Association of triglyceride-glucose index with atherosclerotic cardiovascular disease and mortality among familial hypercholesterolemia patients.

BACKGROUND: Familial hypercholesterolemia (FH) is an inherited metabolic disorder with a high level of low-density lipoprotein cholesterol and the worse prognosis. The triglyceride-glucose (TyG) index, an emerging tool to reflect insulin resistance (IR), is positively associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD) in healthy individuals, but the value of TyG index has never been evaluated in FH patients. This study aimed to determine the association between the TyG index and glucose metabolic indicators, insulin resistance (IR) status, the risk of ASCVD and mortality among FH patients. METHODS: Data from National Health and Nutrition Examination Survey (NHANES) 1999-2018 were utilized. 941 FH individuals with TyG index information were included and categorized into three groups: < 8.5, 8.5-9.0, and > 9.0. Spearman correlation analysis was used to test the association of TyG index and various established glucose metabolism-related indicators. Logistic and Cox regression analysis were used to assess the association of TyG index with ASCVD and mortality. The possible nonlinear relationships between TyG index and the all-cause or cardiovascular death were further evaluated on a continuous scale with restricted cubic spline (RCS) curves. RESULTS: TyG index was positively associated with fasting glucose, HbA1c, fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR) index (all p < 0.001). The risk of ASCVD increased by 74% with every 1 unit increase of TyG index (95%CI: 1.15-2.63, p = 0.01). During the median 114-month follow-up, 151 all-cause death and 57 cardiovascular death were recorded. Strong U/J-shaped relations were observed according to the RCS results (p = 0.0083 and 0.0046 for all-cause and cardiovascular death). A higher TyG index was independently associated with both all-cause death and cardiovascular death. Results remained similar among FH patients with IR (HOMA-IR ≥ 2.69). Moreover, addition of TyG index showed helpful discrimination of both survival from all-cause death and cardiovascular death (p < 0.05). CONCLUSION: TyG index was applicable to reflect glucose metabolism status in FH adults, and a high TyG index was an independent risk factor of both ASCVD and mortality.

Candida parapsilosis infection after double-lung transplantation in a patient with pulmonary fibrosis caused by COVID-19.

Pulmonary fibrosis is a complication in patients with coronavirus disease 2019 (COVID-19). Extensive pulmonary fibrosis is a severe threat to patients' life and lung transplantation is last resort to prolong the life of patients. We reported a case of critical type COVID-19 patient, though various treatment measures were used, including anti-virus, anti-infection, improving immunity, convalescent plasma, prone position ventilation, and airway cleaning by fiber-optic bronchoscope, although his COVID-19 nucleic acid test turned negative, the patient still developed irreversible extensive pulmonary fibrosis, and respiratory mechanics suggested that lung compliance could not be effectively recovered. After being assisted by ventilator and extracorporeal membrane oxygenation for 73 days, he finally underwent double-lung transplantation. On the 2nd day after the operation, the alveolar lavage fluid of transplanted lung was examined by cytomorphology, and the morphology of alveolar epithelial cells was intact and normal. On the 20th day post-transplantation, the chest radiograph showed a large dense shadow in the middle of the right lung. On the 21st day, the patient underwent fiber-optic bronchoscopy, yeast-like fungal spores were found by cytomorphological examination from a brush smear of the right bronchus, which was confirmed as Candida parapsilosis infection by fungal culture. He recovered well due to the careful treatment and nursing in our hospital. Until July 29, 96 days after transplantation, the patient was recovery and discharged from hospital.

An electrochemical biosensor for HER2 detection in complex biological media based on two antifouling materials of designed recognizing peptide and PEG.

A simple tactic for electrochemical determination of a typical biomarker for breast cancer, human epidermal growth factor receptor 2 (HER2), was presented via the construction of a low fouling sensing interface functionalized with polyethylene glycol (PEG) and peptide. The HER2 biosensor was developed based on an electrode modified by the conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) and Au nanoparticles (AuNPs) as the sensing substrate, and followed by the immobilization of an antifouling PEG and a peptide with both recognizing and antifouling properties. Thanks to the combined antifouling effect of the PEG and peptide, and the specific recognizing ability of the peptide to the target HER2, the developed electrochemical biosensor exhibited strong antifouling performances in complex biofluids, such as human blood and serum, and it was capable of assaying target HER2 within a very wide linear range (1.0 pg mL-1 to 1.0 µg mL-1), with an ultralow limit of detection (0.44 pg mL-1). The combination of two kinds of antifouling biomaterials (PEG and peptide) offered an effective strategy for the development of low fouling sensing platforms suitable for practical assay in complex biotic environments.

