Time to Benefit and Harm of Direct Oral Anticoagulants in Device-Detected Atrial Fibrillation: A Pooled Analysis of the NOAH-AFNET 6 and ARTESiA Trials.

BACKGROUND: Direct oral anticoagulants (DOACs) reduce stroke risk in patients with device-detected atrial fibrillation (DD-AFib) but increase major bleeding risk. The time to benefit (TTB) and time to harm (TTH) are not well quantified. OBJECTIVE: To determine TTB and TTH in DOACs-treated DD-AFib patients. METHODS: Studies were identified from PubMed searching until November 2023. The primary efficacy outcome was the time to first stroke event, and the primary safety outcome was the time to the first major bleeding event. Pooled hazard ratio (HR) and its confidence interval (CI) were calculated through reconstructed patient-level data and study-level data. Weibull model and Markov chain Monte Carlo simulation were applied to determine time to specific absolute risk change thresholds. RESULTS: Two trials involving DOACs, NOAH-AFNET 6 and ARTESiA, were identified, which randomized 6,548 adults with mean age over 75 and a median atrial high-rate episode duration ranging from 1.5 to 2.8 hours. DOACs decreased the risk of stroke (HR 0.67, 95% CI: 0.50 to 0.90) but increased the risk of major bleeding (HR 1.57, 95% CI: 1.21 to 2.04). A TTB of 2.67 years was needed to prevent one stroke per 100 DOACs-treated patients, while a TTH of 1.67 years was needed to observe one major bleeding. CONCLUSIONS: In elderly patients with low durations of DD-AFib, DOACs result in a delayed and restricted stroke-preventive benefit while posing an early-onset bleeding risk. Our findings offer new insights into the risk-benefit profile and provide clinicians an additional dimension to facilitate shared decision-making discussions with patients.

Photochemical reduction of CO2 into CO coupling with triethanolamine decomposition.

In this work, the impacts of triethanolamine (TEOA) on the performance of photochemical CO2 reduction were investigated in a simple homogeneous system. We demonstrates that CO2 can be converted into CO coupling with the decomposition of triethanolamine in TEOA aqueous solution without other additives under light irradiation. About 7.5 µmol CO product is achieved within 7 h with a maximum apparent quantum yield (AQY) of 0.086% at 254 nm. The isotope labelling experiment confirms that CO product originates from the reduction of CO2 rather than the decomposition of TEOA. In addition, the photochemical system exhibits excellent stability, no obvious inactivation is observed during long-term photochemical CO2 reduction reaction. This work provides a deep understanding of the effects of TEOA on the performance of photocatalytic CO2 reduction. Upon utilizing TEOA as a sacrificial electron donor in photocatalytic system, the contribution of TEOA must be considered once evaluating the catalytic activity of catalysts.

Intestinal homeostasis in the gut-lung-kidney axis: a prospective therapeutic target in immune-related chronic kidney diseases.

In recent years, the role of intestinal homeostasis in health has received increasing interest, significantly improving our understanding of the complex pathophysiological interactions of the gut with other organs. Microbiota dysbiosis, impaired intestinal barrier, and aberrant intestinal immunity appear to contribute to the pathogenesis of immune-related chronic kidney diseases (CKD). Meanwhile, the relationship between the pathological changes in the respiratory tract (e.g., infection, fibrosis, granuloma) and immune-related CKD cannot be ignored. The present review aimed to elucidate the new underlying mechanism of immune-related CKD. The lungs may affect kidney function through intestinal mediation. Communication is believed to exist between the gut and lung microbiota across long physiological distances. Following the inhalation of various pathogenic factors (e.g., particulate matter 2.5 mum or less in diameter, pathogen) in the air through the mouth and nose, considering the anatomical connection between the nasopharynx and lungs, gut microbiome regulates oxidative stress and inflammatory states in the lungs and kidneys. Meanwhile, the intestine participates in the differentiation of T cells and promotes the migration of various immune cells to specific organs. This better explain the occurrence and progression of CKD caused by upper respiratory tract precursor infection and suggests the relationship between the lungs and kidney complications in some autoimmune diseases (e.g., anti-neutrophil cytoplasm antibodies -associated vasculitis, systemic lupus erythematosus). CKD can also affect the progression of lung diseases (e.g., acute respiratory distress syndrome and chronic obstructive pulmonary disease). We conclude that damage to the gut barrier appears to contribute to the development of immune-related CKD through gut-lung-kidney interplay, leading us to establish the gut-lung-kidney axis hypothesis. Further, we discuss possible therapeutic interventions and targets. For example, using prebiotics, probiotics, and laxatives (e.g., Rhubarb officinale) to regulate the gut ecology to alleviate oxidative stress, as well as improve the local immune system of the intestine and immune communication with the lungs and kidneys.

