Discovery of novel diaryl substituted isoquinolin-1(2H)-one derivatives as hypoxia-inducible factor-1 signaling inhibitors for the treatment of rheumatoid arthritis.

Since synovial hypoxic microenvironment significantly promotes the pathological progress of rheumatoid arthritis (RA), hypoxia-inducible factor 1 (HIF-1) has been emerged as a promising target for the development of novel therapeutic agents for RA treatment. In this study, we designed and synthesized a series of diaryl substituted isoquinolin-1(2H)-one derivatives as HIF-1 signaling inhibitors using scaffold-hopping strategy. By modifying the substituents on N-atom and 6-position of isoquinolin-1-one, we discovered compound 17q with the most potent activities against HIF-1 (IC50 = 0.55 µM) in a hypoxia-reactive element (HRE) luciferase reporter assay. Further pharmacological studies revealed that 17q concentration-dependently blocked hypoxia-induced HIF-1α protein accumulation, reduced inflammation response, inhibited cellular invasiveness and promoted VHL-dependent HIF-1α degradation in human RA synovial cell line. Moreover, 17q improved the pathological injury of ankle joints, decreased angiogenesis and attenuated inflammation response in the adjuvant-induced arthritis (AIA) rat model, indicating the promising therapeutic potential of compound 17q as an effective HIF-1 inhibitor for RA therapy.

Chylous leakage after esophagectomy for esophageal cancer: a systematic review.

BACKGROUND: Chylous leakage is a rare complication following esophagectomy; however, it can lead to mortality. We aimed to systematically evaluate the factors that may lead to increased chylous leakage after esophagectomy. METHODS: Three databases (PubMed, Embase, and Cochrane Library) were systematically searched for all studies investigating the occurrence of chylous leakage after esophagectomy. RESULTS: A total of 32 studies were identified, including 26 randomized controlled trials and 3 cohort and case-control studies, each. The overall incidence of chylous leakage was 4.7% (278/5,971 cases). Analysis of preoperative, intraoperative, and postoperative factors showed that most of the qualitative analysis results did not significantly increase the incidence of chylous leakage. In some quantitative analyses, the chylous leakage rate was significantly lower in the thoracic duct mass ligation group than in the conservative treatment group (relative risk [RR] = 0.33; 95% confidence interval [CI], 0.13-0.83; I2 = 0.0%; P = 0.327). Direct oral feeding significantly reduced chylous leakage compared with jejunostomy (RR = 0.06; 95% CI 0.01-0.33; I2 = 0.0%; P = 0.335). However, preoperative inspiratory muscle training (RR = 1.66; 95% CI, 0.21-12.33; I2 = 55.5%; P = 0.134), preoperative chemoradiotherapy (RR = 0.99; 95% CI, 0.55-1.80; I2 = 0.0%; P = 0.943), and robotic assistance (RR = 1.62; 95% CI, 0.92-2.86; I2 = 0.0%; P = 0.814) did not significantly reduce the incidence of chylous leakage. CONCLUSIONS: Ligation of the thoracic duct and direct oral feeding can reduce the incidence of chylous leakage after esophagectomy in patients with esophageal cancer. Other contributing factors remain unclear and require validation in further high-quality studies.

The effects of Mediterranean diet on cardiovascular risk factors, glycemic control and weight loss in patients with type 2 diabetes: a meta-analysis.

To explore the impact of the Mediterranean diet on cardiovascular risk factors, glycemic control and weight loss in patients with type 2 diabetes(T2D) by a meta-analysis of randomized controlled trials (RCTs). We systematically searched PubMed, Cochrance Library, EMBASE and four Chinese databases to identify RCTs that compared the Mediterranean diet with control diets in patients with T2D up to December 2021. The Risk of Bias of the included studies was assessed using the version 2 of the Cochrane risk-of-bias tools for randomized trials (ROB 2). Seven RCTs with 1371 patients met the eligibility criteria and entered into the meta-analysis. Compared to control diets, the beneficial effects of Mediterranean diet were not statistically significant in high-density lipoprotein (MD = 2.33; 95% CI: -0.27 to 4.92), low-density lipoprotein (MD = -2.34; 95% CI -5.67 to 0.99) and total cholesterol (MD = 2.60; 95% CI: -0.95 to 6.15). But Mediterranean diet led to reduce the level of diastolic blood pressure (MD = -1.20; 95% CI: -2.21 to -0.19) and systolic blood pressure (MD = -4.17; 95% CI: -7.12 to -1.22). Meanwhile, Mediterranean diet showed beneficial effects in glycemic control (HbA1[%]: MD = -0.39, 95% CI: -0.58 to -0.20; fasting plasma glucose: MD = -15.12, 95% CI: -24.69 to -5.55) and weight loss (BMI: MD = -0.71, 95% CI: -1.30 to -0.78; WC: MD = -1.69; 95% CI: -3.35 to -0.02) compared to the control diets. The meta-analysis presented evidence supporting the beneficial effects of the Mediterranean diet on blood pressure, glycemic control, and weight loss. However, the impact of the Mediterranean diet on the lipid profile was not found to be significant, warranting further verification. This Meta-analysis was registered on the INPLASY website (Registration number: INPLASY 202160096).

