Heterometallic-organic cages with customized cavities: constructed by bottom-up step-wise coordination-driven self-assembly.

accurately synthesizing coordination-driven metal-organic cages with customized shape and cavity remain a great challenge for chemists. In this work, a bottom-up step-wise coordination-driven self-assembly approach was put forward. Employing this strategy, three terpyridyl heterometallic-organic truncated tetrahedral cages with different sizes and cavity were precisely synthesized. Firstly, the coordination of tripodal organic ligands with Ru2+ afforded dendritic metal-organic ligands L1-L3. Then the Ru building blocks complexed with Fe2+ and shrunk to form the desired heterometallic-organic cages (C1-C3). These discrete heterometallic-organic supramolecular cages were fully characterized and displayed the large and open cavities varied from 7205 Å3 to 9384 Å3. Notably, these cages could not be directly constructed by single-step assembly process using initial organic ligands or dimeric metal-organic ligands, indicative of the irreplaceability of a bottom-up step-wise assembly strategy for size-customized architectures. This work paves a new way for precisely constructing metal-organic cages with well-defined cavities.

Association between prescription opioid use and heart failure: Cohort studies and Mendelian randomization analysis.

BACKGROUND: Prescription opioid use (POU) has been shown to lead to cardiovascular disease (CVD), but its association with heart failure has not been well studied. We investigated the potential causal association between POU and HF using cohort studies and Mendelian Randomization (MR) analysis. METHODS: Initially, we examined the longitudinal association between POU and HF using the data from the Health and Retirement Study (HRS) and the UK biobank. Next, we employed a two-sample MR analysis using summary statistics from genome-wide association studies (GWAS) to assess the potential causal associations between POU and HF. RESULTS: During a median of 3.8 and 13.8 years of follow-up, there were 441(8.04 per 1000 person-year) and 16,170 (3.96 per 1000 person-year) HF cases in the HRS and the UK biobank, respectively. After adjusting for covariates, participants who used prescription opioids had a 32% increased risk of developing HF, compared with non-users (HR = 1.32, 95%CI: 1.26-1.38, P < 0.001). In the MR analysis, summary statistics for POU were obtained from 78,808 UK Biobank study participants, and summary data for HF were obtained from 218,792 participants of a European population. A causal effect of genetic liability for POU on an increased risk of HF (OR = 1.16, 95% CI = 1.06, 1.27, P = 0.001) was suggested. The results were generally consistent in the sensitivity analysis, and no pleiotropy or heterogeneity were observed. CONCLUSIONS: POU is associated with a high risk of HF. Our findings provide new insight into prescription opioid use among populations at risk of heart failure. More studies are needed to validate our results and further investigate the underlying mechanisms.

Long-Term Visit-to-Visit Blood Pressure Variability and Cognitive Decline Among Patients With Hypertension: A Pooled Analysis of 3 National Prospective Cohorts.

BACKGROUND: A limited number of studies investigated the association between blood pressure variability (BPV) and cognitive impairment in patients with hypertension. This study aimed to identify the longitudinal association between BPV and cognitive decline and the role of blood pressure (BP) control in this association. METHODS AND RESULTS: Participants with hypertension from the HRS (Health and Retirement Study), the ELSA (English Longitudinal Study of Ageing), and the CHARLS (China Health and Retirement Longitudinal Study) were included. Variation independent of the mean (VIM) was adopted to measure BPV. Cognitive function was measured by standard questionnaires, and a standardized Z score was calculated. Linear mixed-model and restricted cubic splines were adopted to explore the association between BPV and cognitive decline. The study included 4853, 1616, and 1432 eligible patients with hypertension from the HRS, ELSA, and CHARLS, respectively. After adjusting for covariates, per-SD increment of VIM of BP was significantly associated with global cognitive function decline in Z scores in both systolic BP (pooled ß, -0.045 [95% CI, -0.065 to -0.029]) and diastolic BP (pooled ß, -0.022 [95% CI, -0.040 to -0.004]) among hypertensive patients. Similar inverse associations were observed in patients with hypertension taking antihypertensive drugs and in patients with hypertension with well-controlled BP. CONCLUSIONS: High BPV was independently associated with a faster cognitive decline among patients with hypertension, even those with antihypertensive medications or well-controlled BP. Further studies are needed to confirm our results and determine whether reducing BPV can prevent or delay cognitive decline.

