Pulmonary Veins Function as Echo Chambers in Persistent Atrial Fibrillation: Circuitous Re-Entry Generates Outgoing Wavefronts.

BACKGROUND: Although the substrate in persistent atrial fibrillation (PeAF) is not limited to the pulmonary veins (PVs), PV isolation (PVI) remains the cornerstone ablation strategy. OBJECTIVES: The aim of this study was to describe the mechanism of outgoing wavefronts (WFs) originating in the PV sleeves during PeAF. METHODS: Eleven patients presenting for first-time PeAF ablation were recruited (mean age 63.1 ± 10.9 years, 91% men). A 64-electrode catheter (Constellation; 38 mm) was positioned within the PV under fluoroscopic guidance. An inverse mapping technique was used to reconstruct unipolar atrial electrograms on the PV surface, and the resulting phase maps were used to identify incoming and outgoing WFs at the PV junction and to classify focal and re-entrant activity within the PV sleeves. RESULTS: During PeAF, the PVs gave rise to outgoing WFs with a frequency of 3.7 s-1 (Q1-Q3: 3.4-5.4 s-1) compared with 3.6 s-1 (Q1-Q3: 2.8-4.2 s-1) for incoming WFs. Circuitous macroscopic re-entry was the dominant mechanism driving outgoing WFs (frequency of re-entry 2.7 s-1 [Q1-Q3: 2.0-3.3 s-1] compared with focal activity 1.4 s-1 [Q1-Q3: 1.1-1.5 s-1]; P < 0.006). This was initiated by incoming WFs in 80% of cases. Consecutive focal activation from the same location was infrequent (10.0% ± 6.6%, n = 10). Rotors ≥360° were never observed. The median ratio (R) of outgoing to incoming WF frequency was 1.14 (Q1-Q3: 0.84-1.75), with R > 1 in 6 of 11 PVs. CONCLUSIONS: Electric activity generated by PV sleeves during PeAF is due mainly to circuitous re-entry initiated by incoming waves, frequently with R > 1. That is, the PVs act less as drivers of atrial fibrillation than as "echo chambers" that sustain and amplify fibrillatory activity.

Structural and biochemical analysis of family 92 carbohydrate-binding modules uncovers multivalent binding to ß-glucans.

Carbohydrate-binding modules (CBMs) are non-catalytic proteins found appended to carbohydrate-active enzymes. Soil and marine bacteria secrete such enzymes to scavenge nutrition, and they often use CBMs to improve reaction rates and retention of released sugars. Here we present a structural and functional analysis of the recently established CBM family 92. All proteins analysed bind preferentially to ß-1,6-glucans. This contrasts with the diversity of predicted substrates among the enzymes attached to CBM92 domains. We present crystal structures for two proteins, and confirm by mutagenesis that tryptophan residues permit ligand binding at three distinct functional binding sites on each protein. Multivalent CBM families are uncommon, so the establishment and structural characterisation of CBM92 enriches the classification database and will facilitate functional prediction in future projects. We propose that CBM92 proteins may cross-link polysaccharides in nature, and might have use in novel strategies for enzyme immobilisation.

Concurrent Ammonia Synthesis and Alcohol Oxidation Boosted by Glutathione-Capped Quantum Dots under Visible Light.

Mother nature accomplishes efficient ammonia synthesis via cascade N2 oxidation by lightning strikes followed with enzyme-catalyzed nitrogen oxyanion (NOx -, x = 2,3) reduction. The protein environment of enzymatic centers for NOx --to-NH4 + process greatly inspires the design of glutathione-capped (GSH) quantum dots (QDs) for ammonia synthesis under visible light (440 nm) in tandem with plasma-enabled N2 oxidation. Mechanistic studies reveal that GSH induces positive shift of surface charge to strengthen the interaction between NOx - and QDs. Upon visible light irradiation of QDs, the balanced and rapid hole and electron transfer furnish GS·radicals for 2e-/2H+ alcohol oxidation and H·for 8e-/10H+ NO3 --to-NH4 + reduction simultaneously. For the first time, mmol-scale ammonia synthesis is realized with apparent quantum yields of 5.45% ± 0.64%, and gram-scale synthesis of value-added acetophenone and NH4Cl proceeds with 1:4 stoichiometry and stability, demonstrating promising multielectron and multiproton ammonia synthesis efficiency and sustainability with nature-inspired artificial photocatalysts.

