Staged suppression of microglial autophagy facilitates regeneration in CNS demyelination by enhancing the production of linoleic acid.

Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic-lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic-lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic-lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.

Soluble TREM2 triggers microglial dysfunction in neuromyelitis optica spectrum disorders.

Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.

Bruton's tyrosine kinase inhibition ameliorated neuroinflammation during chronic white matter ischemia.

Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.

Biomimetic Dual-Network Collagen Fibers with Porous and Mechanical Cues Reconstruct Neural Stem Cell Niche via AKT/YAP Mechanotransduction after Spinal Cord Injury.

Tissue engineering scaffolds can mediate the maneuverability of neural stem cell (NSC) niche to influence NSC behavior, such as cell self-renewal, proliferation, and differentiation direction, showing the promising application in spinal cord injury (SCI) repair. Here, dual-network porous collagen fibers (PCFS) are developed as neurogenesis scaffolds by employing biomimetic plasma ammonia oxidase catalysis and conventional amidation cross-linking. Following optimizing the mechanical parameters of PCFS, the well-matched Young's modulus and physiological dynamic adaptability of PCFS (4.0 wt%) have been identified as a neurogenetic exciter after SCI. Remarkably, porous topographies and curving wall-like protrusions are generated on the surface of PCFS by simple and non-toxic CO2 bubble-water replacement. As expected, PCFS with porous and matched mechanical properties can considerably activate the cadherin receptor of NSCs and induce a series of serine-threonine kinase/yes-associated protein mechanotransduction signal pathways, encouraging cellular orientation, neuron differentiation, and adhesion. In SCI rats, implanted PCFS with matched mechanical properties further integrated into the injured spinal cords, inhibited the inflammatory progression and decreased glial and fibrous scar formation. Wall-like protrusions of PCFS drive multiple neuron subtypes formation and even functional neural circuits, suggesting a viable therapeutic strategy for nerve regeneration and functional recovery after SCI.

Phylogenomics and divergence pattern of Polygonatum (Asparagaceae: Polygonateae) in the north temperate region.

Polygonatum is the largest genus of tribe Polygonateae (Asparagaceae) and is widely distributed in the temperate Northern Hemisphere, especially well diversified in southwestern China to northeastern Asia. Phylogenetic relationships of many species are still controversial. Hence it is necessary to clarify their phylogenetic relationships and infer possible reticulate relationships for the genus. In this study, genome-wide data of 43 species from Polygonatum and its closely related taxa were obtained by Hyb-Seq sequencing. The phylogenetic trees constructed from genome-wide nuclear and chloroplast sequences strongly supported the monophyly of Polygonatum with division into three major clades. A high level of incongruence was detected between nuclear and chloroplast trees as well as among gene trees within the genus, but all occurred within each major clade. However, introgression tests and reticulate evolution analyses revealed low level of gene flow and weak introgression events in the genus, suggesting hybridization and introgression were not dominant during the evolutionary diversification of Polygonatum in the Northern Hemisphere. This study provides important insights into reconstructing evolutionary relationships and speciation pattern of taxa from the north temperate flora.

Ldl-stimulated microglial activation exacerbates ischemic white matter damage.

The role of microglia in triggering the blood-brain barrier (BBB) impairment and white matter damage after chronic cerebral hypoperfusion is unclear. Here we demonstrated that the vessel-adjacent microglia were specifically activated by the leakage of plasma low-density lipoprotein (LDL), which led to BBB breakdown and ischemic demyelination. Interestingly, we found that LDL stimulation enhanced microglial phagocytosis, causing excessive engulfment of myelin debris and resulting in an overwhelming lipid burden in microglia. Surprisingly, these lipid-laden microglia exhibited a suppressed profile of inflammatory response and compromised pro-regenerative properties. Microglia-specific knockdown of LDLR or systematic medication lowering circulating LDL-C showed protective effects against ischemic demyelination. Overall, our findings demonstrated that LDL-stimulated vessel-adjacent microglia possess a disease-specific molecular signature, characterized by suppressed regenerative properties, which is associated with the propagation of demyelination during ischemic white matter damage.

