Pan AMPK Activation Protects Tubules in Rat Ischemic Acute Kidney Injury.

Acute Kidney Injury (AKI) is characterized by an abrupt decline in kidney function and has been associated with excess risks of death, kidney disease progression, and cardiovascular events. The kidney has a high energetic demand with mitochondrial health being essential to renal function and damaged mitochondria has been reported across AKI subtypes. 5' adenosine monophosphate-activated protein kinase (AMPK) activation preserves cellular energetics through improvement of mitochondrial function and biogenesis when ATP levels are low such as under ischemia-induced AKI. We developed a selective potent small molecule pan AMPK activator, compound 1, and tested its ability to increase AMPK activity and preserve kidney function during ischemia/reperfusion injury in rats. A single administration of 1 caused sustained activation of AMPK for at least 24 hours, protected against acute tubular necrosis, and reduced clinical markers of tubular injury such as NephroCheck and Fractional Excretion of Sodium (FENa). Reduction in plasma creatinine and increased Glomerular Filtration Rate (GFR) indicated preservation of kidney function. Surprisingly, we observed a strong diuretic effect of AMPK activation associated with natriuresis both with and without AKI. Our findings demonstrate that activation of AMPK leads to protection of tubular function under hypoxic/ischemic conditions which holds promise as a potential novel therapeutic approach for AKI. Significance Statement No approved pharmacological therapies currently exist for acute kidney injury. We developed Compound 1 which dose-dependently activated AMPK in the kidney and protected kidney function and tubules after ischemic renal injury in the rat. This was accompanied by natriuresis in injured as well as uninjured rats.

Kynurenine 3-monooxygenase limits de novo NAD+ synthesis through dietary tryptophan in renal proximal tubule epithelial cell models.

Nicotinamide adenine dinucleotide (NAD+) is a pivotal coenzyme, essential for cellular reactions, metabolism, and mitochondrial function. Depletion of kidney NAD+ levels and reduced de novo NAD+ synthesis through the tryptophan-kynurenine pathway are linked to acute kidney injury (AKI), whereas augmenting NAD+ shows promise in reducing AKI. We investigated de novo NAD+ biosynthesis using in vitro, ex vivo, and in vivo models to understand its role in AKI. Two-dimensional (2-D) cultures of human primary renal proximal tubule epithelial cells (RPTECs) and HK-2 cells showed limited de novo NAD+ synthesis, likely due to low pathway enzyme gene expression. Using three-dimensional (3-D) spheroid culture model improved the expression of tubular-specific markers and enzymes involved in de novo NAD+ synthesis. However, de novo NAD+ synthesis remained elusive in the 3-D spheroid culture, regardless of injury conditions. Further investigation revealed that 3-D cultured cells could not metabolize tryptophan (Trp) beyond kynurenine (KYN). Intriguingly, supplementation of 3-hydroxyanthranilic acid into RPTEC spheroids was readily incorporated into NAD+. In a human precision-cut kidney slice (PCKS) ex vivo model, de novo NAD+ synthesis was limited due to substantially downregulated kynurenine 3-monooxygenase (KMO), which is responsible for KYN to 3-hydroxykynurenine conversion. KMO overexpression in RPTEC 3-D spheroids successfully reinstated de novo NAD+ synthesis from Trp. In addition, in vivo study demonstrated that de novo NAD+ synthesis is intact in the kidney of the healthy adult mice. Our findings highlight disrupted tryptophan-kynurenine NAD+ synthesis in in vitro cellular models and an ex vivo kidney model, primarily attributed to KMO downregulation.NEW & NOTEWORTHY Nicotinamide adenine dinucleotide (NAD+) is essential in regulating mitochondrial function. Reduced NAD+ synthesis through the de novo pathway is associated with acute kidney injury (AKI). Our study reveals a disruption in de novo NAD+ synthesis in proximal tubular models, but not in vivo, attributed to downregulation of enzyme kynurenine 3-monooxygenase (KMO). These findings highlight a crucial role of KMO in governing de novo NAD+ biosynthesis within the kidney, shedding light on potential AKI interventions.

Surface-independent CO2 and CO reduction on two-dimensional kagome metal KV3Sb5.