Lamin A/C mediates microglial activation by modulating cell proliferation and immune response.

Lamin A/C is involved in macrophage activation and premature aging, also known as progeria. As the resident macrophage in brain, overactivation of microglia causes brain inflammation, promoting aging and brain disease. In this study, we investigated the role of Lamin A/C in microglial activation and its impact on progeria using Lmna-/- mice, primary microglia, Lmna knockout (Lmna-KO) and Lmna-knockdown (Lmna-KD) BV2 cell lines. We found that the microglial activation signatures, including cell proliferation, morphology changes, and proinflammatory cytokine secretion (IL-1ß, IL-6, and TNF-α), were significantly suppressed in all Lamin A/C-deficient models when stimulated with LPS. TMT-based quantitative proteomic and bioinformatic analysis were further applied to explore the mechanism of Lamin A/C-regulated microglia activation from the proteome level. The results revealed that immune response and phagocytosis were impaired in Lmna-/- microglia. Stat1 was identified as the hub protein in the mechanism by which Lamin A/C regulates microglial activation. Additionally, DNA replication, chromatin organization, and mRNA processing were also altered by Lamin A/C, with Ki67 fulfilling the main hub function. Lamin A/C is a mechanosensitive protein and, the immune- and proliferation-related biological processes are also regulated by mechanotransduction. We speculate that Lamin A/C-mediated mechanotransduction is required for microglial activation. Our study proposes a novel mechanism for microglial activation mediated by Lamin A/C.

Economic evaluation of stent retrievers in basilar artery occlusion: An analysis from Chinese healthcare system perspective.

PURPOSE: This study aimed to investigate the cost-effectiveness of stent retriever (SR) versus best medical management (BMM) in patients with basilar artery occlusion (BAO) in China. METHODS: We used a two-step approach to compare the cost-effectiveness of SR plus BMM with that of BMM alone over 20 years. A decision tree was initially constructed for the first 3 months, followed by a Markov model for the subsequent period. Collected data on clinical aspects were extracted from the BAOCHE investigation, while costs-related information was sourced from previously published research. The key metric for evaluating the primary outcome was the incremental cost-effectiveness ratio (ICER), achieved $/QALY. The threshold for identifying SR as highly cost-effective was set at an ICER below $12,551/QALY, SR was deemed cost-effective if the ICER ranged from $12,551 to $37,654 per QALY. Uncertainty was addressed using scenario, one-way sensitivity, and probabilistic sensitivity analyses (PSA). FINDINGS: For Chinese patients with BAO, the 20-year cost per patient was $8678 with BMM alone and $21,988 for SR plus BMM. Effectiveness was 1.45 QALY for BMM alone, and 2.77 QALY for SR plus BMM. The ICER of SR + BMM versus BMM alone was $10,050 per QALY. The scenario and one-way sensitivity analyses revealed that in certain situations the ICER could exceed $12,551 per QALY, but remain below $37,654 per QALY. Results from the PSA suggested that SR was likely to be cost-effective for Chinese patients with BAO, with a probability exceeding 98% when considering a willingness-to-pay (WTP) threshold of $12,551 per QALY. IMPLICATIONS: Our study indicates that SR is an intervention option that is highly likely to be cost-effective for Chinese patients with BAO, with a probability of over 98% under the current WTP threshold of $12,551 per QALY.

MicroRNA-200 Loaded Lipid Nanoparticles Promote Intestinal Epithelium Regeneration in Canonical MicroRNA-Deficient Mice.

