Human molybdenum exposure risk in industrial regions of China: New critical effect indicators and reference dose.

Evidence increasingly suggests molybdenum exposure at environmental levels is still associated with adverse human health, emphasizing the necessity to establish a more protective reference dose (RfD). Herein, we conducted a study measuring 15 urinary metals and 30 clinical health indicators in 2267 participants residing near chemical enterprises across 11 Chinese provinces to investigate their relationships. The kidney and cystatin-C emerged as the most sensitive organ and critical effect indicator of molybdenum exposure, respectively. Odds of cystatin-C-defined chronic kidney disease (CKD) in the highest quantile of molybdenum exposure significantly increased by 133.5% (odds ratio [OR]: 2.34, 95% CI: 1.78, 3.11) and 75.8% (OR: 1.76, 95% CI: 1.24, 2.49) before and after adjusting for urinary 14 metals, respectively. Intriguingly, cystatin-C significantly mediated 15.9-89.5% of molybdenum's impacts on liver and lung function, suggesting nephrotoxicity from molybdenum exposure may trigger hepatotoxicity and pulmonary toxicity. We derived a new RfD for molybdenum exposure (0.87 µg/kg-day) based on cystatin-C-defined estimated glomerular filtration rate by employing Bayesian Benchmark Dose modeling analysis. This RfD is significantly lower than current exposure guidance values (5-30 µg/kg-day). Remarkably, >90% of participants exceeded the new RfD, underscoring the significant health impacts of environmental molybdenum exposure on populations in industrial regions of China.

Staphylococcus Aureus Membrane Vesicles Kill Tumor Cells Through a Caspase-1-Dependent Pyroptosis Pathway.

Introduction: Nanosized outer membrane vesicles (OMVs) from Gram-negative bacteria have attracted increasing interest because of their antitumor activity. However, the antitumor effects of MVs isolated from Gram-positive bacteria have rarely been investigated. Methods: MVs of Staphylococcus aureus USA300 were prepared and their antitumor efficacy was evaluated using tumor-bearing mouse models. A gene knock-in assay was performed to generate luciferase Antares2-MVs for bioluminescent detection. Cell counting kit-8 and lactic dehydrogenase release assays were used to detect the toxicity of the MVs against tumor cells in vitro. Active caspase-1 and gasdermin D (GSDMD) levels were determined using Western blot, and the tumor inhibition ability of MVs was determined in B16F10 cells treated with a caspase-1 inhibitor. Results: The vesicular particles of S. aureus USA300 MVs were 55.23 ± 8.17 nm in diameter, and 5 µg of MVs remarkably inhibited the growth of B16F10 melanoma in C57BL/6 mice and CT26 colon adenocarcinoma in BALB/c mice. The bioluminescent signals correlated well with the concentrations of the engineered Antares2-MVs (R2 = 0.999), and the sensitivity for bioluminescence imaging was 4 × 10-3 µg. Antares2-MVs can directly target tumor tissues in vivo, and 20 µg/mL Antares2-MVs considerably reduced the growth of B16F10 and CT26 tumor cells, but not non-carcinomatous bEnd.3 cells. MV treatment substantially increased the level of active caspase-1, which processes GSDMD to trigger pyroptosis in tumor cells. Blocking caspase-1 activation with VX-765 significantly protected tumor cells from MV killing in vitro and in vivo. Conclusion: S. aureus MVs can kill tumor cells by activating the pyroptosis pathway, and the induction of pyroptosis in tumor cells is a promising strategy for cancer treatment.

Cobalt-based hybrid nanoparticles loaded with curcumin for ligand-enhanced synergistic nanocatalytic therapy/chemotherapy combined with calcium overload.

