Phenylmethylsiloxanes in indoor dust from residential area of China: Source, occurrence, bioavailability and exposure assessment.

Phenylmethylsiloxanes, as modified products of dimethylsiloxanes, have been used in personal care products (PCPs) and household appliances, with indoor dust serving as one potential reservoir due to their particle-binding properties. This study measured six isomers of two phenylmethylsiloxanes (P3 and P4) in PCPs (99 %) intakes of phenylmethylsiloxanes for adults, while dust ingestion/adsorption (0.19 ng/d) may play important roles for toddlers/infants with little usage of phenylmethylsiloxanes-containing PCPs. Additionally, total daily intakes of PhMeSi(OH)2 (0.30-0.84 ng/d) via ingestion and dermal absorption of dust were higher than P3 (0.06-0.31 ng/d) and P4 (0.02-0.09 ng/d), suggesting exposure risk of degradation product of phenylmethylsiloxanes deserving attention.

A TrkB cleavage fragment in hippocampus promotes Depressive-Like behavior in mice.

Decreased hippocampal tropomyosin receptor kinase B (TrkB) level is implicated in the pathophysiology of stress-induced mood disorder and cognitive decline. However, how TrkB is modified and mediates behavioral responses to chronic stress remains largely unknown. Here the effects and mechanisms of TrkB cleavage by asparagine endopeptidase (AEP) were examined on a preclinical murine model of chronic restraint stress (CRS)-induced depression. CRS activated IL-1ß-C/EBPß-AEP pathway in mice hippocampus, accompanied by elevated TrkB 1-486 fragment generated by AEP. Specifi.c overexpression or suppression of AEP-TrkB axis in hippocampal CaMKIIα-positive cells aggravated or relieved depressive-like behaviors, respectively. Mechanistically, in addition to facilitating AMPARs internalization, TrkB 1-486 interacted with peroxisome proliferator-activated receptor-δ (PPAR-δ) and sequestered it in cytoplasm, repressing PPAR-δ-mediated transactivation and mitochondrial function. Moreover, co-administration of 7,8-dihydroxyflavone and a peptide disrupting the binding of TrkB 1-486 with PPAR-δ attenuated depression-like symptoms not only in CRS animals, but also in Alzheimer's disease and aged mice. These findings reveal a novel role for TrkB cleavage in promoting depressive-like phenotype.

Unraveling the rapid ion migration in perovskite solar cells by circuit-switched transient photoelectric technique.

Ion migration activated by illumination is a critical factor responsible for the performance decline and stability degradation of perovskite solar cells (PSCs). While ion migration has been widely believed to be much slower than charge transport, recent research suggests that, despite the lack of understanding of the mechanism, it may also be involved in a series of rapid photoelectric responses of PSCs. Here, we report an improved circuit-switched transient photoelectric technique with nanosecond temporal resolution, which enables quantitative characterization of ion migration dynamics in PSCs across a fairly broad time window. Specifically, ion migration occurring within microseconds after illumination (corresponding to a diffusion length of ∼10-7 cm) is unambiguously identified. In conjunction with the composition engineering protocol, we justify that it arises from the short-range migration of halide anions and organic cations around the contact/perovskite interface. The rapid ion migration kinetics revealed in this work strongly complement the well-established ion migration model, which offers new insights into the mechanism of ion-carrier interaction in PSC devices.

Synthesis, Herbicidal Activity against Barnyard Grass, and Photolytic Behavior of Aryl 2,6-Dipyrimidinoxybenzoates.