Two-dimensional kagome metals possess rich band structure characteristics, including Dirac points, flat bands, and van Hove singularities, because of their special geometric structures. Furthermore, kagome metals AV3Sb5 (A = K, Rb, and Cs) have garnered significant attention due to their nontrivial topological electronic structures. In this study, we theoretically demonstrate that the KV3Sb5 (001) surface is conducive to CO2 and CO reduction. The thermodynamic stability and electrochemical states of various surface types are investigated. The reaction paths reveal that the product is identical on different surfaces, and the free energy profiles exhibit low onset potentials. This paper elucidates the effect of two-dimensional topological kagome metals on CO2 and CO reduction.

DNA Methylation Biomarkers as Prediction Tools for Therapeutic Response and Prognosis in Intermediate-Stage Hepatocellular Carcinoma.

INTRODUCTION: Alfa-fetoprotein (AFP), as the main serum tumor marker of hepatocellular carcinoma (HCC), is limited in terms of specificity and ability to predict outcomes. This study investigated the clinical utility of DNA methylation biomarkers to predict therapeutic responses and prognosis in intermediate-stage HCC. METHODS: This study enrolled 72 patients with intermediate-stage HCC who underwent locoregional therapy (LRT) between 2020 and 2021. The immediate therapeutic response and disease status during a two-year follow-up were recorded. Analysis was performed on 10 selected DNA methylation biomarkers via pyrosequencing analysis of plasma collected before and after LRT. RESULTS: Analysis was performed on 53 patients with complete responses and 19 patients with disease progression after LRT. The mean follow-up duration was 2.4 ± 0.6 years. A methylation prediction model for tumor response (MMTR) and a methylation prediction model for early progression (MMEP) were constructed. The area under the curve (AUC) for sensitivity and specificity of MMTR was 0.79 for complete response and 0.759 for overall survival. The corresponding AUCs for sensitivity and specificity of AFP and protein induced by vitamin K absence-II (PIVKA-II) were 0.717 and 0.708, respectively. Note that the MMTR index was the only significant predictor in multivariate analysis. The AUC for sensitivity and specificity of the MMEP in predicting early progression was 0.79. The corresponding AUCs for sensitivity and specificity of AFP and PIVKA-II were 0.758 and 0.714, respectively. Multivariate analysis revealed that platelet count, beyond up-to-7 criteria, and the MMEP index were strongly correlated with early tumor progression. Combining the indexes and serum markers further improved the predictive accuracy (AUC = 0.922). Multivariate analysis revealed the MMEP index was the only independent risk factor for overall survival. DISCUSSION/CONCLUSIONS: This study indicates that these methylation markers could potentially outperform current serum markers in terms of accuracy and reliability in assessing treatment response and predicting outcomes. Combining methylation markers and serum markers further improved predictive accuracy, indicating that a multi-marker approach may be more effective in clinical practice. These findings suggest that DNA methylation biomarkers may be a useful tool for managing intermediate-stage HCC patients and guiding personalized treatment, particularly for those who are at high risk for close surveillance or adjuvant treatment after LRT.

Creation of Dual Thermally Activated Delayed-Fluorescence Exciplexes in a Bulk Emitting Layer and Its Interface with an Electron Transport Layer for Promoting the Performance of Thermally Activated Delayed-Fluorescence Organic Light-Emitting Diodes Fabricated by a Solution Process.

An exciplex, which is composed of electron donor and acceptor molecules and formed by intermolecular charge transfer, is an excited-state species that is able to emit light or transfer its energy to a lower-energy emitter. In reported exciplex-based organic light-emitting diodes (OLEDs), their working mechanism is to generate exciplexes either in the bulk emitting layer (bulk exciplex) or at its interface with an electron transport layer (interface exciplex); both types give promising device performance. Here, we propose a novel strategy of creating both types of exciplexes simultaneously (dual exciplexes) for the generation of more exciplexes for better device performance as indicated in the improved photoluminescence quantum yield (PLQY). Impressively, the dual exciplex-based device with blue thermally activated delayed fluorescence (TADF) emitter 9,9-dimethyl-9,10-dihydroacridine-2,4,6-triphenyl-1,3,5-triazine (DMAC-TRZ) exhibits a record-high maximum external quantum efficiency (EQEmax) of 26.7% among the solution-processed TADF blue OLEDs. By further doping with the red-emitting phosphor emitter into the EML, the white device also gives a record-high EQEmax of 24.1% among the solution-processed TADF-phosphor hybrid white OLEDs (T-P WOLEDs) with the Commission Internationale de L'Eclairage (CIE) coordinates of (0.34, 0.42), color rendering index of 70, and correlated color temperature of 5198 K. Furthermore, both blue and white devices show an ultralow efficiency roll-off with external quantum efficiencies at a practical brightness value of 1000 cd m-2 (EQE1000) of 25.1 and 23.9%, respectively. This is the first report of employing a dual exciplex-based OLED with excellent device performance.