Biosynthesis and Anticancer Activity of Genistein Glycoside Derivatives.

As a beneficial natural flavonoid, genistein has demonstrated a wide range of biological functions via regulating a number of targets and signaling pathways, such as anti-cancer, antioxidant, antibacterial, antiinflammatory, antifungal, antiviral, iron chelation, anti-obesity, anti-diabetes, and anti-hypertension. PubMed/Medline and Web of Science were searched using appropriate keywords until the end of December 2023. Despite its many potential benefits, genistein's clinical application is limited by low hydrophilicity, poor solubility, and suboptimal bioavailability due to its structure. These challenges can be addressed through the conversion of genistein into glycosides. Glycosylation of active small molecules may enhance their solubility, stability, and biological activity. In recent years, extensive research has been conducted on the synthesis, properties, and anticancer activity of glycoconjugates. Previous reviews were devoted to discussing the biological activities of genistin, with a little summary of the biosynthesis and the structure-activity relationship for their anticancer activity of genistein glycoside derivatives. Therefore, we summarized recent advances in the biosynthesis of genistein glycosylation and discussed the antitumor activities of genistein glycoside derivatives in a structure-activity relationship, which may provide important information for further development of genistein derivatives.

Noninvasive Artificial Intelligence System for Early Predicting Residual Cancer Burden during Neoadjuvant Chemotherapy in Breast Cancer.

OBJECTIVE: To develop an artificial intelligence (AI) system for the early prediction of residual cancer burden (RCB) scores during neoadjuvant chemotherapy (NAC) in breast cancer. SUMMARY BACKGROUND DATA: RCB III indicates drug resistance in breast cancer, and early detection methods are lacking. METHODS: This study enrolled 1048 patients with breast cancer from four institutions, who were all receiving NAC. Magnetic resonance images were collected at the pre- and mid-NAC stages, and radiomics and deep learning features were extracted. A multitask AI system was developed to classify patients into three groups (RCB 0-I, II, and III ) in the primary cohort (PC, n=335). Feature selection was conducted using the Mann-Whitney U- test, Spearman analysis, least absolute shrinkage and selection operator regression, and the Boruta algorithm. Single-modality models were developed followed by model integration. The AI system was validated in three external validation cohorts. (EVCs, n=713). RESULTS: Among the patients, 442 (42.18%) were RCB 0-I, 462 (44.08%) were RCB II and 144 (13.74%) were RCB III. Model-I achieved an area under the curve (AUC) of 0.975 in the PC and 0.923 in the EVCs for differentiating RCB III from RCB 0-II. Model-II distinguished RCB 0-I from RCB II-III, with an AUC of 0.976 in the PC and 0.910 in the EVCs. Subgroup analysis confirmed that the AI system was consistent across different clinical T stages and molecular subtypes. CONCLUSIONS: The multitask AI system offers a noninvasive tool for the early prediction of RCB scores in breast cancer, supporting clinical decision-making during NAC.

Clinical efficacy of tumor organoid-guided cancer therapy for locally advanced unresectable or metastatic breast cancer.