The therapeutic efficacy of Fenton or Fenton-like nanocatalysts is usually restricted by the inappropriate pH value and limited concentration of hydrogen peroxide (H2O2) at the tumor site. Herein, calcium carbonate (CaCO3)-mineralized cobalt silicate hydroxide hollow nanocatalysts (CSO@CaCO3, CC) were synthesized and loaded with curcumin (CCC). This hybrid system can simultaneously realize nanocatalytic therapy, chemotherapy and calcium overload. With the stabilization of liposomes, CCC is able to reach the tumor site smoothly. The CaCO3 shell first degrades in an acidic tumor environment, releasing Cur and Ca2+, and the pH value of the tumor is increased simultaneously. Then the exposed CSO catalyzes the Fenton-like reaction to convert H2O2 into ˙OH and enhances the cytotoxicity of curcumin (Cur) by catalytically oxidizing it to a ˙Cur radical. Curcumin not only induces the chemotherapy effect but also serves as a nucleophilic ligand and an electron donor in the catalytic system, enhancing the Fenton-like activity of CCC by electron transfer. In addition, calcium overload also amplifies the efficacy of ROS-based therapy. In vitro and in vivo results show that CCC exhibited an excellent synergistic tumor inhibition effect without any clear side effect. This work proposes a novel concept of nanocatalytic therapy/chemotherapy synergistic mechanism by the ligand-induced enhancement of Fenton-like catalytic activity, and inspires the construction of combined therapeutic nanoplatforms and multifunctional nanocarriers for drug and ion delivery in the future.

Network pharmacology, bioinformatics, and experimental validation to identify the role of Hedyotis diffusa willd against gastric cancer through the activation of the endoplasmic reticulum stress.

Background: Globally, gastric cancer (GC) is recognized as the third leading cause of cancer-related deaths and the fifth most prevalent malignant disease. Multiple studies have indicated that Hedyotis diffusa Willd, in pinyin, called Bai Hua She Cao (BHSSC), a traditional Chinese medicine (TCM) is an herbal remedy for cancer treatment. However, the specific mechanisms underlying its anti-tumor properties and mode of action are still unclear. Methods: To determine the role of BHSSC in GC, candidate target genes were selected from The Encyclopedia of Traditional Chinese Medicine (ETCM) and analyzed using network pharmacology, bioinformatics, and experimental validation. Differentially expressed genes (DEGs) associated with gastric cancer were obtained from RNA sequencing (RNA-seq) data sourced from The Cancer Genome Atlas-Stomach adenocarcinoma (TCGA-STAD). The Reactome Pathway was examined using Analysis Tools, while KEGG pathways were analyzed using KOBAS. Gene Ontology (GO) evaluations were performed using WebGestalt and DAVID. The relationships between proteins were investigated using the STRING database. Furthermore, cell viability, colony formation, and cell migration ability were conducted in gastric cancer cells, BGC-823 and MGC-803. Results: Network pharmacology and bioinformatics analyses revealed a significant association between BHSSC and metabolic pathways. In vitro experiments demonstrated that BHSSC effectively suppressed gastric cancer cell proliferation and colony formation, inhibited cell migration, and activated the endoplasmic reticulum (ER) stress. Furthermore, it was found that enhancement of the expression of IRE1α and BIP is the mechanism by which BHSSC activates ER stress. Conclusions: The findings suggest that BHSSC exerts its effects through modulation of metabolic pathways, leading to the suppression of cell proliferation, inhibition of cell migration, and activation of the endoplasmic reticulum. These results provide valuable insights into the mechanisms underlying the therapeutic effects of BHSSC in GC and support its potential as a novel treatment option.

Synergistic regulation of chloride anion recognition using a triple-functional sites receptor with two different cationic effectors.

The synergistic regulation of the multi-functional sites on one receptor molecule with different cationic effectors for anion recognition is scarce to be well understood from the experiment and theory. In this work, a new anion receptor with three functional zones including ether hole, biurea and double bipyridine groups (EUPR) is designed expecting to enhance the chloride anion recognition together with a rational synthesis path being proposed based on four simple and mature organic reaction steps. The conformational structures of the designed receptor EUPR and the binding behaviors for three kinds of ions (Cl-, Na+, and Ag+) are deeply investigated by using density functional theoretical calculations. It is found that Cl- binding via the hydrogen bond interaction can be significantly enhanced and synergistically regulated by the two kinds of cations and the corresponding conformational changes of receptor EUPR. Especially, the conformational pre-organization of receptor caused by the encapsulation of sodium ion into ether hole is benefit to the binding for Cl- in both thermodynamics and kinetics. Na+ binding, in turn, can ever be enhanced by chloride anion, whereas it seems that Ag+ binding cannot always be enhanced by chloride anion, reflecting an electrical complementary matching and mutual enhancement effect for different counter ions. Moreover, solvent effect calculations indicate that EUPR may be an ideal candidate structure for Cl- recognition by strategy of counter ion enhancement in water. Additionally, a visual study of intermolecular noncovalent interaction (NCI) and molecular electrostatic potential (ESP) are used for the analysis on the nature of interactions between receptor and bound ions.

