Dynamics, association, and temporal sequence of cognitive function and frailty: a longitudinal study among Chinese community-dwelling older adults.

BACKGROUND: Little is known about the association of longitudinal dynamics between cognitive function and frailty in Chinese older adults. The temporal sequences between cognitive function and frailty remains unclear. Our study investigates this directionality association using longitudinal data. METHODS: Latent growth and multivariate latent growth models were employed to examine dynamics of cognition and frailty and their association among 2824 older adults in China. Cross-lagged panel analyses were used to assess the temporal sequences between frailty and cognition. The relation between cognitive domains and frailty was also examined using aforementioned methods. RESULTS: Cognitive function was negatively associated with frailty status. Higher initial level of cognition indicated lower baseline level (ß=-0.175, P < 0.001) and change rate (ß=-0.041, P = 0.002) of frailty. We observed a reciprocal association between frailty and cognitive function rather than a unidirectional causal relationship. The initial cognitive performance for all components were negatively associated with baseline (ß ranged between - 0.098 to -0.023) and change rate (ß ranged between - 0.007 to -0.024) of frail status. No consistent associations between change rate of cognitive components and either initial level or change rate of frailty were detected. CONCLUSIONS: Our study detected a reciprocal association between cognition and frailty rather than a unidirectional causal relationship. Our results also revealed different connections between cognitive performance and frailty across diverse cognitive domains.

Integrated metabolic and transcriptomic profiles reveal the germination-associated dynamic changes for the seeds of Cassia obtusifolia L.

INTRODUCTION: The seeds of Cassia obtusifolia L. (Cassiae [C.] semen) have been widely used as both food and traditional Chinese medicine in China. OBJECTIVES: We aimed to analyze the metabolic mechanisms underlying C. semen germination. MATERIALS AND METHODS: Different samples of C. semen at various germination stages were collected. These samples were subjected to 1 H-NMR and UHPLC/Q-Orbitrap-MS-based untargeted metabolomics analysis together with transcriptomics analysis. RESULTS: A total of 50 differential metabolites (mainly amino acids and sugars) and 20 key genes involved in multiple pathways were identified in two comparisons of different groups (36 h vs 12 h and 84 h vs 36 h). The metabolite-gene network for seed germination was depicted. In the germination of C. semen, fructose and mannose metabolism was activated in the testa rupture period, indicating more energy was needed (36 h). In the embryonic axis elongation period (84 h), the pentose and glucuronate interconversions pathway and the phenylpropanoid biosynthesis pathway were activated, which suggested some nutrient sources (nitrogen and sugar) were in demand. Furthermore, oxygen, energy, and nutrition should be supplied throughout the whole germination process. These global views open up an integrated perspective for understanding the complex biological regulatory mechanisms during the germination process of C. semen.

LSTMAtU-Net: A Precipitation Nowcasting Model Based on ECSA Module.

Precipitation nowcasting refers to the use of specific meteorological elements to predict precipitation in the next 0-2 h. Existing methods use radar echo maps and the Z-R relationship to directly predict future rainfall rates through deep learning methods, which are not physically constrained, but suffer from severe loss of predicted image details. This paper proposes a new model framework to effectively solve this problem, namely LSTMAtU-Net. It is based on the U-Net architecture, equipped with a Convolutional LSTM (ConvLSTM) unit with the vertical flow direction and depthwise-separable convolution, and we propose a new component, the Efficient Channel and Space Attention (ECSA) module. The ConvLSTM unit with the vertical flow direction memorizes temporal changes by extracting features from different levels of the convolutional layers, while the ECSA module innovatively integrates different structural information of each layer of U-Net into the channelwise attention mechanism to learn channel and spatial information, thereby enhancing attention to the details of precipitation images. The experimental results showed that the performance of the model on the test dataset was better than other examined models and improved the accuracy of medium- and high-intensity precipitation nowcasting.

Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging.

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

Metabolomic Study on Iohexol-Induced Nephrotoxicity in Rats Based on NMR and LC-MS Analyses.

