Cu,Ce-containing phosphotungstates as laccase-like nanozyme for colorimetric detection of Cr(VI) and Fe(â ¢).

Herein, a nanocomposite of Cu,Ce-containing phosphotungstates (Cu,Ce-PTs) with outstanding laccase-like activity was fabricated via a one-pot microwave-assisted hydrothermal method. Notably, it was discovered that both Fe3+ and Cr6+ could significantly enhance the electron transfer rates of Ce3+ and Ce4+, along with generous Cu2+ with high catalytic activity, thereby promoting the laccase-like activity of Cu,Ce-PTs. The proposed system can be used for the detection of Fe3+ and Cr6+ in a range of 0.667-333.33 µg/mL and 0.033-33.33 µg/mL with a low detection limit of 0.135 µg/mL and 0.0288 µg/mL, respectively. The proposed assay exhibits excellent reusability and selectivity and can be used in traditional Chinese medicine samples analysis.

Electroacupuncture alleviates neuropathic pain by regulating hippocampal SP/NK1R/ARRB1 pathway. / 电针调控海马SP/NK1R/ARRB1é€šè·¯ç¼“è§£å¤§é¼ ç¥žç»ç— ç†æ€§ç–¼ç—›çš„ç ”ç©¶.

OBJECTIVES: To observe the effect of electroacupuncture (EA) on pain, anxiety like behavior, and substance P(SP) /neurokinin-1 receptor (NK1R) /ß -arrestin 1(ARRB1) pathway related protein expression in hippocampus of chronic constriction injury (CCI) rats, so as to explore its mechanisms underlying improvement of neuropathic pain. METHODS: Twenty-seven male SD rats were randomly divided into sham operation, model and EA groups, with 9 rats in each group. The CCI model was established by ligature of the left sciatic nerve. On the 8th day following modeling, EA (2 Hz, 0.5-1.5 mA) was applied to the left "Huantiao" (GB34) and "Yanglingquan" (GB34) for 30 min, once every other day for 13 times. Mechanical paw withdrawal threshold (MWT), thermal paw withdrawal threshold (TWL) and difference of the weight distribution of the hind limbs were detected before operation and at the 5th, 9th, 17th, 25th and 33rd days after operation. Open field test was used to evaluate the anxiety-like behavior of rats. The content of SP in hippocampus was determined by ELISA. The protein expression of NK1R and ARRB1 in hippocampus was detected by Western blot. RESULTS: Compared with the sham operation group, the MWT and TWL of the left hind limb at the 5th, 9th, 17th, 25th and 33rd days after operation, the time of entering the central area and the total distance of movement, and the content of SP in the hippocampus were significantly decreased (P<0.001, P<0.01), while the difference of the weight distribution of the hind limbs at the 5th, 9th, 17th, 25th and 33rd days after operation and the protein expression of NK1R and ARRB1 were significantly increased (P<0.001, P<0.05) in the model group. After EA intervention, the MWT and TWL of the left hind limb, the time of entering the central area and the total moving distance, and the expression of SP in the hippocampus were significantly increased (P<0.01, P<0.001, P<0.05), while the difference in the weight distribution of the hind limbs was significantly reduced, and the expression of NK1R and ARRB1 protein in the hippocampus were significantly decreased (P<0.001, P<0.05) in the EA group. CONCLUSIONS: EA can effectively improve the pain and anxiety behaviors in CCI rats, and reverse the abnormal expression of SP, NK1R and ARRB1 proteins in the hippocampus, which may be related to its effects in regulating the SP/NK1R/ARRB1 pathway in the hippocampus.

Polyunsaturated fatty acids and diabetic microvascular complications: a Mendelian randomization study.

