Ninjurin1 positively regulates osteoclast development by enhancing the survival of prefusion osteoclasts

Osteoclasts (OCs) are bone-resorbing cells that originate from hematopoietic stem cells and develop through the fusion of mononuclear myeloid precursors. Dysregulation of OC development causes bone disorders such as osteopetrosis, osteoporosis, and rheumatoid arthritis. Although the molecular mechanisms underlying osteoclastogenesis have been well established, the means by which OCs maintain their survival during OC development remain unknown. We found that Ninjurin1 (Ninj1) expression is dynamically regulated during osteoclastogenesis and that Ninj1(-/-) mice exhibit increased trabecular bone volume owing to impaired OC development. Ninj1 deficiency did not alter OC differentiation, transmigration, fusion, or actin ring formation but increased Caspase-9-dependent intrinsic apoptosis in prefusion OCs (preOCs). Overexpression of Ninj1 enhanced the survival of mouse macrophage/preOC RAW264.7 cells in osteoclastogenic culture, suggesting that Ninj1 is important for the survival of preOCs. Finally, analysis of publicly available microarray data sets revealed a potent correlation between high NINJ1 expression and destructive bone disorders in humans. Our data indicate that Ninj1 plays an important role in bone homeostasis by enhancing the survival of preOCs

Case report: Investigation of genetic mutations in a case of schistosomus reflexus in a Holstein dairy cattle fetus in Korea

Schistosomus reflexus (SR) is one of the most common congenital anomalies found in cases of cattle dystocia; this disorder occurs mostly in cattle. Congenital anomalies such as SR are caused by various genetic and environmental factors, but no specific cause has been elucidated for SR. This study reports a case of SR in a Holstein dairy cattle fetus with congenital anomalies in Korea. Grossly, a distinct spine curvature was observed between the thoracic and lumbar vertebrae, accompanied by a consequential malformation from the sacrum to the occipital bone. Furthermore, the thoracic and abdominal organs were exposed. In computed tomography (CT) images, mild and severe kyphoscoliosis was observed in T1~11 and L1~6, respectively. Additionally, vertebral dysplasia was observed in S1~5 and Cd 1~5. To pinpoint the causal genes and mutations, we leveraged a custom 50K Hanwoo SNP-Chip and the Online Mendelian Inheritance in Animals (OMIA) database. As a result, we identified a nonsense mutation in apoptotic protease activating factor 1 (APAF1) within HH1 that was associated with a decrease in conception rate and an increase in abortion in Holstein dairy cattle. The genotype of the SR case was A/A, and most of the 1,142 normal Holstein dairy cattle tested as a control group had the genotype G/G. In addition, the A/A genotype did not exist in the control group. Based on the pathological, genetic, and radiological findings, the congenital abnormalities observed were diagnosed as SR

Structural connectivity differs between males and females in the brain object manipulation network.

Object control skills are one of the most important abilities in daily life. Knowledge of object manipulation is an essential factor in improving object control skills. Although males and females equally try to use object manipulation knowledge, their object control abilities often differ. To explain this difference, we investigated how structural brain networks in males and females are differentially organized in the tool-preferring areas of the object manipulation network. The structural connectivity between the primary motor and premotor regions and between the inferior parietal regions in males was significantly higher than that in females. However, females showed greater structural connectivity in various regions of the object manipulation network, including the paracentral lobule, inferior parietal regions, superior parietal cortices, MT+ complex and neighboring visual areas, and dorsal stream visual cortex. The global node strength found in the female parietal network was significantly higher than that in males but not for the entire object manipulation, ventral temporal, and motor networks. These findings indicated that the parietal network in females has greater inter-regional structural connectivity to retrieve manipulation knowledge than that in males. This study suggests that differential structural networks in males and females might influence object manipulation knowledge retrieval

Clinical significance and prognostic role of hypoxia-induced microRNA 382 in gastric adenocarcinoma.

Hypoxia and angiogenesis are critical components in the progression of solid cancer, including gastric cancers (GCs). miR-382 has been identified as a hypoxia-induced miR (hypoxamiR), but the clinical significance in GCs has not been identified yet. To explore the clinical and prognostic importance of miR-382 in GCs, the surgical specimens of 398 patients with GCs in KNU hospital in Korea, the total of 183 patients was randomly selected using simple sampling methods and big data with 446 GCs and 45 normal tissues from the data portal (https://portal.gdc.cancer.gov/) were analysed. Expression of miR-382 as well as miR-210, as a positive control hypoxamiR by qRT-PCR in histologically malignant region of GCs showed significantly positive correlation (R = 0.516, p<0.001). High miR-210 and miR-382 expression was significantly correlated with unfavorable prognosis including advanced GCs (AGC), higher T category, N category, pathologic TNM stage, lymphovascular invasion, venous invasion, and perinueral invasion, respectively (all p<0.05). In univariate analysis, high miR-210 expression was significantly associated with worse overall survival (OS) (p = 0.036) but not high miR-382. In paired 60 gastric normal and cancer tissues, miR-382 expression in cancer tissues was significantly higher than normal counterpart (p = 0.003), but not miR-210 expression. However, by increasing the patient number from the big data analysis, miR-210 as well as miR-382 expression in tumor tissues was significantly higher than the normal tissues. Our results suggest that miR-382, as novel hypoxamiR, can be a prognostic marker for advanced GCs and might be correlated with metastatic potential. miR-382 might play important roles in the aggressiveness, progression and prognosis of GCs. In addition, miR-382 give a predictive marker for progression of GCs compared to the normal or preneoplastic lesion

Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance

Disruption of colonic homeostasis caused by aberrant M1/M2 macrophage polarization and dysbiosis contributes to inflammatory bowel disease (IBD) pathogenesis. However, the molecular factors mediating colonic homeostasis are not well characterized. Here, we found that Ninjurin1 (Ninj1) limits colon inflammation by regulating macrophage polarization and microbiota composition under homeostatic conditions and during colitis development. Ninj1 deletion in mice induced hypersusceptibility to colitis, with increased prevalence of colitogenic Prevotellaceae strains and decreased immunoregulatory Lachnospiraceae strains. Upon co-housing (CoH) with WT mice, Ninj1(-/-) mice showed increased Lachnospiraceae and decreased Prevotellaceae abundance, with subsequent improvement of colitis. Under homeostatic conditions, M1 macrophage frequency was higher in the Ninj1(-/-) mouse colons than wild-type (WT) mouse colons, which may contribute to increased basal colonic inflammation and microbial imbalance. Following colitis induction, Ninj1 expression was increased in macrophages; meanwhile Ninj1(-/-) mice showed severe colitis development and impaired recovery, associated with decreased M2 macrophages and escalated microbial imbalance. In vitro, Ninj1 knockdown in mouse and human macrophages activated M1 polarization and restricted M2 polarization. Finally, the transfer of WT macrophages ameliorated severe colitis in Ninj1(-/-) mice. These findings suggest that Ninj1 mediates colonic homeostasis by modulating M1/M2 macrophage balance and preventing extensive dysbiosis, with implications for IBD prevention and therapy

Regional cerebral oxygen saturation in cardiac arrest survivors undergoing targeted temperature management 36 degrees C versus 33 degrees C: A randomized clinical trial

Aim of study: To investigate whether regional cerebral oxygen saturation (rSO(2)) diers in out-of-hospital cardiac arrest (OHCA) survivors undergoing targeted temperature management (TTM) 36 degrees C versus 33 degrees C. Methods: A randomized clinical trial was conducted at intensive care units in two referral hospitals. Fifty-seven comatose OHCA survivors were randomized into either a 36 degrees C or 33 degrees C group. Patients were cooled and maintained at an oesophageal temperature of either 36 degrees C or 33 degrees C for 24 hours, rewarmed at a rate of 0.25 degrees C/hour, and maintained at &lt;37.5 degrees C until 72 hours. During 72 hours of TTM, rSO(2) was continuously monitored on the left forehead using near-infrared spectroscopy (INVOS (TM) 5100C). The rSO(2) level at 72 hours was compared between the two groups. Next, serial rSO(2) levels for 72 hours were compared using mixed eects regression. The association between rSO(2) levels and 6-month neurological outcomes was also evaluated. Results: There were no significant dierences in the rSO(2) level at 72 hours between the 36 degrees C and 33 degrees C groups (p = 0.372). Furthermore, serial rSO(2) levels for 72 hours of TTM were not dierent between the two groups (p = 0.733). However, low rSO(2) levels, particularly at 24 hours of TTM, were significantly associated with poor 6-month neurological outcomes (odds ratio = 0.899, 95% confidence interval: 0.831-0.974). The area under the receiver operating characteristic curve of the rSO(2) level at 24 hours for poor neurological outcomes was 0.800. Conclusions: Regardless of target temperatures, low rSO(2) levels during TTM were significantly associated with poor 6-month neurological outcomes in OHCA survivors.Y

Differential TM4SF5-mediated SIRT1 modulation and metabolic signaling in nonalcoholic steatohepatitis progression

Nonalcoholic fatty liver disease is a chronic condition involving steatosis, steatohepatitis and fibrosis, and its progression remains unclear. Although the tetraspanin transmembrane 4 L six family member 5 (TM4SF5) is involved in hepatic fibrosis and cancer, its role in nonalcoholic steatohepatitis (NASH) progression is unknown. We investigated the contribution of TM4SF5 to liver pathology using transgenic and KO mice, diet- or drug-treated mice,in vitroprimary cells, and in human tissue. TM4SF5-overexpressing mice exhibited nonalcoholic steatosis and NASH in an age-dependent manner. Initially, TM4SF5-positive hepatocytes and liver tissue exhibited lipid accumulation, decreased Sirtuin 1 (SIRT1), increased sterol regulatory-element binding proteins (SREBPs) and inactive STAT3 via suppressor of cytokine signaling (SOCS)1/3 upregulation. In older mice, TM4SF5 promoted inflammatory factor induction, SIRT1 expression and STAT3 activity, but did not change SOCS or SREBP levels, leading to active STAT3-mediated ECM production for NASH progression. A TM4SF5-associated increase in chemokines promoted SIRT1 expression and progression to NASH with fibrosis. Suppression of the chemokine CCL20 reduced immune cell infiltration and ECM production. Liver tissue from high-fat diet- or CCl4-treated mice and human patients exhibited TM4SF5-dependent steatotic or steatohepatitic livers with links between TM4SF5-mediated SIRT1 modulation and SREBP or SOCS/STAT3 signaling axes. TM4SF5-mediated STAT3 activation in fibrotic NASH livers increased collagen I and laminin gamma 2. Both collagen I alpha 1 and laminin gamma 2 suppression resulted in reduced SIRT1 and active STAT3, but no change in SREBP1 or SOCS, and abolished CCl4-mediated mouse liver damage. TM4SF5-mediated signaling pathways that involve SIRT1, SREBPs and SOCS/STAT3 promoted progression to NASH. Therefore, TM4SF5 and its downstream effectors may be promising therapeutic targets to treat nonalcoholic fatty liver disease. (c) 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.N