A nature-inspired multifunctional adhesive for cartilage tissue-biomaterial integration.

Surgical adhesives play a crucial role in tissue integration and repair, yet their application in wet conditions has been severely limited by inadequate adhesive strength and subpar biocompatibility. Furthermore, tissue adhesives have rarely been reported in cartilage tissue repair. In this study, a three-armed dopamine-modified hyaluronic acid derivative adhesive was prepared to function as a bio-inspired adhesive in moist environments. To meet the clinical requirements for cartilage tissue adhesion, we studied its chemical structure, including microscopic morphology, adhesion properties with materials and tissues, in vivo degradation rules, and biological evaluation. The OGMHA8-DOPA adhesive with the optimal aldehyde substitution degree and dopamine-grafting rate was determined by analyzing the experimental conditions. SEM results revealed that the cartilage tissue adhered to a porous interconnected structure. The excellent biocompatibility of the material not only facilitated chondrocyte adhesion but also supported their proliferation on its surface. Animal experiments have demonstrated that this material has no observable inflammatory response or incidence of fibrous capsule formation. The degradation timeline of the material extends beyond the duration of two weeks. The dopamine-modified adhesive exhibited a tight interfacial binding force between the biomaterial and cartilage tissue and excellent biocompatibility in watery tissue, revealing its potential for application in cartilage tissue repair and minimally invasive surgery.

Glutathione S-Transferase α4 Alleviates Hyperlipidemia-Induced Vascular Neointimal Hyperplasia in Arteriovenous Grafts via Inhibiting Endoplasmic Reticulum Stress.

ABSTRACT: Neointimal hyperplasia causes the failure of coronary artery bypass grafting. Our previous studies have found that endothelial dysfunction is 1 candidate for triggering neointimal hyperplasia, but which factors are involved in this process is unclear. Glutathione S-transferase α4 (GSTA4) plays an important role in metabolizing 4-hydroxynonenal (4-HNE), a highly reactive lipid peroxidation product, which causes endothelial dysfunction or death. Here, we investigated the role of GSTA4 in neointima formation after arteriovenous grafts (AVGs) with or without high-fat diet (HFD). Compared with normal diet, HFD caused endothelial dysfunction and increased neointima formation, concomitantly accompanied by downregulated expression of GSTA4 at the mRNA and protein levels. In vitro, overexpression of GSTA4 attenuated 4-HNE-induced endothelial dysfunction and knockdown of GSTA4 aggravated endothelial dysfunction. Furthermore, silencing GSTA4 expression facilitated the activation of 4-HNE-induced endoplasmic reticulum stress and inhibition of endoplasmic reticulum stress pathway alleviated 4-HNE-induced endothelial dysfunction. In addition, compared with wild-type mice, mice with knockout of endothelial-specific GSTA4 (GSTA4 endothelial cell KO) exhibited exacerbated vascular endothelial dysfunction and increased neointima formation caused by HFD. Together, these results demonstrate the critical role of GSTA4 in protecting the function of endothelial cells and in alleviating hyperlipidemia-induced vascular neointimal hyperplasia in arteriovenous grafts.

Trem2 deficiency attenuates microglial phagocytosis and autophagic-lysosomal activation in white matter hypoperfusion.

Chronic cerebral hypoperfusion leads to sustained demyelination and a unique response of microglia. Triggering receptor expressed on myeloid cells 2 (Trem2), which is expressed exclusively on microglia in the central nervous system (CNS), plays an essential role in microglial response in various CNS disorders. However, the specific role of Trem2 in chronic cerebral hypoperfusion has not been elucidated. In this study, we investigated the specific role of Trem2 in a mouse model of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis (BCAS). Our results showed that chronic hypoperfusion induced white matter demyelination, microglial phagocytosis, and activation of the microglial autophagic-lysosomal pathway, accompanied by an increase in Trem2 expression. After Trem2 knockout, we observed attenuation of white matter lesions and microglial response. Trem2 deficiency also suppressed microglial phagocytosis and relieved activation of the autophagic-lysosomal pathway, leading to microglial polarization towards anti-inflammatory and homeostatic phenotypes. Furthermore, Trem2 knockout inhibited lipid droplet accumulation in microglia in vitro. Collectively, these findings suggest that Trem2 deficiency ameliorated microglial phagocytosis and autophagic-lysosomal activation in hypoperfusion-induced white matter injury, and could be a promising target for the treatment of chronic cerebral hypoperfusion.