Intestinal epithelium undergoes regeneration after injuries, and the disruption of this process can lead to inflammatory bowel disease and tumorigenesis. Intestinal stem cells (ISCs) residing in the crypts are crucial for maintaining the intestinal epithelium's homeostasis and promoting regeneration upon injury. However, the precise role of DGCR8, a critical component in microRNA (miRNA) biogenesis, in intestinal regeneration remains poorly understood. In this study, we provide compelling evidence demonstrating the indispensable role of epithelial miRNAs in the regeneration of the intestine in mice subjected to 5-FU or irradiation-induced injury. Through a comprehensive pooled screen of miRNA function in Dgcr8-deficient organoids, we observe that the loss of the miR-200 family leads to the hyperactivation of the p53 pathway, thereby reducing ISCs and impairing epithelial regeneration. Notably, downregulation of the miR-200 family and hyperactivation of the p53 pathway are verified in colonic tissues from patients with active ulcerative colitis (UC). Most importantly, the transient supply of miR-200 through the oral delivery of lipid nanoparticles (LNPs) carrying miR-200 restores ISCs and promotes intestinal regeneration in mice following acute injury. Our study implies the miR-200/p53 pathway as a promising therapeutic target for active UC patients with diminished levels of the miR-200 family. Furthermore, our findings suggest that the clinical application of LNP-miRNAs could enhance the efficacy, safety, and acceptability of existing therapeutic modalities for intestinal diseases.

Circular RNAs in vascular diseases.

Vascular diseases are the leading cause of morbidity and mortality worldwide and are urgently in need of diagnostic biomarkers and therapeutic strategies. Circular RNAs (circRNAs) represent a unique class of RNAs characterized by a circular loop configuration and have recently been identified to possess a wide variety of biological functions. CircRNAs exhibit exceptional stability, tissue specificity, and are detectable in body fluids, thus holding promise as potential biomarkers. Their encoding function and stable gene expression also position circRNAs as an excellent alternative to gene therapy. Here, we briefly review the biogenesis, degradation, and functions of circRNAs. We summarize circRNAs discovered in major vascular diseases such as atherosclerosis and aneurysms, with a particular focus on molecular mechanisms of circRNAs identified in vascular endothelial cells and smooth muscle cells, in the hope to reveal new directions for mechanism, prognosis and therapeutic targets of vascular diseases.

Epigenetic landscape reveals MECOM as an endothelial lineage regulator.

A comprehensive understanding of endothelial cell lineage specification will advance cardiovascular regenerative medicine. Recent studies found that unique epigenetic signatures preferentially regulate cell identity genes. We thus systematically investigate the epigenetic landscape of endothelial cell lineage and identify MECOM to be the leading candidate as an endothelial cell lineage regulator. Single-cell RNA-Seq analysis verifies that MECOM-positive cells are exclusively enriched in the cell cluster of bona fide endothelial cells derived from induced pluripotent stem cells. Our experiments demonstrate that MECOM depletion impairs human endothelial cell differentiation, functions, and Zebrafish angiogenesis. Through integrative analysis of Hi-C, DNase-Seq, ChIP-Seq, and RNA-Seq data, we find MECOM binds enhancers that form chromatin loops to regulate endothelial cell identity genes. Further, we identify and verify the VEGF signaling pathway to be a key target of MECOM. Our work provides important insights into epigenetic regulation of cell identity and uncovered MECOM as an endothelial cell lineage regulator.

Effect of lipoxin A4 on the osteogenic differentiation of periodontal ligament stem cells under lipopolysaccharide-induced inflammatory conditions.

Lipoxin A4 (LXA4) has been identified as the braking signal of inflammation, but the specific role of LXA4 in regulating the regenerative potential of periodontal ligament stem cells (PDLSCs) remains unclear. The aim of this study was to investigate whether and, if so, how LXA4 improves the osteogenic differentiation of PDLSCs in a lipopolysaccharide (LPS)-induced inflammatory environment. We detected the effects of LXA4 on the osteogenic differentiation of PDLSCs in vitro and explored the bone regenerative potential of LXA4-treated inflammatory PDLSCs in vivo using a calvarial critical sized defect model in male rats. RNA sequencing, real-time PCR and western blot were performed to elucidate the relevant potential mechanisms. Results showed that LXA4 promoted the proliferation, migration and osteogenic differentiation of PDLSCs in vitro, and effectively improved the impaired osteogenic capacity of PDLSCs induced by LPS both in vitro and in vivo. Mechanistically, LXA4 significantly promoted the PI3K/AKT phosphorylation under inflammatory conditions. Additionally, LY294002 (a PI3K inhibitor) blocked the effect of LXA4, suggesting that the PI3K/AKT pathway is a key signaling pathway that mediates the effect of LXA4 on the osteogenesis of inflammatory PDLSCs. These findings indicate LXA4 may be a promising strategy for periodontal regeneration using inflammatory PDLSCs.

