Hepatitis B virus hijacks TSG101 to facilitate egress via multiple vesicle bodies.

Hepatitis B virus (HBV) chronically infects 296 million individuals and there is no cure. As an important step of viral life cycle, the mechanisms of HBV egress remain poorly elucidated. With proteomic approach to identify capsid protein (HBc) associated host factors and siRNA screen, we uncovered tumor susceptibility gene 101 (TSG101). Knockdown of TSG101 in HBV-producing cells, HBV-infected cells and HBV transgenic mice suppressed HBV release. Co-immunoprecipitation and site mutagenesis revealed that VFND motif in TSG101 and Lys-96 ubiquitination in HBc were essential for TSG101-HBc interaction. In vitro ubiquitination experiment demonstrated that UbcH6 and NEDD4 were potential E2 ubiquitin-conjugating enzyme and E3 ligase that catalyzed HBc ubiquitination, respectively. PPAY motif in HBc and Cys-867 in NEDD4 were required for HBc ubiquitination, TSG101-HBc interaction and HBV egress. Transmission electron microscopy confirmed that TSG101 or NEDD4 knockdown reduces HBV particles count in multivesicular bodies (MVBs). Our work indicates that TSG101 recognition for NEDD4 ubiquitylated HBc is critical for MVBs mediated HBV egress.

Orthostatic blood pressure changes do not influence cognitive outcomes following intensive blood pressure control.

BACKGROUND: Effects of intensive blood pressure (BP) control on cognitive outcomes in patients with excess orthostatic BP changes are unclear. We aimed to evaluate whether orthostatic BP changes modified the effects of BP intervention on cognitive impairment. METHODS: We analyzed 8547 participants from the Systolic Blood Pressure Intervention Trial Memory and cognition IN Decreased Hypertension. Associations between orthostatic BP changes and incident cognitive outcomes were evaluated by restricted cubic spline curves based on Cox models. The interactions between orthostatic BP changes and intensive BP intervention were assessed. RESULTS: The U-shaped associations were observed between baseline orthostatic systolic BP changes and cognitive outcomes. However, there were insignificant interactions between either change in orthostatic systolic BP (P for interaction = 0.81) or diastolic BP (P for interaction = 0.32) and intensive BP intervention for the composite outcome of probable dementia or mild cognitive impairment (MCI). The hazard ratio of intensive versus standard target for the composite cognitive outcome was 0.82 (95% CI 0.50-1.35) in those with an orthostatic systolic BP reduction of >20 mmHg and 0.41 (95% CI 0.21-0.80) in those with an orthostatic systolic BP increase of >20 mmHg. Results were similar for probable dementia and MCI. The annual changes in global cerebral blood flow (P for interaction = 0.86) consistently favored intensive BP treatment across orthostatic systolic BP changes. CONCLUSION: Intensive BP control did not have a deteriorating effect on cognitive outcomes among hypertensive patients experiencing significant postural BP changes.

Evaluation of an algorithm-guided photoplethysmography for atrial fibrillation burden using a smartwatch.

BACKGROUND: Wearable devices based on the PPG algorithm can detect atrial fibrillation (AF) effectively. However, further investigation of its application on long-term, continuous monitoring of AF burden is warranted. METHOD: The performance of a smartwatch with continuous photoplethysmography (PPG) and PPG-based algorithms for AF burden estimation was evaluated in a prospective study enrolling AF patients admitted to Beijing Anzhen Hospital for catheter ablation from September to November 2022. A continuous Electrocardiograph patch (ECG) was used as the reference device to validate algorithm performance for AF detection in 30-s intervals. RESULTS: A total of 578669 non-overlapping 30-s intervals for PPG and ECG each from 245 eligible patients were generated. An interval-level sensitivity of PPG was 96.3% (95% CI 96.2%-96.4%), and specificity was 99.5% (95% CI 99.5%-99.6%) for the estimation of AF burden. AF burden estimation by PPG was highly correlated with AF burden calculated by ECG via Pearson correlation coefficient (R2 = 0.996) with a mean difference of -0.59 (95% limits of agreement, -7.9% to 6.7%). The subgroup study showed the robust performance of the algorithm in different subgroups, including heart rate and different hours of the day. CONCLUSION: Our results showed the smartwatch with an algorithm-based PPG monitor has good accuracy and stability in continuously monitoring AF burden compared with ECG patch monitors, indicating its potential for diagnosing and managing AF.

