SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung\u27s disease.

Hirschsprung\u27s disease (HSCR) is a rare congenital disease caused by impaired proliferation and migration of neural crest cells. We investigated changes in expression of microRNAs (miRNAs) and the genes they regulate in tissues of patients with HSCR. Quantitative real-time PCR and immunoblot analyses were used to measure levels of miRNA, mRNAs, and proteins in colon tissues from 69 patients with HSCR and 49 individuals without HSCR (controls). Direct interactions between miRNAs and specific mRNAs were indentified in vitro, while the function role of miR-218-1 was investigated by using miR-218 transgenic mice. An increased level of miR-218-1 correlated with increased levels of SLIT2 and decreased levels of RET and PLAG1 mRNA and protein. The reductions in RET and PLAG1 by miR-218-1 reduced proliferation and migration of SH-SY5Y cells. Overexpression of the secreted form of SLIT2 inhibited cell migration via binding to its receptor ROBO1. Bowel tissues from miR-218-1 transgenic mice had nerve fibre hyperplasia and reduced numbers of gangliocytes, compared with wild-type mice. Altered miR-218-1 regulation of SLIT2, RET and PLAG1 might be involved in the pathogenesis of HSCR

Two-phase Framework for Automatic Kidney and Kidney Tumor Segmentation

Precise segmentation of kidney and kidney tumor is essential for computer aided diagnosis. Considering the diverse shape, low contrast with surrounding tissues and small tumor volumes, it’s still challenging to segment kidney and kidney tumor accurately. To solve this problem, we proposed a two-phase framework for automatic segmentation of kidney and kidney tumor. In the first phase, the approximate localization of kidney and kidney tumor is predicted by a coarse segmentation network to overcome GPU memory limitation. Taking the coarse prediction from first phase as input, the region of kidney and tumor is cropped and trained in an enhanced two-stage network to achieve a fine-grained segmentation result in the second phase. Besides, our network prediction flows into multiple post-processing steps to remove false positive such as cyst by taking medical prior knowledge into consideration. Data argumentation through registration and ensemble models are used to further enhance performance

Homozygous mutation in DNALI1 leads to asthenoteratozoospermia by affecting the inner dynein arms

Asthenozoospermia is the most common cause of male infertility. Dynein protein arms play a crucial role in the motility of sperm flagella and defects in these proteins generally impair the axoneme structure and affect sperm flagella function. In this study, we performed whole exome sequencing for a cohort of 126 infertile patients with asthenozoospermia and identified homozygous DNALI1 mutation in one patient from a consanguineous family. This identified homozygous mutation was verified by Sanger sequencing. In silico analysis showed that this homozygous mutation is very rare, highly pathogenic, and very conserved. Sperm routine analysis confirmed that the motility of the spermatozoa from the patient significantly decreased. Further sperm morphology analysis showed that the spermatozoa from the patient exhibited multiple flagella morphological defects and a specific loss in the inner dynein arms. Fortunately, the patient was able to have his child via intracytoplasmic sperm injection treatment. Our study is the first to demonstrate that homozygous DNALI1 mutation may impair the integration of axoneme structure, affect sperm motility and cause asthenoteratozoospermia in human beings