Effect of robotic versus open pancreaticoduodenectomy on postoperative length of hospital stay and complications for pancreatic head or periampullary tumours: a multicentre, open-label randomised controlled trial.

BACKGROUND: The flexibility of the robotic system in resection and reconstruction provides potential benefits in pancreaticoduodenectomy. Increasingly, robotic pancreaticoduodenectomy (RPD) has been reported with favourable outcomes, but high-level evidence is still scarce. We aimed to compare the short-term postoperative outcomes of RPD with those of open pancreaticoduodenectomy (OPD), and hypothesised that postoperative length of hospital stay would be shorter after RPD than after OPD. METHODS: This multicentre, open-label randomised controlled trial was conducted at three high-volume hospitals in China. Patients were considered for participation in this trial if they were aged 18-75 years, had a resectable benign, premalignant, or malignant tumour in the pancreatic head or periampullary region; and were suitable for both RPD and OPD. Patients with distant metastases were excluded. Block randomisation was done with random block sizes of four, stratified by centre. Allocation was concealed via individual, sequentially numbered, opaque sealed envelopes. Eligible patients were randomly assigned to the RPD group or the OPD group in a 1:1 ratio by a masked research assistant. Surgeons and patients were not masked to trial group, but data collectors, postoperative outcome assessors, and data analysts were. All patients underwent RPD or OPD according to previously reported techniques. Participating surgeons had surpassed the learning curves of at least 40 RPD and 60 OPD procedures. The primary outcome was postoperative length of hospital stay, which was analysed in the modified intention-to-treat (mITT) population. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR2200056809) and is complete. FINDINGS: Between March 5 and Dec 20, 2022, 292 patients were screened for eligibility, of whom 164 were enrolled and randomly assigned to the RPD group (n=82) or the OPD group (n=82). 161 patients who underwent surgical resection were included in the mITT analysis (81 in the RPD group and 80 in the OPD group). 94 (58%) participants were male and 67 (42%) were female. Postoperative length of hospital stay was significantly shorter in the RPD group than in the OPD group (median 11·0 days [IQR 9·0 to 19·5] vs 13·5 days [11·5 to 18·0]; median difference -2·0 [95% CI -4·0 to 0·0]; p=0·029). During a follow-up period of 90 days, six (7%) of 81 patients in the RPD group and five (6%) of 80 patients in the OPD group required readmission. Reasons for readmission were intra-abdominal haemorrhage (one in each group), vomiting (two in the RPD group and one in the OPD group), electrolyte disturbance (one in each group), and fever (two in each group). There were two (1%) in-hospital deaths within 90 days of surgery, one in each group. The postoperative 90-day mortality rate (difference -0·02% [-5·6 to 5·5]; p=1·00) and the incidence of severe complications (ie, Clavien-Dindo grade ≥3; difference -1·5% [-14·5 to 11·4]; p=0·82) were similar between the two groups. INTERPRETATION: For surgeons who had passed the learning curve, RPD was safe and feasible with the advantage of shorter postoperative length of hospital stay than OPD. Future research should focus on the medium-term and long-term outcomes between RPD and OPD. FUNDING: None.

Ramelteon alleviates myocardial ischemia/reperfusion injury (MIRI) through Sirt3--dependent regulation of cardiomyocyte apoptosis.