Screening and identification of genes involved in ß-alanine biosynthesis in Bacillus subtilis.

ß-alanine is the only naturally occurring ß-amino acid, which is widely used in medicine, food, and feed fields, and generally produced through synthetic biological methods based on engineered strains of Escherichia coli or Corynebacterium glutamicum. However, the ß-alanine biosynthesis in Bacillus subtilis, a traditional industrial model microorganism of food safety grade, has not been thoroughly explored. In this study, the native l-aspartate-α-decarboxylase was overexpressed in B. subtilis 168 to obtain an increase of 842% in ß-alanine production. A total of 16 single-gene knockout strains were constructed to block the competitive consumption pathways to identify a total of 6 genes (i.e., ptsG, fbp, ydaP, yhfS, mmgA, and pckA) involved in ß-alanine synthesis, while the multigene knockout of these 6 genes obtained an increased ß-alanine production by 40.1%. Ten single-gene suppression strains with the competitive metabolic pathways inhibited revealed that the inhibited expressions of genes glmS, accB, and accA enhanced the ß-alanine production. The introduction of heterologous phosphoenolpyruvate carboxylase increased the ß-alanine production by 81.7%, which was 17-fold higher than that of the original strain. This was the first study using multiple molecular strategies to investigate the biosynthetic pathway of ß-alanine in B. subtilis and to identify the genetic factors limiting the excessive synthesis of ß-alanine by microorganisms.

The Effect of Transcranial Electrical Stimulation on the Recovery of Sleep Quality after Sleep Deprivation Based on an EEG Analysis.

Acute sleep deprivation can reduce the cognitive ability and change the emotional state in humans. However, little is known about how brain EEGs and facial expressions change during acute sleep deprivation (SD). Herein, we employed 34 healthy adult male subjects to undergo acute SD for 36 h, during which, their emotional states and brain EEG power were measured. The subjects were divided randomly into electronic stimulation and control groups. We performed TDCS on the left dorsolateral prefrontal cortex for 2 mA and 30 min in the TDCS group. These results indicated that the proportion of disgusted expressions in the electrical stimulation group was significantly less than the controls after 36 h post-acute SD, while the proportion of neutral expressions was increased post-restorative sleep. Furthermore, the electrical stimulation group presented a more significant impact on slow wave power (theta and delta) than the controls. These findings indicated that emotional changes occurred in the subjects after 36 h post-acute SD, while electrical stimulation could effectively regulate the cortical excitability and excitation inhibition balance after acute SD.

Designing Highly Precise Overlay Targets for Asymmetric Sidewall Structures Using Quasi-Periodic Line Widths and Finite-Difference Time-Domain Simulation.

The present study introduces an optimized overlay target design to minimize the overlay error caused by asymmetric sidewall structures in semiconductor manufacturing. To achieve this goal, the overlay error formula was derived by separating the asymmetric bottom grating structure into symmetric and asymmetric parts. Based on this formula, it was found that the overlay target design with the linewidth of the bottom grating closed to the grating period could effectively reduce the overlay error caused by the sidewall asymmetry structure. Simulation results demonstrate that the proposed design can effectively control the measurement error of different wavelengths within ±0.3 nm, even under varying sidewall angles and film thicknesses. Overall, the proposed overlay target design can significantly improve the overlay accuracy in semiconductor manufacturing processes.

[Methyl ferulic acid ameliorates ethanol-induced L02 cell steatosis through microRNA-378b-mediated CaMKK2-AMPK pathway].