Inhibition of hepatic natural killer cell function via the TIGIT receptor in schistosomiasis-induced liver fibrosis.

Schistosomiasis is a zoonotic parasitic disease. Schistosoma japonicum eggs deposited in the liver tissue induce egg granuloma formation and liver fibrosis, seriously threatening human health. Natural killer (NK) cells kill activated hepatic stellate cells (HSCs) or induce HSC apoptosis and inhibit the progression of liver fibrosis. However, the function of NK cells in liver fibrosis caused by S. japonicum infection is significantly inhibited. The mechanism of this inhibition remains unclear. Twenty mice were percutaneously infected with S. japonicum cercariae. Before infection and 2, 4, 6, and 8 weeks after infection, five mice were euthanized and dissected at each time point. Hepatic NK cells were isolated and transcriptome sequenced. The sequencing results showed that Tigit expression was high at 4-6 weeks post infection. This phenomenon was verified by reverse transcription quantitative PCR (RT-qPCR) and flow cytometry. NK cells derived from Tigit-/- and wild-type (WT) mice were co-cultured with HSCs. It was found that Tigit-/- NK cells induced apoptosis in a higher proportion of HSCs than WT NK cells. Schistosomiasis infection models of Tigit-/- and WT mice were established. The proportion and killing activity of hepatic NK cells were significantly higher in Tigit-/- mice than in WT mice. The degree of liver fibrosis in Tigit-/- mice was significantly lower than that in WT mice. NK cells were isolated from Tigit-/- and WT mice and injected via the tail vein into WT mice infected with S. japonicum. The degree of liver fibrosis in mice that received NK cell infusion reduced significantly, but there was no significant difference between mice that received NK cells from Tigit-/- and WT mice, respectively. Our findings indicate that Tigit knockout enhanced the function of NK cells and reduced the degree of liver fibrosis in schistosomiasis, thus providing a novel strategy for treating hepatic fibrosis induced by schistosomiasis.

Transmembrane BAX inhibitor motif containing 6 suppresses presenilin-2 to preserve mitochondrial integrity after myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion (I/R) damage is characterized by mitochondrial damage in cardiomyocytes. Transmembrane BAX inhibitor motif containing 6 (TMBIM6) and presenilin-2 (PS2) participate in multiple mitochondrial pathways; thus, we investigated the impact of these proteins on mitochondrial homeostasis during an acute reperfusion injury. Myocardial post-ischemic reperfusion stress impaired myocardial function, induced structural abnormalities and promoted cardiomyocyte death by disrupting the mitochondrial integrity in wild-type mice, but not in TMBIM6 transgenic mice. We found that TMBIM6 bound directly to PS2 and promoted its post-transcriptional degradation. Knocking out PS2 in mice reduced I/R injury-induced cardiac dysfunction, inflammatory responses, myocardial swelling and cardiomyocyte death by improving the mitochondrial integrity. These findings demonstrate that sufficient TMBIM6 expression can prevent PS2 accumulation during cardiac I/R injury, thus suppressing reperfusion-induced mitochondrial damage. Therefore, TMBIM6 and PS2 are promising therapeutic targets for the treatment of cardiac reperfusion damage.

Monitoring Substantia Nigra Degeneration Using Free Water Imaging across Prodromal and Clinical Parkinson's Disease.

