First comprehensive assessment of dietary chlorinated paraffins intake and exposure risk for the rural population of the Tibetan Plateau, China.

Knowledge regarding the occurrence of short-chain and medium-chain chlorinated paraffins (SCCPs and MCCPs) in foodstuffs and their dietary exposure risks for rural Tibetan residents remains largely unknown. Herein, we collected main foodstuffs (including highland barley, vegetables, Tibetan butter, mutton, and yak beef) across the rural Tibetan Plateau and characterized the CP profiles and concentrations. The highest SCCPs concentrations were detected in Tibetan butter (geometric mean (GM): 240.6 ng/g wet weight (ww)), followed by vegetables (59.4 ng/g ww), mutton (51.4 ng/g ww), highland barley (46.3 ng/g ww), and yak beef (31.7 ng/g ww). For MCCPs, the highest concentrations were also detected in Tibetan butter (319.5 ng/g ww), followed by mutton (181.9 ng/g ww), vegetables (127.0 ng/g ww), yak beef (71.2 ng/g ww), and highland barley (30.3 ng/g ww). The predominant congener profiles of SCCPs were C13Cl7-8 in mutton and yak beef, C10Cl7-8 in Tibetan butter, and C10-11Cl6-7 in highland barley and vegetables. The predominant congener profiles of MCCPs were C14Cl7-9 in all sample types. Combined with our previous results of free-range chicken eggs, the median estimated daily intakes (EDIs) of SCCPs and MCCPs via diet for Tibetan rural adults and children was estimated to be 728.8 and 1853.9 ng/kg bw/day and 2565.6 and 5952.8 ng/kg bw/day, respectively. In the worst scenario, MCCPs might induce potential health risks for rural Tibetan population. To our knowledge, this is the first systematic dietary exposure research of SCCPs and MCCPs in the remote rural areas.

Remarkable Contamination of Short- and Medium-Chain Chlorinated Paraffins in Free-Range Chicken Eggs from Rural Tibetan Plateau.

Rapid social-economic development introduces modern lifestyles into rural areas, not only bringing numerous modern products but also new pollutants, such as chlorinated paraffins (CPs). The rural Tibetan Plateau has limited industrial activities and is a unique place to investigate this issue. Herein we collected 90 free-range chicken egg pool samples across the rural Tibetan Plateau to evaluate the pollution status of CPs. Meanwhile, CPs in related soils, free-range chicken eggs from Jiangxi, and farmed eggs from markets were also analyzed. The median concentrations of SCCPs (159 ng g-1 wet weight (ww)) and MCCPs (1390 ng g-1 ww) in Tibetan free-range chicken eggs were comparable to those from Jiangxi (259 and 938 ng g-1 ww) and significantly higher than those in farmed eggs (22.0 and 81.7 ng g-1 ww). In the rural Tibetan Plateau, the median EDI of CPs via egg consumption by adults and children were estimated to be 81.6 and 220.2 ng kg-1 bw day-1 for SCCPs and 483.4 and 1291 ng kg-1 bw day-1 for MCCPs, respectively. MCCPs might pose potential health risks for both adults and children in the worst scenario. Our study demonstrates that new pollutants should not be ignored and need further attention in remote rural areas.

Computed tomography imaging and clinical characteristics of pulmonary ground-glass nodules ≤2 cm with micropapillary pattern.

BACKGROUND: The aim of this study was to investigate the imaging features, lymph node metastasis, and genetic mutations in micropapillary lung adenocarcinoma (imaging with mixed ground-glass nodules) ≤2 cm, to provide a more precise and refined basis for the selection of lung segment resection. METHODS: A retrospective analysis of 162 patients with surgically resected pathologically confirmed cancers ≤2.0 cm in diameter (50 cases of micropapillary mixed ground-glass nodules [mGGNs], 50 cases of nonmicropapillary mGGNs, and 62 cases of micropapillary SNs [solid nodules]) was performed. mGGNs were classified into five categories according to imaging features. The distribution of these five morphologies in micropapillary with mGGN and nonmicropapillary with mGGN was analyzed. The postoperative pathology and prognosis of lymph node metastasis were also compared between micropapillary mGGNs and micropapillary with SNs. After searching the TCGA database, we demonstrated heterogeneity, high malignancy and high risk of microcapillary lung cancer cancers. RESULTS: Different pathological subtypes of mGGN differed in morphological features (p < 0.05). The rate of lymph node metastasis was significantly higher in micropapillary mGGNs than in nonmicropapillary mGGNs. In the TCGA database samples, lactate transmembrane protein activity, collagen transcription score, and fibroblast EMT score were remarkably higher in micropapillary adenocarcinoma. Other pathological subtypes had a better survival prognosis and longer disease-free survival compared with micropapillary adenocarcinoma. CONCLUSION: mGGNs ≤2 cm with a micropapillary pattern have a higher risk of lymph node metastasis compared with SNs, and computed tomography (CT) imaging features can assist in their diagnosis.

