai Mountain was established to explore the damage and changes of forest vegetation disturbed by the typhoon in cold temperate zone and to reveal the regulation of damage on vegetation and post-disaster change as well as the driving factors. The remote sensing data were used to classify research area based on the degree of vegetation damage and post-disaster change. A total of 40 plots were set up for vegetation survey. According to the damage degree of forest structure, three levels of severity of damage to vegetation in the cold temperate zone of Changbai Mountain were classified including gently, moderately, and severely damaged, in which moderately damaged area was largest, followed by gently damaged area and severely damaged area. Tree damage significantly differed among three level areas, with 20%, 50% and 85% reduction of the abundance of dominant trees in gently, moderately and severely damaged areas, respectively. The wind resistance ability of B. errmanii was higher than that of Picea jezoensis. The wind resistance ability of B. errmanii with larger diameter grade was higher than that of those with smaller diameter grade. The severity of damage to vegetation was strongly correlated with slope, with lower severity on the steeper slop area. From 1987 to 2017, the vegetation of wind disaster area significantly changed. The study area could be classified into three levels based on the degree of changing: fast, medium, and slow, with largest area in medium changed, followed by slowly and fast changed. The degree of vegetation changes was strongly correlated with altitude, with slower change at higher altitude area. The recovery rate of trees was slow, with P. jezoensis recovering slightly quicker than B. errmanii. The vegetation change mainly occurred in shrub and herb layers. Shrub layer recovered better than the herb layer in the fast changed area, while herb layer recovered better than the shrub layer in the medium changed area. In the slowly changed area, herb layer was generally low and dense with varying shrub layer.

Association between autonomic dysfunction and olfactory dysfunction in Parkinson's disease in southern Chinese.

BACKGROUND: The aim was to investigate the autonomic dysfunction between Parkinson's disease (PD) patients with olfactory dysfunction and PD patients without olfactory dysfunction in southern Chinese population. METHODS: Fifty-six PD patients with olfactory dysfunction and 44 patients without olfactory dysfunction were included. All patients were evaluated by Sniffin' sticks (SS-16), scales for outcomes in Parkinson's disease-autonomic questionnaire, Hamilton anxiety rating scale and Hamilton depression rating scale RESULTS: The score of subpart of gastrointestinal symptoms and subpart of urinary symptoms were different in two groups (gastrointestinal symptoms: p value: 0.024; urinary symptoms: p value: 0.008). As for each question items, questions 2, 8, 10, 11, 13, 14 were correlated with SS-16 scores (Question 2: p value: 0.013; question 6: p value: 0.006; question 8: p value: 0.025; question 10: p value: 0.005; question 11: p value: 0.022; question 13: p value: < 0.001; question 14: p value: 0.038). Question 10 and 14 were associated with olfactory dysfunction after adjusting disease duration and gender (Question 10: p value: 0.011, OR: 3.91; Question 14: p value: 0.027, OR: 3.27). CONCLUSIONS: Gastrointestinal, urinary and a part of cardiovascular symptoms of SCOPA-AUT were associated with olfactory dysfunction in PD patients.

Effect of Resveratrol on Sirtuins, OPA1, and Fis1 Expression in Adult Zebrafish Retina.

Purpose: We determined whether sirtuins (SIRT1-SIRT7) are expressed in the zebrafish retina, evaluated the modulatory effect of resveratrol in the normal retina, and examined N-Methyl-D-aspartic acid (NMDA)-induced zebrafish retinal damage associated with mitochondrial sirtuins and mitochondrial fusion and fission mediators, OPA1 and Fis1. Methods: Sirtuins, OPA1, and Fis1 mRNA expression was analyzed by RT-PCR and quantitative real time PCR (qPCR) in adult zebrafish (AB type) retina and liver. qPCR showed an effect of resveratrol on SIRTs (SIRT1, 3, 4, 5) and OPA1 and Fis1 in low and high concentrations (5 and 50 mg/L) at different time points (0, 1, 24, and 48 hours) in the retina. Western blots were performed to examine the expression of SIRTs and OPA1 proteins under high concentrations of resveratrol for 24 hours. Hematoxylin and eosin staining, qPCR and mitochondrial copy number, and DNA damage assays then were used to confirm the protective effects of resveratrol on NMDA-induced retinal damage. Results: The seven sirtuins and OPA1 were highly expressed in zebrafish retina compared to the liver. Treatment with resveratrol promoted SIRT1, mitochondrial sirtuins, and OPA1 gene and protein expression, and improved mitochondrial DNA repair in adult zebrafish retina. Interestingly, the effect of resveratrol on SIRT4 gene and protein expression was significantly higher in the zebrafish retina. Importantly, resveratrol offered protection against NMDA-induced retinal damage by activating the SIRT1 gene and subsequent protein expression. Mitochondrial sirtuins and OPA1 genes likely had a role in regulating mitochondrial dynamics. Conclusions: To our knowledge, our study is the first composite analysis of sirtuins in adult zebrafish retina and provides sufficient evidence that resveratrol, as an activator of SIRT1, protects NMDA-induced zebrafish retinal damage by potentially mediating mitochondrial sirtuins and OPA1 genes.

