Deoxyribonuclease 1-like 3 Inhibits Hepatocellular Carcinoma Progression by Inducing Apoptosis and Reprogramming Glucose Metabolism

HCC has remained one of the challenging cancers to treat, owing to the paucity of drugs targeting the critical survival pathways. Considering the cancer cells are deficient in DNase activity, the increase of an autonomous apoptisis endonuclease should be a reasonable choice for cancer treatment. In this study, we investigated whether DNASE1L3, an endonuclease implicated in apoptosis, could inhibit the progress of HCC. We found DNASE1L3 was down-regulated in HCC tissues, whereas its high expression was positively associated with the favorable prognosis of patients with HCC. Besides, serum DNASE1L3 levels were lower in HCC patients than in healthy individuals. Functionally, we found that DNASE1L3 inhibited the proliferation of tumor cells by inducing G0/G1 cell cycle arrest and cell apoptosis in vitro. Additionally, DNASE1L3 overexpression suppressed tumor growth in vivo. Furthermore, we found that DNASE1L3 overexpression weakened glycolysis in HCC cells and tissues via inactivating the rate-limiting enzymes involved in PTPN2-HK2 and CEBPβ-p53-PFK1 pathways. Finally, we identified the HBx to inhibit DNASE1L3 expression by up-regulating the expression of ZNF384. Collectively, our findings demonstrated that DNASE1L3 could inhibit the HCC progression through inducing cell apoptosis and weakening glycolysis. We believe DNASE1L3 could be considered as a promising prognostic biomarker and therapeutic target for HCC.     

mTOR pathway regulates the differentiation of peripheral blood Th2/Treg cell subsets in patients with pemphigus vulgaris

Pemphigus vulgaris (PV) is a chronic and potentially life-threatening autoimmune blistering disease.Aberrant mTOR pathway activity is involved in many autoimmun...     

CHCHD2 and CHCHD10 regulate mitochondrial dynamics and integrated stress response

Mitochondrial dysfunction is becoming one of the main pathology factors involved in the etiology of neurological disorders. Recently, mutations of the coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and 10 (CHCHD10) which encode two homologous proteins that belong to the mitochondrial CHCH domain protein family, are linked to Parkinson’s disease and amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), respectively. However, the physiological and pathological roles of these twin proteins have not been well elaborated. Here, we show that, in physiological conditions, CHCHD2 and CHCHD10 interact with OMA1 and suppress its enzyme activity, which not only restrains the initiation of the mitochondrial integrated response stress (mtISR), but also suppresses the processing of OPA1 for mitochondrial fusion. Further, during mitochondria stress-induced by carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment, CHCHD2 and CHCHD10 translocate to the cytosol and interacte with eIF2a, which attenuates mtISR overactivation by suppressing eIF2a phosphorylation and its downstream response. As such, knockdown of CHCHD2 and CHCHD10 triggers mitochondrial ISR, and such cellular response is enhanced by CCCP treatment. Therefore, our findings demonstrate the first “mtISR suppressor” localized in mitochondria for regulating stress responses in mammalian cells, which has a profound pathological impact on the CHCH2/CHCH10-linked neurodegenerative disorder.Subject terms: Stress signalling, Mitochondria     

A lethal model of Leptospira infection in hamster nasal mucosa

Leptospirosis is a fatal zoonosis caused by contact between skin or a mucosal surface and contaminated soil or water. Hamsters were infected by intraperitoneal injection fto establish experimental leptospirosis, which is not a natural route of infection. There are no reports of nasal mucosal infection in hamsters. In this study, infection of the nasal mucosa was performed to establish a model of natural infection. Both methods of infection can cause lethal models with similar symptoms in the later stages of infection, such as weight loss, blood concentration, increased neutrophils (GRAN), and decreased lymphocytes (LYM) in the blood, severe organ damage and liver function obstruction. The burden of Leptospira in the organs and blood was lower in the mucosal inoculation groups at 1 day after infection. However, mucosal infection induced a higher Leptospira burden in urine than intraperitoneal infection in the late stages of infection. After nasal mucosal infection, antibody levels were higher and lasted longer. These results indicated that the route of nasal mucosal infection is a good choice for studying leptospirosis in hamsters.     

NKG2D discriminates diverse ligands through selectively mechano‐regulated ligand conformational changes

Stimulatory immune receptor NKG2D binds diverse ligands to elicit differential anti‐tumor and anti‐virus immune responses. Two conflicting degeneracy recognition models based on static crystal structures and in‐solution binding affinities have been considered for almost two decades. Whether and how NKG2D recognizes and discriminates diverse ligands still remain unclear. Using live‐cell‐based single‐molecule biomechanical assay, we characterized the in situ binding kinetics of NKG2D interacting with different ligands in the absence or presence of mechanical force. We found that mechanical force application selectively prolonged NKG2D interaction lifetimes with the ligands MICA and MICB, but not with ULBPs, and that force‐strengthened binding is much more pronounced for MICA than for other ligands. We also integrated steered molecular dynamics simulations and mutagenesis to reveal force‐induced rotational conformational changes of MICA, involving formation of additional hydrogen bonds on its binding interface with NKG2D, impeding MICA dissociation under force. We further provided a kinetic triggering model to reveal that force‐dependent affinity determines NKG2D ligand discrimination and its downstream NK cell activation. Together, our results demonstrate that NKG2D has a discrimination power to recognize different ligands, which depends on selective mechanical force‐induced ligand conformational changes.     

Selective Laser Melting Molding of Individualized Femur Implant:Design,Process,Optimization

Efective Selective Laser Melting(SLM)molding methods for femur implant design and molding can improve femur implant surgerysucess rates and enhance patients quality of life.In this study,an individualized femur implant and individualized biological fixed-typefenur implant were designed using the parametric modeling method.The implants were then directly manufactured via SLM moldingtechnology as the forming process was carefuly analyzed.The results indicate that the proposed implant allows for favorable conjunctionof the reconstructed implant model with the surrounding bone tissues under the premise of a relatively small amount of bone-cutting.Theproposed implant also shows even pore distribution,good overall connectivity,relatively high bearing capacity,favorable overlappingbetween supports,and strong inter-pore connectivity.Only a small amount of powder adheres onto the surface and can be directly usedafter simple sand blasting and polishing.The comprehensive analyses of fenur implant modeling and molding methods given in this papermay provide a sound foundation for the design and direct manufacture of individualized femur implants in the future.