Effects of intensive blood pressure control on cardiovascular and cognitive outcomes in patients with atrial fibrillation: insights from the SPRINT trial.

AIMS: Patients with atrial fibrillation (AF) have an increased risk of cardiovascular events and dementia, even if anticoagulated. Hypertension is highly prevalent in AF population; however, the optimal blood pressure (BP) target for AF patients remains unknown. METHODS AND RESULTS: We conducted subgroup analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) to examine whether AF modified the treatment effects of intensive BP control on cardiovascular and cognitive outcomes using Cox proportional hazards regression and likelihood ratio tests. Among 9361 randomized participants, 778 (8.3%) had baseline AF, and 695 (89.3%) completed at least one follow-up cognitive assessment. Intensive BP control reduced the similar relative risk of cardiovascular events irrespective of the presence of AF, with all interaction P-values > 0.05. Patients with AF experienced a greater absolute risk reduction in the composite primary cardiovascular outcome (12.3 vs. 5.6 events per 1000 person-years) with intensive treatment, compared with those without AF. However, intensive BP control increased the risk of probable dementia in patients with AF [hazard ratio (HR), 2.22; 95% confidence interval (CI), 1.03-4.80], while reducing the dementia risk in patients without AF (HR, 0.75; 95% CI, 0.60-0.95; P = 0.009 for interaction). There were no significant interactions between the presence of AF and intensive BP treatment for mild cognitive impairment. CONCLUSION: Patients with AF experienced greater absolute cardiovascular benefits with intensive BP treatment, but may need to be cautious of an increased risk of dementia. This post hoc analysis should be considered as hypothesis generating and merit further study. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.

Association Between Atrial Fibrillation and Domain-Specific Cognitive Decline　- Insights From the Systolic Blood Pressure Intervention Trial.

BACKGROUND: There is a dearth of evidence to characterize longitudinal changes in domain-specific cognitive function related to atrial fibrillation (AF).Methods and Results: This study enrolled 2,844 participants from the Systolic Blood Pressure Intervention Trial (SPRINT). Cognitive function was assessed at baseline and biennially during the follow-up period. Declines in global function and 4 major cognitive domains (i.e., memory, processing speed, language, and executive function) were fitted and compared between participants with and without AF using robust linear mixed-effect models. There were 252 participants with prevalent AF (mean [±SD] age 72.0±8.5 years; 30% women) and 2,592 participants without AF (mean age 67.9±8.4 years; 38% women). The annual decline in global function scores was greater among participants with than without AF (-0.016 vs. -0.012 points); however, the difference was not statistically significant (P=0.33). Processing speed declined faster in participants with prevalent AF, with a distinct difference of -0.013 points/year (95% CI -0.024~-0.001 points/year; P=0.02). For the memory, executive function, and language domains, there were no significant differences in the rate of cognitive decline between participants with and without AF. CONCLUSIONS: In this post hoc analysis of the SPRINT trial, processing speed was the most prominent cognitive domain affected by AF, which may be beneficial for the early screening of cognitive dysfunction.

Factors associated with depression and anxiety among caregivers of patients with atrial fibrillation.