BACKGROUND: Substantia nigra (SN) free water has been suggested as a good surrogate marker in Parkinson's disease (PD). However, its usefulness for diagnosing prodromal PD (pPD) and monitoring disease progression warrants further validation. OBJECTIVE: The aim was to investigate SN free water values across prodromal and clinical stages of PD. METHODS: Four groups were enrolled in this study: 48 healthy controls (HC), 43 pPD patients, 50 de novo PD (dnPD) patients, and 49 medicated PD (mPD) patients. Based on diffusion tensor images, free water maps were calculated, and SN free water values were extracted from the anterior SN (ASN) and posterior SN (PSN). The SN free water values were compared among the four groups, and associations between free water and clinical symptoms were explored. The distinguishing power of PSN free water was evaluated using the receiver operating characteristic curve analysis. Follow-up was performed for 14 pPD patients. RESULTS: PSN free water in the pPD group was significantly higher than that in the HC group and significantly lower than that in the dnPD group. Surprisingly, the mPD group showed decreased PSN free water compared to the dnPD group. There was a positive correlation between motor symptoms and PSN free water in the pPD and dnPD groups. Longitudinal analysis showed a significant increase in PSN free water in pPD patients over time. CONCLUSIONS: The PSN free water increased from prodromal to early clinical stages, but the trend might be reversed in late disease stages. This biphasic trend should be considered when applying this marker in future studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Assessment of solar energy potential in China using an ensemble of photovoltaic power models.

Development of solar energy is one of the key solutions towards carbon neutrality in China. The output of solar energy is dependent on weather conditions and shows distinct spatiotemporal characteristics. Previous studies have explored the photovoltaic (PV) power potential in China but with single models and low-resolution radiation data. Here, we estimated the PV power potential in China for 2016-2019 using an ensemble of 11 PV models based on hourly solar radiation at the resolution of 5 km retrieved by the Himawari-8 geostationary satellite. On the national scale, the ensemble method revealed an annual average PV power potential of 242.79 kWh m-2 with the maximum in the west (especially the Tibetan Plateau) and the minimum in the southeast (especially the Sichuan Basin). The multi-model approach shows inter-model spreads of 6 %-7 % distributed uniformly in China, suggesting a robust spatial pattern predicted by these models. The seasonal variation in general shows the largest PV power generation in summer months except for Tibetan Plateau, where the peak value appears in spring because the high cloud coverage dampens the regional solar radiation in summer. On the national scale, the deseasonalized PV power potential shows a high correlation with cloud coverage (R2 = 0.71, p < 0.01) but a low correlation with aerosol optical depth (R2 = 0.08, p < 0.05). Sensitivity experiments show that national PV power potential increases by 0.55 % per 1 W m-2 increase of radiation and 0.78 % per 1 m s-1 increase of wind speed, but decreases by 0.46 % per 1 °C increase of air temperature. These sensitivities provide a solid foundation for the future projection of PV power potential in China under climate change.

Immune evasion of neutralizing antibodies by SARS-CoV-2 Omicron.

Since its emergence at the end of 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the infection of more than 600 million people worldwide and has significant damage to global medical, economic, and political structures. Currently, a highly mutated variant of concern, SARS-CoV-2 Omicron, has evolved into many different subvariants mainly including BA.1, BA.2, BA.3, BA.4/5, and the recently emerging BA.2.75.2, BA.2.76, BA.4.6, BA.4.7, BA.5.9, BF.7, BQ.1, BQ.1.1, XBB, XBB.1, etc. Mutations in the N-terminal domain (NTD) of the spike protein, such as A67V, G142D, and N212I, alter the antigenic structure of Omicron, while mutations in the spike receptor binding domain (RBD), such as R346K, Q493R, and N501Y, increase the affinity for angiotensin-converting enzyme 2 (ACE2). Both types of mutations greatly increase the capacity of Omicron to evade immunity from neutralizing antibodies, produced by natural infection and/or vaccination. In this review, we systematically assess the immune evasion capacity of SARS-CoV-2, with an emphasis on the neutralizing antibodies generated by different vaccination regimes. Understanding the host antibody response and the evasion strategies employed by SARS-CoV-2 variants will improve our capacity to combat newly emerging Omicron variants.

Spatially Separated Redox Cocatalysts on Ferroelectric Nanoplates for Improved Piezophotocatalytic CO2 Reduction and H2O Oxidation.