TREM2 deficiency inhibits microglial activation and aggravates demyelinating injury in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disorder of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are activated and play a pivotal role in response to tissue injury. Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by microglia and promotes microglial activation, survival and phagocytosis. Here, we identify a critical role for TREM2 in microglial activation and function during AQP4-IgG and complement-induced demyelination. TREM2-deficient mice had more severe tissue damage and neurological impairment, as well as fewer oligodendrocytes with suppressed proliferation and maturation. The number of microglia clustering in NMOSD lesions and their proliferation were reduced in TREM2-deficient mice. Moreover, morphology analysis and expression of classic markers showed compromised activation of microglia in TREM2-deficient mice, which was accompanied by suppressed phagocytosis and degradation of myelin debris by microglia. These results overall indicate that TREM2 is a key regulator of microglial activation and exert neuroprotective effects in NMOSD demyelination.

Association between Kidney Function and the Burden of Cerebral Small Vessel Disease: An Updated Meta-Analysis and Systematic Review.

INTRODUCTION: Due to anatomical and functional similarities in microvascular beds, the brain and kidney share distinctive susceptibilities to vascular injury and common risk factors of small vessel disease. The aim of this updated meta-analysis is to explore the association between kidney function and the burden of cerebral small vessel disease (CSVD). METHODS: PubMed, EMBASE, and Cochrane Library were systematically searched for observational studies that explored the association between the indicators of kidney function and CSVD neuroimaging markers. The highest-adjusted risk estimates and their 95% confidence intervals (CIs) were aggregated using random-effect models. RESULTS: Twelve longitudinal studies and 51 cross-sectional studies with 57,030 subjects met the inclusion criteria of systematic review, of which 52 were included in quantitative synthesis. According to the pooled results, we found that low estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2) was associated with cerebral microbleeds (odds ratio (OR) = 1.55, 95% CI = 1.26-1.90), white matter hyperintensities (OR = 1.40, 95% CI = 1.05-1.86), and lacunar infarctions (OR = 1.50, 95% CI = 1.18-1.92), but not with severe perivascular spaces (OR = 1.20, 95% CI = 0.77-1.88). Likewise, patients with proteinuria (OR = 1.75, 95% CI = 1.47-2.09) or elevated serum cystatin C (OR = 1.51, 95% CI = 1.25-1.83) also had an increased risk of CSVD. CONCLUSION: The association between kidney function and CSVD has been comprehensively updated through this study, that kidney insufficiency manifested as low eGFR, proteinuria, and elevated serum cystatin C was independently associated with CSVD burden.

Photoinduced Decarbonylative Rearrangement of Diazabicyclo[2.2.2]Octenones: A Photochemical Approach of Diazabicyclo[4.1.0]heptene Skeleton from Masked o-Benzoquinone.

We report a photoinduced decarbonylative rearrangement of diazabicyclo[2.2.2]octenone in the facile synthesis of a functionalized diazabicyclo[4.1.0]heptene skeleton, a unique derivative of the hydropyridazine type structure which could be found in a variety of biologically active natural products. The scope of functional group compatibility in the photoreaction was examined by taking advantage of the easy access of the heterobicyclo[2.2.2] structure from the Diels-Alder reaction of masked o-benzoquinones. 4-Phenyl-1,2,4-triazoline-3,5-dione served as the dienophile which provided the adjacent N-N unit in hexahydropyridazine-type products of subsequent photorearrangement.

Effects of xenon anesthesia on postoperative neurocognitive disorders: a systematic review and meta-analysis.