Reperfusion stands as a pivotal intervention for ischemic heart disease. However, the restoration of blood flow to ischemic tissue always lead to further damage, which is known as myocardial ischemia/reperfusion injury (MIRI). Ramelteon is an orally administered drug used to improve sleep quality, which is famous for its high bioadaptability and absence of notable addictive characteristics. However, the specific mechanism by which it improves MIRI is still unclear. Sirtuin-3 (Sirt3), primarily located in mitochondria, is crucial in mitigating many cardiac diseases, including MIRI. Based on the structure of Sirt3, we simulated molecular docking and identified several potential amino acid binding sites between it and ramelteon. Therefore, we propose a hypothesis that ramelteon may exert cardioprotective effects by activating the Sirt3 signaling pathway. Our results showed that the activation levels and expression level of Sirt3 were significantly decreased in MIRI tissue and H2O2 stimulated H9C2 cells, while ramelteon treatment upregulated Sirt3 activity and expression. After treat with 3-TYP, a classic Sirt3 activity inhibitor, we constructed myocardial ischemia/reperfusion surgery in vivo and induced H9C2 cells with H2O2 in vitro. The results showed that the myocardial protection and anti-apoptotic effects of ramelteon were antagonized by 3-TYP, indicating that the activation of Sirt3 is a key mechanism for ramelteon to exert myocardial protection. In summary, our results confirm a novel mechanism by which ramelteon improves MIRI by activating Sirt3 signaling pathway, providing strong evidence for the treatment of MIRI with ramelteon.

International consensus guidelines on robotic pancreatic surgery in 2023.

Background: With the rapid development of robotic surgery, especially for the abdominal surgery, robotic pancreatic surgery (RPS) has been applied increasingly around the world. However, evidence-based guidelines regarding its application, safety, and efficacy are still lacking. To harvest robust evidence and comprehensive clinical practice, this study aims to develop international guidelines on the use of RPS. Methods: World Health Organization (WHO) Handbook for Guideline Development, GRADE Grid method, Delphi vote, and the AGREE-II instrument were used to establish the Guideline Steering Group, Guideline Development Group, and Guideline Secretary Group, formulate 19 clinical questions, develop the recommendations, and draft the guidelines. Three online meetings were held on 04/12/2020, 30/11/2021, and 25/01/2022 to vote on the recommendations and get advice and suggestions from all involved experts. All the experts focusing on minimally invasive surgery from America, Europe and Oceania made great contributions to this consensus guideline. Results: After a systematic literature review 176 studies were included, 19 questions were addressed and 14 recommendations were developed through the expert assessment and comprehensive judgment of the quality and credibility of the evidence. Conclusions: The international RPS guidelines can guide current practice for surgeons, patients, medical societies, hospital administrators, and related social communities. Further randomized trials are required to determine the added value of RPS as compared to open and laparoscopic surgery.

Gastric cancer patient-derived organoids model for the therapeutic drug screening.

BACKGROUND: Gastric cancer (GC) is a highly heterogeneous disease featuring many various histological and molecular subtypes. Therefore, it is imperative to have well-characterized in vitro models for personalized treatment development. Gastric cancer patient-derived organoids (PDOs), re-capitulating in vivo conditions, exhibit high clinical efficacy in predicting drug sensitivity to facilitate the development of cancer precision medicine. METHODS: PDOs were established from surgically resected GC tumor tissues. Histological and molecular characterization of PDOs and primary tissues were performed via IHC and sequencing analysis. We also conducted drug sensitivity tests using PDO cultures with five chemotherapeutic drugs and twenty-two targeted drugs. RESULTS: We have successfully constructed a PDOs biobank that included EBV+, intestinal/CIN, diffuse/GS, mixed and Her2+ GC subtypes, and these PDOs captured the pathological and genetic characteristics of corresponding tumors and exhibited different sensitivities to the tested agents. In a clinical case study, we performed an additional drug sensitivity test for a patient who reached an advanced progressive stage after surgery. We discovered that the combination of napabucasin and COTI-2 exhibited a stronger synergistic effect than either drug alone. CONCLUSION: PDOs maintained the histological and genetic characteristics of original cancer tissues. PDOs biobank opens up new perspectives for studying cancer cell biology and personalized medicine as a preclinical study platform.

SurgNet: Self-Supervised Pretraining With Semantic Consistency for Vessel and Instrument Segmentation in Surgical Images.