Background: Observational studies and clinical trials have implicated polyunsaturated fatty acids (PUFAs) in potentially safeguarding against diabetic microvascular complication. Nonetheless, the causal nature of these relationships remains ambiguous due to conflicting findings across studies. This research employs Mendelian randomization (MR) to assess the causal impact of PUFAs on diabetic microvascular complications. Methods: We identified instrumental variables for PUFAs, specifically omega-3 and omega-6 fatty acids, using the UK Biobank data. Outcome data regarding diabetic microvascular complications were sourced from the FinnGen Study. Our analysis covered microvascular outcomes in both type 1 and type 2 diabetes, namely diabetic neuropathy (DN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). An inverse MR analysis was conducted to examine the effect of diabetic microvascular complications on PUFAs. Sensitivity analyses were performed to validate the robustness of the results. Finally, a multivariable MR (MVMR) analysis was conducted to determine whether PUFAs have a direct influence on diabetic microvascular complications. Results: The study indicates that elevated levels of genetically predicted omega-6 fatty acids substantially reduce the risk of DN in type 2 diabetes (odds ratio (OR): 0.62, 95% confidence interval (CI): 0.47-0.82, p = 0.001). A protective effect against DR in type 2 diabetes is also suggested (OR: 0.75, 95% CI: 0.62-0.92, p = 0.005). MVMR analysis confirmed the stability of these results after adjusting for potential confounding factors. No significant effects of omega-6 fatty acids were observed on DKD in type 2 diabetes or on any complications in type 1 diabetes. By contrast, omega-3 fatty acids showed no significant causal links with any of the diabetic microvascular complications assessed. Conclusions: Our MR analysis reveals a causal link between omega-6 fatty acids and certain diabetic microvascular complications in type 2 diabetes, potentially providing novel insights for further mechanistic and clinical investigations into diabetic microvascular complications.

Combining lymph node ratio to develop prognostic models for postoperative gastric neuroendocrine neoplasm patients.

BACKGROUND: Lymph node ratio (LNR) was demonstrated to play a crucial role in the prognosis of many tumors. However, research concerning the prognostic value of LNR in postoperative gastric neuroendocrine neoplasm (NEN) patients was limited. AIM: To explore the prognostic value of LNR in postoperative gastric NEN patients and to combine LNR to develop prognostic models. METHODS: A total of 286 patients from the Surveillance, Epidemiology, and End Results database were divided into the training set and validation set at a ratio of 8:2. 92 patients from the First Affiliated Hospital of Soochow University in China were designated as a test set. Cox regression analysis was used to explore the relationship between LNR and disease-specific survival (DSS) of gastric NEN patients. Random survival forest (RSF) algorithm and Cox proportional hazards (CoxPH) analysis were applied to develop models to predict DSS respectively, and compared with the 8th edition American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging. RESULTS: Multivariate analyses indicated that LNR was an independent prognostic factor for postoperative gastric NEN patients and a higher LNR was accompanied by a higher risk of death. The RSF model exhibited the best performance in predicting DSS, with the C-index in the test set being 0.769 [95% confidence interval (CI): 0.691-0.846] outperforming the CoxPH model (0.744, 95%CI: 0.665-0.822) and the 8th edition AJCC TNM staging (0.723, 95%CI: 0.613-0.833). The calibration curves and decision curve analysis (DCA) demonstrated the RSF model had good calibration and clinical benefits. Furthermore, the RSF model could perform risk stratification and individual prognosis prediction effectively. CONCLUSION: A higher LNR indicated a lower DSS in postoperative gastric NEN patients. The RSF model outperformed the CoxPH model and the 8th edition AJCC TNM staging in the test set, showing potential in clinical practice.

Optimized workflow of EV enrichment from human plasma samples for downstream mass spectrometry analysis.