Alcoholic liver disease(ALD), with its increasing morbidity and mortality, has seriously and extensively affected the health of people worldwide. Methyl ferulic acid(MFA) has been proven to significantly inhibit alcohol-induced lipid production in L02 cells through the AMP-activated protein kinase(AMPK) pathway, but its in-depth mechanism remains unclear. This study aimed to further clarify the mechanism of MFA in improving lipid accumulation in L02 cells through the microRNA-378b(miR-378b)-mediated calcium/calmodulin-dependent protein kinase kinase 2(CaMKK2)-AMPK signaling pathway based on existing researches. L02 cells were induced by 100 mmol·L~(-1) ethanol for 48 h to establish the model of ALD in vitro, and 100, 50, and 25 µmol·L~(-1) concentration of MFA was treated. MiR-378b plasmids(containing the overexpression plasmid-miR-378b mimics, silence plasmid-miR-378b inhibitor, and their respective negative control-miR-378b NCs) were transfected into L02 cells by electroporation to up-regulate or down-regulate the levels of miR-378b in L02 cells. The levels of total cholesterol(TC) and triglyceride(TG) in cells were detected by commercial diagnostic kits and automatic biochemical analyzers. The expression levels of miR-378b in L02 cells were detected by real-time quantitative polymerase chain reaction(qRT-PCR). CaMKK2 mRNA levels were detected by PCR, and protein expressions of related factors involved in lipid synthesis, decomposition, and transport in lipid metabolism were detected by Western blot. The results displayed that ethanol significantly increased TG and TC levels in L02 cells, while MFA decreased TG and TC levels. Ethanol up-regulated the miR-378b level, while MFA effectively inhibited the miR-378b level. The overexpression of miR-378b led to lipid accumulation in ethanol-induced L02 cells, while the silence of miR-378b improved the lipid deposition induced by ethanol. MFA activated the CaMKK2-AMPK signaling pathway by lowering miR-378b, thus improving lipid synthesis, decomposition, and transport, which improved lipid deposition in L02 cells. This study shows that MFA improves lipid deposition in L02 cells by regulating the CaMKK2-AMPK pathway through miR-378b.

The risk of all-cause death with dapagliflozin versus placebo: a systematic review and meta-analysis of phase III randomized controlled trials.

BACKGROUND: Dapagliflozin has proven cardioprotective and nephroprotective effects. However, the risk of all-cause death with dapagliflozin remains unclear. RESEARCH DESIGN AND METHODS: We performed a meta-analysis of phase III randomized controlled trials (RCTs) for the risk of all-cause death and safety events with dapagliflozin compared to placebo. PubMed and EMBASE were searched from inception to 20 September 2022. RESULTS: Five trials were included in the final analysis. Compared with the placebo, dapagliflozin demonstrated an 11.2% reduction in the risk of all-cause death (OR 0.88, 95% CI 0.81-0.94). No statistically significant difference in urinary tract infection (OR: 0.95, 95% CI: 0.78 to 1.17), bone fracture (OR: 1.06, 95% CI: 0.94 to 1.20), and amputation (OR: 1.01, 95% CI: 0.82 to 1.23) was observed between patients treated with dapagliflozin and placebo. Compared with placebo, dapagliflozin was associated with a significant reduction in acute kidney injury (OR: 0.71, 95% CI: 0.60 to 0.83), and increased the risk of genital infection (OR: 8.21, 95% CI: 4.19 to 16.12). CONCLUSIONS: Dapagliflozin was associated with significantly reduced all-cause death and increased genital infection. Dapagliflozin was safe concerning urinary tract infection, bone fracture, amputation, and acute kidney injury, compared with the placebo.

Indirect comparison of SGLT2 inhibitors in patients with established heart failure: evidence based on Bayesian methods.

AIMS: Head-to-head comparisons among SGLT2 inhibitors treatments in established heart failure remain absent. We conducted a systematic review of dedicated heart failure trials to assess indirectly the composite outcomes and individual clinical endpoints among SGLT2 inhibitor treatments. METHODS AND RESULTS: We systematically reviewed randomized controlled trials comparing SGLT2 inhibitors versus placebo in patients with established heart failure. A Bayesian approach to network meta-analysis was applied. Five trials including four treatment strategies were included in this study. The composite of cardiovascular death or hospitalization for heart failure showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 1.00, 95% CI 0.66-1.55), dapagliflozin and sotagliflozin (OR 1.54, 95% CI 0.91-2.65), and empagliflozin and sotagliflozin (OR 1.53, 95% CI 0.90-2.69). All-cause mortality showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 0.92, 95% CI 0.711-1.18), dapagliflozin and sotagliflozin (OR 1.05, 95% CI 0.68-1.59), and empagliflozin and sotagliflozin (OR 1.14, 95% CI 0.74-1.73). Cardiovascular death showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 0.94, 95% CI 0.71-1.23), dapagliflozin and sotagliflozin (OR 0.96, 95% CI 0.61-1.55), and empagliflozin and sotagliflozin (OR 1.03, 95% CI 0.64-1.66). Hospitalization for heart failure showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 1.13, 95% CI 0.64-1.97), dapagliflozin and sotagliflozin (OR 1.56, 95% CI 0.74-3.15), and empagliflozin and sotagliflozin (OR 1.39, 95% CI 0.68-2.78). CONCLUSIONS: In patients with established heart failure, there was no significant difference of the major efficacy outcomes among SGLT2 inhibitor treatments; however, sotagliflozin may be associated with the lowest risk of the composite of cardiovascular death or hospitalization for heart failure, and dapagliflozin may be associated with the lowest risk of all-cause and cardiovascular mortality.