AIMS AND OBJECTIVES: To assess the prevalence and associated factors of depression and anxiety among caregivers of patients with atrial fibrillation. BACKGROUND: Depression and anxiety are common in caregivers of patients with cardiovascular diseases, including heart failure and coronary artery disease. However, studies about depression and anxiety among caregivers of patients with atrial fibrillation are limited. DESIGN: Cross-sectional study. METHODS: We enrolled 465 dyads of patients with atrial fibrillation and their primary family caregivers from Beijing Anzhen Hospital between September 2020 and March 2021. The patient-caregiver dyads were excluded if primary family caregivers had previous mental disorders before the patient diagnosis of atrial fibrillation. Depression and anxiety of patients and caregivers were measured by Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 scale. Multivariate logistic regression analysis was used to assess factors associated with depression and anxiety of caregivers. STROBE guidelines were followed to report this study. RESULTS: The prevalence of caregiver depression (Patient Health Questionnaire-9 score ≥5) and anxiety (Generalized Anxiety Disorder-7 score ≥5) was 14.0% and 13.5% respectively. Caregiver number of comorbidities ≥2 and patient depression were significantly associated with caregiver depression. Caregiver age ≥65 years, caregiver female sex and patient anxiety were predictors of caregiver anxiety. CONCLUSIONS: Depression and anxiety are common in caregivers of patients with AF. Better management of caregiver mental problems and associated factors may benefit both patients and caregivers. RELEVANCE TO CLINICAL PRACTICE: Clinicians and nurses should pay more attention to depression and anxiety in caregivers of patients with atrial fibrillation, and provide support to caregivers in most need.

Understanding the Role of Populus ECERIFERUM2-Likes in the Biosynthesis of Very-Long-Chain Fatty Acids for Cuticular Waxes.

Cuticular waxes are derived from very-long-chain fatty acid (VLCFA) precursors made by the concerted action of four enzymes that form the fatty acid (FA) elongation complex. The condensing enzyme of the complex confers specificity to substrates of different chain lengths, yet on its own cannot account for the biosynthesis of VLCFAs longer than 28 carbons (C28). Recent evidence from Arabidopsis thaliana points to a synergistic role of clade II BAHD acyltransferases and condensing enzymes in the elongation of VLCFAs beyond C28. In Populus trichocarpa, clade II is composed of seven uncharacterized paralogous genes (PtCER2-like1-7). In the present study, five of these genes were heterologously expressed in yeast and their respective FA profiles were determined. PtCER2-likes differentially altered the accumulation of C28 and C30 FAs when expressed in the presence of the condensing enzyme AtCER6. Among these, PtCER2-like5 produced the highest levels of C28 FAs in yeast and its expression was localized to the epidermis in ß-glucuronidase-reporter poplar lines, consistent with a role in cuticular wax biosynthesis. Complementation of the A. thaliana cer2-5 mutant with PtCER2-like5 increased the levels of C28-derived cuticular waxes at the expense of C30-derived components. Together, these results demonstrate that the role of CER2-likes in cuticular wax biosynthesis is conserved in Populus clade II BAHD acyltransferases.

Inhibition of Cdk5 in PV Neurons Reactivates Experience-Dependent Plasticity in Adult Visual Cortex.

Cyclin-dependent kinase 5 (Cdk5) has been shown to play a critical role in brain development, learning, memory and neural processing in general. Cdk5 is widely distributed in many neuron types in the central nervous system, while its cell-specific role is largely unknown. Our previous study showed that Cdk5 inhibition restored ocular dominance (OD) plasticity in adulthood. In this study, we specifically knocked down Cdk5 in different types of neurons in the visual cortex and examined OD plasticity by optical imaging of intrinsic signals. Downregulation of Cdk5 in parvalbumin-expressing (PV) inhibitory neurons, but not other neurons, reactivated adult mouse visual cortical plasticity. Cdk5 knockdown in PV neurons reduced the evoked firing rate, which was accompanied by an increment in the threshold current for the generation of a single action potential (AP) and hyperpolarization of the resting membrane potential. Moreover, chemogenetic activation of PV neurons in the visual cortex can attenuate the restoration of OD plasticity by Cdk5 inhibition. Taken together, our results suggest that Cdk5 in PV interneurons may play a role in modulating the excitation and inhibition balance to control the plasticity of the visual cortex.

Ulinastatin attenuates LPS-induced inflammation in mouse macrophage RAW264.7 cells by inhibiting the JNK/NF-κB signaling pathway and activating the PI3K/Akt/Nrf2 pathway.