Patient-derived organoids (PDOs) may facilitate treatment selection. This retrospective cohort study evaluated the feasibility and clinical benefit of using PDOs to guide personalized treatment in metastatic breast cancer (MBC). Patients diagnosed with MBC were recruited between January 2019 and August 2022. PDOs were established and the efficacy of customized drug panels was determined by measuring cell mortality after drug exposure. Patients receiving organoid-guided treatment (OGT) were matched 1:2 by nearest neighbor propensity scores with patients receiving treatment of physician's choice (TPC). The primary outcome was progression-free survival. Secondary outcomes included objective response rate and disease control rate. Targeted gene sequencing and pathway enrichment analysis were performed. Forty-six PDOs (46 of 51, 90.2%) were generated from 45 MBC patients. PDO drug screening showed an accuracy of 78.4% (95% CI 64.9%-91.9%) in predicting clinical responses. Thirty-six OGT patients were matched to 69 TPC patients. OGT was associated with prolonged median progression-free survival (11.0 months vs. 5.0 months; hazard ratio 0.53 [95% CI 0.33-0.85]; p = .01) and improved disease control (88.9% vs. 63.8%; odd ratio 4.26 [1.44-18.62]) compared with TPC. The objective response rate of both groups was similar. Pathway enrichment analysis in hormone receptor-positive, human epidermal growth factor receptor 2-negative patients demonstrated differentially modulated pathways implicated in DNA repair and transcriptional regulation in those with reduced response to capecitabine/gemcitabine, and pathways associated with cell cycle regulation in those with reduced response to palbociclib. Our study shows that PDO-based functional precision medicine is a feasible and effective strategy for MBC treatment optimization and customization.

High Level of Serum Complement C3 Expression is Associated with Postoperative Vasculopathy Progression in Moyamoya Disease.

Background: The immune system plays an important role in the onset and development of moyamoya disease (MMD), but the specific mechanisms remain unclear. This study aimed to explore the relationship between the expression of complements and immunoglobulin in serum and progression of MMD. Methods: A total of 84 patients with MMD and 70 healthy individuals were enrolled. Serum immunoglobulin and complement C3 and C4 expression were compared between healthy individuals and MMD patients. Follow-up was performed at least 6 months post-operation. Univariate and multivariate analysis after adjusting different covariates were performed to explore predictive factors associated with vasculopathy progression. A nomogram basing on the results of multivariate analysis was established to predict vasculopathy progression. Results: Compared to healthy individuals, MMD patients had significantly lower expression of serum complements C3 (P = 0.003*). Among MMD patients, C3 was significantly lower in those with late-stage disease (P = 0.001*). Of 84 patients, 27/84 (32.1%) patients presented with vasculopathy progression within a median follow-up time of 13.0 months. Age (P=0.006*), diastolic blood pressure (P=0.004*) and serum complement C3 expression (P=0.015*) were associated with vasculopathy progression after adjusting different covariables. Conclusion: Complement C3 is downregulated in moyamoya disease and decreases even further in late-Suzuki stage disease. Age, diastolic blood pressure and serum complement C3 expression are associated with vasculopathy progression, suggesting that the complement might be involved in the development of moyamoya disease.

[Digital study on proximal clavicle anatomical plate based on 3D printing technology].

OBJECTIVE: To explore feasibility of 3D metal printing technology combined with virtual design proximal clavicle anatomical plate. METHODS: A 52-year-old male healthy volunteer was retrospectively selected to design proximal clavicle anatomical plate system by using Mimics15.01,NX12.0 and other software. STL data were input into 3D printer to print 1:1 clavicle model and proximal clavicle anatomical plate. The fit of the plate was tested in vitro and the accuracy of screw position was evaluated by imaging. Printing time of model,nail path design and fabrication time of the anatomical plate at proximal clavicle were recorded. RESULTS: The 3D metal printing proximal clavicle anatomical plate fitted well to clavicle model,orientation of proximal clavicle locking screw was accurate,and X-ray and CT scan showed the screw position was good. Printing time of model,the time of nail path design,and the time of making anatomical plate of proximal clavicle were 120,15 and 300 min respectively. CONCLUSION: The proximal clavicular anatomical plate system based on 3D metal printing technology could achieve good lamination of proximal clavicular fracture plate and precise screw placement,providing a new and accurate surgical method for the treatment of the proximal clavicular fracture.

Consumption of Citric Acid by Bees Promotes the Gland Development and Enhances Royal Jelly Quality.