The latest clinical trials have reported conflicting outcomes regarding the effectiveness of xenon anesthesia in preventing postoperative neurocognitive dysfunction; thus, this study assessed the existing evidence. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases from inception to April 9, 2023, for randomized controlled trials of xenon anesthesia in postoperative patients. We included English-language randomized controlled studies of adult patients undergoing surgery with xenon anesthesia that compared its effects to those of other anesthetics. Duplicate studies, pediatric studies, and ongoing clinical trials were excluded. Nine studies with 754 participants were identified. A forest plot revealed that the incidence of postoperative neurocognitive dysfunction did not differ between the xenon anesthesia and control groups (P = 0.43). Additionally, xenon anesthesia significantly shortened the emergence time for time to opening eyes (P < 0.001), time to extubation (P < 0.001), time to react on demand (P = 0.01), and time to time and spatial orientation (P = 0.04). However, the Aldrete score significantly increased with xenon anesthesia (P = 0.005). Postoperative complications did not differ between the anesthesia groups. Egger's test for bias showed no small-study effect, and a trim-and-fill analysis showed no apparent publication bias. In conclusion, xenon anesthesia probably did not affect the occurrence of postoperative neurocognitive dysfunction. However, xenon anesthesia may effectively shorten the emergence time of certain parameters without adverse effects.

Sleep disturbances, glycaemic control, stress, and coping among diabetic patients: A structural equation modelling approach.

BACKGROUND: Sleep disturbances are more prevalent in diabetic patients than in the general population and may consequently be comorbid with hyperglycaemia. OBJECTIVE: The two study aims were to (1) verify the factors associated with sleep disturbances and glycaemic control and (2) further understand the mediation effects of coping and social support in the relationship among stress, sleep disturbances, and glycaemic control. METHODS: A cross-sectional study design was used. Data were collected at two metabolic clinics in southern Taiwan. The study recruited 210 patients with type II diabetes mellitus who were aged 20 years or above. Demographic information and data on stress, coping, social support, sleep disturbances, and glycaemic control were collected. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality, and PSQI scores >5 were considered to indicate sleep disturbances. Structural equation modelling (SEM) approaches were employed to analyse the path association for sleep disturbances in diabetic patients. RESULTS: The mean age of the 210 participants was 61.43 (standard deviation, SD 11.41) years old, and 71.9 % reported sleep disturbances. The final path model had acceptable model fit indices. Stress perception was divided into stress perceived positively and negatively. Stress perceived positively was associated with coping (ß = 0.46, p < .01) and social support (ß = 0.31, p < .01), whereas stress perceived negatively was significantly associated with sleep disturbances (ß = 0.40, p < .001). CONCLUSIONS: The study shows that sleep quality is essential to glycaemic control, and stress perceived negatively might play a critical role to sleep quality.

[Related factors of endogenous erythropoietin and its association with 10-year risks of cardiovascular disease in a community-based Chinese study].