Blood vessel and surgical instrument segmentation is a fundamental technique for robot-assisted surgical navigation. Despite the significant progress in natural image segmentation, surgical image-based vessel and instrument segmentation are rarely studied. In this work, we propose a novel self-supervised pretraining method (SurgNet) that can effectively learn representative vessel and instrument features from unlabeled surgical images. As a result, it allows for precise and efficient segmentation of vessels and instruments with only a small amount of labeled data. Specifically, we first construct a region adjacency graph (RAG) based on local semantic consistency in unlabeled surgical images and use it as a self-supervision signal for pseudo-mask segmentation. We then use the pseudo-mask to perform guided masked image modeling (GMIM) to learn representations that integrate structural information of intraoperative objectives more effectively. Our pretrained model, paired with various segmentation methods, can be applied to perform vessel and instrument segmentation accurately using limited labeled data for fine-tuning. We build an Intraoperative Vessel and Instrument Segmentation (IVIS) dataset, comprised of ~3 million unlabeled images and over 4,000 labeled images with manual vessel and instrument annotations to evaluate the effectiveness of our self-supervised pretraining method. We also evaluated the generalizability of our method to similar tasks using two public datasets. The results demonstrate that our approach outperforms the current state-of-the-art (SOTA) self-supervised representation learning methods in various surgical image segmentation tasks.

Ultrahigh Capacity from Complexation-Enabled Aluminum-Ion Batteries with C70 as the Cathode.

Restricted by the available energy storage modes, currently rechargeable aluminum-ion batteries (RABs) can only provide a very limited experimental capacity, regardless of the very high gravimetric capacity of Al (2980 mAh g-1 ). Here, a novel complexation mechanism is reported for energy storage in RABs by utilizing 0D fullerene C70 as the cathode. This mechanism enables remarkable discharge voltage (≈1.65 V) and especially a record-high reversible specific capacity (750 mAh g-1 at 200 mA g-1 ) of RABs. By means of in situ Raman monitoring, mass spectrometry, and density functional theory (DFT) calculations, it is found that this elevated capacity is attributed to the direct complexation of one C70 molecule with 23.5 (super)halogen moieties (superhalogen AlCl4 and/or halogen Cl) in average, forming (super)halogenated C70 ·(AlCl4 )m Cln-m complexes. Upon discharging, decomplexation of C70 ·(AlCl4 )m Cln-m releases AlCl4 - /Cl- ions while preserving the intact fullerene cage. This work provides a new route to realize high-capacity and long-life batteries following the complexation mechanism.

Beauvericin exerts an anti-tumor effect on hepatocellular carcinoma by inducing PI3K/AKT-mediated apoptosis.

Beauvericin is a world-spread mycotoxin isolated from the traditional Chinese medicine, Bombyx batryticatus (BB), which has been widely used to treat various neoplastic diseases. This study investigated the anti-hepatocellular carcinoma (HCC) activity of beauvericin and its potential mechanism. In this study, H22-bearing mice were intraperitoneally injected with 3, 5, 7 mg/kg of beauvericin once per-week over a three-week period. TUNEL staining determined the extent of tumor apoptosis induced by beauvericin. ELISA kits detected the level of IL-2, Perforin, and TNF-α, IFN-γ level in the serum. H22 hepatoma cells were exposed to beauvericin (5, 10, and 20 µmol/L) to investigate the underlying pathway. CCK-8 assay was used to observe the influence of beauvericin on the growth of H22 cells. Flow cytometry was used to detect the cell apoptosis and ROS level. Western blotting was performed to detect apoptotic and PI3K/AKT pathway protein production. The results showed that beauvericin could remarkably inhibit the growth of HCC in mice, combined with elevated TNF-α and IL-2. In vitro, beauvericin significantly promoted the generation of ROS, up-regulated Bax/Bcl-2 ratio and cleaved caspase-9, cleaved caspase-3 levels, down-regulated p-PI3K/PI3K ratio, p-AKT/AKT ratio, promoted the apoptosis of H22 cells, and inhibited the growth of H22 cells. Remarkably, treatment with PI3K/AKT activator (740Y-P and SC79) could prevent beauvericin-induced H22 cell apoptosis. These findings collectively indicate that beauvericin inhibits HCC growth by inducing apoptosis via the PI3K/AKT pathway.

Nanoscale Saturn Systems Based on C60/70 Bucky Ball and a Newly Designed [4]Cyclopara-1,2-diphenylethylene Hoop: A Strategy for Fullerene Encapsulation Release and Selective Recognition for C70.

