Alzheimer's disease (AD) is the major form of dementia in the elderly and is closely related to the toxic effects of microglia sustained activation. In AD, sustained microglial activation triggers impaired synaptic pruning, neuroinflammation, neurotoxicity, and cognitive deficits. Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with regulating microglia function. Here, we use RNA sequencing to identify a deubiquitinase YOD1 as a regulator of microglial function and AD pathology. Further study showed that YOD1 knockout significantly improved the migration, phagocytosis, and inflammatory response of microglia, thereby improving the cognitive impairment of AD model mice. Through LC-MS/MS analysis combined with Co-IP, we found that Myosin heavy chain 9 (MYH9), a key regulator maintaining microglia homeostasis, is an interacting protein of YOD1. Mechanistically, YOD1 binds to MYH9 and maintains its stability by removing the K48 ubiquitin chain from MYH9, thereby mediating the microglia polarization signaling pathway to mediate microglia homeostasis. Taken together, our study reveals a specific role of microglial YOD1 in mediating microglia homeostasis and AD pathology, which provides a potential strategy for targeting microglia to treat AD.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Poly(ADP-ribosyl)ation (PARylation) is a specific form of post-translational modification (PTM) predominantly triggered by the activation of poly-ADP-ribose polymerase 1 (PARP1). However, the role and mechanism of PARylation in the advancement of acute kidney injury (AKI) remain undetermined. Here, we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI, consistent with renal biopsy findings in patients with AKI. This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4 (H3K4me3). Furthermore, a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models. Mechanistically, liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1 (RACK1), thereby facilitating its subsequent phosphorylation. Moreover, the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α (HIF-1α) degradation, thereby exacerbating kidney injury. Additionally, we identified a PARP1 proteolysis-targeting chimera (PROTAC), A19, as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34, a previously identified PARP1 inhibitor. Collectively, both genetic and drug-based inhibition of PARylation mitigated kidney injury, indicating that the PARylated RACK1/HIF-1α axis could be a promising therapeutic target for AKI treatment.

BACKGROUND: The contraction behaviors of cardiomyocytes (CMs), especially contraction synchrony, are crucial factors reflecting their maturity and response to drugs. A wider field of view helps to observe more pronounced synchrony differences, but the accompanied greater computational load, requiring more computing power or longer computational time. METHODS: We proposed a method that directly correlates variations in optical field brightness with cardiac tissue contraction status (CVB method), based on principles from physics and photometry, for rapid video analysis in wide field of view to obtain contraction parameters, such as period and contraction propagation direction and speed. RESULTS: Through video analysis of human induced pluripotent stem cell (hiPSC)-derived CMs labeled with green fluorescent protein (GFP) cultured on aligned and random nanofiber scaffolds, the CVB method was demonstrated to obtain contraction parameters and quantify the direction and speed of contraction within regions of interest (ROIs) in wide field of view. The CVB method required less computation time compared to one of the contour tracking methods, the LucasKanade (LK) optical flow method, and provided better stability and accuracy in the results. CONCLUSION This method has a smaller computational load, is less affected by motion blur and out-of-focus conditions, and provides a potential tool for accurate and rapid analysis of cardiac tissue contraction synchrony in wide field of view without the need for more powerful hardware.

BACKGROUND: The contraction behaviors of cardiomyocytes (CMs), especially contraction synchrony, are crucial factors reflecting their maturity and response to drugs. A wider field of view helps to observe more pronounced synchrony differences, but the accompanied greater computational load, requiring more computing power or longer computational time. METHODS: We proposed a method that directly correlates variations in optical field brightness with cardiac tissue contraction status (CVB method), based on principles from physics and photometry, for rapid video analysis in wide field of view to obtain contraction parameters, such as period and contraction propagation direction and speed. RESULTS: Through video analysis of human induced pluripotent stem cell (hiPSC)-derived CMs labeled with green fluorescent protein (GFP) cultured on aligned and random nanofiber scaffolds, the CVB method was demonstrated to obtain contraction parameters and quantify the direction and speed of contraction within regions of interest (ROIs) in wide field of view. The CVB method required less computation time compared to one of the contour tracking methods, the LucasKanade (LK) optical flow method, and provided better stability and accuracy in the results. CONCLUSION This method has a smaller computational load, is less affected by motion blur and out-of-focus conditions, and provides a potential tool for accurate and rapid analysis of cardiac tissue contraction synchrony in wide field of view without the need for more powerful hardware.