Ulinastatin (UTI) is a broad-spectrum serine protease inhibitor isolated and purified from human urine with strong anti-inflammatory and cytoprotective actions, which is widely used for the treatment of various diseases, such as pancreatitis and sepsis. Although the therapeutic effects of UTI are reported to be associated with a variety of mechanisms, the signaling pathways mediating the anti-inflammatory action of UTI remain to be elucidated. In the present study we carried out a systematic study on the anti-inflammatory and anti-oxidative mechanisms of UTI and their relationships in LPS-treated RAW264.7 cells. Pretreatment with UTI (1000 and 5000 U/mL) dose-dependently decreased the mRNA levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, iNOS) and upregulated anti-inflammatory cytokines (IL-10 and TGF-ß1) in LPS-treated RAW264.7 cells. UTI pretreatment significantly inhibited the nuclear translocation of NF-κB by preventing the degradation of IκB-α. UTI pretreatment only markedly inhibited the phosphorylation of JNK at Thr183, but it did not affect the phosphorylation of JNK at Tyr185, ERK-1/2 and p38 MAPK; JNK was found to function upstream of the IκB-α/NF-κB signaling pathway. Furthermore, UTI pretreatment significantly suppressed LPS-induced ROS production by activating PI3K/Akt pathways and the nuclear translocation of Nrf2 via promotion of p62-associated Keap1 degradation. However, JNK was not involved in mediating the anti-oxidative stress effects of UTI. In summary, this study shows that UTI exerts both anti-inflammatory and anti-oxidative effects by targeting the JNK/NF-κB and PI3K/Akt/Nrf2 pathways.

Exploring the TLR and NLR signaling pathway relevant molecules induced by the Theileria annulata infection in calves.

Theileria annulata is the pathogen of bovine tropical theileriosis. It is extremely harmful to the cattle industry, with huge economic losses. The toll-like receptor (TLR) and NOD-like receptor (NLR) signaling pathways are crucial for resistance to infection of the protozoa, such as Plasmodium falciparum, Toxoplasma gondii, and Trypanosoma cruzi. However, the role of these immune-related pathways is unclear during T. annulata infection. In the present study, peripheral blood mononuclear cells and serum were separated from blood samples of calves infected with homogenized tick supernatants carrying T. annulata sporozoites at 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 144 h and 168 h postinoculation. The Custom RT2 Profiler PCR Array was used to explore the mRNA levels of 42 TLR and NLR signaling pathway relevant genes. The TLR1, TLR6, TLR10, NLRP1, and MyD88 genes and their downstream signaling molecules significantly differed after the T. annulata infection in comparison with that of preinfection from 72 h to 168 h postinoculation. The serum concentrations of IL-6, IL-1ß, and TNFα were significantly increased at 96 h and 168 h postinfection. These findings provided novel information to help determine the mechanisms of TLR and NLR signaling pathway involvement in protection against T. annulata infection.

[Resource situation investigation and analysis about endangered Chinese herbal medicine Daphnes Cortex].

In order to figure out the status and distribution of the wild and cultivated resources of traditional Chinese medicine Daphnes Cortex, its suitable habitat and endangering factors were analyzed to provide the basis for its rational use, protection and cultivation.Our research group tooka resources survey in Shanxi, Gansu, Sichuan and Qinghai provinces, which include 23 counties. Investigation and sampling investigation combined with interview were carried out. The total reserve of resources was estimated through route-quadrat method in combination with the vegetation and soil-type map area method. The results indicated that there was no obvious change between the present distribution ranges of the wild Daphnes Cortex and its historical records, but the density of the population has undergone major changes. The wild reserves resources has declined seriously, even on the verge of exhaustion in some regions. According to the survey results, the current total reserve of the wild Daphnes Cortex in the four provinces was no more than 600 tons. Simultaneously, we only found the cultivated resource in a mountain at an altitude of about 2 800 m in Kang county of Gansu province, which cropping scope was about 33 000 m². The cultivated resource can't provide medicinal products at present, because their growing period is too short to have curative effect. Destructive excavation and the longer growth cycle result in a sharp decline of the wild resources reserves, even to the point of extinction. Artificial cultivation of product will become the main source of medicinal resources in the future. Therefore, we must protect its suitable habitat, formulate rational harvesting policy, strengthen the supervision of government departments, collect and establish the germplasm nursery and seed bank. On the basis, we must carry out studies into seed-selecting and breeding as well as rapid propagation and growth technology at once.