CRMP2 and CRMP4 Are Differentially Required for Axon Guidance and Growth in Zebrafish Retinal Neurons.

Axons are directed to their correct targets by guidance cues during neurodevelopment. Many axon guidance cues have been discovered; however, much less known is about how the growth cones transduce the extracellular guidance cues to intracellular responses. Collapsin response mediator proteins (CRMPs) are a family of intracellular proteins that have been found to mediate growth cone behavior in vitro; however, their roles in vivo in axon development are much less explored. In zebrafish embryos, we find that CRMP2 and CRMP4 are expressed in the retinal ganglion cell layer when retinal axons are crossing the midline. Knocking down CRMP2 causes reduced elongation and premature termination of the retinal axons, while knocking down CRMP4 results in ipsilateral misprojections of retinal axons that would normally project to the contralateral brain. Furthermore, CRMP4 synchronizes with neuropilin 1 in retinal axon guidance, suggesting that CRMP4 might mediate the semaphorin/neuropilin signaling pathway. These results demonstrate that CRMP2 and CRMP4 function differentially in axon development in vivo.

Chd7 Is Critical for Early T-Cell Development and Thymus Organogenesis in Zebrafish.

Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome is a congenital disorder affecting multiple organs and mainly caused by mutations in CHD7, a gene encoding a chromatin-remodeling protein. Immunodeficiency and reduced T cells have been noted in CHARGE syndrome. However, the mechanisms underlying T lymphopenia are largely unexplored. Herein, we observed dramatic decrease of T cells in both chd7knockdown and knockout zebrafish embryos. Unexpectedly, hematopoietic stem and progenitor cells and, particularly, lymphoid progenitor cells were increased peripherally in nonthymic areas in chd7-deficient embryos, unlikely to contribute to the T-cell decrease. Further analysis demonstrated that both the organogenesis and homing function of the thymus were seriously impaired. Chd7 might regulate thymus organogenesis through modulating the development of both neural crest cell-derived mesenchyme and pharyngeal endoderm-derived thymic epithelial cells. The expression of foxn1, a central regulator of thymic epithelium, was remarkably down-regulated in the pharyngeal region in chd7-deficient embryos. Moreover, the T-cell reduction in chd7-deficient embryos was partially rescued by overexpressing foxn1, suggesting that restoring thymic epithelium may be a potential therapeutic strategy for treating immunodeficiency in CHARGE syndrome. Collectively, the results indicated that chd7 was critical for thymic development and T-lymphopenia in CHARGE syndrome may be mainly attributed to the defects of thymic organogenesis. The current finding may benefit the diagnosis and therapy of T lymphopenia and immunodeficiency in CHARGE syndrome.

Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals. METHODS: WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5 × 10-5 in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran-Mantel-Haenszel test to compare gene-level variant counts in cases vs controls. RESULTS: No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p = 8.3 × 10-12), SOD1 (p = 8.9 × 10-9) and NEK1 (p = 1.1 × 10-9). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p = 0.04 and p = 7 × 10-3, respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p = 0.14). CONCLUSIONS: While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans.

Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis.

Cross-ethnic genetic studies can leverage power from differences in disease epidemiology and population-specific genetic architecture. In particular, the differences in linkage disequilibrium and allele frequency patterns across ethnic groups may increase gene-mapping resolution. Here we use cross-ethnic genetic data in sporadic amyotrophic lateral sclerosis (ALS), an adult-onset, rapidly progressing neurodegenerative disease. We report analyses of novel genome-wide association study data of 1,234 ALS cases and 2,850 controls. We find a significant association of rs10463311 spanning GPX3-TNIP1 with ALS (p = 1.3 × 10-8), with replication support from two independent Australian samples (combined 576 cases and 683 controls, p = 1.7 × 10-3). Both GPX3 and TNIP1 interact with other known ALS genes (SOD1 and OPTN, respectively). In addition, GGNBP2 was identified using gene-based analysis and summary statistics-based Mendelian randomization analysis, although further replication is needed to confirm this result. Our results increase our understanding of genetic aetiology of ALS.Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Here, Wray and colleagues identify association of the GPX3-TNIP1 locus with ALS using cross-ethnic meta-analyses.

Blocking mTOR Signalling with Rapamycin Ameliorates Imiquimod-induced Psoriasis in Mice.

The mTOR (mechanistic target of rapamycin) inhibitor rapamycin has long been known for its immune suppressive properties, but it has shown limited therapeutic success when given systemically to patients with psoriasis. Recent data have shown that the mTOR pathway is hyperactivated in lesional psoriatic skin, which probably contributes to the disease by interfering with maturation of keratinocytes. This study investigated the effect of topical rapamycin treatment in an imiquimod-induced psoriatic mouse model. The disease was less severe if the mice had received rapamycin treatment. Immunohistological analysis revealed that rapamycin not only prevented the activation of mTOR signalling (P-mTOR and P-S6 levels), but almost normalized the expression of epidermal differentiation markers. In addition, the influx of innate immune cells into the draining lymph nodes was partially reduced by rapamycin treatment. These data emphasize the role of mTOR signalling in the pathogenesis of psoriasis, and support the investigation of topical mTOR inhibition as a novel anti-psoriatic strategy.