An eighth note.

Venous stenosis is the most common cause of arteriovenous fistula (AVF) failure in hemodialysis patients. For patients with AVF stenosis, the pressure over the antecedent part of the AVF stenotic lesion will increase if arterial inflow is sufficient. We report a chronic hemodialysis patient who received an angiographic examination for the juxta-anastomosis stenosis of his AVF. A unique feature of a collateral venous branch antecedent to the stenotic lesion was noted, resembling a musical sign as the "eighth note." After percutaneous transluminal angioplasty, the eighth note attenuated markedly at once. Of note, the eighth note sign is not seen frequently, and thus we postulate that the formation of an eighth note sign on the radiocephalic fistula should fulfill the following requirements, including a sufficient arterial inflow, an adjacent collateral branch close enough to the arteriovenous anastomosis, a severe juxta-anastomotic stenotic lesion, and an intact ulnar venous drainage system.

A systematic review and meta-analysis comparing the diagnostic capability of automated breast ultrasound and contrast-enhanced ultrasound in breast cancer.

Objective: To compare the diagnostic performance of automated breast ultrasound (ABUS) and contrast-enhanced ultrasound (CEUS) in breast cancer. Methods: Published studies were collected by systematically searching the databases PubMed, Embase, Cochrane Library and Web of Science. The sensitivities, specificities, likelihood ratios and diagnostic odds ratio (DOR) were confirmed. The symmetric receiver operator characteristic curve (SROC) was used to assess the threshold of ABUS and CEUS. Fagan's nomogram was drawn. Meta-regression and subgroup analyses were applied to search for sources of heterogeneity among the included studies. Results: A total of 16 studies were included, comprising 4115 participants. The combined sensitivity of ABUS was 0.88 [95% CI (0.73-0.95)], specificity was 0.93 [95% CI (0.82-0.97)], area under the SROC curve (AUC) was 0.96 [95% CI (0.94-0.96)] and DOR was 89. The combined sensitivity of CEUS was 0.88 [95% CI (0.84-0.91)], specificity was 0.76 [95% CI (0.66-0.84)], AUC was 0.89 [95% CI (0.86-0.92)] and DOR was 24. The Deeks' funnel plot showed no existing publication bias. The prospective design, partial verification bias and blinding contributed to the heterogeneity in specificity, while no sources contributed to the heterogeneity in sensitivity. The post-test probability of ABUS in BC was 75%, and the post-test probability of CEUS in breast cancer was 48%. Conclusion: Compared with CEUS, ABUS showed higher specificity and DOR for detecting breast cancer. ABUS is expected to further improve the accuracy of BC diagnosis.

A study on factors associated with age of Alzheimer's disease onset / 中华流行病学杂志

Objective: To understand the distribution characteristics of age of Alzheimer's disease (AD) onset and influencing factors. Methods: Based on the follow-up data of Alzheimer's Disease Neuroimaging Initiative from 2005 to 2022, participants with normal cognition (CN) or mild cognitive impairment (MCI) at baseline survey, and those with progression to AD during follow-up period were selected as study subjects. Univariate analysis and multiple linear regression analysis were performed to explore the associations of gender, race, number of ApoE ε4 genes carried, family history, years of education and marital status with the age of AD onset. Results: A total of 405 participants, with an average age of (74.0±6.9) years at baseline survey, progressed to AD during follow up period. The age of AD onset was (76.6±7.5) years, and age of onset in men was about 1.9 years later than women. Multiple linear regression analysis showed that for each increase in ApoE ε4 gene number, the age of AD onset was about 0.344 years earlier. The age of AD onset was 4.007 years earlier for those with MCI at baseline survey compared with those with CN. Years of education were not significantly associated with the age of onset of AD (P>0.05). Conclusion: Those who carry ApoE ε4 gene, and have MCI at baseline survey might have earlier age of AD onset.