Amide-decorated carbon dots as sensitive and selective probes for fluorescence enhancement detection of cadmium ion.

As highly toxic metal ions, cadmium ions (Cd2+) are prevalent in varying concentrations around the world. The establishment of an accurate and effective method for Cd2+ determination with high sensitivity and selectivity is of particular concern. The present work fabricated a fluorescence chemosensor for the detection of Cd2+ based on functionalized carbon dots (CDs), which were hydrothermally prepared using amidated hyperbranched-polyethyleneimine (HPEI). As investigated by FTIR, NMR, and XPS, the stably grafted amide groups endowed the CDs with thermosensitivity and high cloud point due to the change in hydrophilic-hydrophobic behaviors. The CDs chemosensor with optimal amidation degree exhibited high sensitivity, selectivity, and stability in the determination of Cd2+ from various water environments. Notably, the fluorescence intensity enhanced with the increase of Cd2+ concentration, originating from the improved structure rigidity caused by the interactions between grafted amides and Cd2+. These impressive features made the CDs not only sensitive to detecting Cd2+ in low-concentration solutions with a limit of detection of 3.41 nM (the lowest known value for Cd2+ detection) but also accurate for the quantification in high-concentration solutions with a detectable Cd2+ concentration of 6.0 × 10-2 M. Owing to the broad detection range, the CDs developed in present work show great potential applications in various scenarios.

GPR18 and GPR55-related Ligands Serving as Antagonists or Agonists: Current Situation, Challenges and Perspectives.

GPCR superfamily, the largest known family of membrane receptors, consists of six classes from A to F. GPR18 and GPR55, δ-branch of A class, had been reported to have no confirmed endogenous ligand and were named as "orphan receptors". Previous studies suggest that both GPR18 and GPR55 are possibly related to the migration and proliferation of cancer cells, macrophages and other inflammation-associated immune cells. Thus, they may be potential targets for inflammation, cancer and analgesia therapy. In this paper, we aimed to summarize the chemical structures and bioactivities of the agonists and antagonists of GPR18 and GPR55; moreover, we have briefly discussed the challenges and future perspectives in this field. This review will be beneficial for further design and synthesis of efficient agonists and antagonists towards GPR18 and GPR55- related disease treatment.

Janus (Mo/ß-Mo2C)@C heterostructure as an efficient electrocatalyst for the hydrogen evolution reaction in acidic and alkaline media.

To explore low-cost, high-efficiency, and noble-metal-free catalysts for electrocatalytic water splitting in both acidic and alkaline media, the metal-metal carbide Janus hierarchical structure comprising Mo andß-Mo2C embedded on a carbon layer (Mo/ß-Mo2C)@C is synthesized by a hydrothermal reaction and subsequent low-temperature magnesium thermic process. Systematic characterization by XRD, XPS, Raman scattering, and SEM/TEM reveals the successful formation of metallic Mo andß-Mo2C nanoparticles. The synthesized (Mo/ß-Mo2C)@C has a large specific surface area and boasts highly efficient hydrogen evolution reaction activity including low overpotentials of 152 and 171 mV at a current density of 10 mA cm-2and small Tafel slopes of 51.7 and 63.5 mV dec-1in acidic and alkaline media, respectively. In addition, the catalyst shows outstanding stability for 48 h in both acidic and alkaline media. The excellent catalytic activity originates from more active sites and greater electron conductivity bestowed by the carbon layer, which also improves the long-term stability in both acidic and alkaline solutions.