The glands of bees are responsible for generating and secreting various biologically active substances that significantly impact bee physiological health and adaptability. This study aimed to investigate the effects of adding citric acid (CA) to bee feed on gland development and royal jelly quality. By formulating feed with varying proportions of CA, evaluation was undertaken of pollen feeding by honeybees under laboratory conditions, along with the impact of CA on the development of major glands, to determine suitable addition proportions. Further optimization of the CA proportion involved feeding colonies and evaluating royal jelly production and quality. The results indicated that feed containing 0.75% CA significantly extended the lifespan of bees and increased their pollen consumption. Gland development in bees showed a positive correlation with CA addition within the range of 0.25% to 0.75%, especially at 0.50% and 0.75%, which notably accelerated the development of mandibular, hypopharyngeal, and cephalic salivary glands, with active proliferation and differentiation of glandular cells and maintenance of normal gland size and morphology. CA added to feed stimulated vigorous secretion of wax glands in worker bees, resulting in prolific wax construction. Colonies consuming feed containing 0.50% CA produced royal jelly with significantly reduced moisture and total sugar content and increased levels of 10-HDA, total phenolic acids, total proteins, and acidity. These findings demonstrate that CA consumption significantly prolongs bee lifespan, increases consumption, promotes gland development, and enhances royal jelly quality. This research provides theoretical guidance for beekeeping practices and feed development, contributing to the sustainable advancement of apiculture.

1 H-NMR revealed pyruvate as a differentially abundant metabolite in the venom glands of Apis cerana and Apis mellifera.

As a common defense mechanism in Hymenoptera, bee venom has complex components. Systematic and comprehensive analysis of bee venom components can aid in early evaluation, accurate diagnosis, and protection of organ function in humans in cases of bee stings. To determine the differences in bee venom composition and metabolic pathways between Apis cerana and Apis mellifera, proton nuclear magnetic resonance (1 H-NMR) technology was used to detect the metabolites in venom samples. A total of 74 metabolites were identified and structurally analyzed in the venom of A. cerana and A. mellifera. Differences in the composition and abundance of major components of bee venom from A. cerana and A. mellifera were mapped to four main metabolic pathways: valine, leucine and isoleucine biosynthesis; glycine, serine and threonine metabolism; alanine, aspartate and glutamate metabolism; and the tricarboxylic acid cycle. These findings indicated that the synthesis and metabolic activities of proteins or polypeptides in bee venom glands were different between A. cerana and A. mellifera. Pyruvate was highly activated in 3 selected metabolic pathways in A. mellifera, being much more dominant in A. mellifera venom than in A. cerana venom. These findings indicated that pyruvate in bee venom glands is involved in various life activities, such as biosynthesis and energy metabolism, by acting as a precursor substance or intermediate product.

Isolated anterior cerebral artery occlusion: an atypical form of moyamoya disease.

BACKGROUND: The relationship between anterior cerebral artery (ACA) occlusion and moyamoya disease (MMD) has rarely been studied. In this study, we focused on a special type of MMD: isolated ACA-occlusive MMD. We investigated clinical attributes, genotypes and progression risk factors in patients with ACA-occlusive MMD, providing initial insights into the relationship between ACA occlusion and MMD. METHODS: We retrospectively analysed digital subtraction angiography (DSA) from 2486 patients and diagnosed 139 patients with ACA-occlusive MMD. RNF213 p.R4810K (rs112735431) mutation analysis was performed. Patients were categorised into progression and non-progression groups based on whether they progressed to typical MMD. Differences in clinical characteristics, neuropsychological assessment, radiological findings and genotypes were evaluated. Logistic regression analyses identified risk factors for ACA-occlusive MMD progression. RESULTS: The median age of patients with ACA-occlusive MMD was 36 years, and the primary symptom was transient ischaemic attack (TIA). 72.3% of ACA-occlusive MMD patients had cognitive decline. Of 116 patients who underwent RNF213 gene mutation analysis, 90 patients (77.6%) carried the RNF213 p.R4810K GG allele and 26 (22.4%) carried the GA allele. Of 102 patients with follow-up DSA data, 40 patients (39.2%) progressed. Kaplan-Meier curve estimates indicated a higher incidence of ischaemic stroke in the progression group during follow-up (p=0.035). Younger age (p=0.041), RNF213 p.R4810K GA genotype (p=0.037) and poor collateral compensation from the middle cerebral artery (MCA) to ACA (p<0.001) were risk factors of ACA-occlusive MMD progression to typical MMD. CONCLUSIONS: Cognitive decline and TIA might be the main manifestations of ACA-occlusive MMD. Isolated ACA occlusion may be an early signal of MMD. The initial lesion site of MMD is not strictly confined to the terminal portion of the internal carotid artery. Younger patients, patients with RNF213 p.R4810K GA genotype or those with inadequate MCA-to-ACA compensation are more likely to develop typical MMD.