Exploration and structure-activity relationship research of benzenesulfonamide derivatives as potent TRPV4 inhibitors for treating acute lung injury.

RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 µM and 0.46 ± 0.08 µM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 µM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 µM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.

Summer heatwaves promote harmful algal blooms in the Fuchunjiang Reservoir, an important drinking water source.

Extensive outbreaks of harmful algal blooms (HABs) occurred in the Fuchunjiang Reservoir in 2022, a crucial urban drinking water source, coinciding with extreme summer heatwaves. We hypothesize that these heatwaves contributed to HABs formation and expansion. Leveraging Landsat 8 and Sentinel-2 data, we employed clustering and machine learning methods to quantify the HABs distribution and area. Concurrent meteorological and water quality data aided in uncovering the effects of heatwave on HABs. When applying different methods to extract HABs from remote sensing images, random forest (RF) analyses indicated accuracies of 99.3% and 99.8% for Landsat 8 and Sentinel-2 data, respectively, while classification and regression tree (CART) analyses indicated 99.1% and 99.7% accuracies, respectively. Support vector machine (SVM) exhibited lower accuracies (83.5% and 97.4%). Thus RF, given its smaller differences between satellites and high accuracy, was selected for further analysis. Both satellites detected extensive HABs in 2022, with Sentinel-2 recording a peak area of 24.13 km2 (44.6% of cloud-free water area) on August 11, 2022. Increasing trends with amplified durations were observed for summer heatwaves in Jiande and Tonglu around the Fuchunjiang Reservoir. Notably, these areas experienced extreme heatwaves for 63 and 58 days in 2022, respectively, more than double the 1980-2022 average. From June 1 to October 8, 2022, water temperature peaks significantly coincided with expansive HABs and elevated chlorophyll a (Chl-a) concentration from 4.8 µg/L to 119.2 µg/L during the summer heatwaves. Our findings indicated that the reservoir became more HAB-prone during heatwave events, escalating the drinking water safety risk. These results emphasize the challenges faced by reservoir managers in dealing with climate-induced extreme heatwaves and underscore the urgency for heightened attention from water source management departments.

Identification of dihydroquinolizinone derivatives with nitrogen heterocycle moieties as new anti-HBV agents.

The sustained loss of HBsAg is considered a pivotal indicator for achieving functional cure of HBV. Dihydroquinolizinone derivatives (DHQs) have demonstrated remarkable inhibitory activity against HBsAg both in vitro and in vivo. However, the reported neurotoxicity associated with RG7834 has raised concerns regarding the development of DHQs. In this study, we designed and synthesized a series of DHQs incorporating nitrogen heterocycle moieties. Almost all of these compounds exhibited potent inhibition activity against HBsAg, with IC50 values at the nanomolar level. Impressively, the compound (S)-2a (10 µM) demonstrated a comparatively reduced impact on the neurite outgrowth of HT22 cells and isolated mouse DRG neurons in comparison to RG7834, thereby indicating a decrease in neurotoxicity. Furthermore, (S)-2a exhibited higher drug exposures than RG7834. The potent anti-HBV activity, reduced neurotoxicity, and favorable pharmacokinetic profiles underscore its promising potential as a lead compound for future anti-HBV drug discovery.

A genome-wide association study reveals the relationship between human genetic variation and the nasal microbiome.