A western United States snow reanalysis dataset over the Landsat era from water years 1985 to 2021.

Water stored in mountain snowpacks (i.e., snow water equivalent, SWE) represents an important but poorly characterized component of the terrestrial water cycle. The Western United States snow reanalysis (WUS-SR) dataset is novel in its combination of spatial resolution (~500 m), spatial extent (31°-49° N; 102°-125° W), and temporal continuity (daily over 1985-2021). WUS-SR is generated using a Bayesian framework with model-based snow estimates updated through the assimilation of cloud-free Landsat fractional snow-covered area observations. Over the WUS, the peak SWE verification with independent in situ measurements show correlation coefficient, mean difference (MD), and root mean squared difference (RMSD) of 0.77, -0.15 m, and 0.28 m, respectively. The effects of forest cover and Landsat image availability on peak SWE are assessed. WUS-SR peak SWE is well correlated (ranging from 0.75 to 0.91) against independent lidar-derived SWE taken near April 1st, with MD <0.15 m and RMSD <0.38 m. The dataset is useful for characterizing WUS mountain snow storage, and ultimately for improving snow-derived water resources management.

Therapeutic potential of demethylzeylasteral, a triterpenoid of the genus Tripterygium wilfordii.

Pentacyclic triterpenoids are important natural products widely presenting in nature with rich bioactivities. Tripterygium wilfordii Hook. f., a precious Chinese medicinal material, is used to cure rheumatoid arthritis, nephrotic syndrome, systemic lupus erythematosus. Triterpenoids are one of the important active components of Tripterygium wilfordii Hook. f. Demethylzeylasteral extracted from Tripterygium wilfordii Hook. f. had numerous pharmacological effects, including anticancer, anti-inflammatory, immune suppression, anti-fertility, antivirus, antimicrobial. In this paper, we summarized comprehensively pharmacological activities of demethylzeylasteral for potential application as a therapeutic agent.

Daphnetin, a Coumarin in Genus Stellera Chamaejasme Linn: Chemistry, Bioactivity and Therapeutic Potential.

Coumarins is a huge family of phenolic compounds containing a common structure of 2H-1-benzopyran-2-one. Nowadays, more than 1,300 natural-based coumarins have been identified in a variety of plants, bacteria and fungi, many of them exhibited promising biomedical performance. Daphnetin (7,8-dihydroxycoumarin), a typical coumarin, showed a couple of bioactivities such as anti-cancer, antibacterial, anti-inflammatory and anti-arthritis. In the treatment of diseases, it has been verified that daphnetin has outstanding therapeutic effects on diabetes, arthritis, transplant rejection, cancer and even on central nervous system diseases. In China, it is being used for clinical applications, about 93 patent publications were associated with daphnetin. Due to its wide therapeutic potentials in clinical applications, numerous research on the action mechanisms and synthetic methods of daphnetin have been performed to support the future developments. Herein, we summarized the chemical synthetic methodologies, bioactivities, therapeutic potentials and structure-activity relationships of daphnetin and its derivatives. Moreover, the state-of-the-arts in current daphnetin study and future perspective in this field were discussed. Hopefully, this review would be beneficial for the discovery of new coumarin-based biomedicine in the near future.

Progress in Isoindolone Alkaloid Derivatives from Marine Microorganism: Pharmacology, Preparation, and Mechanism.