In this study, we investigated the characteristics and herbicidal potential of bispyribac phenolic esters, which belong to the 2-(pyrimidin-2-yloxy)benzoic acid (PYB) class of acetohydroxyacid synthase (AHAS-)-inhibiting herbicides. These herbicides are primarily used for controlling Poaceae and broadleaf weeds. Among them, bispyribac-sodium stands out as a representative in this class. Surprisingly, other bispyribac esters, including alkanol and phenol esters exhibit considerably reduced herbicidal activity compared to bispyribac-sodium. In contrast, oxime esters (e.g., pyribenzoxim) demonstrate high activity. To further understand and develop novel PYB herbicides, we synthesized and screened a series of bispyribac phenolic esters while investigating their photochemical behaviors. Several compounds displayed excellent herbicidal activity, with compounds Ia-19 and Ic showing impressive 90% effective dosages for fresh weight inhibition of barnyard grass, measuring 0.55 and 0.60 g a.i./hm2, respectively. These values were approximately half of bispyribac-sodium or pyribenzoxim. The results indicate that the herbicidal activity of phenolic esters is influenced by both their binding ability to the AHAS enzyme and their decomposition into bispyribac acid. For instance, bispyribac phenol ester exhibited considerably reduced receptor affinity compared to bispyribac-sodium, and faced challenges in transforming into bispyribac acid, explaining its diminished herbicidal activity. However, introducing a photosensitive nitro group led to a complete transformation. This modification improved its affinity with AHAS and accelerated its decomposition into bispyribac acid, further accelerated by photocatalysis. Consequently, nitro-containing compounds displayed heightened herbicidal activity. The findings from this study open possibilities for structural optimization of phenolic esters through quantitative structure-activity relationship analysis, potentially regulating their activity-releasing period. Furthermore, the high activity of aromatic heterocyclic esters offers new insights into developing novel PYB herbicides.

Quantitative characterization of resident' exposure to typical semi-volatile organic compounds (SVOCs) around a non-ferrous metal smelting plant.

To comprehensively characterize residents' exposure to major semi-volatile organic compounds (SVOCs), samples of indoor floor wipes, size-segregated airborne particles, gaseous air, food, and paired skin wipes were simultaneously collected from residential areas around a large non-ferrous metal smelting plant as compared with the control areas, and three typical SVOCs (including polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and halogenated PAHs (HPAHs)) were determined. Comparison and correlation analysis among matrices indicated PAHs were the major contaminants emitted from metal smelting activities compared to HPAHs and PCBs, with naphthalene verified as the most important characteristic compound, and their accumulation on skin may be a comprehensive consequence of contact with floor dust and air. While patterns of human exposure pathways for the SVOCs were found to be clearly correlated to their vapor pressure, dermal absorption was the major contributor (51.1-76.3%) to total carcinogenic risk (TCR) of PAHs and HPAHs for surrounding residents, especially for low molecular weight PAHs, but dietary ingestion (98.6%) was the dominant exposure pathway to PCBs. The TCR of PAHs exceeded the acceptable level (1 × 10-4), implying smelting activities obviously elevated the health risk. This study will serve developing pertinent exposure and health risk prevention measures.

A tau fragment links depressive-like behaviors and cognitive declines in Alzheimer's disease mouse models through attenuating mitochondrial function.

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by extracellular senile plaques including amyloid-ß peptides and intracellular neurofibrillary tangles consisting of abnormal Tau. Depression is one of the most common neuropsychiatric symptoms in AD, and clinical evidence demonstrates that depressive symptoms accelerate the cognitive deficit of AD patients. However, the underlying molecular mechanisms of depressive symptoms present in the process of AD remain unclear. Methods: Depressive-like behaviors and cognitive decline in hTau mice were induced by chronic restraint stress (CRS). Computational prediction and molecular experiments supported that an asparagine endopeptidase (AEP)-derived Tau fragment, Tau N368 interacts with peroxisome proliferator-activated receptor delta (PPAR-δ). Further behavioral studies investigated the role of Tau N368-PPAR-δ interaction in depressive-like behaviors and cognitive declines of AD models exposed to CRS. Results: We found that mitochondrial dysfunction was positively associated with depressive-like behaviors and cognitive deficits in hTau mice. Chronic stress increased Tau N368 and promoted the interaction of Tau N368 with PPAR-δ, repressing PPAR-δ-mediated transactivation in the hippocampus of mice. Then we predicted and identified the binding sites of PPAR-δ. Finally, inhibition of AEP, clearance of Tau N368 and pharmacological activation of PPAR-δ effectively alleviated CRS-induced depressive-like behaviors and cognitive decline in mice. Conclusion: These results demonstrate that Tau N368 in the hippocampus impairs mitochondrial function by suppressing PPAR-δ, facilitating the occurrence of depressive-like behaviors and cognitive decline. Therefore, our findings may provide new mechanistic insight in the pathophysiology of depression-like phenotype in mouse models of Alzheimer's disease.

