BACKGROUND: Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH. METHODS: Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL). RESULTS: A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69-1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension ( P  < 0.001, P  = 0.026 and P  = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714-0.787), and CK-18 M30 at Youden's index maximum was 275.7 U/L. Both sensitivity (55% [52%-59%]) and positive predictive value (59%) were not ideal. CONCLUSION This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.
Humans ; Non-alcoholic Fatty Liver Disease/diagnosis* ; Keratin-18 ; Biomarkers ; Biopsy ; Hepatocytes/pathology* ; Apoptosis ; Liver/pathology*

RBM46 is a germ cell-specific RNA-binding protein required for gametogenesis, but the targets and molecular functions of RBM46 remain unknown. Here, we demonstrate that RBM46 binds at specific motifs in the 3'UTRs of mRNAs encoding multiple meiotic cohesin subunits and show that RBM46 is required for normal synaptonemal complex formation during meiosis initiation. Using a recently reported, high-resolution technique known as LACE-seq and working with low-input cells, we profiled the targets of RBM46 at single-nucleotide resolution in leptotene and zygotene stage gametes. We found that RBM46 preferentially binds target mRNAs containing GCCUAU/GUUCGA motifs in their 3'UTRs regions. In Rbm46 knockout mice, the RBM46-target cohesin subunits displayed unaltered mRNA levels but had reduced translation, resulting in the failed assembly of axial elements, synapsis disruption, and meiotic arrest. Our study thus provides mechanistic insights into the molecular functions of RBM46 in gametogenesis and illustrates the power of LACE-seq for investigations of RNA-binding protein functions when working with low-abundance input materials.
Animals ; Mice ; 3' Untranslated Regions/genetics* ; Cell Cycle Proteins/metabolism* ; Gametogenesis/genetics* ; Meiosis/genetics* ; Nuclear Proteins/genetics* ; RNA-Binding Proteins/genetics*

Cyclin-dependent kinase 9 (CDK9) activity is correlated with worse outcomes of triple-negative breast cancer (TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction (PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CˆN ligand and tested their activity against the CDK9-cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.

OBJECTIVE: To measure the dangerous depth and the effective safe depth of needling at acupoints of kidney regions based on MRI imaging, and to provide the imaging support for clinical practice. METHODS: The abdominal enhanced T1 MRI imaging of horizontal plane of 61 healthy subjects was included, the anatomical structure of bilateral Weishu (BL 21), Sanjiaoshu (BL 22), Shenshu (BL 23), Weicang (BL 50), Huangmen (BL 51) and Zhishi (BL 52) was analyzed, and the dangerous depth and effective safe depth of perpendicular and oblique needling were measured between the left and right sides and subjects with different body sizes. RESULTS: There were no significant differences between dangerous depth and effective safe depth of perpendicular and oblique needling at bilateral acupoints of kidney region (P>0.05). The dangerous depth and effective safe depth of perpendicular and oblique needling at bilateral acupoints of kidney region in the moderate group were larger than the underweight group (P<0.05), while those in the overweight group were larger than the moderate group and the underweight group (P<0.05). CONCLUSION The safe depth of needling at acupoints of kidney region is related to body size, for moderate weight and overweight patients, the needling depth could be increased for better efficacy, while for underweight patients, the recommend direction and depth of needling should be restricted to avoid acupuncture accident.
Acupuncture Points ; Acupuncture Therapy/methods* ; Humans ; Kidney/diagnostic imaging* ; Magnetic Resonance Imaging ; Overweight ; Thinness