The nasal cavity harbors diverse microbiota that contributes to human health and respiratory diseases. However, whether and to what extent the host genome shapes the nasal microbiome remains largely unknown. Here, by dissecting the human genome and nasal metagenome data from 1401 healthy individuals, we demonstrated that the top three host genetic principal components strongly correlated with the nasal microbiota diversity and composition. The genetic association analyses identified 63 genome-wide significant loci affecting the nasal microbial taxa and functions, of which 2 loci reached study-wide significance (p < 1.7 × 10-10): rs73268759 within CAMK2A associated with genus Actinomyces and family Actinomycetaceae; and rs35211877 near POM121L12 with Gemella asaccharolytica. In addition to respiratory-related diseases, the associated loci are mainly implicated in cardiometabolic or neuropsychiatric diseases. Functional analysis showed the associated genes were most significantly expressed in the nasal airway epithelium tissue and enriched in the calcium signaling and hippo signaling pathway. Further observational correlation and Mendelian randomization analyses consistently suggested the causal effects of Serratia grimesii and Yokenella regensburgei on cardiometabolic biomarkers (cystine, glutamic acid, and creatine). This study suggested that the host genome plays an important role in shaping the nasal microbiome.

The objectively measured walking speed and risk of hypertension in Chinese older adults: a prospective cohort study.

This study aims to investigate the longitudinal association between objectively measured walking speed and hypertension and to explore the potential effect modification of obesity on this association in Chinese older adults. The data from the Chinese Health and Retirement Prospective Cohort Study (CHARLS) during 2011-2015 was used. Walking speed was assessed by measuring the participants' usual gait in a 2.5 m course, and it was divided into four groups according to the quartiles (Q1, Q2, Q3, and Q4). A total of 2733 participants ≥60 years old were eligible for the analyses. After a follow-up of 4 years, 26.9% occurred hypertension. An inverse association was observed between walking speed and the risk of hypertension. There was an interaction between body mass index (BMI) and walking speed for the hypertension risk (P = 0.010). the association of walking speed with hypertension was stronger in overweight and obese participants (Q2, OR: 0.54, 95%CI = 0.34-0.85, P = 0.009; Q3, OR: 0.69, 95%CI = 0.44-1.08, P = 0.106; Q4, OR: 0.62, 95%CI = 0.39-0.98, P = 0.039). However, this association was not significant among lean ones. A similar trend was observed for systolic and diastolic blood pressure. In conclusion, higher walking speed was longitudinally associated with a lower risk of hypertension in Chinese older adults, especially among overweight and obese participants.

Lipid-like gemcitabine diester-loaded liposomes for improved chemotherapy of pancreatic cancer.

Gemcitabine (GEM) is a non-selective chemotherapeutic agent used in the treatment of pancreatic cancer. Its antitumor efficacy is limited by a short plasma half-life and severe adverse reactions. To overcome these shortcomings, four novel lipid-like GEM diesters were synthesized and encapsulated into liposomes. Through optimization, dimyristoyl GEM (dmGEM)-loaded liposomes (LipodmGEM) were successfully obtained with an almost complete encapsulation efficiency. Compared to free GEM, LipodmGEM showed enhanced cellular uptake and cell apoptosis, improved inhibition of cell migration on AsPC-1 cells and a greatly extended half-life (7.22 vs. 1.78 h). LipodmGEM succeeded in enriching the drug in the tumor (5.28 vs. 0.03 µmol/g at 8 h), overcoming a major shortcoming of GEM, showed excellent anticancer efficacy in vivo and negligible systemic toxicity, superior to GEM. Attractive as well, suspensions of LipodmGEM remained stable at 2-10 °C away from light for no <2 years. Our results suggest that LipodmGEM might become of high interest for treating pancreatic cancer while the simple strategy we reported might be explored as well for converting other antitumor drugs with high water-solubility and short plasma half-life into attractive nanomedicines.

Living alone and the risk of depressive symptoms: a cross-sectional and cohort analysis based on the China Health and Retirement Longitudinal Study.