Linking Transthyretin-Binding Chemicals and Free Thyroid Hormones: In Vitro to In Vivo Extrapolation Based on a Competitive Binding Model.

Large numbers of pollutants competitively inhibit the binding between thyroid hormones and transthyretin (TTR) in vitro. However, the impact of this unintended binding on free thyroid hormones in vivo has not yet been characterized. Herein, we established a quantitative in vitro to in vivo extrapolation (QIVIVE) method based on a competitive binding model to quantify the effect of TTR-binding chemicals on free thyroid hormones in human blood. Twenty-five TTR-binding chemicals including 6 hydroxyl polybromodiphenyl ethers (OH-PDBEs), 6 hydroxyl polychlorobiphenyls (OH-PCBs), 4 halogenphenols, 5 per- and polyfluorinated substances (PFASs), and 4 phenols were selected for investigation. Incorporating the in vitro binding parameters and human exposure data, the QIVIVE model could well predict the in vivo effect on free thyroid hormones. Co-exposure to twenty-five typical TTR-binding chemicals resulted in median increases of 0.080 and 0.060% in circulating levels of free thyroxine (FT4) and free triiodothyronine (FT3) in the general population. Individuals with occupational exposure to TTR-binding chemicals suffered 1.88-32.2% increases in free thyroid hormone levels. This study provides a quantitative tool to evaluate the thyroid-disrupting risks of TTR-binding chemicals and proposes a new framework for assessing the in vivo effects of chemical exposures on endogenous molecules.

Occurrence and risk assessment of organophosphate esters in global aquatic products.

Organophosphate esters (OPEs), as an important class of new pollutants, have been pervasively detected in global aquatic products, arousing widespread public concern due to their potential bioaccumulative behavior and consequent risks. With the continuous improvement of living standards of citizens, there have been constant increment of the proportion of aquatic products in diets of people. The levels of OPEs exposed to residents may also be rising due to the augmented consumption of aquatic products, posing potential hazards on human health, especially for people in coastal areas. The present study integrated the concentrations, profiles, bioaccumulation, and trophic transfer of OPEs in global aquatic products, including Mollusca, Crustacea, and fish, evaluated health risks of OPEs through aquatic products in daily diets by Mont Carol Simulation (MCS), and found Asia has been the most polluted area in terms of the concentration of OPEs in aquatic products, and would have been increasingly polluted. Among all studied OPEs, chlorinated OPEs generally showed accumulation predominance. It is worth noting that some OPEs were found bioaccumulated and/or biomagnified in aquatic ecosystems. Though MCS revealed relative low exposure risks of residents, sensitive and special groups such as children, adolescents, and fishermen may face more serious health risks than the average residents. Finally, knowledge gaps and recommendations for future research are discussed encouraging more long-term and systematic global monitoring, comprehensive studies of novel OPEs and OPEs metabolites, and more toxicological studies to completely evaluate the potential risks of OPEs.

Mechanistic insights into CDCP1 clustering on non-small-cell lung cancer membranes revealed by super-resolution fluorescent imaging.

CDCP1 is a transmembrane protein that is involved in a variety of important biological processes and upregulated in a variety of human solid malignancies; however, its spatial distribution and variation at the molecular level remain unclear. To solve this problem, we first analyzed its expression level and prognostic implications in lung cancer. Then, we used super-resolution microscopy to reveal the spatial organization of CDCP1 at different levels, and found that cancer cells generated more and larger CDCP1 clusters than normal cells. Furthermore, we found that CDCP1 can be integrated into larger and denser clusters as functional domains upon activation. Our findings elucidated the significant differences of CDCP1 clustering characteristics between cancer and normal cells, and revealed the relationship between its distribution and function, which will contribute to a comprehensive understanding of its oncogenic mechanism, and will be of great help for the development of CDCP1-targeted drugs for lung cancer.