To improve the prognosis of bladder and prostate cancer, highly specific and sensitive biomarkers are needed for early detection, prognosis prediction, and therapeutic stratification. Extracellular vesicles (EV) from plasma could fill this gap due to their potential to serve as cancer biomarkers. However, the enrichment of EV is a major challenge, because the highly abundant plasma proteins are interfering with analytical downstream applications like mass spectrometry (MS). Therefore, the purity requirements of the EV samples must be carefully considered when selecting or developing a suitable EV enrichment method. The aim of this study was to compare a self-designed EV enrichment method based on density cushion centrifugation (DCC) combined with size exclusion chromatography (SEC) and concentration (method 1) with the exoRNeasy midi kit from Qiagen (method 2) and with unprocessed plasma. Furthermore, the single steps of method 1 were evaluated for their effectiveness to enrich EV from plasma. The results showed that the EV samples enriched with method 1 contained the highest levels of EV and exosome markers with simultaneously low levels of highly abundant plasma proteins. In summary, the combination of DCC, SEC and concentration proved to be a promising approach to discover EV-based biomarkers from plasma of cancer patients.

Development of Hypoallergenic Derivatives of Cra a 1 with B Cell Epitope Deletion and T Cell Epitope Retention.

Tropomyosin was reported as an important allergen in Crassostrea angulata and designated as Cra a 1. The localization of the T cell epitopes and the reduction of the immunoreactivity of Cra a 1 are still lacking. In this study, four T cell epitopes were identified by using wild-type Cra a 1 (wtCra a 1)-immunized mouse splenocytes cultured with synthetic peptides. The immunoreactivity was maintained after chemical denaturation treatment, indicating that the linear epitope is an immunodominant epitope of wtCra a 1. Furthermore, the hypoallergenic derivative (mCra a 1) was developed by the deletion of linear B cell epitopes and retention of T cell epitopes. mCra a 1 could stimulate CD4+T cell proliferation and upregulate interleukin-10 secretion. Overall, basophil activation by mCra a 1 was low, but its ability to induce T cell proliferation was retained, suggesting that mCra a 1 may serve as a viable candidate for treating oyster allergy.

[Non-targeted renal metabolomics reveals multi-target effects of Dahuang Zhechong Pills on renal aging in rats].

This study aims to observe the effects of the traditional Chinese medicine prescription Dahuang Zhechong Pills(DHZCP on renal aging and explore its potential multi-target effects. Rats were assigned into the normal, model, DHZCP, and vitamin E(VE)groups. Firstly, the rat model of D-galactose(D-gal)-induced renal aging was established. During the modeling period, the rats in the 4 groups were administrated with double distilled water, double distilled water, DHZCP suspension, and VE suspension, respectively,by gavage every day. On day 60 of intervention, the indicators of renal aging and injury in rats were measured, including the function,histopathological characteristics, senescence-associated ß-galactosidase( SA-ß-gal) staining, and expression levels of Klotho and proteins associated with cell cycle arrest and senescence-associated secretory phenotype(SASP) in the renal tissue. Moreover, nontargeted metabolomic analysis of the renal tissue was performed for the 4 groups of rats to screen out the potential biomarkers and metabolic pathways. Finally, the signaling pathways of key targets were preliminarily validated. The results showed that DHZCP and VE significantly improved the renal function, histopathological features of renal tubular/interstitial tissue, and degree of SA-ß-gal staining, up-regulated the expression level of Klotho, and down-regulated the expression levels of proteins associated with cell cycle arrest and SASP in the renal tissue of the aging rats. In addition, DHZCP and VE regulated the metabolites in the renal tissue of the aging rats. There were 21 common differential metabolites. Among them, 5 differential metabolites were significantly increased in the aging rats and recovered after DHZCP or VE treatment, and they were involved in the lipid metabolism and energy metabolism pathways. The areas under the curves of the groups in comparison varied within the range of 0. 88-1. DHZCP regulated multiple signaling pathways, such as the adenosine monophosphate-activated protein kinase(AMPK), cyclic guanosine monophosphate-protein kinase G( c GMP-PKG), cyclic adenylic acid( c AMP), phosphatidylinositol-3-kinase-protein kinase B( PI3K-Akt), mammalian target of rapamycin(mTOR), and autophagy signaling pathways. In addition, it affected the multiple metabolic pathways, such as renin secretion, longevity regulation pathway, diabetic cardiomyopathy, and niacin and nicotinamide metabolism. DHZCP and VE significantly up-regulated the expression level of the key proteins in the AMPK signaling pathway in the renal tissue of the aging rats. In all, DHZCP and VE could mitigate renal aging and injury. DHZCP exerted multi-target effects via multiple signaling pathways and metabolic pathways in the kidney, in which the AMPK signaling pathway may be one of the key targets for action.