Family 92 carbohydrate-binding modules specific for ß-1,6-glucans increase the thermostability of a bacterial chitinase.

In biomass-processing industries there is a need for enzymes that can withstand high temperatures. Extensive research efforts have been dedicated to finding new thermostable enzymes as well as developing new means of stabilising existing enzymes. The attachment of a stable non-catalytic domain to an enzyme can, in some instances, protect a biocatalyst from thermal denaturation. Carbohydrate-binding modules (CBMs) are non-catalytic domains typically found appended to biomass-degrading or modifying enzymes, such as glycoside hydrolases (GHs). Most often, CBMs interact with the same polysaccharide as their enzyme partners, leading to an enhanced reaction rate via the promotion of enzyme-substrate interactions. Contradictory to this general concept, we show an example of a chitin-degrading enzyme from GH family 18 that is appended to two CBM domains from family 92, both of which bind preferentially to the non-substrate polysaccharide ß-1,6-glucan. During chitin hydrolysis, the CBMs do not contribute to enzyme-substrate interactions but instead confer a 10-15 °C increase in enzyme thermal stability. We propose that CBM92 domains may have a natural enzyme stabilisation role in some cases, which may be relevant to enzyme design for high-temperature applications in biorefinery.

Improved Lithium Storage Performance of a TiO2 Anode Material Doped by Co.

TiO2 is a promising anode material for lithium-ion batteries (LIBs) due to its low cost, suitable operating voltage, and excellent structural stability. The inherent poor electron conductivity and low ion diffusion coefficient, however, severely limit its application in lithium storage. Here, Co-doped TiO2 is synthesized by a hydrothermal method as an anode material since Co@TiO2 possesses a large specific surface area and high electronic conductivity. Thanks to the Co dopants, the ion diffusion and electron transport are both greatly improved, which is very beneficial for cycle stability, coulombic efficiency (CE), reversible capacity, and rate performance. As a result, Co@TiO2 shows a high reversible capacity of 227 mAh g-1 at 3 C, excellent rate performance, and cycling stability with a capacity of about 125 mAh g-1 at 10C after 600 cycles (1 C = 170 mA g-1).

Combining Phenylalanine and Leucine Levels Predicts 30-Day Mortality in Critically Ill Patients Better than Traditional Risk Factors with Multicenter Validation.

In critically ill patients, risk scores are used; however, they do not provide information for nutritional intervention. This study combined the levels of phenylalanine and leucine amino acids (PLA) to improve 30-day mortality prediction in intensive care unit (ICU) patients and to see whether PLA could help interpret the nutritional phases of critical illness. We recruited 676 patients with APACHE II scores ≥ 15 or intubated due to respiratory failure in ICUs, including 537 and 139 patients in the initiation and validation (multicenter) cohorts, respectively. In the initiation cohort, phenylalanine ≥ 88.5 µM (indicating metabolic disturbance) and leucine < 68.9 µM (indicating malnutrition) were associated with higher mortality rate. Based on different levels of phenylalanine and leucine, we developed PLA scores. In different models of multivariable analyses, PLA scores predicted 30-day mortality independent of traditional risk scores (p < 0.001). PLA scores were then classified into low, intermediate, high, and very-high risk categories with observed mortality rates of 9.0%, 23.8%, 45.6%, and 81.8%, respectively. These findings were validated in the multicenter cohort. PLA scores predicted 30-day mortality better than APACHE II and NUTRIC scores and provide a basis for future studies to determine whether PLA-guided nutritional intervention improves the outcomes of patients in ICUs.