Erratum: Mechanistic insights into CDCP1 clustering on non-small-cell lung cancer membranes revealed by super-resolution fluorescent imaging.

[This corrects the article DOI: 10.1016/j.isci.2023.106103.].

Source Identification of Organophosphate Esters through the Profiles in Proglacial and Ocean Sediments from Ny-Ålesund, the Arctic.

Little is known about the sources and environmental behavior of organophosphate esters (OPEs) in the Arctic, especially their transformation products. The present study unprecedentedly investigated both 16 tri-OPEs and 8 di-OPEs in proglacial and ocean sediments from Ny-Ålesund, the Arctic. Mean concentrations of tri-OPEs and di-OPEs in proglacial sediments were 487 and 341 pg/g dry weight (dw), respectively, which were significantly lower than those in ocean sediments (1692 and 525 pg/g dw). Ocean sediments might be simultaneously influenced by long-range atmospheric transport (LRAT), oceanic transport, and human activities, whereas proglacial sediments, since they are isolated from human settlements, may be dominantly affected by LRAT. Such source difference was evidenced by the contamination profile of OPEs: chlorinated tri-OPEs with high environmental persistence and high LRAT were dominant in proglacial sediments (66%); however, weakly environmentally persistent and highly hydrophobic aryl tri-OPEs were dominant in ocean sediments (47%), which were plausibly from local emission sources due to their low LRAT potential. Di-OPEs in proglacial and ocean sediments were dominated by groups of parent tri-OPEs with strong photodegradability, such as alkyl (75%) and aryl (58%). A higher mean molar ratio of di-OPE/tri-OPE in the proglacial sediment (14) than that in the ocean sediment (2.2) may be related to its higher photodegradation than that of the ocean sediment.

An unusual sternalis with variation of the contralateral sternocleidomastoid muscle: a case report.

PURPOSE: To report a previously undocumented variant of sternalis. METHODS: An unusual muscle was observed during routine dissection. RESULTS: The sternalis muscle located in the right thoracic region originated from the superior portion of the rectus abdominis sheath and 5-6th costal cartilages, crossed the midline and attached at the sternum. The muscle fibers then ascended with the left sternocleidomastoid muscle as an additional fasciculus, of which the superior ends were finally terminated at the left mastoid process. The sternalis muscle of the thoracic region was innervated by the anterior cutaneous branches of right intercostal nerve, while the additional fasciculus ascended with the left sternocleidomastoid muscle was innervated by the branches of left accessory nerve. CONCLUSIONS: This study presents a unilateral sternalis muscle with the contralateral sternocleidomastoid variation. It will enhance the exhaustive classification of sternalis, and provide significant information to radiologists, angiologists and surgeons for better interpretation of images and safer interventions.

CDCP1: A promising diagnostic biomarker and therapeutic target for human cancer.

CUB domain-containing protein 1 (CDCP1), as an emerging transmembrane protein, is overexpressed in a variety of malignant tumors including respiratory tumors, digestive system cancers, hematological malignancies and urogenital cancers. Several cancer-related proteins have been reported to interact with CDCP1. It acts as a crucial hub in multiple classical signaling pathways of tumorigenesis and progression. Its overexpression and activation are also associated with prognosis and drug resistance. Due to its important roles in malignant tumors, CDCP1 is expected to be a promising therapeutic target for treatment and a new biomarker for diagnosis. In this article, we review the roles of CDCP1 in diagnosis and management of malignant tumors, and also its regulation in several essential tumor-related pathways.

The role of CD47-SIRPα immune checkpoint in tumor immune evasion and innate immunotherapy.