Compound 1 (SMTP-7, also FGFC1), an isoindolone alkaloid from marine fungi Starchbotrys longispora FG216 and fungi Stachybotrys microspora IFO 30018, possessed diverse bioactivities such as thrombolysis, anti-inflammatory and anti-oxidative properties, and so on. It may be widely used for the treatment of various diseases, including cerebral infarction, stroke, ischemia/reperfusion damage, acute kidney injury, etc. Especially in cerebral infarction, compound 1 could reduce hemorrhagic transformation along with thrombolytic therapy, as the traditional therapies are accompanied with bleeding risks. In the latest studies, compound 1 selectively inhibited the growth of NSCLC cells with EGFR mutation, thus demonstrating its excellent anti-cancer activity. Herein, we summarized pharmacological activities, preparation of staplabin congeners-especially compound 1-and the mechanism of compound 1, with potential therapeutic applications.

Lewis base sites of non-oxide supports boost oxygen absorption and activation over supported Pt catalysts.

Formaldehyde (HCHO) oxidation to improve indoor air quality has attracted extensive attention. Designing efficient catalysts for HCHO removal at room temperature still remains challenging. Herein, we report a novel strategy to boost HCHO oxidation by the synergistic effect of Pt nanoparticles and C3N4. The pyridine nitrogen of C3N4 can create Lewis base sites, which function in adsorbing and activating O2 molecules. As the preparation temperature increased, the pyridine nitrogen content increased on the C3N4 surface, leading to a more significant synergistic effect. The mechanism study by in situ DRIFTS indicated that the adsorbed O2 molecules were activated by Pt/C3N4. As a result, the Pt/C3N4-650 has the most outstanding performance for HCHO oxidation at room temperature. HCHO can be completely eliminated with a concentration of 80 ppm at room temperature at a GHSV of 50 000 ml g-1 h-1. This study will provide a new perspective to design efficient HCHO oxidation catalysts.

Alternative Complement Pathway Is Activated and Associated with Galactose-Deficient IgA1 Antibody in IgA Nephropathy Patients.

Background: Galactose-deficient IgA1 (Gd-IgA1) and alternative complement pathway activation are considered to be involved in the pathogenesis of IgA nephropathy (IgAN). Nevertheless, the relationships between alternative pathway activation and disease activity or Gd-IgA1 level remains unclear. Methods: Ninety-eight biopsy-diagnosed IgAN, twenty-five primary focal segmental sclerosis (FSGS) patients and forty-two healthy individuals were recruited in this study. Among them, fifty IgAN patients received immunosuppression. Follow-up blood samples at 1 and 3~6 months after immunosuppression were collected. Plasma levels of complement C5a, factor Ba and Gd-IgA1 were measured and analyzed. Immunostaining for complement was performed in twenty-five IgAN and FSGS patients. Results: At baseline, IgAN patients had higher levels of plasma C5a, factor Ba and Gd-IgA1 than control subjects. Gd-IgA1 levels positively correlated with plasma C5a and factor Ba. In addition, levels of factor Ba and Gd-IgA1 were positively associated with proteinuria and negatively associated with renal function. Immunostaining revealed positive staining for factor Bb and C3c in glomeruli in IgAN patients, but not in FSGS patients. At baseline, patients receiving immunosuppression had more severe proteinuria and higher factor Ba. After 6 months, eGFR declined and proteinuria persisted in patients without immunosuppression. In contrast, patients who received immunosuppression exhibited decreased plasma levels of C5a, factor Ba, and Gd-IgA1 as early as 1 month after treatment. Proteinuria decreased and renal function also remained stable 6 months after immunosuppression. Conclusions: Our results indicate a close relationship between alternative complement pathway activation, Gd-IgA1 concentration and clinical severity of IgAN. Level of complement factor B may be a potential marker for disease activity and therapeutic target in IgAN patients.

Risk of nephrogenic systemic fibrosis in patients with impaired renal function undergoing fixed-dose gadoxetic acid-enhanced magnetic resonance imaging.