BACKGROUND: There were a few studies that examined the longitudinal association between living alone and depressive symptoms, and the vast majority of them were conducted in patients with certain diseases, such as heart failure, cancer, and glaucoma. This study aimed to examine the association between living alone and depressive symptoms in a large representative older Chinese population. METHODS: The China Health and Retirement Longitudinal Study (CHARLS) data from 2015 to 2018 were used. Living alone was defined as participants who did not live with others ever or more than 11 months in the past year at baseline. Depressive symptoms were measured using the 10-item Center for Epidemiological Studies-Depression Scale (CES-D10). The multivariate logistic regression was used to estimate the relationship between living alone and depressive symptoms. RESULTS: There were 5,311 and 2,696 participants ≥ 60 years old included in the cross-sectional and cohort analysis, respectively. The risk of depressive symptoms in participants who lived alone was significantly higher than those who lived with others in both cross-sectional (OR:1.33; 95%CI:1.14,1.54) and cohort analysis (OR:1.23; 95%CI:0.97,1.55). There was a significant interaction between financial support and living alone (Pinteraction = 0.008) on the risk of depressive symptoms. Stratified analyses showed that, compared to those who lived with others, the risk of depressive symptoms in participants who lived alone increased by 83% (OR:1.83; 95%CI:1.26,2.65) in participants receiving lower financial support. However, we did not find statistically significant associations in participants with medium (OR:1.10; 95%CI: 0.74,1.63) and higher financial support (OR: 0.87; 95%CI: 0.53,1.41). CONCLUSION: Living alone was associated with a higher risk of depressive symptoms in the Chinese older population, and this association was moderated by the receipt of financial support. Living alone may be an effective and easy predictor for early identification of high-risk populations of depression in the older population.

The potential DNA methylation markers of cardiovascular disease in patients with type 2 diabetes.

BACKGROUND: DNA methylation is associated with cardiovascular (CV) disease. However, in type 2 diabetes (T2D) patients, the role of gene methylation in the development of CV disease is under-studied. We aimed to identify the CV disease-related DNA methylation loci in patients with T2D and to explore the potential pathways underlying the development of CV disease using a two-stage design. METHODS: The participants were from the Jinan Diabetes Cohort Study (JNDCS), an ongoing longitudinal study designed to evaluate the development of CV risk in patients with T2D. In the discovery cohort, 10 diabetic patients with CV events at baseline were randomly selected as the case group, and another 10 diabetic patients without CV events were matched for sex, age, smoking status, and body mass index as the control group. In 1438 T2D patients without CV disease at baseline, 210 patients with CV events were identified after a mean 6.5-year follow-up. Of whom, 100 patients who experienced CV events during the follow-up were randomly selected as cases, and 100 patients who did not have CV events were randomly selected as the control group in the validation cohort. Reduced representation bisulfite sequencing and Targeted Bisulfite Sequencing were used to measure the methylation profiles in the discovery and validation cohort, respectively. RESULTS: In the discover cohort, 127 DMRs related to CV disease were identified in T2D patients. Further, we validated 23 DMRs mapped to 25 genes, of them, 4 genes (ARSG, PNPLA6, NEFL, and CRYGEP) for the first time were reported. There was evidence that the addition of DNA methylation data improved the prediction performance of CV disease in T2D patients. Pathway analysis identified some significant signaling pathways involved in CV comorbidities, T2D, and inflammation. CONCLUSIONS: In this study, we identified 23 DMRs mapped to 25 genes associated with CV disease in T2D patients, of them, 4 DMRs for the first time were reported. DNA methylation testing may help identify a high CV-risk population in T2D patients.

Investigation of novel 5'-amino adenosine derivatives with potential anti-Zika virus activity.