As a transmembrane protein, CD47 plays an important role in mediating cell proliferation, migration, phagocytosis, apoptosis, immune homeostasis, inhibition of NO signal transduction and other related reactions. Upon the interaction of innate immune checkpoint CD47-SIRPα occurrence, they send a "don't eat me" signal to the macrophages. This signal ultimately helps tumors achieve immune escape by inhibiting macrophage contraction to prevent tumor cells from phagocytosis. Therefore, the importance of CD47-SIRPα immune checkpoint inhibitors in tumor immunotherapy has attracted more attention in recent years. Based on the cognitive improvement of the effect with CD47 in tumor microenvironment and tumor characteristics, the pace of tumor treatment strategies for CD47-SIRPα immune checkpoint inhibitors has gradually accelerated. In this review, we introduced the high expression of CD47 in cancer cells to avoid phagocytosis by immune cells and the importance of CD47 in the structure of cancer microenvironment and the maintenance of cancer cell characteristics. Given the role of the innate immune system in tumorigenesis and development, an improved understanding of the anti-tumor process of innate immune checkpoint inhibitors can lay the foundation for more effective combinations with other anti-tumor treatment strategies.

Mechanistic Insights into Trop2 Clustering on Lung Cancer Cell Membranes Revealed by Super-resolution Imaging.

The transmembrane glycoprotein Trop2 plays important roles in various types of human cancers, especially lung cancer. Although it has been found to form clusters on cancer cell membranes, the factors that affect its clustering are not yet fully understood. Here, using direct stochastic optical reconstruction microscopy (dSTORM), we found that Trop2 generated more, larger, and denser clusters on apical cell membranes than on basal membranes and that the differences might be related to the different membrane structures. Moreover, dual-color dSTORM imaging revealed significant colocalization of Trop2 and lipid rafts, and methyl-ß-cyclodextrin disruption dramatically impaired the formation of Trop2 clusters, indicating a key role of lipid rafts in Trop2 clustering. Additionally, depolymerization of the actin cytoskeleton decreased Trop2 cluster numbers and areas, revealing that actin can stabilize the clusters. More importantly, stimulation of Trop2 in cancer cells hardly changed the cluster morphology, suggesting that Trop2 is activated and forms clusters in cancer cells. Altogether, our work links the spatial organization of Trop2 to different membrane structures and Trop activation and uncovers the essential roles of lipid rafts and actin in Trop2 cluster maintenance.

Comparison of Erythrocyte Membrane Lipid Profiles between NAFLD Patients with or without Hyperlipidemia.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) and hyperlipidemia (HL) are common metabolic disorders due to overnutrition and obesity. NAFLD is often associated with hyperlipidemia. The aim of this study was to identify and compare the erythrocyte membrane lipids profile in NAFLD patients with or without HL. Methods. A total of 112 subjects (with similar age and body mass index) were divided into four groups: (1) normal controls, (2) NAFLD alone, (3) HL alone, and (4) NAFLD combined with HL (NAFLD + HL). Lipid was extracted from the erythrocyte membrane, and lipid profiles of subjects were analyzed by liquid chromatography mass spectrometry (LC-MS). Results. Data sets from 103 subjects were adopted for lipidomic analysis. Significant changes of lipid species were observed in patient groups, especially in the HL group and NAFLD + HL group. The HL group showed increased level of most lipid species, and decreased level of most lipid species was observed in the NAFLD + HL group. The weight percent of myristic acid, stearic acid, erucic acid, and docosahexaenoic acid also showed distinct variation between different groups. Conclusions. NAFLD, HL, and NAFLD + HL all had an impact on lipid profiling of the erythrocyte membrane. The influence of NAFLD alone is less important compared with HL. Some lipids should be highlighted because of their specific role in cell function and systemic metabolism.

Relation of Gut Microbes and L-Thyroxine Through Altered Thyroxine Metabolism in Subclinical Hypothyroidism Subjects.

