s valence electrons in cations of metal oxides serving as descriptors for electron and hole polarons.

In some metal oxides, an excess electron can give rise to the formation of a small polaron localized on a single site. However, there are still some metal oxides that exhibit the formation of a large polaron. The underlying mechanism behind this phenomenon remains unclear. In this study, we investigate polaron formation in metal oxides favorable for polaron formation using different functionals and through a review of the literature. Our findings indicate that the s valence electrons in cations could serve as a descriptor to classify the polarons in materials. In metal oxides with cations having ns (n ⩾ 5) valence electrons, excess charges trend to localize on several sites or form a two-dimensional shape, and even a large polaron, as these s electrons are delocalized in nature and have a large effect on p or d state polarons. The delocalized nature of ns (n ⩽ 4) valence electrons in cations is relatively small and does not affect the localization condition of p or d state polarons. Therefore, the excess charges in these metal oxides with ns (n ⩽ 4) valence electrons prefer to form a small polaron localizing on a single site. This work unveils the impact of the s valence in cations on polaron formation and provides a fundamental understanding of various types of polarons in metal oxides.

Therapeutic targeting at genome mutations of liver cancer by the insertion of HSV1 thymidine kinase through Cas9-mediated editing.

BACKGROUND: Liver cancer is one of the most lethal malignancies for humans. The treatment options for advanced-stage liver cancer remain limited. A new treatment is urgently needed to reduce the mortality of the disease. METHODS: In this report, we developed a technology for mutation site insertion of a suicide gene (herpes simplex virus type 1- thymidine kinase) based on type II CRISPR RNA-guided endonuclease Cas9-mediated genome editing to treat liver cancers. RESULTS: We applied the strategy to 3 different mutations: S45P mutation of catenin beta 1, chromosome breakpoint of solute carrier family 45 member 2-alpha-methylacyl-CoA racemase gene fusion, and V235G mutation of SAFB-like transcription modulator. The results showed that the herpes simplex virus type 1-thymidine kinase insertion rate at the S45P mutation site of catenin beta 1 reached 77.8%, while the insertion rates at the breakpoint of solute carrier family 45 member 2 - alpha-methylacyl-CoA racemase gene fusion were 95.1%-98.7%, and the insertion at V235G of SAFB-like transcription modulator was 51.4%. When these targeting reagents were applied to treat mouse spontaneous liver cancer induced by catenin beta 1S45P or solute carrier family 45 member 2-alpha-methylacyl-CoA racemase, the mice experienced reduced tumor burden and increased survival rate. Similar results were also obtained for the xenografted liver cancer model: Significant reduction of tumor volume, reduction of metastasis rate, and improved survival were found in mice treated with the targeting reagent, in comparison with the control-treated groups. CONCLUSIONS: Our studies suggested that mutation targeting may hold promise as a versatile and effective approach to treating liver cancers.

Post-fertilization 2-ethylhexyl-4-methoxycinnamate (EHMC) exposure affects axonal growth, muscle fiber length, and motor behavior in zebrafish embryos.

Organic UV filters, which are often found in the environment, have been the focus of much public health concern. 2-ethylhexyl-4-methoxycinnamate (EHMC) is one of the most common organic UV filters present in the environment. However, few studies have investigated its developmental neurotoxic (DNT) effects and the underlying molecular mechanisms. In the present study, zebrafish embryos were exposed to low concentration of EHMC (0, 0.01, 0.1, 1 mg/L) in static water starting from 6 h post-fertilization (hpf). Results showed that EHMC exposure caused a reduction in somite count at 13 hpf, a diminishment in head-trunk angle at 30 hpf, a delay in hatching at 48 hpf, and a decrease in head depth and head length at both 30 and 48 hpf. Additionally, EHMC led to abnormal motor behaviors at various developmental stages including altered spontaneous movement at both 23 and 24 hpf, and decreased touch response at 30 hpf. Consistent with these morphological changes and motor behavior deficits, EHMC inhibited axonal growth of primary motor neurons at 30 and 48 hpf, and yielded subtle changes in muscle fiber length at 48 hpf, suggesting the functional relevance of structural changes. Moreover, EHMC exposure induced excessive cell apoptosis in the head and spinal cord regions, increased the production of reactive oxygen species (ROS) and malondialdehyde (MDA), and reduced the level of glutathione (GSH). Defects of lateral line system neuromasts were also observed, but no structural deformity of blood vessels was seen in developing zebrafish. Abnormal expression of axonal growth-related genes (gap43, mbp, shha, and α1-tubulin) and apoptosis-related genes (bax/bcl-2 and caspase-3) revealed potential molecular mechanisms regarding the defective motor behaviors and aberrant phenotype. In summary, our findings indicate that EHMC induced developmental neurotoxicity in zebrafish, making it essential to assess its risks and provide warnings regarding EHMC exposure.

Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.

Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic ß-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-ß1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

Chronic arsenite exposure induced skeletal muscle atrophy by disrupting angiotensin II-melatonin axis in rats.