Overexpression of Grapevine VyTRXy Improves Drought Tolerance by Maintaining Photosynthesis and Enhancing the Antioxidant and Osmolyte Capacity of Plants.

Drought stress profoundly affects plant growth and development, posing a significant challenge that is extensively researched in the field. Thioredoxins (TRXs), small proteins central to redox processes, are crucial to managing both abiotic and biotic stresses. In this research, the VyTRXy gene, cloned from wild Yanshan grapes, was validated as a functional TRX through enzyme activity assays. VyTRXy was found to bolster photosynthesis, augment levels of osmotic regulators, stimulate antioxidant enzyme activities, and strengthen drought resilience in transgenic plants. These enhancements were evidenced by higher survival rates, optimized photosynthetic metrics, increased proline levels, augmented chlorophyll concentration, reduced electrolyte leakage, and decreased malondialdehyde and hydrogen peroxide (H2O2) levels. Furthermore, there was a surge in the activities of enzymes such as catalase, ascorbate peroxidase, glutathione peroxidase, dehydroascorbate reductase, and glutathione reductase, along with an increased expression of TRX peroxidase. Notably, under drought stress, there was a marked elevation in the expression of stress-responsive genes, including the adversity stress-inducible expression gene (NtRD29A) and DRE-binding protein (NtDREB), in transgenic tobacco. This investigation is pivotal in the quest for drought-resistant grapevine varieties and provides significant insights into the molecular functionality of VyTRXy in enhancing grapevine drought tolerance.

Parallel kinetic resolution of aziridines via chiral phosphoric acid-catalyzed apparent hydrolytic ring-opening.

We report a chiral phosphoric acid catalyzed apparent hydrolytic ring-opening reaction of racemic aziridines in a regiodivergent parallel kinetic resolution manner. Harnessing the acyloxy-assisted strategy, the highly stereocontrolled nucleophilic ring-opening of aziridines with water is achieved. Different kinds of aziridines are applicable in the process, giving a variety of enantioenriched aromatic or aliphatic amino alcohols with up to 99% yields and up to >99.5 : 0.5 enantiomeric ratio. Preliminary mechanistic study as well as product elaborations were inducted as well.

New insight into the metabolic mechanism of a novel lipid-utilizing and denitrifying bacterium capable of simultaneous removal of nitrogen and grease through transcriptome analysis.

Introduction: Issues related to fat, oil, and grease from kitchen waste (KFOG) in lipid-containing wastewater are intensifying globally. We reported a novel denitrifying bacterium Pseudomonas CYCN-C with lipid-utilizing activity and high nitrogen-removal efficiency. The aim of the present study was aim to explore the metabolic mechanism of the simultaneous lipid-utilizing and denitrifying bacterium CYCN-C at transcriptome level. Methods: We comparatively investigated the cell-growth and nitrogen-removal performances of newly reported Pseudomonas glycinae CYCN-C under defined cultivation conditions. Transcriptome analysis was further used to investigate all pathway genes involved in nitrogen metabolism, lipid degradation and utilization, and cell growth at mRNA levels. Results: CYCN-C could directly use fat, oil, and grease from kitchen waste (KFOG) as carbon source with TN removal efficiency of 73.5%, significantly higher than that (60.9%) with sodium acetate. The change levels of genes under defined KFOG and sodium acetate were analyzed by transcriptome sequencing. Results showed that genes cyo, CsrA, PHAs, and FumC involved in carbon metabolism under KFOG were significantly upregulated by 6.9, 0.7, 26.0, and 19.0-folds, respectively. The genes lipA, lipB, glpD, and glpK of lipid metabolic pathway were upregulated by 0.6, 0.4, 21.5, and 1.3-folds, respectively. KFOG also improved the denitrification efficiency by inducing the expression of the genes nar, nirB, nirD, and norR of denitrification pathways. Conclusion: In summary, this work firstly provides valuable insights into the genes expression of lipid-utilizing and denitrifying bacterium, and provides a new approach for sewage treatment with reuse of KFOG wastes.