Treatment advice of small molecule antiviral drugs for elderly COVID-19 / 中国药理学通报

COVID-19 has been prevalent for three years. The virulence of SARS-CoV-2 is weaken as it mutates continuously. However, elderly patients, especially those with underlying diseases, are still at high risk of developing severe infections. With the continuous study of the molecular structure and pathogenic mechanism of SARS-CoV-2, antiviral drugs for COVID-19 have been successively marketed, and these anti-SARS-CoV-2 drugs can effectively reduce the severe rate and mortality of elderly patients. This article reviews the mechanism, clinical medication regimens, drug interactions and adverse reactions of five small molecule antiviral drugs currently approved for marketing in China, so as to provide advice for the clinical rational use of anti-SARS-CoV-2 in the elderly.

Chinese college students COVID-19 phobia and negative moods: Moderating effects of physical exercise behavior.

Objective: We investigated the effects of COVID-19 fear on negative moods among college students, and assessed the efficacy of physical exercise behavior as a moderator variable. Methods: This was a cross-sectional study. Students from three colleges and universities in Shangqiu City, Henan Province and Yangzhou City, Jiangsu Province were enrolled in this study, which was performed during the COVID-19 pandemic using an online questionnaire. A total of 3,133 college students completed the questionnaire. Measurement tools included the COVID-19 Phobia Scale (C19P-S), Depression-Anxiety-Stress Self-Rating Scale (DASS), and the Physical Activity Behavior Scale (PARS-3). Results: During the COVID-19 pandemic, the rates of depression, anxiety, and stressful negative moods among college students were 35.5, 65.5, and 10.95%, respectively; there was a positive correlation between COVID-19 fear and negative moods among college students (r = 0.479, p < 0.001), which was negatively correlated with physical exercise behavior (r = -0.4, p < 0.001); the regulating effects of physical exercise behavior were significant (ΔR2 = 0.04, p < 0.001). Conclusion: The rate of negative moods among college students is high, and the fear for COVID-19 is one of the key factors that lead to negative moods. Physical exercise can modulate the impact of COVID-19 fear among college students on negative moods. Studies should elucidate on mental health issues among different populations during the COVID-19 pandemic.

Early administration of ivabradine in patients admitted for acute decompensated heart failure.

Background: Heart rate (HR) control is important in heart failure (HF) patients with reduced ejection fraction, and ivabradine is indicated for patients with chronic HF and sinus rhythm. However, ivabradine is limited in initiation of ivabradine at acute stage of HF. Materials and methods: This multi-institutional retrospective study enrolled 30,639 patients who were admitted for HF from January 01, 2013 to December 31, 2018 at Chang Gung Memorial Hospitals. After applying selection criteria, the eligible patients were divided into ivabradine and non-ivabradine groups according to the initiation of ivabradine at the index hospitalization. HR, clinical outcomes including HF hospitalization, all-cause hospitalization, mortality, the composite of cardiovascular (CV) death or HF hospitalization and newly developed atrial fibrillation, and left ventricular ejection fraction (LVEF) and left atrium size were compared between the ivabradine and non-ivabradine groups after inverse probability of treatment weighting (IPTW) analysis after 12 months. Results: The HR at admission in the ivabradine group (n = 433) was 99.04 ± 20.69/min, compared to 86.99 ± 20.34/min in the non-ivabradine group (n = 9,601). After IPTW, HR was lower in the ivabradine group than that in the non-ivabradine group after 12 months (74.14 ± 8.53 vs. 81.23 ± 16.79 bpm, p = 0.079). However, there were no significant differences in HF hospitalization (HR = 1.02; 95% CI, 0.38-2.79), all-cause hospitalization (HR = 0.95; 95% CI, 0.54-1.68), mortality (HR = 0.87; 95% CI, 0.69-1.08), the composite of CV death or HF hospitalization (HR = 0.87; 95% CI, 0.69-1.08) and newly developed AF between the two groups. In addition, LVEF increased with time in both groups, but there were no significant differences during the observation period. Conclusion: Ivabradine was beneficial in controlling HR when initiated in patients with acute stage of HF, but it did not seem to provide any benefits in reducing HF hospitalization, all-cause hospitalization, and mortality in 1 year after discharge.