ObjectivesThis study aims to use accelerometer to objectively evaluate daily physical activity （PA） and steps of single pregnant women， and preliminarily explore the threshold of daily steps in line with the recommended PA during pregnancy， so as to provide PA guidance for pregnant women. MethodsWomen with singleton pregnancies who had prenatal examination in the the First Affiliated Hospital of Sun Yat-sen University from April 2018 to September 2019 continuously wore an accelerometer for 7 days for three times to measure daily PA. A total of 178 cases were included in this study with the average age 30.0 ± 3.0 years. Data were downloaded by supporting software， and the relationship between daily steps and PA （total PA， light PA and moderate PA） were analyzed by linear correlation analysis. Linear regression analysis and receiver operator characteristic curve （ROC） analysis were both used to explore the threshold steps corresponding to the physical activity recommendation. ResultsThere was no difference in daily total PA， light PA and sedentary behavior time during the three trimesters （P > 0.05）. But the moderate PA decreased with the pregnancy stages increased （25.1±16.1 vs. 23.6±16.5 vs. 21.5±16.1，min/d， P = 0.001）. There was a positive correlation between total PA and daily steps during the three trimesters （The correlation coefficients r of the early pregnancy， mid pregnancy and late pregnancy were 0.87， 0.83 and 0.86， respectively， P < 0.001）； and there was a positive correlation with light PA （r of the three trimesters were 0.79， 0.72 and 0.77， respectively， P < 0.001）. The relationship between moderate PA and daily steps during the three trimesters also had similar results （r of the three trimesters were 0.62， 0.53 and 0.55， respectively， P < 0.001）. The thresholds of daily steps to reach the recommended PA during pregnancy in the early， mid and late pregnancy were 10 925 steps， 11 372 steps and 11 170 steps， respectively. According to ROC analysis， the thresholds of daily steps in the three trimesters were 10 856 steps， 10 480 steps and 9 819 steps， respectively， and the areas under the curve were 0.81， 0.73 and 0.74， respectively （P < 0.001）. ConclusionsThe daily physical activity is mainly walking during pregnancy. Based on accelerometer evaluation， daily walking 9 800 to 11 500 steps could reach the physical activity recommendation during pregnancy.

Objective: This study aims to explore trends in sedentary behavior among Chinese children aged 6-17 years per demographic and social characteristics. Methods: A total of 4,341 children aged 6-17 years who participated in the Results: From 2004 to 2015, sedentary time among children aged 6-17 years increased from 23.9 ± 0.6 h/week to 25.7 ± 0.6 h/week ( Conclusions Sedentary time among Chinese children aged 6-17 years showed an upward trend from 2004 to 2015, especially among children residing in rural areas and regions with low urbanization levels.
Adolescent ; Asian Continental Ancestry Group ; Child ; China ; Female ; Health Surveys ; Humans ; Male ; Sedentary Behavior ; Socioeconomic Factors ; Urbanization

Prohibitin (PHB), an evolutionarily conserved mitochondrial inner membrane protein, is highly expressed in cells that require strong mitochondrial function. Recently, we demonstrated that the deletion of Phb in spermatocytes results in impaired mitochondrial function. In addition, PHB expression in the mitochondrial sheath of human sperm has a significantly negative correlation with mitochondrial reactive oxygen species levels, but a positive one with mitochondrial membrane potential and sperm motility. These results suggest that mitochondrial PHB expression plays a role in sperm motility. However, the mechanism of PHB-mediated regulation of sperm motility remains unknown. Here, we demonstrate for the first time that PHB interacts with protein kinase B (AKT) and exists in a complex with phospho-PHB (pT258) and phospho-AKT in the mitochondrial sheath of murine sperm, as determined using colocalization and coimmunoprecipitation assays. After blocking AKT activity using wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor), murine sperm have significantly ( P < 0.05) decreased levels of phospho-PHB (pT258) and the total and progressive motility. Furthermore, significantly ( P < 0.05) lower levels of phospho-PI3K P85 subunit α+γ (pY199 and pY467) and phospho-AKT (pS473; pT308) are found in sperm from infertile asthenospermic and oligoasthenospermic men compared with normospermic subjects, which suggest a reduced activity of the PI3K/AKT pathway in these infertile subjects. Importantly, these sperm from infertile subjects also have a significantly ( P < 0.05) lower level of phospho-PHB (pT258). Collectively, our findings suggest that the interaction of PHB with AKT in the mitochondrial sheath is critical for sperm motility, where PHB phosphorylation (pT258) level and PI3K/AKT activity are key regulatory factors.