Thyroxine metabolism is an important topic of pathogenesis research and treatment schedule of subclinical hypothyroidism (SCH). L-Thyroxine replacement therapy (LRT) is usually recommended for severe SCH patients only. Our previous studies reported that disordered serum lipid of mild SCH people could also benefit from LRT. However, the benefits were different among individuals, as shown by the variations in drug dosage that required to maintain thyroid-stimulating hormone (TSH) stability. Alternative pathways, such as sulfation and glucuronidation of iodothyronine, may play a role in thyroid hormones metabolism in peripheral tissues aside from thyroid. Conjugated thyroxine can be hydrolyzed and reused in tissues including gastrointestinal tract, in which gut microbiota are one of the most attractive physiological components. On this site, the roles of gut microbiota in thyroidal metabolism should be valued. In this study, a cross-sectional study was performed by analyzing 16S rDNA of gut microbiota in mild SCH patients treated with L-thyroxine or not. Subjects were divided by serum lipid level, L-thyroxine treatment, or L-thyroxine dosage, respectively. Relationship between gut microbiome and serum profile, L-thyroxine treatment, and dose were discussed. Other metabolic disorders such as type 2 diabetes and hypertension were also taken into consideration. It turned out that microbiome varied among individuals divided by dose and the increment of L-thyroxine but not by serum lipid profile. Relative abundance of certain species that were associated with thyroxine metabolism were found varied among different L-thyroxine doses although in relatively low abundance. Moreover, serum cholesterol may perform relevance effects with L-thyroxine in shaping microbiome. Our findings suggested that the differences in L-thyroxine dosage required to maintain TSH level stability, as well as the SCH development, which was displayed by the increased L-thyroxine doses in subsequent follow-up, had relationship with gut microbial composition. The reason may due to the differences in thyroxine metabolic capacity in gut. In addition, the metabolic similarity of iodothyronines and bile acid in gut also provides possibilities for the correlation between host's thyroxine and cholesterol levels. This study was registered with ClinicalTrials.gov as number NCT01848171.

High follicle-stimulating hormone levels accelerate cartilage damage of knee osteoarthritis in postmenopausal women through the PI3K/AKT/NF-κB pathway.

Osteoarthritis is the main cause of pain and disability in the elderly, with the most commonly affected joint being the knee. The prevalence of knee osteoarthritis (KOA) is significantly increased in postmenopausal women, although the mechanisms underlying KOA remain unclear. The present study aimed to investigate the association between follicle-stimulating hormone (FSH) and postmenopausal women with KOA aged between 50 and > 70 years, as well as explore its underlying molecular mechanisms. Here, we report that the 50-60 years age group had the highest level of serum FSH. Compared to the low FSH group (< 40 mIU·mL-1 ) in the same age group, the high FSH group (> 40 mIU·mL-1 ) showed more severe cartilage damage. Furthermore, phosphorylated (p)-phosphoinositide 3-kinase (PI3K)/PI3K, p-AKT/AKT and p-nuclear factor kappa B (NF-κB)/NF-κB levels were significantly higher in the high FSH group compared to the low FSH group. Immunofluorescence experiments showed that FSH stimulation promoted the translocation of NF-κB p65 into the nucleus, and decreased type II collagen and aggrecan in ATDC5 cells. Moreover, we used western blotting in ATDC5 cells to demonstrate that FSH decreased type II collagen and increased p-PI3K/PI3K, p-AKT/AKT, p-NF-κB/NF-κB and p-IKB/IKB in a concentration-dependent manner. Our results suggest that increased FSH levels are associated with KOA for postmenopausal women aged 50-60 years and that high FSH levels might damage the cartilage tissues through the PI3K/AKT/NF-κB pathway.

FSH signaling is involved in affective disorders.

Affective disorders are a set of mental disorders and particularly disrupt the mental health of susceptible women during puberty, pregnancy, parturition and menopause transition, which are characterized by dramatic changes in reproductive hormone profiles. The serum FSH level changes significantly during these periods; yet, the role of FSH in mood regulation is poorly understood. In the current study, FSHR knockout (Fshr-/-) mice displayed enhanced affective disorder behaviors in an open field test and a forced swim test, accompanied by altered gene expression profiles. The differentially expressed genes between Fshr-/- mice and Fshr+/+ mice were enriched in multiple neuroendocrine metabolic pathways. FSHR deletion significantly increased/decreased the mRNA and/or protein expression levels of AOX1, RDH12, HTR3a and HTR4 in mood-mediating brain regions, including the hippocampus and prefrontal cortex. These results reveal that FSH signaling is involved in the development of affective disorders.

Interaction effect of obesity and thyroid autoimmunity on the prevalence of hyperthyrotropinaemia.