A new carbonaceous nanohoop, [4]cyclopara-1,2-diphenylethylene ([4]CPDPE, composed by four 1,2-diphenylethylene units linked via the para of the phenyls), is designed together with two rational synthesis paths being proposed. The Saturn-like host-guest systems formed with the [4]CPDPE nanoring and fullerene C60/70 are explored using density functional theory calculations. The results evidence that the geometry mutual matching between [4]CPDPE and C60/70 is perfect, and the [4]CPDPE⊃C60/70 complexes could be formed spontaneously with high binding energies. Thermodynamic calculation results show that it essentially prefers to selectively recognize C70 over its smaller cousin C60. More interestingly, the [4]CPDPE nanoring could present the regular ring cylinder and the saddle shapes via configuration transformation between its all-trans form and all-cis form, so as to theoretically realize the fullerene encapsulation and release under photoirradiation. Furthermore, the 2:1 interaction structure ([4]CPDPE2⊃Dimer-C60) and properties are investigated. Additionally, the ultraviolet-visible (UV-vis) spectra are simulated, and host-guest noncovalent interaction (NCI) regions are investigated based on the electron density and reduced density gradient (RDG), which may be helpful for a deep understanding of the present designed systems in future.

"Parenchyma transection-first" strategy is superior to "tunnel-first" strategy in robotic spleen-preserving distal pancreatectomy with conservation of splenic vessels.

BACKGROUND: Creating a tunnel between the pancreas and splenic vessels followed by pancreatic parenchyma transection ("tunnel-first" strategy) has long been used in spleen-preserving distal pancreatectomy (SPDP) with splenic vessel preservation (Kimura's procedure). However, the operation space is limited in the tunnel, leading to the risks of bleeding and difficulties in suturing. We adopted the pancreatic "parenchyma transection-first" strategy to optimize Kimura's procedure. METHODS: The clinical data of consecutive patients who underwent robotic SPDP with Kimura's procedure between January 2017 and September 2022 at our center were retrieved. The cohort was classified into a "parenchyma transection-first" strategy (P-F) group and a "tunnel-first" strategy (T-F) group and analyzed. RESULTS: A total of 91 patients were enrolled in this cohort, with 49 in the T-F group and 42 in the P-F group. Compared with the T-F group, the P-F group had significantly shorter operative time (146.1 ± 39.2 min vs. 174.9 ± 46.6 min, P < 0.01) and lower estimated blood loss [40.0 (20.0-55.0) mL vs. 50.0 (20.0-100.0) mL, P = 0.03]. Failure of splenic vessel preservation occurred in 10.2% patients in the T-F group and 2.4% in the P-F group (P = 0.14). The grade 3/4 complications were similar between the two groups (P = 0.57). No differences in postoperative pancreatic fistula, abdominal infection or hemorrhage were observed between the two groups. CONCLUSIONS: The pancreatic "parenchyma transection-first" strategy is safe and feasible compared with traditional "tunnel-first strategy" in SPDP with Kimura's procedure.

Volatile organic compounds and metals/metalloids exposure in children after e-waste control: Implications for priority control pollutants and exposure mitigation measures.

The decade-long effort to control e-waste in China has made significant progress from haphazard disposal to organized recycling, but environmental research suggests that exposure to volatile organic compounds (VOCs) and metals/metalloids (MeTs) still poses plausible health risks. To investigate the exposure risk faced by children and identify corresponding priority control chemicals, we evaluated the carcinogenic risk (CR), non-CR, and oxidative DNA damage risks of VOCs and MeTs exposure in 673 children from an e-waste recycling area (ER) by measuring urinary exposure biomarker levels. The ER children were generally exposed to high levels of VOCs and MeTs. We observed distinctive VOCs exposure profiles in ER children. In particular, the 1,2-dichloroethane/ethylbenzene ratio and 1,2-dichloroethane were promising diagnostic indexes for identifying e-waste pollution due to their high accuracy (91.4%) in predicting e-waste exposure. Exposure to acrolein, benzene, 1,3-butadiene, 1,2-dichloroethane, acrylamide, acrylonitrile, arsenic, vanadium, copper, and lead posed considerable CR or/and non-CR and oxidative DNA damage risks to children, while changing personal lifestyles, especially enhancing daily physical exercise, may facilitate mitigating these chemical exposure risks. These findings highlight that the exposure risk of some VOCs and MeTs is still non-negligible in regulated ER, and these hazardous chemicals should be controlled as priorities.

Co-exposure levels of volatile organic compounds and metals/metalloids in children: Implications for E-waste recycling activity prediction.

