Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer's disease.

Cognitive deterioration and memory decline associated with the progression of Alzheimer's disease (AD) primarily results from synaptic failure. However, current understanding of the upstream regulatory mechanisms controlling synaptic plasticity remains limited. Salt-inducible kinase 3 (SIK3) is central to the signal pathway and is involved in neuronal regulation of sleep duration in mice. We speculated that the SIK3 cascade signaling pathway might contribute to the pathogenesis of AD. Thus, the present study employed AD transgenic mouse models, Morris Water Maze, virus-mediated gene transfer, electrophysiology, co-immunoprecipitation, western blotting, quantitative polymerase chain reaction, immunofluorescence, ChIP-qPCR, Golgi-Cox staining and dendritic spine analysis to investigate this connection. Our results revealed that SIK3 mRNA/protein expression was significantly reduced in middle-aged AD transgenic mouse models and AD patients. Conditional deletion of SIK3 gene in dorsal hippocampal neurons of 5×FAD mice further accelerated cognitive deterioration and impaired synaptic plasticity. In hippocampal neuronal cultures, SIK3 formed a complex with HDAC4, directly phosphorylated HDAC4 and regulated its nuclear cytoplasmic shuttle. Overexpression of SIK3 could facilitate the expression of synaptic plasticity-related genes by directly repressing mef2c or involving the recruitment of histone deacetylase to promoter regions of target genes through regulation of p-HDAC4, and vice versa. Moreover, up-regulation of SLP-S, the truncated fragment of SIK3, in dorsal hippocampal neurons, restored the synaptic plasticity and alleviates the cognitive impairment in 5×FAD mice. Collectively, these findings revealed a novel and important role of SIK3-HDAC4 regulation of synaptic plasticity and propose a new target for therapeutic approaches of cognitive deficits associated with AD.

Interventions and management on multimorbidity: An overview of systematic reviews.

BACKGROUND: Multimorbidity poses an immense burden on the healthcare systems globally, whereas the management strategies and guidelines for multimorbidity are poorly established. We aim to synthesize current evidence on interventions and management of multimorbidity. METHODS: We searched four electronic databases (PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews). Systematic reviews (SRs) on interventions or management of multimorbidity were included and evaluated. The methodological quality of each SR was assessed by the AMSTAR-2 tool, and the quality of evidence on the effectiveness of interventions was assessed by the grading of recommendations assessment, development and evaluation (GRADE) system. RESULTS: A total of 30 SRs (464 unique underlying studies) were included, including 20 SRs of interventions and 10 SRs summarizing evidence on management of multimorbidity. Four categories of interventions were identified: patient-level interventions, provider-level interventions, organization-level interventions, and combined interventions (combining the aforementioned two or three- level components). The outcomes were categorized into six types: physical conditions/outcomes, mental conditions/outcomes, psychosocial outcomes/general health, healthcare utilization and costs, patients' behaviors, and care process outcomes. Combined interventions (with patient-level and provider-level components) were more effective in promoting physical conditions/outcomes, while patient-level interventions were more effective in promoting mental conditions/outcomes and psychosocial outcomes/general health. As for healthcare utilization and care process outcomes, organization-level and combined interventions (with organization-level components) were more effective. The challenges in the management of multimorbidity at the patient, provider and organizational levels were also summarized. CONCLUSION: Combined interventions for multimorbidity at different levels would be favored to promote different types of health outcomes. Challenges exist in the management at the patient, provider, and organization levels. Therefore, a holistic and integrated approach of patient-, provider- and organization- level interventions is required to address the challenges and optimize care of patients with multimorbidity.

[Studies on carcass and meat quality performance of crossbred pigs with graded proportions of Laiwu Black genes].

Sixty pigs, including pure Laiwu Black (LL), pure Large Yorkshire (YY), 1/2 Laiwu (Ymale x Lfemale), 3/4 Laiwu (Lmale x YLfemale) and 1/4 Laiwu (Ymale x YLfemale), were housed in groups with the same diet until 90 kg for slaughter. The objectives were to investigate the effects of graded proportions of Laiwu Black genes on carcass and meat quality performance. Results indicated that different consanguinity had significant effect on carcass weight, carcass length (CL), ham percentage (HP) and backfat thickness (BT) (P<0.05), and had highly significant effect on eye muscle area (EMA) and lean percentage (LP) (P<0.01). Furthermore, CL, HP, EMA and LP tended to increased gradually, but BT tended to decreased gradually as Laiwu Black genes decreased. For meat quality properties, different consanguinity had significant effect on meat color, marbling score, dry matter and crude protein content of muscles (P<0.05), and had highly significant effect on water loss, drip loss and intramuscular fat content of muscles (P<0.01). Compared with the muscle of Large Yorkshire, that of Laiwu Black and its crossbred pigs were bright red in meat color, high in water holding capacity and abundant in intramuscular fat. Results implied that to give attention to both quantity and quality, Laiwu Black surely has usable precious value in superior pig production. Commercial crossbred pigs should have about 1/4 of Laiwu Black genes.