High-Fill-Factor Perovskite Solar Cells via Pseudohalide Salt Modification of the Substrate to Mitigate Nonradiative Recombination at the Interface.

The utilization of the sol-gel method for fabricating planar SnO2 as the electron transport layer (ETL) induces numerous defects on the SnO2 layer surface and perovskite film bottom, causing considerable deterioration of the device performance. Conventional inorganic salt-doped SnO2 precursor solutions used for passivation may cause incomplete substrate coverage due to the presence of inorganic salt crystals, further degrading the device performance. Here, a substrate modification approach involving the pretreatment of a fluorine-doped SnO2 (FTO) substrate with NH4PF6 is proposed. The interaction between PF6- ions and the FTO substrate enhances SnO2 film quality; excess PF6- ions decrease the number of defects on the film surface. NH4+ ions react with an -OH stabilizing agent in the SnO2 solution and are eliminated during annealing. The combined effects suppress nonradiative recombination and ion migration at the ETL-perovskite interface. The corresponding high-quality perovskite solar cells (PSCs) exhibit a fill factor of ∼0.825; PSC efficiency increases from 19.59% to 22.32%.

The effects of rate pressure product at admission on cardiopulmonary function during hospitalization in patients with acute myocardial infarction.

OBJECTIVE: This study aimed to analyze the correlation between the rate pressure product (RPP) and cardiopulmonary function during hospitalization in patients with acute myocardial infarction (AMI). METHODS: A total of 362 patients with AMI were selected for the study, and the median admission RPP was used as the cutoff point to divide the patients into a low-RPP group (n = 181) and a high-RPP group (n = 181). The relationship between the RPP at admission and the cardiopulmonary function during hospitalization was analyzed. RESULTS: The patients in the high-RPP group had a higher body mass index (BMI) (p = 0.014), a higher prevalence of combined hypertension and diabetes mellitus (p < 0.001), a lower incidence of smoking (p = 0.044), and a higher incidence of oscillatory ventilation (6.1% vs. 1.7%, p = 0.029). The differences in RPP at rest, during warm-up, and within 1 and 4 minutes of recovery were statistically significant between the two groups (p < 0.01 on each occasion), while the differences in anaerobic threshold (AT) and watt max (Max) were not statistically significant (p > 0.05 for both). The patients in the low-RPP group had higher oxygen uptake (VO2 [AT]: 14.9 ± 3.4 vs. 14.2 ± 3.6, p = 0.048) and (VO2peak [Max]:18.2 ± 3.8 vs. 17.3 ± 3.8, p = 0.020). The RPP at admission was negatively correlated with VO2 (AT) and VO2peak (p < 0.05) using the regression Equation VO2peak = 33.682 + (-0.012 * RPP at admission/100) + (-0.105 * Age) + (-0.350 * BMI), while there was no correlation between the RPP at admission and VO2 (AT) (p = 0.149). CONCLUSION: The RPP at admission was negatively correlated with cardiopulmonary function during hospitalization in patients with AMI. Patients with a high RPP were more likely to have a combination of obesity, hypertension, diabetes mellitus, and reduced oxygen uptake during exercise, while a high RPP at admission appeared to affect their cardiovascular response indicators during exercise.

SERS-Based Optical Nanobiosensors for the Detection of Alzheimer's Disease.