Utilizing solar and mechanical vibration energy for catalytic CO2 reduction and H2O oxidation is emerging as a promising way to simultaneously generate renewable energy and mitigate climate change, making it possible to integrate two energy resources into a reaction system for artificial piezophotosynthesis. However, the practical applications are hindered by undesirable charge recombination and sluggish surface reaction in the photocatalytic and piezocatalytic processes. This study proposes a dual cocatalyst strategy to overcome these obstacles and improve the piezophotocatalytic performance of ferroelectrics in overall redox reactions. With the photodeposition of AuCu reduction and MnOx oxidation cocatalysts on oppositely poled facets of PbTiO3 nanoplates, band bending occurs along with the formation of built-in electric fields on the semiconductor-cocatalyst interfaces, which, together with an intrinsic ferroelectric field, piezoelectric polarization field, and band tilting in the bulk of PbTiO3, provide strong driving forces for the directional drift of piezo- and photogenerated electrons and holes toward AuCu and MnOx, respectively. Besides, AuCu and MnOx enrich the active sites for surface reactions, significantly reducing the rate-determining barrier for CO2-to-CO and H2O-to-O2 transformation, respectively. Benefiting from these features, AuCu/PbTiO3/MnOx delivers remarkably improved charge separation efficiencies and significantly enhanced piezophotocatalytic activities in CO and O2 generation. This strategy opens a door for the better coupling of photocatalysis and piezocatalysis to promote the conversion of CO2 with H2O.

The C2 and PH domains of CAPS constitute an effective PI(4,5)P2-binding unit essential for Ca2+-regulated exocytosis.

Ca2+-dependent activator proteins for secretion (CAPSs) are required for Ca2+-regulated exocytosis in neurons and neuroendocrine cells. CAPSs contain a pleckstrin homology (PH) domain that binds PI(4,5)P2-membrane. There is also a C2 domain residing adjacent to the PH domain, but its function remains unclear. In this study, we solved the crystal structure of the CAPS-1 C2PH module. The structure showed that the C2 and PH tandem packs against one another mainly via hydrophobic residues. With this interaction, the C2PH module exhibited enhanced binding to PI(4,5)P2-membrane compared with the isolated PH domain. In addition, we identified a new PI(4,5)P2-binding site on the C2 domain. Disruption of either the tight interaction between the C2 and PH domains or the PI(4,5)P2-binding sites on both domains significantly impairs CAPS-1 function in Ca2+-regulated exocytosis at the Caenorhabditis elegans neuromuscular junction (NMJ). These results suggest that the C2 and PH domains constitute an effective unit to promote Ca2+-regulated exocytosis.

Research into the characteristic molecules significantly affecting liver cancer immunotherapy.

Background: The past decade has witnessed unprecedented scientific breakthroughs, including immunotherapy, which has great potential in clinical applications for liver cancer. Methods: Public data were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases and analyzed with R software. Results: The LASSO and SVM-RFE machine learning algorithms identified 16 differentially expressed genes (DEGs) related to immunotherapy, namely, GNG8, MYH1, CHRNA3, DPEP1, PRSS35, CKMT1B, CNKSR1, C14orf180, POU3F1, SAG, POU2AF1, IGFBPL1, CDCA7, ZNF492, ZDHHC22, and SFRP2. Moreover, a logistic model (CombinedScore) was established based on these DEGs, showing an excellent prediction performance for liver cancer immunotherapy. Patients with a low CombinedScore might respond better to immunotherapy. Gene Set Enrichment Analysis showed that many metabolism pathways were activated in patients with a high CombinedScore, including butanoate metabolism, bile acid metabolism, fatty acid metabolism, glycine serine and threonine metabolism, and propanoate metabolism. Our comprehensive analysis showed that the CombinedScore was negatively correlated with the levels of most tumor-infiltrating immune cells and the activities of key steps of cancer immunity cycles. Continually, the CombinedScore was negatively associated with the expression of most immune checkpoints and immunotherapy response-related pathways. Moreover, patients with a high and a low CombinedScore exhibited diverse genomic features. Furthermore, we found that CDCA7 was significantly correlated with patient survival. Further analysis showed that CDCA7 was positively associated with M0 macrophages and negatively associated with M2 macrophages, suggesting that CDCA7 could influence the progression of liver cancer cells by affecting macrophage polarization. Next, single-cell analysis showed that CDCA7 was mainly expressed in prolif T cells. Immunohistochemical results confirmed that the staining intensity of CDCA7 was prominently increased in the nucleus in primary liver cancer tissues compared to adjacent non-tumor tissues. Conclusions: Our results provide novel insights into the DEGs and factors affecting liver cancer immunotherapy. Meanwhile, CDCA7 was identified as a potential therapeutic target in this patient population.