Compensatory growth of Microcystis aeruginosa after copper stress and the characteristics of algal extracellular organic matter (EOM).

Cyanobacterial blooms can impair drinking water quality due to the concomitant extracellular organic matter (EOM). As copper is often applied as an algicide, cyanobacteria may experience copper stress. However, it remains uncertain whether algal growth compensation occurs and how EOM characteristics change in response to copper stress. This study investigated the changes in growth conditions, photosynthetic capacity, and EOM characteristics of M. aeruginosa under copper stress. In all copper treatments, M. aeruginosa experienced a growth inhibition stage followed by a growth compensation stage. Notably, although chlorophyll-a fluorescence parameters dropped to zero immediately following high-intensity copper stress (0.2 and 0.5 mg/L), they later recovered to levels exceeding those of the control, indicating that photosystem II was not destroyed by copper stress. Copper stress influenced the dissolved organic carbon (DOC) content, polysaccharides, proteins, excitation-emission matrix spectra, hydrophobicity, and molecular weight (MW) distribution of EOM, with the effects varying based on stress intensity and growth stage. Principal component analysis revealed a correlation between the chlorophyll-a fluorescence parameters and EOM characteristics. These results imply that copper may not be an ideal algicide. Further research is needed to explore the dynamic response of EOM characteristics to environmental stress.

Design, synthesis and evaluation of C-5 substituted pyrrolopyridine derivatives as potent Janus Kinase 1 inhibitors with excellent selectivity.

The development of highly selective Janus Kinase 1 (JAK1) inhibitors is crucial for improving efficacy and minimizing adverse effects in the clinical treatment of autoimmune diseases. In a prior study, we designed a series of C-5 4-pyrazol substituted pyrrolopyridine derivatives that demonstrated significant potency against JAK1, with a 10 âˆ¼ 20-fold selectivity over Janus Kinase 2 (JAK2). Building on this foundation, we adopted orthogonal strategy by modifying the C-5 position with 3-pyrazol/4-pyrazol/3-pyrrol groups and tail with substituted benzyl groups on the pyrrolopyridine head to enhance both potency and selectivity. In this endeavor, we have identified several compounds that exhibit excellent potency and selectivity for JAK1. Notably, compounds 12b and 12e, which combined 4-pyrazol group at C-5 site and meta-substituted benzyl tails, displayed IC50 value with 2.4/2.2 nM and high 352-/253-fold selectivity for JAK1 over JAK2 in enzyme assays. Additionally, both compounds showed good JAK1-selective in Ba/F3-TEL-JAK1/2 cell-based assays. These findings mark a substantial improvement, as these compounds are 10-fold more potent and over 10-fold more selective than the best compound identified in our previous study. The noteworthy potency and selectivity properties of compounds 12b and 12e suggest their potential utility in furthering the development of drugs for autoimmune diseases.

Clinical and genetic factors associated with contralateral progression in unilateral moyamoya disease: Longitudinal and Cross-Sectional Study.

Objective: This study aimed to explore the long-term outcome of unilateral moyamoya disease and predict the clinical and genetic factors associated with contralateral progression in unilateral moyamoya disease. Methods: We retrospectively recruited unilateral moyamoya disease patients with available genetic data who underwent encephaloduroarteriosynangiosis (EDAS) surgery at our institution from January 2009 to November 2017. Long-term follow-up data, including clinical outcomes, angiographic features, and genetic information, were analyzed. Results: A total of 83 unilateral moyamoya disease patients with available genetic data were enrolled in our study. The mean duration of clinical follow-up was 7.9 ± 2.0 years. Among all patients, 19 patients demonstrated contralateral progression to bilateral disease. Heterozygous Ring Finger Protein 213 p.R4810K mutations occurred significantly more frequently in unilateral moyamoya disease patients with contralateral progression. Furthermore, patients with contralateral progression typically demonstrated an earlier age of onset than those with non-progressing unilateral moyamoya disease. In the contralateral progression group, posterior circulation involvement was observed in 11 (11/19, 57.9%) patients compared to 12 (12/64, 18.8%) in the non-contralateral progression group (P = 0.001). The time to peak of cerebral perfusion and neurological status showed significant postoperative improvement. Conclusion: Long-term follow-up revealed that the EDAS procedure might provide benefits for unilateral moyamoya disease patients. Ring Finger Protein 213 p.R4810K mutations, younger age, and posterior circulation involvement might predict the contralateral progression of unilateral moyamoya disease.