Alzheimer's disease (AD) is a leading cause of dementia, impacting millions worldwide. However, its complex neuropathologic features and heterogeneous pathophysiology present significant challenges for diagnosis and treatment. To address the urgent need for early AD diagnosis, this review focuses on surface-enhanced Raman scattering (SERS)-based biosensors, leveraging the excellent optical properties of nanomaterials to enhance detection performance. These highly sensitive and noninvasive biosensors offer opportunities for biomarker-driven clinical diagnostics and precision medicine. The review highlights various types of SERS-based biosensors targeting AD biomarkers, discussing their potential applications and contributions to AD diagnosis. Specific details about nanomaterials and targeted AD biomarkers are provided. Furthermore, the future research directions and challenges for improving AD marker detection using SERS sensors are outlined.

Prevalence and Risk Factors Underlying Occupational Stress and Depression Among Clinical Nurses in Secondary and Tertiary Hospitals of China During COVID-19 Setting.

Aim: This study was designed to develop an effective measurement tool for occupational stress among medical staff and to identify the underlying risk factors among clinical nurses in China under depression during and after COVID-19. Methods: In the first stage, an occupational stress scale was developed for medical staff based on qualitative and quantitative methods. The dimensions of the scale were based on childhood stress and seven other parameters of working stress. In the second stage, a provincial survey was conducted among clinical nurses in Hainan. The structure of Medical Staff Occupational Stress Scale was tested in secondary and tertiary hospitals. The socio-demographic information, occupational stress (measured using the developed scale), and current depression symptoms (assessed with the nine-item Patient Health Questionnaire) were evaluated. The risk factors for occupational stress-induced depression were tested using multivariate logistic regression. Results: The Medical Staff Occupational Stress Scale consisted of 42 items under eight dimensions with strong reliability and validity. Almost 80% of the clinical nurses reported obvious symptoms of depression. Based on multivariate logistical regression analysis, the significant risk factors for depression in nurses at secondary hospitals and tertiary hospitals were childhood stress, teaching stress, relationship with patient stress, and administration stress. Conclusion: The Medical Staff Occupational Stress Scale utilized in nursing population is based on strong psychometric features. Childhood stress contributes to occupational stress in nurses. The selection of nurses for clinical work may require evaluation of past history for childhood stress to prevent occupational depression. Teaching stress, relationship with patient stress and administration stress play significant roles in the prevention of depression among clinical nurses.

A Nanobody-Bioorthogonal Catalyst Conjugate Triggers Spatially Confined Prodrug Activation for Combinational Chemo-immunotherapy.

Checkpoint inhibitors have been used with chemotherapy to improve antitumor efficacy. However, overcoming the immunosuppressive effect of chemotherapeutics remains a challenge. We report a nanobody-catalyst conjugate Ru-PD-L1 by fusing a ruthenium catalyst to an anti-PD-L1 nanobody. After administration of Ru-PD-L1 and a doxorubicin (DOX) prodrug, Ru-PD-L1 disrupts the PD-L1/PD-1 interaction and catalyzes the uncaging of the DOX prodrug. The spatially confined release of DOX reduces its systemic toxicity and leads to immunogenic cell death (ICD). The induced ICD triggers antitumor immune responses, which are further amplified by PD-L1 blockade to elicit synergistic chemo-immunotherapy, substantially increasing the number of tumor-infiltrating T-cells by 49.7% compared with the controls, thereby exhibiting high antitumor activity and low cytotoxicity in murine models. The combinational treatment could inhibit the growth of mice tumors by 67.7% compared to the control group. This combinational approach circumvents the negative immunogenic effects of chemotherapeutics and provides a potential chemo-immunotherapy strategy for human cancer treatment.

Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response.