NUF2 Promotes Breast Cancer Development as a New Tumor Stem Cell Indicator.

Multiple new subtypes of breast cancer (BRCA) are identified in women each year, rendering BRCA the most common and rapidly expanding form of cancer in females globally. NUF2 has been identified as a prognostic factor in various human cancers, regulating cell apoptosis and proliferation. However, its role in BRCA prognosis has not been clarified. This study explored the role of NUF2 in breast cancer development and prognosis using informatic analysis combined with in vivo intracellular studies. Through the online website TIMER, we evaluated the transcription profile of NUF2 across a variety of different cancer types and found that NUF2 mRNA was highly expressed in BRCA patients. Its transcription level was found to be related to the subtype, pathological stage, and prognosis of BRCA. The R program analysis showed a correlation of NUF2 with cell proliferation and tumor stemness in the BRCA patient samples. Subsequently, the association between the NUF2 expression level and immune cell infiltration was analyzed using the XIANTAO and TIMER tools. The results revealed that NUF2 expression was correlated with the responses of multiple immune cells. Furthermore, we observed the effect of NUF2 expression on tumor stemness in BRCA cell lines in vivo. The experimental results illuminated that the overexpression of NUF2 statistically upregulated the proliferation and tumor stemness ability of the BRCA cell lines MCF-7 and Hs-578T. Meanwhile, the knockdown of NUF2 inhibited the abilities of both cell lines, a finding which was verified by analyzing the subcutaneous tumorigenic ability in nude mice. In summary, this study suggests that NUF2 may play a key role in the development and progression of BRCA by affecting tumor stemness. As a stemness indicator, it has the potential to be one of the markers for the diagnosis of BRCA.

USP25 Ameliorates Pathological Cardiac Hypertrophy by Stabilizing SERCA2a in Cardiomyocytes.

BACKGROUND: Pathological cardiac hypertrophy can lead to heart failure and is one of the leading causes of death globally. Understanding the molecular mechanism of pathological cardiac hypertrophy will contribute to the treatment of heart failure. DUBs (deubiquitinating enzymes) are essential to cardiac pathophysiology by precisely controlling protein function, localization, and degradation. This study set out to investigate the role and molecular mechanism of a DUB, USP25 (ubiquitin-specific peptidase 25), in pathological cardiac hypertrophy. METHODS: The role of USP25 in myocardial hypertrophy was evaluated in murine cardiomyocytes in response to Ang II (angiotensin II) and transverse aortic constriction stimulation and in hypertrophic myocardium tissues of heart failure patients. Liquid chromotography with mass spectrometry/mass spectrometry analysis combined with Co-IP was used to identify SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2A), an antihypertrophy protein, as an interacting protein of USP25. To clarify the molecular mechanism of USP25 in the regulation of SERCA2a, we constructed a series of mutant plasmids of USP25. In addition, we overexpressed USP25 and SERCA2a in the heart with adenoassociated virus serotype 9 vectors to validate the biological function of USP25 and SERCA2a interaction. RESULTS: We revealed increased protein level of USP25 in murine cardiomyocytes subject to Ang II and transverse aortic constriction stimulation and in hypertrophic myocardium tissues of patients with heart failure. USP25 deficiency aggravated cardiac hypertrophy and cardiac dysfunction under Ang II and transverse aortic constriction treatment. Mechanistically, USP25 bound to SERCA2a directly via its USP (ubiquitin-specific protease) domain and cysteine at position 178 of USP25 exerts deubiquitination to maintain the stability of the SERCA2a protein by removing the K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby maintaining calcium handling in cardiomyocytes. Moreover, restoration of USP25 expression via adenoassociated virus serotype 9 vectors in USP25-/- mice attenuated Ang II-induced cardiac hypertrophy and cardiac dysfunction, whereas myocardial overexpression of SERCA2a could mimic the effect of USP25. CONCLUSIONS: We confirmed that USP25 inhibited cardiac hypertrophy by deubiquitinating and stabilizing SERCA2a.

Projections of fire emissions and the consequent impacts on air quality under 1.5 °C and 2 °C global warming.