Employing Atomic Force Microscopy (AFM) for Microscale Investigation of Interfaces and Interactions in Membrane Fouling Processes: New Perspectives and Prospects.

Membrane fouling presents a significant challenge in the treatment of wastewater. Several detection methods have been used to interpret membrane fouling processes. Compared with other analysis and detection methods, atomic force microscopy (AFM) is widely used because of its advantages in liquid-phase in situ 3D imaging, ability to measure interactive forces, and mild testing conditions. Although AFM has been widely used in the study of membrane fouling, the current literature has not fully explored its potential. This review aims to uncover and provide a new perspective on the application of AFM technology in future studies on membrane fouling. Initially, a rigorous review was conducted on the morphology, roughness, and interaction forces of AFM in situ characterization of membranes and foulants. Then, the application of AFM in the process of changing membrane fouling factors was reviewed based on its in situ measurement capability, and it was found that changes in ionic conditions, pH, voltage, and even time can cause changes in membrane fouling morphology and forces. Existing membrane fouling models are then discussed, and the role of AFM in predicting and testing these models is presented. Finally, the potential of the improved AFM techniques to be applied in the field of membrane fouling has been underestimated. In this paper, we have fully elucidated the potentials of the improved AFM techniques to be applied in the process of membrane fouling, and we have presented the current challenges and the directions for the future development in an attempt to provide new insights into this field.

Macroscopic model and statistical model to characterize electromagnetic information of a digital coding metasurface.

A digital coding metasurface is a platform connecting the digital space and electromagnetic wave space, and has therefore gained much attention due to its intriguing value in reshaping wireless channels and realizing new communication architectures. Correspondingly, there is an urgent need for electromagnetic information theory that reveals the upper limit of communication capacity and supports the accurate design of metasurface-based communication systems. To this end, we propose a macroscopic model and a statistical model of the digital coding metasurface. The macroscopic model uniformly accommodates both digital and electromagnetic aspects of the meta-atoms and predicts all possible scattered fields of the digital coding metasurface based on a small number of simulations or measurements. Full-wave simulations and experimental results show that the macroscopic model is feasible and accurate. A statistical model is further proposed to correlate the mutual coupling between meta-atoms with covariance and to calculate the entropy of the equivalent currents of digital coding metasurface. These two models can help reconfigurable intelligent surfaces achieve more accurate beamforming and channel estimation, and thus improve signal power and coverage. Moreover, the models will encourage the creation of a precoding codebook in metasurface-based direct digital modulation systems, with the aim of approaching the upper limit of channel capacity. With these two models, the concepts of current space and current entropy, as well as the analysis of information loss from the coding space to wave space, is established for the first time, helping to bridge the gap between the digital world and the physical world, and advancing developments of electromagnetic information theory and new-architecture wireless systems.

High altitude retinopathy: An overview and new insights.

High altitude retinopathy (HAR) is a common ocular disorder that occurs on ascent to high altitude. There are many clinical symptoms, retinal vascular dilatation, retinal edema and hemorrhage are common. These usually do not or slightly affect vision; rarely, severe cases develop serious or permanent vision loss. At present, the research progress of HAR mainly focuses on hemodynamic changes, blood-retinal barrier damage, oxidative stress and inflammatory response. Although the related studies on HAR are limited, it shows that HAR still belongs to hypoxia, and hypobaric hypoxia plays an aggravating role in promoting the development of the disease. Various studies have demonstrated the correlation of HAR with acute mountain sickness (AMS) and high-altitude cerebral edema (HACE), so a deeper understanding of HAR is important. The slow ascent rates and ascent altitude are the key to preventing any altitude sickness. Research on traditional chinese medicine (TCM) and western medicine has been gradually carried out. Further exploration of the pathogenesis and prevention strategies of HAR will provide better guidance for doctors and high-altitude travelers.

GCY-20 signaling controls suppression of Caenorhabditis elegans egg laying by moderate cold.