Neoadjuvant immune-checkpoint blockade therapy only benefits a limited fraction of patients with glioblastoma multiforme (GBM). Thus, targeting other immunomodulators on myeloid cells is an attractive therapeutic option. Here, we performed single-cell RNA sequencing and spatial transcriptomics of patients with GBM treated with neoadjuvant anti-PD-1 therapy. We identified unique monocyte-derived tumor-associated macrophage subpopulations with functional plasticity that highly expressed the immunosuppressive SIGLEC9 gene and preferentially accumulated in the nonresponders to anti-PD-1 treatment. Deletion of Siglece (murine homolog) resulted in dramatically restrained tumor development and prolonged survival in mouse models. Mechanistically, targeting Siglece directly activated both CD4+ T cells and CD8+ T cells through antigen presentation, secreted chemokines and co-stimulatory factor interactions. Furthermore, Siglece deletion synergized with anti-PD-1/PD-L1 treatment to improve antitumor efficacy. Our data demonstrated that Siglec-9 is an immune-checkpoint molecule on macrophages that can be targeted to enhance anti-PD-1/PD-L1 therapeutic efficacy for GBM treatment.

A near-infrared fluorescent probe for tracking endogenous and exogenous H2O2 in cells and zebrafish.

H2O2 is an important signaling molecule in the body, and its levels fluctuate in many pathological sites, therefore, it can be used as a biomarker for early diagnosis of disease. Since the environment in vivo is extremely complex, it is of great significance to develop a probe that can accurately monitor the fluctuation of H2O2 level without interference from other physiological processes. Based on this, we designed and synthesized two new near-infrared H2O2 fluorescent probes, LTA and LTQ, based on the ICT mechanism. Both of them have good responses to H2O2, but LTA has a faster response speed. In addition, the probe LTA has good biocompatibility, good water solubility, and a large Stokes shift (95 nm). The detection limit is 4.525 µM. The probe was successfully used to visually detect H2O2 in living cells and zebrafish and was successfully used to monitor the changes in H2O2 levels in zebrafish due to APAP-induced liver injury.

Visualize intracellular ß-galactosidase using an asymmetric near-infrared fluorescent probe with a large Stokes shift.

ß-galactosidase (ß-Gal) is an important biomarker of cell senescence and primary ovarian cancer. Therefore, it is of great significance to construct a near-infrared fluorescent probe with deep tissue penetration and a high signal-to-noise ratio for visualization of ß-galactosidase in biological systems. However, most near-infrared probes tend to have small Stokes shifts and low signal-to-noise ratios due to crosstalk between excitation and emission spectra. Using d-galactose residues as specific recognition units and near-infrared dye TJ730 as fluorophores, a near-infrared fluorescence probe SN-CR with asymmetric structure was developed for the detection of ß-Gal. The probe has a fast reaction equilibrium time (<12 min) with ß-Gal, excellent biocompatibility, near-infrared emission (738 nm), low detection limit (0.0029 U/mL), and no crosstalk between the excitation spectrum and emission spectrum (Stokes shifts 142 nm) of the probe. Cell imaging studies have shown that SN-CR can visually trace ß-Gal in different cells and distinguish ovarian cancer cells from other cells.

Design and application of prodrug fluorescent probes for the detection of ovarian cancer cells and release of anticancer drug.

Ovarian cancer is a gynecologic malignancy with high mortality. The main reason is that it is detected at an advanced stage due to a lack of early diagnosis and treatment. Therefore, it is of great interest to develop a chemical tool that can visualize ovarian cancer cells in real-time and eliminate them. Unfortunately, probes that can simultaneously monitor both modes of action for the diagnosis and treatment of ovarian cancer have not been developed. Here, we designed a novel prodrug fluorescent probe (YW-OAc) that not only visually tracks cancer cells but also enables the on-demand delivery of chemotherapeutic agents. By ß-Gal-mediated glycosidic bond hydrolysis, the fluorescent signal changed from blue to green (signal 1), enabling visual tracking of ovarian cancer cells. Subsequently, the identified cancer cells were subjected to precise light irradiation to induce anticancer drug release accompanied by a fluorescence transition from green to blue (signal 2), enabling real-time information on drug release. Thus, the prodrug fluorescent probe YW-OAc provides comprehensive two-step monitoring during cancer cell recognition and clearance. Notably, YW-OAc exhibited high affinity (Km = 3.74 µM), high selectivity, and low detection limit for ß-Gal (0.0035 U/mL). We also demonstrated that YW-OAc can visually trace endogenous ß-Gal in different cells and exhibit high phototoxicity in ovarian cancer cells. We hope that the prodrug fluorescent probe YW-OAc, can be used as an effective tool for biomedical diagnosis and treatment.