OBJECTIVE: To investigate the associated factors of endogenous erythropoietin (EPO) and its association with 10-year risks of atherosclerotic cardiovascular disease in a Chinese community-based general population. METHODS: The participants of this study were from an atherosclerosis cohort survey which was established by the Department of Cardiology, Peking University First Hospital in 2011. The cohort survey was performed in the Gucheng and Pingguoyuan communities of Shijingshan district in Beijing, China. The inclusion criteria of this study were: (1) endogenous EPO was measured; (2) health questionnaire data and other clinical data were complete; (3) participatants who had cardiovascular or cerebrovascular diseases (defined as self-reported coronary heart disease, stroke or transient ischemic attack) or anemia or estimated glomerular filtration rate (eGFR) < 60 mL/(min·1.73 m2) at baseline were excluded. Multivariate linear regression model was used to examine the associated factors of endogenous EPO. The participants were grouped into low (< 5%), moderate (5%-10%) and high risk (≥10%) groups, based on predicted 10-year cardiovascular disease risk using the prediction for atherosclerotic cardiovascular disease risk in China (China-PAR) equations. RESULTS: A total of 4 013 participants were included. Mean age of them was (55.9±8.2) years, 62.2% (n=2 496) of them were female, and 46.3% (n=1 859), 70.9% (n=2 845), 21.9% (n=879) had hypertension, dyslipidemia and diabetes, individually. The average body mass index was (26.1±3.3) kg/m2. The median of EPO level was 12.8 (9.3-17.4) IU/L and 25.1% (n=998) were at high 10-years risk of cardiovascular disease. Hemoglobin (ß=-0.05, 95%CI: -0.07 to -0.04) and eGFR ≥90 mL/(min·1.73 m2) (ß=-0.05, 95%CI: -0.07 to -0.04) were associated with lower in transformed EPO levels while hypertension (ß=0.08, 95%CI: 0.05 to 0.12) and obesity (ß=0.14, 95%CI: 0.09 to 0.18) were associated with higher in transformed EPO levels in multivariate linear regression analyses. Ten-year cardiovascular disease risks were positively associated with in transformed EPO levels (ß=0.07, 95%CI: 0.05 to 0.09). The participants at moderate and high cardiovascular disease risks had significant higher EPO levels than the low risk group (all P < 0.05). CONCLUSION: In community-based Beijing populations, endogenous EPO was associated with hemoglobin, renal function, obesity and hypertension. Individuals at high 10-years cardiovascular disease risks have higher endogenous EPO levels. Endogenous EPO may be a potential risk marker of cardiovascular disease.

Chemoselective Quinoline and Isoquinoline Reduction by Energy Transfer Catalysis Enabled Hydrogen Atom Transfer.

(Hetero)arene reduction is one of the key avenues for synthesizing related cyclic alkenes and alkanes. While catalytic hydrogenation and Birch reduction are the two broadly utilized approaches for (hetero)arene reduction across academia and industry over the last century, both methods have encountered significant chemoselectivity challenges. We hereby introduce a highly chemoselective quinoline and isoquinoline reduction protocol operating through selective energy transfer (EnT) catalysis, which enables subsequent hydrogen atom transfer (HAT). The design of this protocol bypasses the conventional metric of reduction reaction, that is, the reductive potential, and instead relies on the triplet energies of the chemical moieties and the kinetic barriers of energy and hydrogen atom transfer events. Many reducing labile functional groups, which were incompatible with previous (hetero)arene reduction reactions, are retained in this reaction. We anticipate that this protocol will trigger the further advancement of chemoselective arene reduction and enable the current arene-rich drug space to escape from flatland.

[Efficacy and safety of rituximab in children and adolescents with mature B-cell non-Hodgkin's lymphoma: a Meta analysis]. / 利妥昔单抗治疗儿童及青少年成熟Bç»†èƒžéžéœå¥‡é‡‘æ·‹å·´ç˜¤ç–—æ•ˆåŠå®‰å ¨æ€§çš„Meta分析.

OBJECTIVES: To study the efficacy and safety of rituximab combined with chemotherapy in the treatment of children and adolescents with mature B-cell non-Hodgkin's lymphoma (B-NHL) through a Meta analysis. METHODS: The databases including PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, Web of Science, China National Knowledge Infrastructure, Wanfang Data, and Weipu were searched to obtain 10 articles on rituximab in the treatment of mature B-NHL in children and adolescents published up to June 2022, with 886 children in total. With 3-year event-free survival (EFS) rate, 3-year overall survival (OS) rate, complete remission rate, mortality rate, and incidence rate of adverse reactions as outcome measures, RevMan 5.4 software was used for Meta analysis, subgroup analysis, sensitivity analysis, and publication bias analysis. RESULTS: The rituximab+chemotherapy group showed significant increases in the 3-year EFS rate (HR=0.38, 95%CI: 0.25-0.59, P<0.001), 3-year OS rate (HR=0.29, 95%CI: 0.14-0.61, P=0.001), and complete remission rate (OR=3.72, 95%CI: 1.89-7.33, P<0.001) as well as a significant reduction in the mortality rate (OR=0.31, 95%CI: 0.17-0.57, P<0.001), as compared with the chemotherapy group without rituximab. There was no significant difference in the incidence rate of adverse reactions between the two groups (OR=1.28, 95%CI: 0.85-1.92, P=0.24). CONCLUSIONS: The addition of rituximab to the treatment regimen for children and adolescents with mature B-cell non-Hodgkin's lymphoma can bring significant survival benefits without increasing the incidence of adverse reactions.