Organisms sensing environmental cues and internal states and integrating the sensory information to control fecundity are essential for survival and proliferation. The present study finds that a moderate cold temperature of 11°C reduces egg laying in Caenorhabditis elegans. ASEL and AWC neurons sense the cold via GCY-20 signaling and act antagonistically on egg laying through the ASEL and AWC/AIA/HSN circuits. Upon cold stimulation, ASEL and AWC release glutamate to activate and inhibit AIA interneurons by acting on highly and lowly sensitive ionotropic GLR-2 and GLC-3 receptors, respectively. AIA inhibits HSN motor neuron activity via acetylcholinergic ACR-14 receptor signaling and suppresses egg laying. Thus, ASEL and AWC initiate and reduce the cold suppression of egg laying. ASEL's action on AIA and egg laying dominates AWC's action. The biased opposite actions of these neurons on egg laying provide animals with a precise adaptation of reproductive behavior to environmental temperatures.

Identification of patients with nonischemic dilated cardiomyopathy at risk of malignant ventricular arrhythmias: insights from cardiac magnetic resonance feature tracking.

BACKGROUND: Patients with nonischemic dilated cardiomyopathy (NIDCM) are prone to arrhythmias, and the cause of mortality in these patients is either end-organ dysfunction due to pump failure or malignant arrhythmia-related death. However, the identification of patients with NIDCM at risk of malignant ventricular arrhythmias (VAs) is challenging in clinical practice. The aim of this study was to evaluate whether cardiovascular magnetic resonance feature tracking (CMR-FT) could help in the identification of patients with NIDCM at risk of malignant VAs. METHODS: A total of 263 NIDCM patients who underwent CMR, 24-hour Holter electrocardiography (ECG) and inpatient ECG were retrospectively evaluated. The patients with NIDCM were allocated to two subgroups: NIDCM with VAs and NIDCM without VAs. From CMR-FT, the global peak radial strain (GPRS), global longitudinal strain (GPLS), and global peak circumferential strain (GPCS) were calculated from the left ventricle (LV) model. We investigated the possible predictors of NIDCM combined with VAs by univariate and multivariate logistic regression analyses. RESULTS: The percent LGE (15.51 ± 3.30 vs. 9.62 ± 2.18, P < 0.001) was higher in NIDCM patients with VAs than in NIDCM patients without VAs. Furthermore, the NIDCM patients complicated with VAs had significantly lower GPCS than the NIDCM patients without VAs (- 5.38 (- 7.50, - 4.22) vs.-9.22 (- 10.73, - 8.19), P < 0.01). Subgroup analysis based on LGE negativity showed that NIDCM patients complicated with VAs had significantly lower GPRS, GPCS, and GPLS than NIDCM patients without VAs (P < 0.05 for all). Multivariate analysis showed that both GPCS and %LGE were independent predictors of NIDCM combined with VAs. CONCLUSIONS: CMR global strain can be used to identify NIDCM patients complicated with VAs early, specifically when LGE is not present. GPCS < - 13.19% and %LGE > 10.37% are independent predictors of NIDCM combined with VAs.

Advances in ß-Diketocyclisation of Curcumin Derivatives and their Antitumor Activity.

Curcumin, derived from the popular spice turmeric, is a pharmacologically active polyphenol. Curcumin's therapeutic activity has been extensively studied in recent decades, with reports implicating curcumin in many biological activities, particularly, its significant anticancer activity. However, its potential as an oral administration product is hampered by poor bioavailability, which is associated with a variety of factors, including low water solubility, poor intestinal permeability, instability, and degradation at alkaline pH. To improve its bioavailability, modifying ß-diketone curcumin with heterocycles, such as pyrazole, isoxazole and triazole is a powerful strategy. Derivatives are synthesized while maintaining the basic skeleton of curcumin. The ß-diketone cyclized curcumin derivatives are regulators of multiple molecular targets, which play vital roles in a variety of cellular pathways. In some literatures, structurally modified curcumin derivatives have been compared with curcumin, and the former has enhanced biological activity, improved water solubility and stability. Therefore, the scope of this review is to report the most recently synthesized heterocyclic derivatives and to classify them according to their chemical structures. Several of the most important and effective compounds are reviewed by introducing different active groups into the ß-diketone position to achieve better therapeutic efficacy and bioavailability.