Risk assessment of the Xigou debris flow in the Three Gorges Reservoir Area

On June 18, 2018, under the influence of heavy rainfall, a debris flow disaster broke out in Xigou village of the Three Gorges Reservoir Area in Chongqing, causing some residential houses to be buried along with great economic losses. The on-site investigation found many loose solid material sources in the debris flow gully. Under the conditions of heavy rainfall, debris flows are prone to occur again, which would seriously threaten the lives and property of nearby residents. In this paper, taking the Xigou debris flow as a research case, numerical simulation by rapid mass movements simulation (RAMMS) is used to invert the movement process of the 2018 debris flow event; the dynamic calculation parameters of the Xigou debris flow event are obtained; a quantitative hazard prediction of debris flows with different recurrence intervals (30, 50, and 100 years) is carried out in the study area; and risk assessment is conducted based on the vulnerability characteristics of the disaster-bearing bodies in the study area. The results show that the maximum accumulation thickness of debris flow in the 30-year, 50-year, and 100-year recurrence intervals is 6.54 m, 10.18 m, and 10.00 m, respectively, and the debris flow in the 100-year recurrence interval has the widest influence range and greatest hazard. The low-, medium-, and high-risk areas account for 75%, 23%, and 2%, respectively. The high-risk area mainly includes some buildings near the #1 and #2 gullies. This study provides support for the prevention and control of potential debris flow disasters in Xigou village and a scientific basis for disaster prevention and mitigation in the Three Gorges Reservoir area

HCV 6a Prevalence in Guangdong Province Had the Origin from Vietnam and Recent Dissemination to Other Regions of China: Phylogeographic Analyses

Recently in China, HCV 6a infection has shown a fast increase among patients and blood donors, possibly due to IDU linked transmission.We recruited 210 drug users in Shanwei city, Guangdong province. Among them, HCV RNA was detected in 150 (71.4%), both E1 and NS5B genes were sequenced in 136, and 6a genotyped in 70. Of the 6a sequences, most were grouped into three clusters while 23% represent emerging strains. For coalescent analysis, additional 6a sequences were determined among 21 blood donors from Vietnam, 22 donors from 12 provinces of China, and 36 IDUs from Liuzhou City in Guangxi Province. Phylogeographic analyses indicated that Vietnam could be the origin of 6a in China. The Guangxi Province, which borders Vietnam, could be the first region to accept 6a for circulation. Migration from Yunnan, which also borders Vietnam, might be equally important, but it was only detected among IDUs in limited regions. From Guangxi, 6a could have further spread to Guangdong, Yunnan, Hainan, and Hubei provinces. However, evidence showed that only in Guangdong has 6a become a local epidemic, making Guangdong the second source region to disseminate 6a to the other 12 provinces. With a rate of 2.737×10⁻³ (95% CI: 1.792×10⁻³ to 3.745×10⁻³), a Bayesian Skyline Plot was portrayed. It revealed an exponential 6a growth during 1994-1998, while before and after 1994-1998 slow 6a growths were maintained. Concurrently, 1994-1998 corresponded to a period when contaminated blood transfusion was common, which caused many people being infected with HIV and HCV, until the Chinese government outlawed the use of paid blood donations in 1998.With an origin from Vietnam, 6a has become a local epidemic in Guangdong Province, where an increasing prevalence has subsequently led to 6a spread to many other regions of China

Beyond Acephalic Spermatozoa: The Complexity of Intracytoplasmic Sperm Injection Outcomes

This review analyses the genetic mechanisms of acephalic spermatozoa (AS) defects, which are associated with primary infertility in men. Several target genes of headless sperms have been identified but intracytoplasmic sperm injection (ICSI) outcomes are complex. Based on electron microscopic observations, broken points of the sperm neck are AS defects that are based on various genes that can be classified into three subtypes: HOOK1, SUN5, and PMFBP1 genes of subtype II; TSGA10 and BRDT genes of subgroup III, while the genetic mechanism(s) and aetiology of AS defects of subtype I have not been described and remain to be explored. Interestingly, all AS sperm of subtype II achieved better ICSI outcomes than other subtypes, resulting in clinical pregnancies and live births. For subtype III, the failure of clinical pregnancy can be explained by the defects of paternal centrioles that arrest embryonic development; for subtype I, this was due to a lack of a distal centriole. Consequently, the embryo quality and potential ICSI results of AS defects can be predicted by the subtypes of AS defects. However, this conclusion with regard to ICSI outcomes based on subtypes still needs further research, while the existence of quality of oocyte and implantation failure in women cannot be ignored

Senescence Osteoblast-Derived Exosome-Mediated miR-139-5p Regulates Endothelial Cell Functions