Fire is a major source of atmospheric aerosols and trace gases. Projection of future fire activities is challenging due to the joint impacts of climate, vegetation, and human activities. Here, we project global changes of fire-induced particulate matter smaller than 2.5 µm (PM2.5) and ozone (O3) under 1.5 °C/2 °C warming using a climate-chemistry-vegetation coupled model in combination with site-level and satellite-based observations. Compared to the present day, fire emissions of varied air pollutants increase by 10.0%-15.4% at the 1.5 °C warming period and 15.1%-22.5% at the 2 °C warming period, with the most significant enhancements in Amazon, southern Africa, and boreal Eurasia. The warmer climate promotes fuel dryness and the higher leaf area index increases fuel availability, leading to escalated fire flammability globally. However, moderate declines in fire emissions are predicted over the Sahel region, because the higher population density increases fire suppressions and consequently inhibits fire activities over central Africa. Following the changes in fire emissions, the population-weighted exposure to fire PM2.5 increases by 5.1% under 1.5 °C warming and 13.0% under 2 °C warming. Meanwhile, the exposure to fire O3 enhances by 10.2% and 16.0% in response to global warming of 1.5 °C and 2 °C, respectively. As a result, limiting global temperature increase to 1.5 °C can greatly reduce the risks of exposure to fire-induced air pollution compared to 2 °C.

Construction of Z scheme S-g-C3N4/Bi5O7I photocatalysts for enhanced photocatalytic removal of Hg0 and carrier separation.

Photocatalysis has demonstrated the potential to solve challenges in various practical application fields such as energy and environmental science due to its environmental friendliness. However, the photocatalytic activity is mainly affected by the weak absorption of visible light and the low separation efficiency of photogenerated carriers. Herein, an S-doped g-C3N4/Bi5O7I heterojunction was designed by the calcination method. It was found that S doping not only reduces the band gap of g-C3N4, which raises the optical absorption boundary of g-C3N4 from 465 nm to 550 nm. At the same time, the introduction of S elements leads to new doping energy levels, which can act as photogenerated electron trapping centers and thus inhibit the complexation of photogenerated carriers. Second, the construction of the heterojunction greatly facilitates the transport of carriers and the separation of electrons and holes driven by the built-in electric field. Finally, the abundant oxygen vacancies in the system result in defective energy levels that not only promote the activation of molecular oxygen, but also act as photogenerated electron traps, which further boost the separation of electron-hole pairs. Benefiting from the optimized performance, the photocatalytic reaction rates of S-doped g-C3N4/Bi5O7I are 5.2 and 2.1 times higher than those of g-C3N4 and Bi5O7I, respectively. This work provides a viable idea for the potential development of non-metal doping combined with heterojunction photocatalytic systems.

Study on the performance of novel nanomaterials for detection of biomarkers such as PCT based on immunochromatography sensitivity.

In this study, by comparing the UV-vis spectral characteristics of colloidal gold and colloidal gold enhancer, and their differences as immunochromatographic tracers in the qualitative detection of PCT, IL-6, Hp and quantitative determination of PCT performance, the factors that may affect the sensitivity were discussed. The results show that the absorbance at 520 nm of CGE diluted 20-fold and colloidal gold diluted 2-fold were comparable, and the sensitivity of CGE immunoprobe for qualitative detection of PCT, IL-6 and Hp was higher than that of colloidal gold immunoprobe, and the reproducibility and accuracy of both immunoprobes for quantitative detection of PCT were good. Indicating that the high sensitivity of CGE immunoprobe detection is mainly due to the absorption coefficient of CGE at 520 nm is about 10 times that of colloidal gold immunoprobe, CGE has stronger light absorption capacity and stronger quenching effect on rhodamine 6 G on the nitrocellulose membrane surface of the test strip.

Metagenomic insights into the effects of benzyl dodecyl dimethyl ammonium bromide (BDAB) shock on bacteria-driven nitrogen removal in a moving-bed biofilm reactor (MBBR).