Predicting hepatocellular carcinoma: A new non-invasive model based on shear wave elastography.

BACKGROUND: Integrating conventional ultrasound features with 2D shear wave elastography (2D-SWE) can potentially enhance preoperative hepatocellular carcinoma (HCC) predictions. AIM: To develop a 2D-SWE-based predictive model for preoperative identification of HCC. METHODS: A retrospective analysis of 884 patients who underwent liver resection and pathology evaluation from February 2021 to August 2023 was conducted at the Oriental Hepatobiliary Surgery Hospital. The patients were divided into the modeling group (n = 720) and the control group (n = 164). The study included conventional ultrasound, 2D-SWE, and preoperative laboratory tests. Multiple logistic regression was used to identify independent predictive factors for malignant liver lesions, which were then depicted as nomograms. RESULTS: In the modeling group analysis, maximal elasticity (Emax) of tumors and their peripheries, platelet count, cirrhosis, and blood flow were independent risk indicators for malignancies. These factors yielded an area under the curve of 0.77 (95% confidence interval: 0.73-0.81) with 84% sensitivity and 61% specificity. The model demonstrated good calibration in both the construction and validation cohorts, as shown by the calibration graph and Hosmer-Lemeshow test (P = 0.683 and P = 0.658, respectively). Additionally, the mean elasticity (Emean) of the tumor periphery was identified as a risk factor for microvascular invasion (MVI) in malignant liver tumors (P = 0.003). Patients receiving antiviral treatment differed significantly in platelet count (P = 0.002), Emax of tumors (P = 0.033), Emean of tumors (P = 0.042), Emax at tumor periphery (P < 0.001), and Emean at tumor periphery (P = 0.003). CONCLUSION: 2D-SWE's hardness value serves as a valuable marker for enhancing the preoperative diagnosis of malignant liver lesions, correlating significantly with MVI and antiviral treatment efficacy.

Clinical evaluation of droplet digital PCR in the early identification of suspected sepsis patients in the emergency department: a prospective observational study.

Background: Rapid and accurate diagnosis of the causative agents is essential for clinical management of bloodstream infections (BSIs) that might induce sepsis/septic shock. A considerable number of suspected sepsis patients initially enter the health-care system through an emergency department (ED), hence it is vital to establish an early strategy to recognize sepsis and initiate prompt care in ED. This study aimed to evaluate the diagnostic performance and clinical value of droplet digital PCR (ddPCR) assay in suspected sepsis patients in the ED. Methods: This was a prospective single-centered observational study including patients admitted to the ED from 25 October 2022 to 3 June 2023 with suspected BSIs screened by Modified Shapiro Score (MSS) score. The comparison between ddPCR and blood culture (BC) was performed to evaluate the diagnostic performance of ddPCR for BSIs. Meanwhile, correlative analysis between ddPCR and the inflammatory and prognostic-related biomarkers were conducted to explore the relevance. Further, the health economic evaluation of the ddPCR was analyzed. Results: 258 samples from 228 patients, with BC and ddPCR performed simultaneously, were included in this study. We found that ddPCR results were positive in 48.13% (103 of 214) of episodes, with identification of 132 pathogens. In contrast, BC only detected 18 positives, 88.89% of which were identified by ddPCR. When considering culture-proven BSIs, ddPCR shows an overall sensitivity of 88.89% and specificity of 55.61%, the optimal diagnostic power for quantifying BSI through ddPCR is achieved with a copy cutoff of 155.5. We further found that ddPCR exhibited a high accuracy especially in liver abscess patients. Among all the identified virus by ddPCR, EBV has a substantially higher positive rate with a link to immunosuppression. Moreover, the copies of pathogens in ddPCR were positively correlated with various markers of inflammation, coagulation, immunity as well as prognosis. With high sensitivity and specificity, ddPCR facilitates precision antimicrobial stewardship and reduces health care costs. Conclusions: The multiplexed ddPCR delivers precise and quantitative load data on the causal pathogen, offers the ability to monitor the patient's condition and may serve as early warning of sepsis in time-urgent clinical situations as ED. Importance: Early detection and effective administration of antibiotics are essential to improve clinical outcomes for those with life-threatening infection in the emergency department. ddPCR, an emerging tool for rapid and sensitive pathogen identification used as a precise bedside test, has developed to address the current challenges of BSI diagnosis and precise treatment. It characterizes sensitivity, specificity, reproducibility, and absolute quantifications without a standard curve. ddPCR can detect causative pathogens and related resistance genes in patients with suspected BSIs within a span of three hours. In addition, it can identify polymicrobial BSIs and dynamically monitor changes in pathogenic microorganisms in the blood and can be used to evaluate antibiotic efficacy and survival prognosis. Moreover, the copies of pathogens in ddPCR were positively correlated with various markers of inflammation, coagulation, immunity. With high sensitivity and specificity, ddPCR facilitates precision antimicrobial stewardship and reduces health care costs.