PURPOSE: The role of thyroid autoimmunity in the association between obesity and hyperthyrotropinaemia remains unclear. We aimed to assess the relationship between obesity, autoimmunity, and hyperthyrotropinaemia. METHODS: In this population-based cross-sectional study, 12531 Chinese individuals (18-80 years) with thyroid function test were categorized into three groups by body mass index (BMI) and were categorized into three layers by thyroid autoantibodies. Multivariate logistic regression was employed to assess the correlation and interaction effect. RESULTS: There was no significant difference in prevalence of hyperthyrotropinaemia (P = 0.637) among three BMI groups. After stratification, the difference of serum thyrotropin (P < 0.01) and prevalence of hyperthyrotropinaemia (P < 0.01) between the three groups have significant linear trends at the positive levels of thyroid peroxidase antibody (TPOAb) or/and thyroglobulin antibody (TgAb). When TPOAb and TgAb were positive, the risk of hyperthyrotropinaemia increased 1.857-fold in overweight group and 2.201-fold in obese group compared with normal group. Compared with negative TPOAb and TgAb, the risk of hyperthyrotropinaemia for individuals with two positive antibodies increased 3.310-fold, 4.969-fold, and 5.122-fold in the three BMI groups. The adjusted OR (95% CI) for interaction were 1.033 (0.752-1.419) for overweight and one positive antibodies, 1.935 (1.252-2.990) for overweight and two positive antibodies, 1.435 (0.978-2.105) for obesity and one positive antibodies and 2.191 (1.252-3.832) for obesity and two positive antibodies. CONCLUSION: Overweight and obesity were associated with hyperthyrotropinaemia only in presence of thyroid autoimmunity, and obesity might aggravate the pathogenic effect of autoimmunity on hyperthyrotropinaemia. There was an interaction effect between obesity and autoimmunity on the prevalence of hyperthyrotropinaemia.

Variation of Trop2 on non-small-cell lung cancer and normal cell membranes revealed by super-resolution fluorescence imaging.

Transmembrane glycoprotein Trop2 is related to many epithelial carcinomas. It not only plays roles in promoting fetal lung growth but also participates in tumor genesis, malignant transformation, and tumor dissemination. However, the detailed distribution of Trop2 at the molecular level remains unknown. Herein, we used direct stochastic optical reconstruction microscopy to reveal the spatial organization of Trop2 on the membranes of cultured and primary lung cancer cells and normal cells. All types of cancer cells presented more localizations of Trop2 than normal cells. By SR-Teseller cluster analysis, we found that Trop2 existed in the form of clusters on all the membranes; however, cancer cells generated more and larger clusters consisting of more molecules than normal cells. Our findings shed light on the heterogeneous distribution of membrane Trop2 and highlighted the significant differences of its clustering characteristics between lung cancer cells and normal cells, which laid the basis for further studying the mechanism and functions of Trop2 clustering in lung cancer.

Mobilization and transport of metal-rich colloidal particles from mine tailings into soil under transient chemical and physical conditions.

Exposed mine tailing wastes with considerable heavy metals can release hazardous colloidal particles into soil under transient chemical and physical conditions. Two-layered packed columns with tailings above and soils below were established to investigate mobilization and transport of colloidal particles from metal-rich mine tailings into soil under transient infiltration ionic strength (IS: 100, 20, 2 mM) and flow rate (FR: 20.7, 41, and 62.3 mm h(-1)), with Cu and Pb as representatives of the heavy metals. Results show that the tailing particles within the colloidal size (below 2 µm) were released from the columns. A step-decrease in infiltration IS and FR enhanced, whereas a step-increase in the IS and FR restrained the release of tailing particles from the column. The effects of step-changing FR were unexpected due to the small size of the released tailing particles (220-342 nm, being not sensitive to hydrodynamic shear force), the diffusion-controlled particle release process and the relatively compact pore structure. The tailing particles present in the solution with tested IS were found negatively charged and more stable than soil particles, which provides favorable conditions for tailing particles to be transported over a long distance in the soil. The mobilization and transport of Cu and Pb from the tailings into soil were mediated by the tailing particles. Therefore, the inherent toxic tailing particles could be considerably introduced into soil under certain conditions (IS reduction or FR decrease), which may result in serious environmental pollution.