Metagenomic Analysis of Microbial Alliances for Efficient Degradation of PHE: Microbial Community Structure and Reconstruction of Metabolic Network.

Polycyclic aromatic hydrocarbons are a widespread organic pollutant worldwide. In this study, a highly efficient phenanthrene (PHE)-degrading microbial community was enriched from oil extraction soil, which could degrade 500 mg/L PHE within 4 days. Using 16S rRNA sequencing, the dominant bacteria in this community at the phylum level were found to be Proteobacteria, Actinobacteria, and Firmicutes. Metagenomic annotation of genes revealed the metabolic pathways and the contribution of different bacteria to the degradation process. Pseudomonadaceae contributed multiple functional genes in the degradation process. This study revealed the functional genes, metabolic pathways, and microbial interactions of the microbial community, which are expected to provide guidance for practical management.

Research progress of the POP fugacity model: a bibliometrics-based analysis.

With the emergence of environmental issues regarding persistent organic pollutants (POPs), fugacity models have been widely used in the concentration prediction and exposure assessment of POPs. Based on 778 relevant research articles published between 1979 and 2020 in the Web of Science Core Collection (WOSCC), the current research progress of the fugacity model on predicting the fate and transportation of POPs in the environment was analyzed by CiteSpace software. The results showed that the research subject has low interdisciplinarity, mainly involving environmental science and environmental engineering. The USA was the most paper-published country, followed by Canada and China. The publications of the Chinese Academy of Sciences, Lancaster University, and Environment Canada were leading. Collaboration between institutions was inactive and low intensity. Keyword co-occurrence analysis showed that polychlorinated biphenyls, organochlorine pesticides, and polycyclic aromatic hydrocarbons were the most concerning compounds, while air, water, soil, and sediment were the most concerning environmental media. Through co-citation cluster analysis, in addition to the in-depth exploration of traditional POPs, research on emerging POPs such as cyclic volatile methyl siloxane and dechlorane plus were new research frontiers. The distribution and transfer of POPs in the soil-air environment have attracted the most attention, and the regional grid model based on fugacity has been gradually improved and developed. The co-citation high-burst detection showed that the research hotspots gradually shifted from pollutant persistence and long-range transport potential to pollutant distribution rules among the different environmental media and the long-distance transmission simulation.

Genetic Variants in Double-Strand Break Repair Pathway Genes to Predict Platinum-Based Chemotherapy Prognosis in Patients With Lung Cancer.

Objective: The purpose of this study was to investigate the associations of genetic variants in double-strand break (DSB) repair pathway genes with prognosis in patients with lung cancer treated with platinum-based chemotherapy. Methods: Three hundred ninety-nine patients with lung cancer who received platinum-based chemotherapy for at least two cycles were included in this study. A total of 35 single nucleotide polymorphisms (SNPs) in DSB repair, base excision repair (BER), and nucleotide excision repair (NER) repair pathway genes were genotyped, and were used to evaluate the overall survival (OS) and the progression-free survival (PFS) of patients who received platinum-based chemotherapy using Cox proportional hazard models. Results: The PFS of patients who carried the MAD2L2 rs746218 GG genotype was shorter than that in patients with the AG or AA genotypes (recessive model: p = 0.039, OR = 5.31, 95% CI = 1.09-25.93). Patients with the TT or GT genotypes of TNFRSF1A rs4149570 had shorter OS times than those with the GG genotype (dominant model: p = 0.030, OR = 0.57, 95% CI = 0.34-0.95). We also investigated the influence of age, gender, histology, smoking, stage, and metastasis in association between SNPs and OS or PFS in patients with lung cancer. DNA repair gene SNPs were significantly associated with PFS and OS in the subgroup analyses. Conclusion: Our study showed that variants in MAD2L2 rs746218 and TNFRSF1A rs4149570 were associated with shorter PFS or OS in patients with lung cancer who received platinum-based chemotherapy. These variants may be novel biomarkers for the prediction of prognosis of patients with lung cancer who receive platinum-based chemotherapy.

[Source Analysis and Composition Characteristics of Water-soluble Ions During Spring Festival in Ningbo].