BACKGROUND: Syndrome is one of the most important concepts in Chinese medicine (CM) theory. However, it was not well accounted in most of randomized controlled trials (RCTs). OBJECTIVES: To determine whether CM syndrome differentiation affects the treatment results, functional constipation (FC) was selected as a target disease, and MaZiRenWan (, MZRW), a classic CM formula commonly used for constipation with excessive heat syndrome, was selected for study. METHODS: It is an 18-week prospective double-blinded, doubledummy RCT, including 2-week run-in, 8-week treatment and 8-week post treatment follow-up. A total of 120 FC patients diagnosed as excessive heat syndrome will be recruited from the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine and the Baokang Affiliated Hospital of Tianjin University of Traditional Chinese Medicine. Patients will be randomly allocated into fixed MZRW (f_MZRW) granule group, modified MZRW (m_MZRW) granule group or bisacodyl group. For m_MZRW group, no more than two herbal granules can be added according to the syndrome differentiation for individual participants. The primary end point is the mean of complete spontaneous bowel movements (CSBMs) per week during the treatment period. Secondary end points include mean of CSBMs per week during follow-up, stool form, global symptom improvement, constipation and constipation-related symptoms assessment, CM syndrome change, and reported adverse events. DISCUSSION This trial is designed to evaluate the effectiveness of these three interventions for FC patients with the CM syndrome of excessive heat, and to determine the change of CM syndrome and the progress of disease during the treatment course. The results are important to explore whether syndrome differentiation is important for the therapeutic effect of a formula on a disease. [Trial registration: Chinese Clinical Trial Registry (Reg No. ChiCTR-TRC-13003742); protocol version: MZRW/NSFC-81173363 (2015.05.04)].
Constipation ; diagnosis ; drug therapy ; Double-Blind Method ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; Medicine, Chinese Traditional ; Outcome Assessment (Health Care) ; Prospective Studies ; Randomized Controlled Trials as Topic

BACKGROUND AND PURPOSE: Vasa vasorum (VV) have been believed to be rare or non-existent in small-caliber intracranial arteries. In a series of human cerebral artery specimens, we identified and examined the distribution of VV in association with co-existing intracranial atherosclerosis. METHODS: We obtained cerebral artery specimens from 32 consecutive autopsies of subjects aged 45 years or above. We scrutinized middle cerebral artery (MCA), vertebral artery (VA), and basilar artery (BA) for the presence of adventitial VV. We described the distribution of VV, and the characteristics of co-existing atherosclerotic lesions. RESULTS: Among 157 intracranial arteries, adventitial VV were present in 74 of the 157 specimens (47%), involving MCA (n=13, 18%), BA (n=14, 19%), and VA (n=47, 64%). Although qualitatively these 74 adventitial VV distributed similarly in arteries with or without atherosclerotic lesions (disease-free arteries n=4/8; arteries of pre-atherosclerosis n=17/42; and arteries of progressive atherosclerosis n=53/107), the presence of adventitial VV in intracranial VA was associated with a heavier plaque load (1.72±1.66 mm2 vs. 0.40±0.32 mm2, P < 0.001), severer luminal stenosis (25%±21% vs. 12%±9%, P=0.002), higher rate of concentric lesions (79% vs. 36%, P=0.002), and denser intraplaque calcification (44% vs. 0%, P=0.003). Histologically, intracranial VA with VV had a larger diameter (3.40±0.79 mm vs. 2.34±0.58 mm, P < 0.001), thicker arterial wall (0.31±0.13 mm vs. 0.23±0.06 mm, P=0.002), and a larger intima-media (0.19±0.09 mm vs. 0.13± 0.04 mm, P=0.003) than VA without VV. CONCLUSIONS: Our study demonstrated the distribution of adventitial VV within brain vasculature and association between vertebral VV and progressive atherosclerotic lesions with a heavier plaque load and denser intraplaque calcification.
Arteries ; Atherosclerosis ; Autopsy ; Basilar Artery ; Brain ; Cerebral Arteries ; Constriction, Pathologic ; Humans ; Intracranial Arteriosclerosis* ; Middle Cerebral Artery ; Phenobarbital ; Vasa Vasorum* ; Vertebral Artery

Repair of lower abdominal incisional hernia is always a surgical challenge. TAPE technique has been described for the repair of supra-pubic midline incisional hernia with satisfactory outcome. Its indication can be extended for treatment of non-midline lower abdominal hernia. Peritoneal incision is created just below the hernia defect with pre-peritoneal dissection to expose supra-pubic preperitoneal space with Cooper's ligament exposed. Non-adhesive mesh then placed over preperitoneal space and partially intra-peritoneally, and cover the whole extra-peritoneal space prepared to ensure enough overlapping. Mesh is fixed by tackers for intra-peritoneal part, most inferior fixation points were at peritoneal incision line. Extra-peritoneal part of meshes is fixed at the safety zone and covered up by the peritoneal flap to avoid mesh migration. Fixation of the meshes at the lateral aspects were facilitated by the peritoneal flap and subsequent fibrosis and adhesion to the extra-peritoneal structures in cases of lateral lower abdominal hernia. Repair of midline and lateral lower abdominal incisional hernia with this novel modified technique with prosthetic mesh is safe and effective. A larger case series and longer follow-up is required for validation of this technique.
Fibrosis ; Follow-Up Studies ; Hernia ; Hernia, Abdominal ; Hernia, Ventral* ; Incisional Hernia ; Ligaments