2.1 µm multi-quantum well laser epitaxially grown on on-axis (001) InP/SiO2/Si substrate fabricated by ion-slicing.

A cost-effective method to achieve a 2-3 µm wavelength light source on silicon represents a major challenge. In this study, we have developed a novel approach that combines an epitaxial growth and the ion-slicing technique. A 2.1 µm wavelength laser on a wafer-scale heterogeneous integrated InP/SiO2/Si (InPOI) substrate fabricated by ion-slicing technique was achieved by epitaxial growth. The performance of the lasers on the InPOI are comparable with the InP, where the threshold current density (Jth) was 1.3 kA/cm2 at 283 K when operated under continuous wave (CW) mode. The high thermal conductivity of Si resulted in improved high-temperature laser performance on the InPOI. The proposed method offers a novel means of integrating an on-chip light source.

Mapping of lymph node metastasis from esophageal squamous cell carcinoma after neoadjuvant treatment: a prospective analysis from a high-volume institution in China.

The study aimed to describe the prevalence of lymph node metastases per lymph node station for esophageal squamous cell carcinoma (ESCC) after neoadjuvant treatment. Clinicopathological variables of ESCC patients were retrieved from the prospective database of the Surgical Esophageal Cancer Patient Registry in West China Hospital, Sichuan University. A two-field lymphadenectomy was routinely performed, and an extensive three-field lymphadenectomy was performed if cervical lymph node metastasis was suspected. According to AJCC/UICC 8, lymph node stations were investigated separately. The number of patients with metastatic lymph nodes divided by those who underwent lymph node dissection at that station was used to define the percentage of patients with lymph node metastases. Data are also separately analyzed according to the pathological response of the primary tumor, neoadjuvant treatment regimens, pretreatment tumor length, and tumor location. Between January 2019 and March 2023, 623 patients who underwent neoadjuvant therapy followed by transthoracic esophagectomy were enrolled. Lymph node metastases were found in 212 patients (34.0%) and most frequently seen in lymph nodes along the right recurrent nerve (10.1%, 58/575), paracardial station (11.4%, 67/587), and lymph nodes along the left gastric artery (10.9%, 65/597). For patients with pretreatment tumor length of >4 cm and non-pathological complete response of the primary tumor, the metastatic rate of the right lower cervical paratracheal lymph nodes is 10.9% (10/92) and 10.6% (11/104), respectively. For patients with an upper thoracic tumor, metastatic lymph nodes were most frequently seen along the right recurrent nerve (14.2%, 8/56). For patients with a middle thoracic tumor, metastatic lymph nodes were most commonly seen in the right lower cervical paratracheal lymph nodes (10.3%, 8/78), paracardial lymph nodes (10.2%, 29/285), and lymph nodes along the left gastric artery (10.4%, 30/289). For patients with a lower thoracic tumor, metastatic lymph nodes were most frequently seen in the paracardial station (14.2%, 35/247) and lymph nodes along the left gastric artery (13.1%, 33/252). The study precisely determined the distribution of lymph node metastases in ESCC after neoadjuvant treatment, which may help to optimize the extent of lymphadenectomy in the surgical management of ESCC patients after neoadjuvant therapy.