BACKGROUND: The contraction behaviors of cardiomyocytes (CMs), especially contraction synchrony, are crucial factors reflecting their maturity and response to drugs. A wider field of view helps to observe more pronounced synchrony differences, but the accompanied greater computational load, requiring more computing power or longer computational time. METHODS: We proposed a method that directly correlates variations in optical field brightness with cardiac tissue contraction status (CVB method), based on principles from physics and photometry, for rapid video analysis in wide field of view to obtain contraction parameters, such as period and contraction propagation direction and speed. RESULTS: Through video analysis of human induced pluripotent stem cell (hiPSC)-derived CMs labeled with green fluorescent protein (GFP) cultured on aligned and random nanofiber scaffolds, the CVB method was demonstrated to obtain contraction parameters and quantify the direction and speed of contraction within regions of interest (ROIs) in wide field of view. The CVB method required less computation time compared to one of the contour tracking methods, the LucasKanade (LK) optical flow method, and provided better stability and accuracy in the results. CONCLUSION This method has a smaller computational load, is less affected by motion blur and out-of-focus conditions, and provides a potential tool for accurate and rapid analysis of cardiac tissue contraction synchrony in wide field of view without the need for more powerful hardware.

With the increasing aging of the population in China,the problem of cognitive decline with age is becoming more prominent,and how to move forward to maintain and improve cognitive function in older adults has become an important research topic.Active participation in social activities has a protective effect on cognitive function in older adults.This paper summarizes the concepts of social activities,relationships with cognitive function,and strategies for promoting interventions.The corresponding nursing inspirations were proposed,aiming to provide new perspectives for improving cognitive function in older adults.

Objective:To investigate the mechanism by which histone deacetylase 6 (HDAC6) exerts immune protective effects in Chlamydia trachomatis respiratory tract infection. Methods:Wild-type (WT) C57BL/6 mice and HDAC6 gene knockout (HDAC6 -/-) mice were used to establish mouse models of Chlamydia muridarum ( Cm) respiratory infection by nasal inhalation of Cm. qPCR and Western blot were used to detect the relative expression of HDAC6 in lung tissues of WT mice after Cm infection. Intracellular factor staining was used to detect the percentages and absolute numbers of CD4 + T cell subsets (Th1, Th17 and Th2 cells)in mouse lung tissues after infection. The levels of IL-4 in spleen cell culture supernatants were measured by ELISA. One-way or two-way analysis of variance (ANOVA) was used for statistical analysis. Results:Cm respiratory tract infection significantly promoted the expression of HDAC6 at both mRNA and protein levels in lung tissues of WT mice ( P<0.001). HDAC6 -/- mice lost more weight than WT mice and took longer to recover to the normal level. Chlamydia load ( P<0.001 and P<0.05) and pathological damage ( P<0.05 and P<0.000 1) in lung tissues were more serious in HDAC6 -/- mice than in WT mice at 7 and 14 d after infection. Neither the percentage nor the absolute number of Th1 (CD4 + IFN-γ + T) and Th17 (CD4 + IL-17 + T) cells showed significant differences between WT and HDAC6 -/- mice, while the percentage and absolute number of Th2 (CD4 + IL-4 + T) cells increased in HDAC6 -/- mice ( P<0.05 and P<0.01). Moreover, in HDAC6 -/- mice, the expression of IL-4 mRNA increased ( P<0.000 1) and the level of IL-4 in the splenic cell culture supernatants increased ( P<0.01). Conclusions:HDAC6 plays an immune protective role in Cm infection. It can reduce the susceptibility of host to Cm respiratory tract infection and alleviates the pathological damage in lung tissues by inhibiting the immune response of Th2 cells.