Current Status and Correlation of Physical Activity and Tendency to Problematic Mobile Phone Use in College Students.

OBJECTIVE: To explore the effect of problematic mobile phone use on college students' physical activity and their relationships. METHODS: A cross-sectional study was conducted among 3980 college students from three universities in Jiangsu province by random cluster sampling. The International Physical Activity Questionnaire Short (IPAQ-SF) measured college students' physical activity. The Mobile Phone Addiction Tendency Scale for College Students (MPATS) measured problematic mobile phone use tendencies. College students' physical activity was measured by the International Physical Activity Questionnaire Short (IPAQ-SF), and the Mobile Phone Addiction Tendency Scale measured their mobile phone addiction tendency for College Students (MPATS). RESULTS: (1) The proportions of the low-, medium-, and high-intensity physical activity were 83.5%, 10.7%, and 5.8%, respectively, with gender differences; The score of problematic mobile phone use tendency was 38.725 ± 15.139. (2) There were significant differences in problematic mobile phone use tendency among college students with different physical activity intensity (F = 11.839, p < 0.001, η2 = 0.007). (3) The level of physical activity was significantly correlated with the tendency of problematic mobile phone use (r = -0.173, p < 0.001). (4) Physical activity of college students could significantly predict the tendency of problematic mobile phone use (F (3,3605) = 11.296, p < 0.001). CONCLUSIONS: The physical activity of college students was mainly moderate to low intensity, while the tendency of problematic mobile phone use was high. College students' physical activity level was one of the important constraints of problematic mobile phone use tendency.

Epidemiological Study of Physical Activity, Negative Moods, and Their Correlations among College Students.

OBJECTIVE: Negative moods in college students have caused frequent extreme behaviors. This study analyzed the current status and correlation between physical activity and negative moods in college students. METHODS: A cross-sectional study design was used in the present research. Data on college students' physical activity and negative moods were collected using the Sports Questionnaire Star software. The questionnaires were administered to college students in five colleges and universities in Henan and Jiangsu Provinces, China, and a total of 3711 correctly completed questionnaires were returned. Data on sociological and demographic information, the International Physical Activity Questionnaire Short Form (IPAQ-SF), and the Depression Anxiety and Stress Scale (DASS) were collected. The research was conducted in December 2021. RESULTS: The low-intensity physical activity rate among college students was 55.56%, while depression, anxiety, and stress symptoms were detected in 35.14%, 65.29%, and 10.99%of the college students, respectively. Depression (K = 35.58, p < 0.001) and anxiety (K = 15.56, p < 0.001) rates were significantly different among the different physical activity intensity groups. The proportion of students who perform high-intensity physical activities was lower than those who perform low- and moderate-intensity physical activities. CONCLUSION: Low physical activity and high anxiety are evident among college students, and prolonged moderate-to-low-intensity physical activity (including static behavior) induces depression and anxiety. In the future, further studies can be conducted on improving the physical activity intensity of college students, improving the mental health monitoring and intervention systems of college students, and exploring the dose-effect relationship between physical activity and negative moods.

Photochemistry Journey to Multielectron and Multiproton Chemical Transformation.

The odyssey of photochemistry is accompanied by the journey to manipulate "electrons" and "protons" in time, in space, and in energy. Over the past decades, single-electron (1e-) photochemical transformations have brought marvelous achievements. However, as each photon absorption typically generates only one exciton pair, it is exponentially challenging to accomplish multielectron and proton photochemical transformations. The multistep differences in thermodynamics and kinetics urgently require us to optimize light harvesting, expedite consecutive electron transfer, manipulate the interaction of catalysts with substrates, and coordinate proton transfer kinetics to furnish selective bond formations. Tandem catalysis enables orchestrating different photochemical events and catalytic transformations from subpicoseconds to seconds, which facilitates multielectron redox chemistries and brings consecutive, value-added reactivities. Joint efforts in molecular and material design, mechanistic understanding, and theoretical modeling will bring multielectron and proton synthetic opportunities for fuels, fertilizers, and chemicals with enhanced versatility, efficiency, selectivity, and scalability, thus taking better advantage of photons (i.e., sunlight) for our sustainable society.