A new mechanism of thyroid hormone receptor ß agonists ameliorating nonalcoholic steatohepatitis by inhibiting intestinal lipid absorption via remodeling bile acid profiles.

Excessive dietary calories lead to systemic metabolic disorders, disturb hepatic lipid metabolism, and aggravate nonalcoholic steatohepatitis (NASH). Bile acids (BAs) play key roles in regulating nutrition absorption and systemic energy homeostasis. Resmetirom is a selective thyroid hormone receptor ß (THRß) agonist and the first approved drug for NASH treatment. It is well known that the THRß activation could promote intrahepatic lipid catabolism and improve mitochondrial function, however, its effects on intestinal lipid absorption and BA compositions remain unknown. In the present study, the choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) and high-fat diet plus CCl4 (HFD+CCl4)-induced NASH mice were used to evaluate the effects of resmetirom on lipid and BA composition. We showed that resmetirom administration (10 mg·kg-1·d-1, i.g.) significantly altered hepatic lipid composition, especially reduced the C18:2 fatty acyl chain-containing triglyceride (TG) and phosphatidylcholine (PC) in the two NASH mouse models, suggesting that THRß activation inhibited intestinal lipid absorption since C18:2 fatty acid could be obtained only from diet. Targeted analysis of BAs showed that resmetirom treatment markedly reduced the hepatic and intestinal 12-OH to non-12-OH BAs ratio by suppressing cytochrome P450 8B1 (CYP8B1) expression in both NASH mouse models. The direct inhibition by resmetirom on intestinal lipid absorption was further verified by the BODIPY gavage and the oral fat tolerance test. In addition, disturbance of the altered BA profiles by exogenous cholic acid (CA) supplementation abolished the inhibitory effects of resmetirom on intestinal lipid absorption in both normal and CDAHFD-fed mice, suggesting that resmetirom inhibited intestinal lipid absorption by reducing 12-OH BAs content. In conclusion, we discovered a novel mechanism of THRß agonists on NASH treatment by inhibiting intestinal lipid absorption through remodeling BAs composition, which highlights the multiple regulation of THRß activation on lipid metabolism and extends the current knowledge on the action mechanisms of THRß agonists in NASH treatment.

Magnitude of Urine Albumin and KIM-1 Changes Can be Used to Differentiate Glomerular Injury From Tubular Injury in Rats.

Emerging urinary kidney safety biomarkers have been evaluated in recent years and have been shown to be superior to the serum parameters blood urea nitrogen (BUN) and creatinine (sCr) for monitoring kidney injury in the proximal tubule. However, their potential application in differentiating the location of the initial kidney injury (eg, glomerulus vs tubule) has not been fully explored. Here, we assessed the performance of two algorithms that were constructed using either an empirical or a mathematical model to predict the site of kidney injury using a data set consisting of 22 rat kidney toxicity studies with known urine biomarker and histopathologic outcomes. Two kidney safety biomarkers used in both models, kidney injury molecule 1 (KIM-1) and albumin (ALB), were the best performers to differentiate glomerular injury from tubular injury. The performance of algorithms using these two biomarkers against the gold standard of kidney histopathologic examination showed high sensitivity in differentiating the location of the kidney damage to either the glomerulus or the proximal tubules. These data support the exploration of such an approach for use in clinical settings, leveraging urinary biomarker data to aid in the diagnosis of either glomerular or tubular injury where histopathologic assessments are not conducted.

New G-Triplex DNA Dramatically Activates the Fluorescence of Thioflavin T and Acts as a Turn-On Fluorescent Sensor for Uracil-DNA Glycosylase Activity Detection.