Objective:To digitally measure the three-dimensional (3D) size of primary tooth crowns and the dimensions of the dental arch in children with individual normal primary dentition, preliminarily obtaining baseline data on the 3D size of primary tooth crowns as well as the length and width of the dental arch, and their influence factors. This study aims to provide a data foundation for the design of reference models for primary dentition.Methods:From May to June 2021, 122 caries-free children aged 3.5-4.5 years with individual normal occlusion were selected from five kindergartens in Haidian District, Beijing. Impressions were taken and plaster models were cast. After preliminary screening, 67 eligible models were scanned to obtain digital dental models. Digital measurement software was used for landmark-based measurements. Parameters included 3D crown dimensions (mesiodistal diameter, buccolingual diameter, and occlusogingival height), dental arch dimensions (length and width at specific regions), and occlusal measurements (overjet and overbite at the primary central incisors, and Bolton index for anterior and full dentition). Gender differences in crown dimensions and bilateral symmetry of homologous teeth, as well as the correlations between arch dimensions and gender, height, weight, and body mass index (BMI) were analyzed.Results:The homonymous teeth of 67 children exhibited strong bilateral symmetry in all 3D dimensions ( P>0.05). Gender differences were observed in the buccolingual dimension for all deciduous molars except for the right mandibular first deciduous molar ( P<0.05). For the occlusogingival dimension, gender differences were found in the right maxillary first and second deciduous molars, left maxillary first deciduous molar, and left mandibular first and second deciduous molars ( P<0.05). For the mesiodistal dimension, only the left mandibular second deciduous molar and right mandibular deciduous canine showed gender differences ( P<0.05). All significant differences above indicated larger dimensions in boys compared to girls. In both maxillary and mandibular arches, the lengths and widths at various locations were significantly larger in boys than in girls ( P<0.05). Univariate correlation analysis revealed that body weight was positively correlated with the width of the terminal plane in both the maxilla and mandible and the total length of the mandibular dental arch, while BMI was positively correlated with the width of the maxillary terminal plane and the widths at all measured sites in the mandible ( P<0.05). Multiple regression analysis demonstrated that, after controlling for relevant variables, BMI was a significant positive predictor for the lengths and widths at various sites of the dental arch ( P<0.05), and height was a positive predictor for dental arch length ( P<0.05), as well as body weight was a positive predictor for the width in the molar region ( P<0.05). Overjet at the primary central incisors was 2.28 (1.57, 2.66) mm, and overbite was 1.13 (0.75, 1.92) mm. The anterior Bolton index was 0.79±0.03, and the overall Bolton index was 0.94±0.03. Conclusions:Primary tooth crowns of individual normal occlusion children demonstrate strong bilateral symmetry in homologous teeth. Most primary molars exhibit gender differences in buccolingual and occlusogingival dimensions, with larger values in boys. Arch dimensions (length and width) are consistently larger in boys.

Objective:To analyze the baseline characteristics and prognostic factors of Pneumocystis carinii pneumonia (PCP) in patients with liver diseases (LD), and to develop the nomogram prognosis model. Methods:The patients with liver diseases complicated with PCP (LD-PCP) who admitted to Beijing Youan Hospital, Capital Medical University from January 1st, 2021 to October 31st, 2024 were enrolled in this study. This study was a retrospective case-control study. Data were collected, including baseline characteristics at admission and clinical outcomes. Multivariate logistic regression analysis was employed to identify the independent risk factors of poor prognosis in LD-PCP patients. Subsequently, a nomogram was developed to construct the prognostic model. The performance of this model was evaluated using the receiver operater characteristic (ROC) curve and calibration curve.Results:A total of 61 patients with LD-PCP were enrolled, including 21 in the death group and 40 in the survival group. Multivariate logistic regression analysis revealed that co-infection with Aspergillus and elevated lactate dehydrogenase (LDH) levels were independent risk factors for mortality in patients with LD-PCP (odds ratio ( OR)=12.802, 95% confidence interval ( CI) 1.334 to 122.845, P=0.027; OR=1.009, 95% CI 1.002 to 1.016, P=0.014). The predictive value of prognostic model based on the nomogram was better evidenced by the ROC curve, which yielded an area under the curve (AUC) of 0.835 (95% CI 0.725 to 0.944), with the sensitivity of 71.4% and the specificity of 87.5%. The predictive accuracy of the model was further validated by the calibration curve, and the Brier value was 0.151, the model fitting line had a high degree of agreement with the standard reference line ( P=0.953). Conclusions:Co-infection with Aspergillus and LDH levels are independent risk factors for the poor prognosis of patients with LD-PCP. The prognosis model based on the nomogram has better predictive value and clinical practicality, which could identify high-risk patients in the early stage, and provide theoretical guidance on the patient management.