The pathogenesis of osteoporosis is considered extremely intricate. Osteoblast differentiation and angiogenesis can greatly affect bone development and formation, given their coupling role in these processes. Exosome-mediated miRNA regulates cellular senescence, proliferation, and differentiation. However, whether senescent osteoblasts can regulate the senescence of vascular endothelial cell by miRNA through exosomal pathway remains unclear. In this study, senescent osteoblasts could regulate endothelial cell function, promote cell senescence and apoptosis, and decrease cell proliferation via exosomal pathway. miR-139-5p showed high expression in senescent osteoblasts and their exosomes. After senescent osteoblast-derived exosome treatment, miR-139-5p was also upregulated in endothelial cells. Furthermore, transfection of miR-139-5p mimic promoted the senescence and apoptosis of vascular endothelial cells and inhibited their proliferation and migration, whereas transfection of miR-139-5p inhibitor rescued the effect of D-galactose. Using double luciferase assay, TBX1 was confirmed to be a direct target gene of miR-139-5p. In conclusion, senescent osteoblast-derived exosome-mediated miR-139-5p regulated endothelial cell function via exosomal pathway. Our study revealed the role of osteoblast-derived exosomes in the bone environment during aging, providing a clue for inventing a new target therapy

Novel Gene Regulation in Normal and Abnormal Spermatogenesis

Spermatogenesis is a complex and dynamic process which is precisely controlledby genetic and epigenetic factors. With the development of new technologies (e.g., single-cell RNA sequencing), increasingly more regulatory genes related to spermatogenesis have been identified. In this review, we address the roles and mechanisms of novel genes in regulating the normal and abnormal spermatogenesis. Specifically, we discussed the functions and signaling pathways of key new genes in mediating the proliferation, differentiation, and apoptosis of rodent and human spermatogonial stem cells (SSCs), as well as in controlling the meiosis of spermatocytes and other germ cells. Additionally, we summarized the gene regulation in the abnormal testicular microenvironment or the niche by Sertoli cells, peritubular myoid cells, and Leydig cells. Finally, we pointed out the future directions for investigating the molecular mechanisms underlying human spermatogenesis. This review could offer novel insights into genetic regulation in the normal and abnormal spermatogenesis, and it provides new molecular targets for gene therapy of male infertility

Aberrant Reduction of MiR-141 Increased CD47/CUL3 in Hirschsprung's Disease

Background: MiR-141 has been confirmed to be associated with various human diseases. However, whether miR-141 is involved in the pathogenesis of Hirschsprung's disease (HSCR) remains unknown. Here, we design the experiment to reveal the relationship between miR-141 and HSCR. Methods: Quantitative real-time PCR and Western blot were used to detect the expression levels of miR-141 and its potential genes in 70 tissues of HSCR compared with 60 controls. Bisulfite sequencing PCR (BSP) assay was applied to explain the possible mechanism of the aberrant expression level of miR-141. We employed a dual-luciferase reporter assay to validate the regulation relation between miR-141 and CD47/CUL3. Cell migration, proliferation, apoptosis, and cell cycle progression were examined by transwell assay, MTT assay, and flow cytometry, respectively. Results: MiR-141 was down-regulated whereas CD47 and CUL3 expression was increased in colon tissues from patients with HSCR compared with control group, The increased level of CD47 and CUL3 induced by miR-141 reduced proliferation and migration of 293T and SH-SY5Y cells. Furthermore, this suppression was reversed by reducing of CD47 and CUL3. Hypermethylation of a CpG Island in the promoter region of miR-141 gene was confirmed in HSCR tissues. Conclusion: Aberrant reduction of miR-141 may play an important role in the pathogenesis of HSCR with the inhibiting affection on cell migration and proliferation abilities. The present study demonstrates for the first time the role of miR-141 and its target genes in the occurrence of HSCR, and provides us a new direction for the study of the pathogenesis of Hirschsprung's disease