Identifying informal e-waste recycling activity is crucial for preventing health hazards caused by e-waste pollution. This study attempted to build a prediction model for e-waste recycling activity based on the differential exposure biomarkers of the populations between the e-waste recycling area (ER) and non-ER. This study recruited children in ER and non-ER and conducted a quasi-experiment among the adult investigators to screen differential exposure or effect biomarkers by measuring urinary 25 volatile organic compound (VOC) metabolites, 18 metals/metalloids, and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Compared with children of the non-ER, the ER children had higher metal/metalloid (e.g., manganese [Mn], lead [Pb], antimony [Sb], tin [Sn], and copper [Cu]) and VOC exposure (e.g., carbon-disulfide, acrolein, and 1-bromopropane) levels, oxidative DNA damage, and non-carcinogenic risks. Individually added 8-OHdG, VOC metabolites, and metals/metalloids to the support vector machine (SVM) classifier could obtain similar classification effects, with the area under curve (AUC) ranging from 0.741 to 0.819. The combined inclusion of 8-OHdG and differential VOC metabolites, metals/metalloids, and mixed indexes (e.g., product items or ratios of different metals/metalloids) in the SVM classifier showed the highest performance in predicting e-waste recycling activity, with an AUC of 0.914 and prediction accuracy of 83.3 %. "Sb × Mn", followed by "Sn × Pb/Cu", "Sb × Mn/Cu", and "Sn × Pb", were the top four important features in the models. Compared with non-ER children, the levels of urinary Mn, Pb, Sb, Sn, and Cu in ER children were 1.2 to 2.4 times higher, while the levels of "Sb × Mn", "Sn × Pb/Cu", "Sb × Mn/Cu", and "Sn × Pb" were 3.5 to 4.7 times higher, suggesting that these mixed indexes could amplify the differences between e-waste exposed and non-e-waste exposed populations. With the continued inclusion of new biomarkers of e-waste pollution in the future, our prediction model is promising for screening informal e-waste recycling sites.

Xp21 DNA microdeletion syndrome in a Chinese family: clinical features show retinitis pigmentosa and chronic granuloma.

Xp21 DNA microdeletion syndrome is a very rare disease characterized by retinitis pigmentosa (RP), chronic granulomatous disease (CGD), and McLeod syndrome (MLS). Due to the complex and diverse clinical manifestations, early diagnosis remains a challenge for many physicians. In this study, for the purpose of determining the pathogenic gene variants and definitive diagnosis in a patient medically backgrounded with RP and CGD from a normal Chinese family, whole-exome sequencing (WES) was performed in this proband and copy number variation (CNV) was further verified in other family members by qPCR. A genetic evaluation revealed that the short arm of the X chromosome in the proband had a deletion CNV Xp21.1p11.4 (37431123-38186681) of approximately 0.755 Mb in size, and contained three contiguous OMIM genes as X-linked Kx blood group antigen (XK), cytochrome b-245 beta chain (CYBB), and RP GTPase regulator (RPGR). The qPCR results confirmed the copy number loss in Xp21.1p11.4 present in the proband and his unaffected mother. According to the American College of Medical Genetics and Genomics (ACMG) guidelines for the CNV interpretation, the deletion of this segment was a pathogenic variant. Our results provided evidence that CNV deletion of Xp21.1p11.4 in the short arm of the X chromosome was a pathogenic variant in such Chinese RP and CGD family, and the McLeod phenotype was not yet available. This study suggests that genetic testing is essential for a definitive diagnosis, which should better assist physicians in prediction, diagnosis, genetic counseling, and guidance for Xp21 DNA microdeletion syndrome.

Tadalafil increases the antitumor activity of 5-FU through inhibiting PRMT5-mediated glycolysis and cell proliferation in colorectal cancer.