Activation of Sphingomyelin Phosphodiesterase 3 in Liver Regeneration Impedes the Progression of Colorectal Cancer Liver Metastasis Via Exosome-Bound Intercellular Transfer of Ceramides.

BACKGROUND & AIMS: The machinery that prevents colorectal cancer liver metastasis (CRLM) in the context of liver regeneration (LR) remains elusive. Ceramide (CER) is a potent anti-cancer lipid involved in intercellular interaction. Here, we investigated the role of CER metabolism in mediating the interaction between hepatocytes and metastatic colorectal cancer (CRC) cells to regulate CRLM in the context of LR. METHODS: Mice were intrasplenically injected with CRC cells. LR was induced by 2/3 partial hepatectomy (PH) to mimic the CRLM in the context of LR. The alteration of corresponding CER-metabolizing genes was examined. The biological roles of CER metabolism in vitro and in vivo were examined by performing a series of functional experiments. RESULTS: Induction of LR augmented apoptosis but promoted matrix metalloproteinase 2 (MMP2) expression and epithelial-mesenchymal transition (EMT) to increase the invasiveness of metastatic CRC cells, resulting in aggressive CRLM. Up-regulation of sphingomyelin phosphodiesterase 3 (SMPD3) was determined in the regenerating hepatocytes after LR induction and persisted in the CRLM-adjacent hepatocytes after CRLM formation. Hepatic Smpd3 knockdown was found to further promote CRLM in the context of LR by abolishing mitochondrial apoptosis and augmenting the invasiveness in metastatic CRC cells by up-regulating MMP2 and EMT through promoting the nuclear translocation of ß-catenin. Mechanistically, we found that hepatic SMPD3 controlled the generation of exosomal CER in the regenerating hepatocytes and the CRLM-adjacent hepatocytes. The SMPD3-produced exosomal CER critically conducted the intercellular transfer of CER from the hepatocytes to metastatic CRC cells and impeded CRLM by inducing mitochondrial apoptosis and restricting the invasiveness in metastatic CRC cells. The administration of nanoliposomal CER was found to suppress CRLM in the context of LR substantially. CONCLUSIONS: SMPD3-produced exosomal CER constitutes a critical anti-CRLM mechanism in LR to impede CRLM, offering the promise of using CER as a therapeutic agent to prevent the recurrence of CRLM after PH.

Insulin-like peptide 5 is associated with insulin resistance in women with polycystic ovary syndrome.

AIMS: Insulin-like peptide 5 (INSL5) plays an important part in metabolic processes in vitro and in vivo. We hypothesized that INSL5 levels are associated with the presence of polycystic ovary syndrome (PCOS) and insulin resistance (IR). METHODS: Circulating INSL5 levels were measured by an enzyme-linked immunosorbent assay in the PCOS group (n = 101) and control (n = 78) groups. The relationship between INSL5 and IR was evaluated by using regression models. RESULTS: The levels of circulating INSL5 were elevated in the individuals with PCOS (P < 0.001) and significantly associated with homeostasis model assessment of insulin resistance (HOMA-IR, r = 0.434, P < 0.001; HOMA-IS, r = 0.432, P < 0.001; QUICKI, r = -0.504, P < 0.001). The subjects in the highest tertile of INSL5 levels were more likely to have PCOS (odds ratio: 12.591, 95 % confidence interval 2.616-60.605) as compared with the lowest tertile after adjustment for potential confounders. Furthermore, the multiple linear regression analyses after adjustment for confounders showed an independent association between INSL5 levels and HOMA-IR (ß = 0.024, P < 0.001). CONCLUSIONS: Circulating INSL5 concentration is linked to PCOS, possibly through increased insulin resistance.