Advances in neuronal reprogramming for neurodegenerative diseases: Strategies, controversies, and opportunities.

Neuronal death is often observed in central nervous system injuries and neurodegenerative diseases. The mammalian central nervous system manifests limited neuronal regeneration capabilities, and traditional cell therapies are limited in their potential applications due to finite cell sources and immune rejection. Neuronal reprogramming has emerged as a novel technology, in which non-neuronal cells (e.g. glial cells) are transdifferentiated into mature neurons. This process results in relatively minimal immune rejection. The present review discuss the latest progress in this cutting-edge field, including starter cell selection, innovative technical strategies and methods of neuronal reprogramming for neurodegenerative diseases, as well as the potential problems and controversies. The further development of neuronal reprogramming technology may pave the way for novel therapeutic strategies in the treatment of neurodegenerative diseases.

Sensory Nerve Regulation via H3K27 Demethylation Revealed in Akermanite Composite Microspheres Repairing Maxillofacial Bone Defect.

Maxillofacial bone defects exhibit intricate anatomy and irregular morphology, presenting challenges for effective treatment. This study aimed to address these challenges by developing an injectable bioactive composite microsphere, termed D-P-Ak (polydopamine-PLGA-akermanite), designed to fit within the defect site while minimizing injury. The D-P-Ak microspheres biodegraded gradually, releasing calcium, magnesium, and silicon ions, which, notably, not only directly stimulated the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) but also activated sensory nerve cells to secrete calcitonin gene-related peptide (CGRP), a key factor in bone repair. Moreover, the released CGRP enhanced the osteogenic differentiation of BMSCs through epigenetic methylation modification. Specifically, inhibition of EZH2 and enhancement of KDM6A reduced the trimethylation level of histone 3 at lysine 27 (H3K27), thereby activating the transcription of osteogenic genes such as Runx2 and Osx. The efficacy of the bioactive microspheres in bone repair is validated in a rat mandibular defect model, demonstrating that peripheral nerve response facilitates bone regeneration through epigenetic modification. These findings illuminated a novel strategy for constructing neuroactive osteo-inductive biomaterials with potential for further clinical applications.

Association between preprocedural serum potassium level and atrial fibrillation recurrence after catheter ablation.

BACKGROUND: The association between serum potassium and atrial fibrillation (AF) recurrence after catheter ablation remains unclear. OBJECTIVE: To investigate whether preprocedural serum potassium influences AF recurrence in patients underwent catheter ablation. METHODS: We used data of AF patients who underwent de novo catheter ablation from the prospective Chinese Atrial Fibrillation Registry Study (CAFR). Patients with prior ablation and without baseline serum potassium were excluded. The primary outcome was 1-year AF recurrence after 3-month blanking period from the ablation. Restricted cubic spline and Cox proportional models were used to compare outcomes across serum potassium categories. RESULTS: A total of 4838 AF patients with de novo catheter ablation was enrolled. At 1 year, AF recurrence occurred in 1347 (27.8%) patients. The relationship between preprocedural serum potassium and 1-year AF recurrence after ablation presented as U-shape (P for nonlinear = 0.048). Compared with the group of serum potassium within 4.41-4.60 mmol/L, the risk of AF recurrence increased significantly in the lowest serum potassium group (≤4.00 mmol/L) after multivariate analysis (HR 1.26, 95% CI 1.06-1.51, P = 0.010). Other categories with lower or higher serum potassium levels including 4.01-4.20 mmol/L (HR=1.18), 4.21-4.40 mmol/L (HR=1.16), 4.61-4.80 mmol/L (HR=1.07) and ≥4.81 mmol/L (HR=1.11) showed nonsignificant higher recurrence risk. CONCLUSIONS: The relationship between preprocedural potassium and AF recurrence was U-shaped, with an optimal potassium range (4.41-4.60 mmol/L). Lower potassium level is associated with increased AF recurrence risk after catheter ablation.

Small Left Ventricle in Patients With Atrial Fibrillation Is Associated With Increased Cardiovascular Risk.