PURPOSE: To assess the risk of nephrogenic systemic fibrosis (NSF) in patients with renal impairment undergoing gadoxetic acid-enhanced magnetic resonance imaging. METHODS: This retrospective study included patients who had an estimated glomerular filtration rate (eGFR) below 60 mL/min per 1.73 m2 or had undergone dialysis around the time of gadoxetic acid exposure from January 2010 to November 2019. All patients received at least one intravenous injection of gadoxetic acid at a fixed dose of 2.5 mmol. The primary endpoint was the development of NSF after exposure to gadoxetic acid based on Girardi's clinicopathological scoring system. RESULTS: A total of 204 patients with renal impairment received 424 injections of gadoxetic acid, of which 131 and 54 had an eGFR of 30-59 and < 30 mL/min per 1.73 m2, respectively, and 19 had undergone hemodialysis. Eighty-two patients received multiple injections, with 23 receiving five or more injections. The dose of each exposure ranged from 0.02 to 0.07 mmol/kg and the cumulative doses ranged from 0.02 to 0.45 mmol/kg. Thirty-three patients had concomitant Child-Pugh class B or C cirrhosis. No NSF was detected during follow-up (median 20 months; range 6 days to 111 months). The upper bound of the 95% confidence interval for NSF risk was 2.2% and 1.1% per patient and examination, respectively. CONCLUSION: No NSF was detected in this study. However, it is premature to ascertain the risk of NSF using gadoxetic acid in patients with renal impairment and further studies are warranted.

Novel Bioactive Polyketides Isolated from Marine Actinomycetes: An Update Review from 2013 to 2019.

Marine organism-associated actinobacteria represent a valuable resource for marine drugs due to their abundant secondary metabolites. The special environments in the ocean, for instance, high salt, high pressure, low temperature and oligotrophy, not only adapt to survival of actinomycetes but also enhance molecular diversity of actinomycete secondary metabolites production, thus making marine actinomycetes important sources of marine-based bioactive compounds, especially polyketides. Herein, we summarized the structures and pharmacological activities of polyketides from actinobacteria associated with marine organisms from 2013 to 2019; moreover, the main source species of actinomycetes were discussed as well. We expected that this review would be helpful for future in-depth research and development of marine-based bioactive polyketides.

6-(3,4-Di-fluoro-phen-yl)-7,8,13,14-tetra-hydro-dibenzo[c,k]phenanthridine.

In the title compound, C27H19F2N, the five-fused-ring system is highly puckered and the dihedral angle between the central pyridine ring and pendant di-fluoro-benzene ring is 45.12 (12)°. In the crystal, inversion dimers linked by pairwise weak C-H⋯N hydrogen bonds generate R 2 2(12) loops and the dimers are further linked by weak C-H⋯F inter-actions to form [01] chains.

Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway.

Human epidemiologic studies and laboratory investigations in animal models suggest that exposure to general anesthetic agents (GAs) have harmful effects on brain development. The mechanism underlying this putative iatrogenic condition is not clear and there are currently no accepted strategies for prophylaxis or treatment. Recent evidence suggests that anesthetics might cause persistent deficits in synaptogenesis by disrupting key events in neurodevelopment. Using an in vitro model consisting of dissociated primary cultured mouse neurons, we demonstrate abnormal pre- and post-synaptic marker expression after a clinically-relevant isoflurane anesthesia exposure is conducted during neuron development. We find that pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) pathway can reverse the observed changes. Isoflurane exposure increases expression of phospho-S6, a marker of mTOR pathway activity, in a concentration-dependent fashion and this effect occurs throughout neuronal development. The mTOR 1 complex (mTORC1) and the mTOR 2 complex (mTORC2) branches of the pathway are both activated by isoflurane exposure and this is reversible with branch-specific inhibitors. Upregulation of mTOR is also seen with sevoflurane and propofol exposure, suggesting that this mechanism of developmental anesthetic neurotoxicity may occur with all the commonly used GAs in pediatric practice. We conclude that GAs disrupt the development of neurons during development by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition.

Genome of Wild Mandarin and Domestication History of Mandarin.