BACKGROUND: Protein arginine methyltransferase 5 (PRMT5) is upregulated in multiple tumors and plays a pivotal role in cancer cell proliferation. However, the role of PRMT5 in colorectal cancer remains poorly understood. METHODS: We detected the expression level of PRMT5 and glycolytic enzymes using online databases and colorectal cancer cell lines by immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting. And MTT and colony formation assays were conducted to investigate cell proliferation. Then, we evaluated ECAR and OCR levels using a biological energy analyzer to investigate the energy status of colorectal cancer, and the transcriptional regulation was detected by dual luciferase reporter assay and ChIP assay. Finally, the efficacy of combined treatment of tadalafil and 5-FU was verified. RESULTS: PRMT5 was highly expressed in colorectal cancer tissues compared with their normal counterparts and correlated with poor prognosis in CRC patients. Then, we demonstrated that PRMT5 knockdown or loss of function attenuated the viability of CRC cells, while overexpression of PRMT5 promoted cell proliferation. Mechanistically, PRMT5 enhanced glycolysis through transcriptionally activating LDHA expression. In addition, the PRMT5 inhibitor, tadalafil, rendered CRC cells sensitive to antitumor agent 5-FU in vitro and in vivo. CONCLUSIONS: Our data indicates that PRMT5 promoted colorectal cancer proliferation partially through activating glycolysis and may be a potential target for colorectal cancer therapy.

DPBET: A dual-path lung nodules segmentation model based on boundary enhancement and hybrid transformer.

Accurate segmentation of lung nodules is an important basis for the subsequent differentiation of benign and malignant pathological types, which is conducive to early detection of lung cancer. Due to the local feature extraction characteristics of convolution and the limited receptive field of continuous down-sampling, the existing deep convolutional neural networks (CNN) for lung nodules segmentation cause the loss of information of lesion boundaries and locations. To address this issue, a dual-path lung nodules segmentation model based on boundary enhancement and hybrid transformer (DPBET) is proposed in this paper. The model consists of a global path, an edge path, and a feature aggregation module. In the global path, a de-redundant transformer module with explicit guidance is proposed, called Cascade-Axial-Prune Transformer (CAP-Trans). It is combined with CNN to form a hybrid architecture to generate a global representation of the target lesion. In the edge path, an edge detection operator is introduced to construct a lung nodule edge enhancement dataset, which improves the dataset utilization while providing more prior knowledge of the target lesion boundar. In addition, the Down-Attention Sample (DASample) as a basic encoding block is designed to effectively perceive local features of different ranges and scales in the down-sampling process of lung nodule feature extraction. Finally, a feature aggregation module is designed to fuse the outputs of the two paths to get the final segmentation result. Our DPBET can delineate the boundaries of various types of pulmonary nodules, with an average DSC of 89.86% and an average Sensitivity of 90.50% on the public dataset LIDC-IDRI. Compared with the state-of-the-art approaches, a substantial improvement has been achieved. The experimental results demonstrate that DPBET can use edge enhancement to promote the global-edge consistency relationship, and the network architecture is effective in lung nodule segmentation.

An aptasensor for cadmium ions detection based on PEI-MoS2@Au NPs 3D flower-like nanocomposites and Thi-PtPd NPs core-shell sphere.

A novel ultrasensitive electrochemical aptasensor was proposed for quantitative detection of Cd2+. To this end, flower-like polyethyleneimine-functionalized molybdenum disulfide-supported gold nanoparticles (PEI-MoS2 NFs@Au NPs) were used as substrates for the modification of bare gold electrodes (AuE). PEI-MoS2 NFs@Au NPs not only possessed excellent biocompatibility and large specific surface area to enhance the cDNA loading capacity, but also possessed good conductivity to accelerate the electron transfer rate. Furthermore, the preparation of dendritic platinum-palladium nanoparticles (PtPd NPs) can effectively load Cd2+-aptamer. Thionine and aptamers were loaded onto PtPd NPs to construct Thi-PtPd NPs-aptamer signal probes. The signal probes were captured by the cDNA immobilized on the electrode via base-pairing rule, and the signal of Thi was detected by differential pulse voltammetry (DPV). In the presence of Cd2+, aptamer-cDNA unwinded, and the combination of aptamer and Cd2+ caused the signal probes to fall off the electrode and the electrical signal decreases. Under optimal conditions, the proposed aptasensor exhibited a linear relationship between the logarithm of Cd2+ concentration and the current response over a wide range of 1 × 10-3 nM to 1 × 102 nM, with a detection limit of 2.34 × 10-4 nM. At the same time, the aptasensor was used to detect Cd2+ in tap water with satisfactory results. In addition, it has good reproducibility, selectivity and stability, and has broad application prospects in heavy metal analysis.