G-triplexes are G-rich oligonucleotides composed of three G-tracts and have absorbed much attention due to their potential biological functions and attractive performance in biosensing. Through the optimization of loop compositions, DNA lengths, and 5'-flanking bases of G-rich sequences, a new stable G-triplex sequence with 14 bases (G3-F15) was discovered to dramatically activate the fluorescence of Thioflavin T (ThT), a water-soluble fluorogenic dye. The fluorescence enhancement of ThT after binding with G3-F15 reached 3200 times, which was the strongest one by far among all of the G-rich sequences. The conformations of G3-F15 and G3-F15/ThT were studied by circular dichroism. The thermal stability measurements indicated that G3-F15 was a highly stable G-triplex structure. The conformations of G3-F15 and G3-F15/ThT in the presence of different metal cations were studied thoroughly by fluorescent spectroscopy, circular dichroism, and nuclear magnetic resonance. Furthermore, using the G3-F15/ThT complex as a fluorescent probe, a robust and simple turn-on fluorescent sensor for uracil-DNA glycosylase activity was developed. This study proposes a new systematic strategy to explore new functional G-rich sequences and their ligands, which will promote their applications in diagnosis, therapy, and biosensing.

Spatial - temporal mapping of urine cadmium levels in China during 1980 - 2040: Dietary improvements lower exposure amid rising pollution.

Persistent cadmium exposure poses significant health risks to the Chinese population, underscored by its prevalence as an environmental contaminant. This study leverages a machine-learning model, fed with a comprehensive dataset of environmental and socio-economic factors, to delineate trends in cadmium exposure from 1980 to 2040. We uncovered that urinary cadmium levels peaked at 1.09 µg/g Cr in the mid-2000 s. Encouragingly, a decline is projected to 0.92 µg/g Cr by 2025, tapering further to 0.87 µg/g Cr by 2040. Despite this trend, regions heavily influenced by industrialization, such as Hunan and Guizhou, as well as industrial counties in Jilin, report stubbornly high levels of exposure. Our demographic analysis reveals a higher vulnerability among adults & adolescents over 14, with males displaying elevated cadmium concentrations. Alarmingly, the projected data suggests that by 2040, an estimated 41% of the population will endure exposure beyond the safety threshold set by the European Food Safety Authority. Our research indicates disproportionate cadmium exposure impacts, necessitating targeted interventions and policy reforms to protect vulnerable groups and public health in China.

Photocatalytic Enantioselective Radical Cascade Multicomponent Minisci Reaction of ß-Carbolines Using Diazo Compounds as Radical Precursors.

Here, a photocatalytic asymmetric multicomponent cascade Minisci reaction of ß-carbolines with enamides and diazo compounds is reported, enabling an effective enantioselective radical C─H functionalization of ß-carbolines with high yields and enantioselectivity (up to 83% yield and 95% ee). This enantioselective multicomponent Minisci protocol exhibits step economy, high chemo-/enantio-selective control, and good functional group tolerance, allowing access to a variety of valuable chiral ß-carbolines. Notably, diazo compounds are suitable radical precursors in enantioselective cascade radical reactions. Moreover, the efficiency and practicality of this approach are demonstrated by the asymmetric synthesis of bioactive compounds and natural products.

Cadmium Exposure was Associated with Sex-Specific Thyroid Dysfunction: Consistent Evidence from Two Independent Cross-Sectional Studies Based on Urinary and Blood Cadmium Measurements.