The Zika virus (ZIKV) infections remains a global health threat. However, no approved drug for treating ZIKV infection. We previously found TZY12-9, a 5'-amino NI analog, that showed anti-ZIKV activity without chemical phosphorylation. Here, a series of 5'-amino NI analogs were synthesized and evaluated. The compound XSJ2-46 exhibited potent in vitro activity without requiring chemical phosphorylation, favorable pharmacokinetic and acute toxicity profiles. Preliminary mechanisms of anti-ZIKV activity of XSJ2-46 were investigated via a series of ZIKV non-structural protein inhibition assays and host cell RNA-seq. XSJ2-46 acted at the replication stage of viral infection cycle, and exhibited reasonable inhibition of RNA-dependent RNA polymerases (RdRp) with an IC50 value of 8.78 µM, while not affecting MTase. RNA-seq analysis also revealed differential expression genes involved in cytokine and cytokine receptor pathway in ZIKV-infected U87 cells treated with XSJ2-46. Importantly, treatment with XSJ2-46 (10 mg/kg/day) significantly enhanced survival protection (70% survival) in ZIKV-infected ICR mice. Additionally, XSJ2-46 administration resulted in a significant decrease in serum levels of ZIKV viral RNA in the IFNα/ß receptor-deficient (Ifnar-/-) A129 mouse model. Therefore, the remarkable in vitro and in vivo anti-ZIKV activity of compound XSJ2-46 highlights the promising research direction of utilizing the 5'-amino NI structure skeleton for developing antiviral NIs.

A Novel lncRNA FUAT1/TNS4 Axis Confers Chemoresistance by Suppressing Reactive Oxygen Species-Mediated Apoptosis in Gastric Cancer.

Aims: Reactive oxygen species (ROS) play a vital role in conveying the cytotoxicity and resistance of most chemotherapy drugs. Therefore, gaining a comprehensive understanding of the intricate activities against oxidative stress in cancer cells may provide valuable insights into the discovery of common mechanisms underlying chemoresistance. Results: We identified a novel long noncoding RNA (lncRNA), designated fluorouracil-associated transcript-1 (FUAT1), as a key nongenetic player involved in ROS-mediated intrinsic chemoresistance by employing a unique screening strategy based on transcriptome sequencing (RNA-Seq) technology. To investigate the precise role of the FUAT1 regulatory axis in chemoresistance, we conducted a series of in vitro and in vivo assays including gain/loss-of-function and rescue experiments. Mechanistically, our findings revealed that FUAT1 upregulates Tensin 4 (TNS4) by sponging miR-140-5p, which allows gastric cancer cells to survive chemotherapy by inhibiting ROS-mediated apoptosis. Clinically, we observed that the FUAT1/TNS4 regulatory axis is negatively associated with overall survival and progression-free survival among gastric and colon cancer patients treated with 5-fluorouracil adjuvant chemotherapy. Innovation: We devised a novel screening strategy distinct from conventional approaches using drug-resistant strains. Through this approach, we identified the previously unrecognized lncRNA FUAT1/TNS4 axis that plays a critical role in ROS-mediated intrinsic chemoresistance. Conclusions: Our findings shed light on fundamental adaptive mechanisms employed by cancer cells to respond to chemotherapy and provide new insights into developing strategies aiming at overcoming chemoresistance.

Non-Contrast Cine Cardiac Magnetic Resonance Derived-Radiomics for the Prediction of Left Ventricular Adverse Remodeling in Patients With ST-Segment Elevation Myocardial Infarction.