BACKGROUND: It is still unclear whether small left ventricle (LV) is an adverse structural prognostic feature in patients with atrial fibrillation (AF). OBJECTIVES: The purpose of this study was to evaluate the association between small LV and risk of cardiovascular events in AF population. METHODS: From the China-AF registry, 7,764 patients with AF were enrolled and divided into groups with normal, small, and large LV size based on left ventricular end-diastolic dimension (LVEDD) measurement per the American Society of Echocardiography references. Cox models were used to assess the association between LV size or LVEDD with composite cardiovascular events (cardiovascular death, ischemic stroke or systemic embolism, or major bleeding). RESULTS: There were 308 (4.0%) participants assessed with small LV who were older, with lower body mass and blood pressure, and fewer comorbidities, and 429 (5.5%) were identified with large LV. Compared with the normal LV group, small LV and large LV were significantly associated with higher incidence of composite cardiovascular events (adjusted HR [aHR]: 1.54 [95% CI: 1.07-2.20] for small LV; aHR: 1.36 [95% CI: 1.02-1.81] for large LV) and cardiovascular death (aHR: 1.94 [95% CI: 1.14-3.28] for small LV; aHR: 1.83 [95% CI: 1.24-2.69] for large LV). Small LV was also associated with increased risk of major bleeding [aHR: 2.21 [95% CI: 1.01-4.86]). A U-shaped relationship between LVEDD and composite cardiovascular events was identified (Pnonlinear < 0.001). CONCLUSIONS: In a prospective AF cohort, small LV was independently associated with an increased risk of cardiovascular events, which needed consideration in risk stratification and management for patients with AF. (ChiCTR-OCH-13003729).

A genetically encodable and fluorogenic photo-crosslinker via photo-induced defluorination acyl fluoride exchange.

We report a genetically encodable m-trifluoromethylaniline modified L-lysine (m-TFMAK) which defluorinates upon light activation and covalently conjugates to native residues via acyl fluoride exchange. The encoded m-TFMAK photo-crosslinks with temporal controllability, residue selectivity, and fluorogenic tracking features, making it suitable for identifying protein interactions in living systems.

Exploring the mechanism of Xiaoqinglong decoction in the treatment of infantile asthma based on network pharmacology and molecular docking.

To explore the mechanism of Xiaoqinglong decoction (XQLD) in the treatment of infantile asthma (IA) based on network pharmacology and molecular docking. The active ingredients of fdrugs in XQLD were retrieved from Traditional Chinese Medicine Systems Pharmacology database and then the targets of drug ingredients were screened. The disease targets of IA were obtained from OMIM and Gencards databases, and the intersection targets of XQLD in the treatment of IA were obtained by Venny 2.1 mapping of ingredient targets and disease targets. Cytoscape software was used to construct active ingredient-intersection target network. The potential targets of XQLD in the treatment of IA were analyzed by protein-protein interaction network using STRING platform, and the Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were obtained by R Studio software. AutoDock was used to perform molecular docking for verification. In this study, 150 active ingredients of XQLD were obtained, including quercetin, kaempferol, ß-sitosterol, luteolin, stigmasterol, and so on. And 92 intersection targets of drugs and diseases were obtained, including interleukin 6 (IL6), cystatin 3, estrogen receptor 1, hypoxia inducible factor 1A, HSP90AA1, epidermal growth factor receptor and so on. There were 127 items of Gene Ontology enrichment analysis and 125 Kyoto Encyclopedia of Genes and Genomes enrichment results, showing that apoptosis, IL-17 signaling pathway, tumor necrosis factor signaling pathway, P13K-Akt signaling pathway and other pathways may play a key role in the treatment of IA by XQLD. The results of molecular docking showed that the key active ingredients including quercetin, kaempferol, ß-sitosterol, luteolin, stigmasterol, and the core targets including IL6, cystatin 3, estrogen receptor 1, hypoxia inducible factor 1A, HSP90AA1, and epidermal growth factor receptor had good binding activity. Through network pharmacology and molecular docking, the potential targets and modern biological mechanisms of XQLD in the treatment of IA were preliminarily revealed in the study, which will provide reference for subsequent animal experiments and clinical trials.