Water-soluble ions and some trace gases during the Spring Festival in Ningbo were observed using an ion online gas composition and aerosol monitoring system. Combined with meteorological elements data, the source analysis and composition characteristics of water-soluble ions and trace gases were analyzed. The average concentration of ρ(PM2.5) during the observation period was 33.1 µg·m-3, and there was light pollution. The order of concentration of water-soluble ions was NO3->SO42->NH4+>K+>Cl->Na+>Ca2+>Mg2+. The secondary inorganic ions ρ(NO3-), ρ(SO42-), and ρ(NH4+) were the most water-soluble ions, which were 12.5, 10.5, and 7.2 µg·m-3, respectively. According to the PMF source analysis, firecracker combustion, secondary generation (background, industrial source), and dust sources were the major sources of fine particles during the observation period, and their contribution rates of PM2.5 were 21.9%, 64.5%, and 13.6%, respectively. When the secondary generation was the main pollution, NH4+ accounted for 92.2% of the cations. When firecracker combustion was the main pollution from New Year's Eve to the second day, the proportion of K+ions significantly increased. Dust sources were affected by regional transport from the northwest direction. When the dust source was the main pollution, the proportion of K++Ca2+and Na++Mg2+ increased.

Identification of essential ß-oxidation genes and corresponding metabolites for oestrogen degradation by actinobacteria.

Steroidal oestrogens (C18 ) are contaminants receiving increasing attention due to their endocrine-disrupting activities at sub-nanomolar concentrations. Although oestrogens can be eliminated through photodegradation, microbial function is critical for removing oestrogens from ecosystems devoid of sunlight exposure including activated sludge, soils and aquatic sediments. Actinobacteria were found to be key oestrogen degraders in manure-contaminated soils and estuarine sediments. Previously, we used the actinobacterium Rhodococcus sp. strain B50 as a model microorganism to identify two oxygenase genes, aedA and aedB, involved in the activation and subsequent cleavage of the estrogenic A-ring respectively. However, genes responsible for the downstream degradation of oestrogen A/B-rings remained completely unknown. In this study, we employed tiered comparative transcriptomics, gene disruption experiments and mass spectrometry-based metabolite profile analysis to identify oestrogen catabolic genes. We observed the up-regulation of thiolase-encoding aedF and aedK in the transcriptome of strain B50 grown with oestrone. Consistently, two downstream oestrogenic metabolites, 5-oxo-4-norestrogenic acid (C17 ) and 2,3,4-trinorestrogenic acid (C15 ), were accumulated in aedF- and aedK-disrupted strain B50 cultures. Disruption of fadD3 [3aα-H-4α(3'-propanoate)-7aß-methylhexahydro-1,5-indanedione (HIP)-coenzyme A-ligase gene] in strain B50 resulted in apparent HIP accumulation in oestrone-fed cultures, indicating the essential role of fadD3 in actinobacterial oestrogen degradation. In addition, we detected a unique meta-cleavage product, 4,5-seco-estrogenic acid (C18 ), during actinobacterial oestrogen degradation. Differentiating the oestrogenic metabolite profile and degradation genes of actinobacteria and proteobacteria enables the cost-effective and time-saving identification of potential oestrogen degraders in various ecosystems through liquid chromatography-mass spectrometry analysis and polymerase chain reaction-based functional assays.

Chloroplast import of an intermembrane space protein is facilitated by translocon components Toc75 and Tic236.

Chloroplasts are divided into six subcompartments: the outer membrane, intermembrane space, and inner membrane of the envelope, the stroma, the thylakoid membrane, and the thylakoid lumen. Compared with our knowledge of protein import into other subcompartments, extremely little is known about how proteins are imported into the intermembrane space of the envelope. Tic22 was one of the first proteins identified as localizing to the intermembrane space and the only one for which import has been analyzed in some detail. However, conflicting results have been obtained concerning whether the general translocon is used to import Tic22 into the intermembrane space. Taking advantage of available translocon component mutants, we reanalyzed import of Tic22. We reveal reduced in vitro import of Tic22 preprotein (prTic22) into chloroplasts isolated from the Arabidopsis mar1 and tic236 mutants, which are functional knockdown mutants of the outer-membrane channel Toc75 and the intermembrane space linker Tic236, respectively. Import competition experiments also showed that prTic22 import was reduced by excess amounts of a stroma-targeted preprotein. Our results indicate that prTic22 uses at least part of the general translocon for import into the intermembrane space.