Copper-Based Metal-Organic Framework with a Tetraphenylethylene-Tetrazole Linker for Visible-Light-Driven CO2 Photoconversion.

The design of efficient and inexpensive photocatalysts for CO2 photoreduction under visible light is of great significance for the sustainable development of the entire society. Herein, a copper-based metal-organic framework (MOF) (CUST-804) using a bulky tetraphenylethylene-tetrazole linker is synthesized and successfully used as a photocatalyst for CO2 reduction. The structural characterizations, as well as the photophysical properties, are investigated systematically. In the heterogeneous catalytic system, CUST-804 exhibits a robust CO production activity up to 2.71 mmol g-1 h-1 with excellent recyclability along with a selectivity of 82.8%, which is comparable with those of the reported copper-based MOF system. Theoretical calculations demonstrated that, among three kinds of coordinated model, only the 5-coordinated Cu site is active for CO2 reduction, in which the *COOH intermediate is stabilized and CO is readily desorbed. The results obtained herein can provide fresh insights into the realization of efficient copper-functionalized crystalline photocatalysts for CO2 reduction.

Effects of caregiver counselling on medication persistence and adherence in patients with dementia at a pharmacist-managed clinic: A pilot study.

WHAT IS KNOWN AND OBJECTIVE: Low treatment persistence and adherence in patients with dementia results in a rapid loss of disease control. This pilot study evaluated the impact of pharmacist-provided caregiver counselling on treatment persistence, adherence, quality of life (QoL) in patients with dementia, as well as caregiver's knowledge of dementia, and caregiver burden. METHODS: This prospective, randomized controlled study was performed at a hospital-based pharmacist-managed clinic from December 2017 to December 2019. Patients with mild-to-moderate Alzheimer's disease (AD), initiating cholinesterase inhibitors within 3 months, and coming with their caregivers were included and randomized 1:1 to intervention or control group. The intervention group received pharmacist counselling and education sheets about AD, whereas the control group only received standard of care. Patients' treatment persistence and adherence were assessed at months 3, 6, 9, and 12; QoL, and caregiver burden were assessed at baseline and month 12. Caregiver's knowledge of dementia was assessed at baseline and 2 weeks after counselling in the intervention group. Nonparametric statistics and generalized estimating equation models were used for statistical analysis. RESULTS AND DISCUSSION: A total of 40 patients and 40 caregivers were included, with 20 pairs for each group. One-year medication persistence (16/20 vs. 16/20) and adherence rates (87%-99%) were high in both groups without significant differences. Dementia knowledge scores improved significantly after counselling in the intervention group (77.5 vs. 95.8, p < 0.01). Although the change of caregiver burden was non-significant between groups, the score decreased in the intervention group (-0.89; p = 0.78) but increased in the control group (+6.01; p = 0.07). WHAT IS NEW AND CONCLUSION: In this pilot study, pharmacist's counselling for patients with dementia and their caregivers is feasible and can enhance caregiver knowledge of dementia. Further study with larger scale is needed to confirm the impact on these outcomes.

Analysis of time-series gene expression data to explore mechanisms of isoniazid-induced liver toxicity.

Isoniazid (INH) is a first-line anti-tuberculosis drug which can cause idiosyncratic liver injury, while the underlying mechanisms need to be further elucidated. In this study, we explored the time series gene expression profiling of a hepatocyte cell line under isoniazid treatment. Through cluster analysis and enrichment analysis of differentially expressed genes, we revealed a total of 6 gene clusters and a series of pathways related to hepatotoxicity, and 13 key candidate genes were identified according to the protein-protein interaction (PPI) network analysis and maSigPro analysis. These findings lay a foundation for understanding the mechanisms of isoniazid -induced liver toxicity and provide new target genes for the monitoring and treatment of INH-induced hepatotoxicity in the future.