OBJECTIVE: To investigate the predictive value of radiomics features based on cardiac magnetic resonance (CMR) cine images for left ventricular adverse remodeling (LVAR) after acute ST-segment elevation myocardial infarction (STEMI). MATERIALS AND METHODS: We conducted a retrospective, single-center, cohort study involving 244 patients (random-split into 170 and 74 for training and testing, respectively) having an acute STEMI (88.5% males, 57.0 ± 10.3 years of age) who underwent CMR examination at one week and six months after percutaneous coronary intervention. LVAR was defined as a 20% increase in left ventricular end-diastolic volume 6 months after acute STEMI. Radiomics features were extracted from the one-week CMR cine images using the least absolute shrinkage and selection operator regression (LASSO) analysis. The predictive performance of the selected features was evaluated using receiver operating characteristic curve analysis and the area under the curve (AUC). RESULTS: Nine radiomics features with non-zero coefficients were included in the LASSO regression of the radiomics score (RAD score). Infarct size (odds ratio [OR]: 1.04 (1.00-1.07); P = 0.031) and RAD score (OR: 3.43 (2.34-5.28); P < 0.001) were independent predictors of LVAR. The RAD score predicted LVAR, with an AUC (95% confidence interval [CI]) of 0.82 (0.75-0.89) in the training set and 0.75 (0.62-0.89) in the testing set. Combining the RAD score with infarct size yielded favorable performance in predicting LVAR, with an AUC of 0.84 (0.72-0.95). Moreover, the addition of the RAD score to the left ventricular ejection fraction (LVEF) significantly increased the AUC from 0.68 (0.52-0.84) to 0.82 (0.70-0.93) (P = 0.018), which was also comparable to the prediction provided by the combined microvascular obstruction, infarct size, and LVEF with an AUC of 0.79 (0.65-0.94) (P = 0.727). CONCLUSION: Radiomics analysis using non-contrast cine CMR can predict LVAR after STEMI independently and incrementally to LVEF and may provide an alternative to traditional CMR parameters.

Associations of pyrethroid exposure with skeletal muscle strength and mass.

This study aimed to examine the associations of pyrethroid exposure with handgrip strength and skeletal muscle mass and potential modification effects in US adults. The data from the National Health and Nutrition Examination Survey was used. Handgrip strength was determined with a handgrip dynamometer, and we quantified muscle mass by using the appendicular skeletal muscle index (ASMI). Urinary 3-Phenoxybenzoic Acid (3-PBA), a validated biomarker for pyrethroid exposure, was used in the primary analysis. After adjusting for other covariates, participants exposed to the highest tertile of 3-PBA exposure had significantly lower handgrip strength (ß = -1.88, 95% CI: -3.29, -0.23, P = 0.026) than those exposed to the lowest tertile of 3-PBA. Similarly, the 3-PBA exposure was marginally significantly associated with ASMI (Tertile 3 vs. Tertile 1: ß = -0.07, 95% CI: -0.14, -0.01, P = 0.056). Significant interactions were found between 3-PBA and body mass index (BMI) on handgrip strength and ASMI (P interaction < 0.05), which indicated a potential moderation effect of BMI on the associations. In conclusion, pyrethroid exposure was adversely associated with handgrip strength and skeletal muscle mass, especially in overweight and obese populations. Further studies are warranted to confirm our results and to explore the potential mechanisms.

High Crystallinity 2D π-d Conjugated Conductive Metal-Organic Framework for Boosting Polysulfide Conversion in Lithium-Sulfur Batteries.

The catalytic performance of metal-organic frameworks (MOFs) in Li-S batteries is significantly hindered by unsuitable pore size, low conductivity, and large steric contact hindrance between the catalytic site and lithium polysulfide (LPSs). Herein, the smallest π-conjugated hexaaminobenzene (HAB) as linker and Ni(II) ions as skeletal node are in situ assembled into high crystallinity Ni-HAB 2D conductive MOFs with dense Ni-N4 units via dsp2 hybridization on the surface of carbon nanotube (CNT), fabricating Ni-HAB@CNT as separator modified layer in Li-S batteries. As-obtained unique π-d conjugated Ni-HAB nanostructure features ordered micropores with suitable pore size (≈8 Å) induced by HAB ligands, which can cooperate with dense Ni-N4 chemisorption sites to effectively suppress the shuttle effect. Meanwhile, the conversion kinetics of LPSs is significantly accelerated owing to the small steric contact hindrance and increased delocalized electron density endued by the planar tetracoordinate structure. Consequently, the Li-S battery with Ni-HAB@CNT modified separator achieves an areal capacity of 6.29 mAh cm-2 at high sulfur loading of 6.5 mg cm-2 under electrolyte/sulfur ratio of 5 µL mg-1 . Moreover, Li-S single-electrode pouch cells with modified separators deliver a high reversible capacity of 791 mAh g-1 after 50 cycles at 0.1 C with electrolyte/sulfur ratio of 6 µL mg-1 .