Population-based studies on the association between cadmium (Cd) exposure and thyroid function are limited and have shown conflicting results. Two independent cross-sectional studies using different Cd biomarkers were carried out in six rural areas with different soil Cd levels in China. Thyroid dysfunction was defined based on levels of thyroid stimulating hormone (TSH) and free thyroxine (FT4). Multivariable linear regression, multiple logistic regression, and restrictive cubic splines models were used to estimate the association between Cd and thyroid dysfunction. For both of the two independent studies, higher Cd levels were observed to be associated with lower TSH levels and higher risk of thyroid dysfunction. The negative relationship between urinary Cd and TSH was found in both total participants (ß = - 0.072, p = 0.008) and males (ß = - 0.119, p = 0.020) but not in females; however, the negative relationship between blood Cd and TSH was only found in females (ß = - 0.104, p = 0.024). Higher urinary Cd was associated with higher risk of thyroid dysfunction (OR = 1.77, p = 0.031), while higher blood Cd was associated with higher risk of thyroid dysfunction (OR = 1.95, p = 0.011). Results from the two independent cross-sectional studies consistently suggested that higher Cd levels were associated with sex-specific thyroid dysfunction.

Unveiling the role of PD-L1 in vascular endothelial dysfunction: Insights into the mtros/NLRP3/caspase-1 mediated pyroptotic pathway.

BACKGROUND: Programmed death ligand-1(PD-L1) has been postulated to play a crucial role in the regulation of barrier functions of the vascular endothelium, yet how this novel molecule mediates dysfunction in endothelial cells (ECs) during acute lung injury (ALI) remains largely unknown. METHODS: PD-L1 siRNA and plasmids were synthesized and applied respectively to down- or up-regulate PD-L1 expression in human lung microvascular endothelial cells (HMVECs). RNA sequencing was used to explore the differentially expressed genes following PD-L1 overexpression. The expression levels of tight junction proteins (ZO-1 and occludin) and the signaling pathways of NLRP-3/caspase-1/pyroptosis were analyzed. A mouse model of indirect ALI was established through hemorrhagic shock (HEM) followed by cecal ligation and puncture (CLP), enabling further investigation into the effects of intravenous delivery of PD-L1 siRNA. RESULTS: A total of 1502 differentially expressed genes were identified, comprising 532 down-regulated and 970 up-regulated genes in ECs exhibiting PD-L1overexpression. Enrichment of PD-L1-correlated genes were observed in the NOD-like receptor signaling pathway and the TNF signaling pathway. Western blot assays confirmed that PD-L1 overexpression elevated the expression of NLRP3, cleaved-caspase-1, ASC and GSDMD, and concurrently diminished the expression of ZO-1 and occludin. This overexpression also enhanced mitochondrial oxidative phosphorylation and mitochondrial reactive oxygen species (mtROS) production. Interestingly, mitigating mitochondrial dysfunction with mitoQ partially countered the adverse effects of PD-L1 on the functionality of ECs. Furthermore, intravenous administration of PD-L1 siRNA effectively inhibited the activation of the NLRP3 inflammasome and pyroptosis in pulmonary ECs, subsequently ameliorating lung injury in HEM/CLP mice. CONCLUSION: PD-L1-mediated activation of the inflammasome contributes significantly to the disruption of tight junction and induction of pyroptosis in ECs, where oxidative stress associated with mitochondrial dysfunction serves as a pivotal mechanism underpinning these effects.

Mutation of Disulfide Bond Sites Reduces the Immunoreactivity of Cra a 4 by Changing the Structural Characteristics.

Sarcoplasmic calcium-binding protein (Cra a 4) from Crassostrea angulata belongs to the EF-hand superfamily, and understanding of its structure-allergenicity relationship is still insufficient. In this study, chemical denaturants were used to destroy the structure of Cra a 4, showing that disruption of the structure reduced its IgG-/IgE-binding activity. To explore which critical amino acid site affects the allergenicity of Cra a 4, the mutants were obtained by site-directed mutations in the disulfide bonds site (C97), conformational epitopes (I105, D114), or Ca2+-binding region (D106, D110) and their IgG-/IgE-binding activity was reduced significantly using serological tests. Notably, C97A had the lowest immunoreactivity. In addition, two conformational epitopes of Cra 4 were verified. Meanwhile, the increase of the α-helical content, surface hydrophobicity, and surface electrostatic potential of C97A affected its allergenicity. Overall, the understanding of the structure-allergenicity relationship of Cra a 4 allowed the development of a hypoallergenic mutant.