The use of disinfectants made from quaternary ammonium compounds (QACs) has greatly increased since the outbreak of SARS-CoV-2. However, the effect of QACs on wastewater treatment performance is still unclear. In this study, a commonly used QAC, i.e., benzyl dodecyl dimethyl ammonium bromide (BDAB), was added to a moving-bed biofilm reactor (MBBR) to investigate BDAB's effect on nutrient removal. When the BDAB concentration was increased to 50 mg L-1, the ammonia removal efficiency (ARE) greatly decreased, as did the nitrate production rate constants (NPR). This inhibition was partly recovered by decreasing the BDAB concentration to 30 mg L-1. Metagenomic sequencing revealed the functional genera present during different stages of the control (Rc) and BDAB-added reactors (Re). The enriched genera (Rudaea, Nitrosospira, Sphingomonas, and Rhodanobacter) in Rc mainly related to the nitrogen metabolism, while the enriched genera in Re was BDAB-concentration dependent. Functional genes analysis suggested that a lack of ammonia oxidase-encoding genes (amoABC) may have caused a decrease in ARE in Re, while the efflux pump-encoding genes emrE, mdfA, and oprM and a gene encoding BAC oxygenase (oxyBAC) were responsible for BDAB resistance. The increase in the total abundance of antibiotic resistance genes (ARGs) in Re revealed a potential risk arising from BDAB. Overall, this study revealed the potential effect and ecological risks of BDAB introduction in WWTPs.

Repurposed pizotifen malate targeting NRF2 exhibits anti-tumor activity through inducing ferroptosis in esophageal squamous cell carcinoma.

Targeted therapy attempts are needed to enhance esophageal squamous cell carcinoma (ESCC) patients' overall survival and satisfaction of life. Nuclear factor erythroid 2-related factor 2 (NRF2), as a high-confidence cancer driver gene, controls the antioxidant response, metabolic balance and redox homeostasis in cancer and is regarded as a potent molecular target for cancer treatment. Here, we attempted to find a new NRF2 inhibitor and study the underlying molecular mechanism in ESCC. We found that up-regulated NRF2 protein was negatively correlated with patient prognosis and promoted tumor proliferation in ESCC. Moreover, Pizotifen malate (PZM), a FDA-approved medication, bound to the Neh1 domain of NRF2 and prevented NRF2 protein binding to the ARE motif of target genes, suppressing transcription activity of NRF2. PZM treatment suppressed tumor development in ESCC PDX model by inducing ferroptosis via down-regulating the transcription of GPX4, GCLC, ME1 and G6PD. Our study illustrates that the over expression of NRF2 indicates poor prognosis and promotes tumor proliferation in ESCC. PZM, as a novel NRF2 inhibitor, inhibits the tumor growth by inducing ferroptosis and elucidates a potent NRF2-based therapy strategy for patients with ESCC.

2-Hydroxypropyl Group Linked Derivatives of Indole Azoles as Potential Multifunctional Antibacterial Candidates for Effectively Inhibiting the Activity of MRSA and Responding Inflammatory Factors.

The increasing resistance of methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics has led to escalating efforts to design and synthesize new structural agents with significant antimicrobial potential. A novel class of 2-hydroxypropyl group linked derivatives of indole azoles was developed as potential antibacterial agents. Bioactivity screening results demonstrated that metronidazole-modified indole derivative 4 a had excellent antibacterial capacity against MRSA (MIC=6 µM), which was about 4 times that of norfloxacin (MIC=25 µM). Highly active hybrid 4 a did not cause obvious drug-resistance in MRSA after multiple generations (15 passage operations). Compound 4 a showed low toxicity to normal mammalian cells (RAW 264.7). Molecular docking and molecular electrostatic potential (MEP) surface studies were used to map hydrogen bond interactions and the electron distribution in the highly active compounds. In addition, the preliminary exploration of the antibacterial mechanism revealed that the active molecule 4 a could infiltrate the membrane of MRSA and insert into MRSA DNA to prevent its replication, thus activating strong inhibition of the bacteria. Furthermore, highly active derivative 4 a could better respond to inflammatory factors (IL-6, IL-10, TNF-α and PGE-2), and it is less likely to cause inflammatory complications, hence diversifying the functions of antibacterial candidate molecules. These findings effectively indicate the potential of the bioactive hybrid 4 a as a multifunctional anti-MRSA agent. Further exploration of the development of antimicrobials combining these kinds of 2-hydroxypropyl group linked indole derivatives is of great value.