Photo-induced defluorination acyl fluoride exchange as a fluorogenic photo-click reaction for photo-affinity labeling.

Photo-click chemistry has emerged as a powerful tool for revolutionizing bioconjugation technologies in pharmacological and various biomimetic applications. However, enriching the photo-click reactions to expand the bioconjugation toolkit remains challenging, especially when focusing on spatiotemporal control endowed by light activation. Herein, we describe a photo-induced defluorination acyl fluoride exchange (photo-DAFEx) as a novel type of photo-click reaction that is mediated through acyl fluorides produced by the photo-defluorination of m-trifluoromethylaniline to covalently conjugate with primary/secondary amines and thiols in an aqueous environment. (TD)-DFT calculations, together with experimental discovery, indicate that the m-NH2PhF2C(sp3)-F bond in the excited triplet state is cleaved by water molecules, which is key to inducing defluorination. Intriguingly, the benzoyl amide linkages built by this photo-click reaction exhibited a satisfactory fluorogenic performance, which allowed visualization of its formation in situ. Accordingly, this photo-controlled covalent strategy was exploited not only for the decoration of small molecules, peptide cyclization and functionalization of proteins in vitro, but also for designing photo-affinity probes targeting endogenous carbonic anhydrase II (hCA-II) in living cells.

Morphology modulation of artificial muscles by thermodynamic-twist coupling.

Human muscles can grow and change their length with body development; therefore, artificial muscles that modulate their morphology according to changing needs are needed. In this paper, we report a strategy to transform an artificial muscle into a new muscle with a different morphology by thermodynamic-twist coupling, and illustrate its structural evolution during actuation. The muscle length can be continuously modulated over a large temperature range, and actuation occurs by continuously changing the temperature. This strategy is applicable to different actuation modes, including tensile elongation, tensile contraction and torsional rotation. This is realized by twist insertion into a fibre to produce torsional stress. Fibre annealing causes partial thermodynamic relaxation of the spiral molecular chains, which serves as internal tethering and inhibits fibre twist release, thus producing a self-supporting artificial muscle that actuates under heating. At a sufficiently high temperature, further relaxation of the spiral molecular chains occurs, resulting in a new muscle with a different length. A structural study provides an understanding of the thermodynamic-twist coupling. This work provides a new design strategy for intelligent materials.

Genetic Evidence for Causal Association Between Atrial Fibrillation and Dementia: A Mendelian Randomization Study.

Background The knowledge gap regarding whether the correlation between atrial fibrillation (AF) and dementia in observational studies is causation or driven by other shared risk factors remains substantially unfilled. Methods and Results We performed a comprehensive 2-sample Mendelian randomization study to evaluate the causal effect of AF on overall dementia and its subtypes, including vascular dementia, Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. The primary results in inverse variance-weighted analyses were further validated by various Mendelian randomization sensitivity analyses. Additionally, we conducted multivariable Mendelian randomization to examine 10 candidate mediators of the causal association of AF and dementia. Genetic predisposition to AF was modestly associated with an increased risk of overall dementia (odds ratio, 1.140 [95% CI, 1.023-1.271]; P=0.018) and strongly associated with vascular dementia (odds ratio, 1.350 [95% CI, 1.076-1.695]; P=0.010). Genetically predicted AF indicated neutral effects on Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. In multivariable Mendelian randomization analysis, the total effect of AF on overall dementia was remarkably attenuated by adjusting for genetic effect for ischemic stroke (odds ratio, 1.068 [95% CI, 0.953-1.197]; P=0.259) and low cardiac output (odds ratio, 1.046 [95% CI, 0.926-1.181]; P=0.475), indicating that the causal association of genetically predicted AF with dementia was potentially mediated by ischemic stroke and low cardiac output. The causal effect of genetically predicted AF on dementia was independent of cerebral small-vessel disease and brain volume phenotypes. Conclusions Our findings provided novel evidence supporting the causal effect of genetically predicted AF on dementia mediated by ischemic stroke and low cardiac output. Future clinical trials are warranted to evaluate the potential role of appropriate AF management in dementia prevention.