Iohexol, the raw material of nonionic X-ray computed tomography (X-CT) contrast medium, is usually injected into the vein before CT angiography diagnosis. It is used for angiography, urography, and lymphography. With the advantages of low contrast density and good tolerance, it is currently one of the most popular contrast media. However, the renal toxicity of iohexol seriously affects its safety use. Therefore, it is of great importance to identify new potential diagnostic biomarkers and therapeutic targets in the process of contrast medium-induced acute kidney injury (CI-AKI) in order to safely use iohexol in clinical practice. In this study, in order to understand the metabolic mechanism of CI-AKI, ultra-high-performance liquid chromatography/quadrupole-Orbitrap-mass spectrometry and 1H NMR-based metabolomic techniques were utilized to study the metabolic spectra of kidney, plasma, and urine from CI-AKI rats, and a total of 30 metabolites that were closely related to kidney injury were screened out, which were mainly related to 9 metabolic pathways. The results further indicated that iohexol might intensify kidney dysfunction in vivo by disrupting the metabolic pathways in the body, especially through blocking energy metabolism, amino acid metabolism, and promoting inflammatory reactions.

Iron chelation of hetrombopag in aplastic anemia: a post hoc analysis of a phase II study.

Hetrombopag is the only CFDA-approved thrombopoietin (TPO) receptor agonist for severe aplastic anemia (SAA) in China. Its chemical structure has an iron chelation domain. To explore the iron chelation effect of hetrombopag, we performed a post hoc analysis of the phase II clinical trial (NCT03557099). Thirty-five immunosuppressive therapy (IST)-refractory SAA patients were enrolled in the study, and the longitudinal changes of serum ferritin (SF) were assessed. At 18 weeks post-hetrombopag initiation, 51.4% of patients showed decreased SF levels by a median of 49.0 (18.1-95.5) % from baseline (median ΔSF decrease value, 917.2 ng/ml, range from 104.0 to 7030.0 ng/ml). A decrease in SF was found in 75.0% of hematologic responders and 31.6% of non-responders. Among the 24 patients with iron overload, 12 had decreased SF levels by up to 51% of the baseline. Patients with normal SF levels also showed decreased SF levels, and iron deficiency occurred in two patients. In conclusion, hetrombopag showed a powerful and rapid iron chelation effect.

Sequential acid/reduction response of triblock copolymeric nanomicelles to release camptothecin and toll-like receptor 7/8 agonist for orchestrated chemoimmunotherapy.

BACKGROUND: Immunosuppressive tumor immune microenvironment (TIME) lowers immunotherapy effectiveness. Additionally, low penetration efficiency and unpredictable drug release in tumor areas restrict tumor therapy. METHODS: A triblock copolymeric micelle (NanoPCPT+PIMDQ) was developed to carry the chemotherapeutic drug camptothecin (CPT) and the TLR7/8 agonist 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c] quinoline-4-amine (IMDQ) to achieve deep tumor penetration and on-demand drug release by responding to acid and reduction stimuli sequentially. The synergistic antitumour efficacy of NanoPCPT+PIMDQ was assessed both in vitro and in vivo. RESULTS: NanoPCPT+PIMDQ is composed of a hydrophilic PEG(polyethylene glycol) outer layer, an acid-sensitive EPEMA middle layer, and a drug inner core. Upon intratumoral injection, (i) NanoPCPT+PIMDQ first responds to the acidic tumor microenvironment and disintegrates to PIMDQ and PCPT, penetrating deep regions of the tumor; (ii) tumor cells are killed by the released CPT; (iii) DCs are activated by PIMDQ to increase the infiltration of cytotoxic T lymphocyte (CTL); and (iv) both downregulated Foxp3+ Tregs by CPT and repolarized M2 macrophages by PIMDQ can relieve the TIME. CONCLUSION: This pH/GSH-responsive triblock polymer-drug conjugate reduces immunosuppression and enhances the infiltration of CTLs by codelivering CPT and IMDQ in a controllable manner, providing a promising platform for synergistic tumor chemoimmunotherapy.

The path linking excessive daytime sleepiness and activity of daily living in Parkinson's disease: the longitudinal mediation effect of autonomic dysfunction.

