mTOR hypoactivity leads to trophectoderm cell failure by enhancing lysosomal activation and disrupting the cytoskeleton in preimplantation embryo.

BACKGROUND: Metabolic homeostasis is closely related to early impairment of cell fate determination and embryo development. The protein kinase mechanistic target of rapamycin (mTOR) is a key regulator of cellular metabolism in the body. Inhibition of mTOR signaling in early embryo causes postimplantation development failure, yet the mechanisms are still poorly understood. METHODS: Pregnancy mice and preimplantation mouse embryo were treated with mTOR inhibitor in vivo and in vitro respectively, and subsequently examined the blastocyst formation, implantation, and post-implantation development. We used immunofluorescence staining, RNA-Seq smart2, and genome-wide bisulfite sequencing technologies to investigate the impact of mTOR inhibitors on the quality, cell fate determination, and molecular alterations in developing embryos. RESULTS: We showed mTOR suppression during preimplantation decreases the rate of blastocyst formation and the competency of implantation, impairs the post implantation embryonic development. We discovered that blocking mTOR signaling negatively affected the transformation of 8-cell embryos into blastocysts and caused various deficiencies in blastocyst quality. These included problems with compromised trophectoderm cell differentiation, as well as disruptions in cell fate specification. mTOR suppression significantly affected the transcription and DNA methylation of embryos. Treatment with mTOR inhibitors increase lysosomal activation and disrupts the organization and dynamics of the actin cytoskeleton in blastocysts. CONCLUSIONS: These results demonstrate that mTOR plays a crucial role in 8-cell to blastocyst transition and safeguards embryo quality during early embryo development.

Intensive Intervention Improves Outcomes for Chronic Obstructive Pulmonary Disease Patients: A Medical Consortium-Based Management.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Strategies involving multidimensional approaches for the treatment of COPD are needed. This study aimed to evaluate the efficiency of medical consortium-based management for COPD. Patients were grouped in accordance with whether the hospitals they went to were under the medical consortium. We enrolled 141 COPD patients in the management group and 147 COPD patients in the control group. There was no predetermined sex and disease severity inclusion or exclusion criteria. Patients in the control group were managed by standard care, while patients in the management group were managed with intensive medical intervention jointly by specialists in the hospital and general practitioners and healthcare workers in community health centers. There was no difference in the basal demographics between the two groups. The basal condition of the management group was worse than that of the control group, demonstrated by a higher CAT score and a lower pulmonary function index. Half-year intensive intervention decreased CAT score from 17.28 to 15.62 and the Barthel ADL index from 73 to 60 in the management group, which was associated with better pulmonary rehabilitation, pursed-lip breathing, oxygen usage, and medicine regularity. The benefits became more obvious after one-year intensive intervention in the management group. There was a difference in mMRC grades and smoking cessation between the two groups. This study shows that a one-year intensive intervention improves the patients' health status and pulmonary function, suggesting that our medical consortium-based management is effective in the treatment of COPD.