A tunable perfect absorber based on a black phosphorus/bowtie shaped cavity hybrid metasurface.

The practical application of black phosphorus (BP) is limited by its low absorption characteristics. In this work, we propose a perfect absorber based on a BP and bowtie shaped cavity, which has high tunability and excellent optical performance. This absorber effectively increases the light-matter interaction and achieves perfect absorption by using a monolayer BP and a reflector to form a Fabry-Perot cavity. We study the influence of structural parameters on the absorption spectrum and realize the adjustment of frequency and absorption in a certain range. Applying an external electric field on the surface of BP by electrostatic gating, we can change its carrier concentration to control its optical properties. In addition, we can flexibly tune the absorption and Q-factor by varying the polarization direction of incident light. This absorber has promising applications in optical switches, sensing, and slow light, which provides a new perspective for the practical application of BP and a foundation for future research, offering possibilities for more applications.

Design, synthesis and antitubercular activity of novel N-(amino)piperazinyl benzothiazinones with improved safety.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) remains a major global health problem and new therapeutic antitubercular agents are urgent needed. Among the novel antituberculosis drugs in the pipeline, Benzothiazinones (BTZs) are among the most potent antituberculosis agents against both drug-susceptible and multidrug-resistant (MDR) tuberculosis. Our group has focused on structural modifications of the side chain at C-2 position of the BTZ core and WAP-2101/2102 with excellent in vitro activity were discovered in our lab. However, the severe in vivo toxicity was observed during subsequent acute toxicity evaluation. Herein, a series of novel N-(amino)piperazinyl benzothiazinone derivatives were designed and synthesized as new anti-TB agents to reduce the in vivo toxicity. Our results show that majority of them exhibit the same potent or comparable activity against both MTB H37Rv and MDR-MTB strains (MIC: 4.00 - <1 ng/mL) as PBTZ169. Especially, compound 2c with low cardiac toxicity, low cell cytotoxicity and acceptable oral pharmacokinetic (PK) profiles have low acute toxicity in mice (LD50 > 500 mg/kg), suggesting it may serve as a promising lead compound for further antitubercular drug discovery.

Environmental noise exposure and health outcomes: an umbrella review of systematic reviews and meta-analysis.

BACKGROUND: Environmental noise is becoming increasingly recognized as an urgent public health problem, but the quality of current studies needs to be assessed. To evaluate the significance, validity and potential biases of the associations between environmental noise exposure and health outcomes. METHODS: We conducted an umbrella review of the evidence across meta-analyses of environmental noise exposure and any health outcomes. A systematic search was done until November 2021. PubMed, Cochrane, Scopus, Web of Science, Embase and references of eligible studies were searched. Quality was assessed by AMSTAR and Grading of Recommendations, Assessment, Development and Evaluation (GRADE). RESULTS: Of the 31 unique health outcomes identified in 23 systematic reviews and meta-analyses, environmental noise exposure was more likely to result in a series of adverse outcomes. Five percent were moderate in methodology quality, the rest were low to very low and the majority of GRADE evidence was graded as low or even lower. The group with occupational noise exposure had the largest risk increment of speech frequency [relative risk (RR): 6.68; 95% confidence interval (CI): 3.41-13.07] and high-frequency (RR: 4.46; 95% CI: 2.80-7.11) noise-induced hearing loss. High noise exposure from different sources was associated with an increased risk of cardiovascular disease (34%) and its mortality (12%), elevated blood pressure (58-72%), diabetes (23%) and adverse reproductive outcomes (22-43%). In addition, the dose-response relationship revealed that the risk of diabetes, ischemic heart disease (IHD), cardiovascular (CV) mortality, stroke, anxiety and depression increases with increasing noise exposure. CONCLUSIONS: Adverse associations were found for CV disease and mortality, diabetes, hearing impairment, neurological disorders and adverse reproductive outcomes with environmental noise exposure in humans, especially occupational noise. The studies mostly showed low quality and more high-quality longitudinal study designs are needed for further validation in the future.