BACKGROUND: Excessive daytime sleepiness (EDS) and autonomic dysfunction have been verified to impair activity of daily living (ADL) in patients with Parkinson's disease (PD). Whether EDS can affect ADL in PD patients through autonomic dysfunction is still unclear. The purpose of this study is to explore the longitudinal mediation effect of autonomic dysfunction between EDS and ADL. METHODS: Data used in this study were from six-follow-up visits of 413 patients with newly diagnosed PD from the Parkinson's Progression Markers Initiative (PPMI). We used latent growth mediation modeling (LGMM) to explore whether the autonomic dysfunction is a longitudinal mediator between EDS and ADL. RESULTS: The results showed that as the disease progresses, EDS (P < 0.001) and autonomic dysfunction (P < 0.001) gradually worsened and ADL (P < 0.001) gradually decreased in PD patients. In addition, the more severe the patients' EDS symptom, the more worsened the symptoms of autonomic dysfunction, which result in a decrease in ADL. Both the intercept (95% CI: 0.142, 0.308) and the slope (95% CI: 0.083, 0.331) of autonomic dysfunction showed a partial mediating effect, and a longitudinal mediation effect was presented. CONCLUSION: Longitudinal changes in EDS affect the ADL of PD patients directly or indirectly by affecting the symptoms of autonomic dysfunction. Controlling the symptoms of autonomic dysfunction may improve the ADL of PD patients with EDS.

Cost-effectiveness of comprehensive preventive measures for coal workers' pneumoconiosis in China.

BACKGROUND: Coal workers' pneumoconiosis (CWP) remains one of the most severe occupational diseases in China. Despite the implementation of CWP comprehensive preventive measures, the unreasonable allocation of investment by coal enterprises limits the effect of preventing CWP, especially when the health resources are inadequate. This study aims to evaluate the cost-effectiveness of comprehensive measures for CWP from the perspective of coal enterprises. METHODS: Comprehensive measures and two primary interventions (engineering controls and individual protective equipment) were selected. A time-dependent Markov model was developed to evaluate cost and quality-adjusted life-years (QALYs). The input data were collected from the survey and literature. A hypothetical null situation, in which the currently implemented interventions were eliminated, was used as a comparator based on the generalised cost-effectiveness analysis (GCEA) recommended by the World Health Organization (WHO). The primary outcomes of the model were reported in terms of incremental cost-effectiveness ratios (ICERs). Uncertainty was verified using one-way and probabilistic sensitivity analyses. RESULTS: The QALYs of the comprehensive measures, engineering controls, and individual protective equipment were 17.60, 17.50, and 16.85 years, respectively. Compared with null, the ICERs of the interventions were 65,044.73, 30,865.15, and 86,952.41 RMB/QALY, respectively. Individual protective equipment was dominated by an ICER of -11,416.02 RMB/QALY compared to engineering controls. Sensitivity analysis suggested the robustness of the results. CONCLUSIONS: The comprehensive preventive measures for CWP that are currently implemented in Chinese state-owned mines are cost-effective. In comprehensive measures, engineering controls are more cost-effective than individual protective equipment. Investment in engineering controls should be increased to improve the cost-effectiveness of preventing CWP.

Metrological properties of neuropsychological tests for measuring cognitive change in individuals with prodromal Alzheimer's disease.

OBJECTIVES: In Alzheimer's Disease (AD) research, choosing appropriate method for measuring change in cognitive function over time can be challenging. The aim for this study was to examine the sensitivity of four neuropsychological tests used to measure cognition during the transition from mild cognitive impairment (MCI) to AD, and the impacts of associated covariates. METHODS: We enrolled 223 patients with MCI who progressed to AD and had completed multiple follow-up assessments in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We constructed nonlinear mixed model for multivariate longitudinal data assuming that multiple neuropsychological tests would exhibit nonlinear transformation of a common factor in the latent cognitive process underlying the progression from MCI to AD. RESULTS: The Clinical Dementia Rating-Sum of the Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale (11 items; ADAS-11) were more sensitive to cognitive changes in individuals with higher cognitive function, the Functional Activities Questionnaire (FAQ) was more sensitive to cognitive changes in individuals with middle cognitive function, and the Mini-Mental State Examination (MMSE) was more sensitive to cognitive changes in individuals with lower cognitive function. Gender (p = 0.0139) and educational level (p = 0.0094) had varying effects on different tests, such that men performed better on the FAQ and CDR-SB, and individuals with higher educational level tended to perform better on the FAQ and MMSE. CONCLUSIONS: When choosing appropriate neuropsychological tests in cognitive measurements, the cognitive functional level of the patient as well as the impacts of covariates should be considered.