Mandarin (Citrus reticulata) is one of the most important citrus crops worldwide. Its domestication is believed to have occurred in South China, which has been one of the centers of mandarin cultivation for four millennia. We collected natural wild populations of mandarin around the Nanling region and cultivated landraces in the vicinity. We found that the citric acid level was dramatically reduced in cultivated mandarins. To understand genetic basis of mandarin domestication, we de novo assembled a draft genome of wild mandarin and analyzed a set of 104 citrus genomes. We found that the Mangshan mandarin is a primitive type and that two independent domestication events have occurred, resulting in two groups of cultivated mandarins (MD1 and MD2) in the North and South Nanling Mountains, respectively. Two bottlenecks and two expansions of effective population size were identified for the MD1 group of cultivated mandarins. However, in the MD2 group there was a long and continuous decrease in the population size. MD1 and MD2 mandarins showed different patterns of interspecific introgression from cultivated pummelo species. We identified a region of high divergence in an aconitate hydratase (ACO) gene involved in the regulation of citrate content, which was possibly under selection during the domestication of mandarin. This study provides concrete genetic evidence for the geographical origin of extant wild mandarin populations and sheds light on the domestication and evolutionary history of mandarin.

Super-Enhancers and Broad H3K4me3 Domains Form Complex Gene Regulatory Circuits Involving Chromatin Interactions.

Stretched histone regions, such as super-enhancers and broad H3K4me3 domains, are associated with maintenance of cell identity and cancer. We connected super-enhancers and broad H3K4me3 domains in the K562 chronic myelogenous leukemia cell line as well as the MCF-7 breast cancer cell line with chromatin interactions. Super-enhancers and broad H3K4me3 domains showed higher association with chromatin interactions than their typical counterparts. Interestingly, we identified a subset of super-enhancers that overlap with broad H3K4me3 domains and show high association with cancer-associated genes including tumor suppressor genes. Besides cell lines, we could observe chromatin interactions by a Chromosome Conformation Capture (3C)-based method, in primary human samples. Several chromatin interactions involving super-enhancers and broad H3K4me3 domains are constitutive and can be found in both cancer and normal samples. Taken together, these results reveal a new layer of complexity in gene regulation by super-enhancers and broad H3K4me3 domains.

Roles, Functions, and Mechanisms of Long Non-coding RNAs in Cancer.

Long non-coding RNAs (lncRNAs) play important roles in cancer. They are involved in chromatin remodeling, as well as transcriptional and post-transcriptional regulation, through a variety of chromatin-based mechanisms and via cross-talk with other RNA species. lncRNAs can function as decoys, scaffolds, and enhancer RNAs. This review summarizes the characteristics of lncRNAs, including their roles, functions, and working mechanisms, describes methods for identifying and annotating lncRNAs, and discusses future opportunities for lncRNA-based therapies using antisense oligonucleotides.

Nonsense-mediated mRNA decay of collagen -emerging complexity in RNA surveillance mechanisms.

Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved mRNA surveillance system that degrades mRNA transcripts that harbour a premature translation-termination codon (PTC), thus reducing the synthesis of truncated proteins that would otherwise have deleterious effects. Although extensive research has identified a conserved repertoire of NMD factors, these studies have been performed with a restricted set of genes and gene constructs with relatively few exons. As a consequence, NMD mechanisms are poorly understood for genes with large 3' terminal exons, and the applicability of the current models to large multi-exon genes is not clear. In this Commentary, we present an overview of the current understanding of NMD and discuss how analysis of nonsense mutations in the collagen gene family has provided new mechanistic insights into this process. Although NMD of the collagen genes with numerous small exons is consistent with the widely accepted exon-junction complex (EJC)-dependent model, the degradation of Col10a1 transcripts with nonsense mutations cannot be explained by any of the current NMD models. Col10a1 NMD might represent a fail-safe mechanism for genes that have large 3' terminal exons. Defining the mechanistic complexity of NMD is important to allow us to understand the pathophysiology of the numerous genetic disorders caused by PTC mutations.