Arsenic is a well-known environmental toxicant and emerging evidence suggests that arsenic exposure has potential skeletal muscle toxicity; however, the underlying mechanism has not yet been clarified. The aim of this study was to investigate the correlation among adverse effects of subchronic and chronic environmental arsenic exposure on skeletal muscle as well as specific myokines secretion and angiotensin II (AngII)-melatonin (MT) axis in rats. Four-week-old rats were exposed to arsenite (iAs) in drinking water at environmental relevant concentration of 10 ppm for 3 or 9 months. Results indicated that the gastrocnemius muscle had atrophied and its mass was decreased in rats exposed to arsenite for 9 months, whereas, they had no significant changes in rats exposed to arsenite for 3 months. The levels of serum-specific myokine irisin and gastrocnemius muscle insulin-like growth factor-1 (IGF-1) were increased in 3-month exposure group and decreased in 9-month exposure group, while serum myostatin (MSTN) was increased significantly in 9-month exposure group. In addition, serum AngII level increased both in 3- and 9-month exposure groups, while serum MT level increased in 3-month exposure group and decreased in 9-month exposure group. Importantly, the ratio of AngII to MT level in serum increased gradually with the prolongation of arsenite exposure. It showed a certain correlation between AngII-MT axis and gastrocnemius muscle mass, gastrocnemius muscle level of IGF-1 or serum levels of irisin and MSTN. In conclusion, the disruption of AngII-MT axis balance may be a significant factor for skeletal muscle atrophy induced by chronic environmental arsenic exposure.

Role of YES1 signaling in tumor therapy resistance.

YES proto-oncogene 1 (YES1) is an SRC family kinase (SFK) that plays a key role in cancer cell proliferation, adhesion, invasion, survival, and angiogenesis during tumorigenesis and tumor development. Reports suggest that YES1 amplification is associated with resistance to chemotherapeutic drugs and tyrosine kinase inhibitors (TKIs) in human malignancies. However, the mechanisms of drug resistance have not been fully elucidated. In this article, we review the literature on YES1 and discuss the implications of YES1 signaling for targeted therapy and chemotherapy resistance in malignancies. Moreover, recent advances in targeted therapy for YES1-amplified malignancies are summarized. Finally, we conclude that targeting YES1 may reverse drug resistance and serve as a valuable tumor treatment strategy.

Matrix in River Water, Sediments, and Biofilms Mitigates Mercury Toxicity to Medaka (Oryzias Latipes).

Impacts of an environmental matrix on mercury (Hg) bioavailability and toxicity to medaka (Oryzias latipes) were investigated in matrix-free controls and treatments with a stepwise increased environmental matrix of river water, sediments, and biofilms. Generally, river water enhanced but the presence of sediments and biofilms reduced Hg bioavailability to medaka up to 105 times, so that Hgtotal concentrations/amounts among different environmental media cannot mirror Hg availability and toxicity to medaka. On average, 12.9 and 12.4% of Hg in medaka was, respectively, methylated to methylmercury (MeHg) in matrix-free and -containing treatments, indicating no influence of the environmental matrix on Hg methylation in medaka. All oxidative stress, inflammatory injury, and malformation parameters correlated strongly and significantly with Hgtotal and MeHg concentrations in medaka, notably with steeper slopes in matrix-free controls than in matrix-containing treatments, highlighting that the environmental matrix mitigated Hg and MeHg toxicity to medaka. Moreover, oxidative stress was more strongly mitigated than inflammatory injury according to the stronger decreases of the regression line slopes from matrix-free to -containing treatments. Here, we have newly identified that the potential of the environmental matrix to decrease Hg bioavailability and mitigate Hg toxicity to fish together could buffer Hg ecotoxicity in the aquatic environment.

The stage-dependent prognostic role of ARID1A in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death. Although novel treatment currently achieves a better response, the majority of HCC patients develop resistance and cannot benefit. Hence, novel biomarkers for guiding therapy and predicting the prognosis are needed. Methods: Tissue microarrays of 206 HCC patients were used, and ARID1A expression was determined by immunohistochemistry. Databases were used for the verification and expansion of our results. The "rms" package of R software was used for the construction of the nomogram. Results: ARID family alterations were associated with disease-free survival (P=0.0325) and overall survival (OS) (P=0.0076). Subgroup analysis confirmed the prognostic effect of ARID1A, ARID1B, and ARID2 alterations. In addition, ARID family genomic alterations, especially ARID1A, were closely related to poor progression-free survival (ARID: P=0.0011; ARID1A: P=0.0082) and OS (ARID: P=0.0161; ARID1A: P=0.0220) after sorafenib treatment. ARID1A expression was found to display a stage-dependent effect on the prognosis, serving as a risk factor in stage I-II patients (P<0.0001) and a protective factor in stage III-IV patients (P=0.0180). Conclusions: ARID1A has dual roles in HCC in a tumor stage-dependent manner, and further study is required to uncover the complex function of ARID1A in HCC development, disease progression, and therapy.

Subchronic Arsenite Exposure Induced Atrophy and Erythropoietin Sensitivity Reduction in Skeletal Muscle Were Relevant to Declined Serum Melatonin Levels in Middle-Aged Rats.

Arsenic is a kind of widespread environmental toxicant with multiorgan-toxic effects, and arsenic exposure is associated with the occurrence and development of many chronic diseases. The influence of environmental arsenic exposure on skeletal muscle, which is a vital organ of energy and glucose metabolism, has received increasing attention. This study aimed to investigate the types of inorganic arsenic-induced skeletal muscle injury, and the potential regulatory effects of melatonin (MT) and erythropoietin (EPO) in young (3-month-old) and middle-aged (12-month-old) rats. Our results showed that 1 mg/L sodium arsenite exposure for 3 months could accelerate gastrocnemius muscle atrophy and promote the switch of type II fibers to type I fibers in middle-aged rats; however, it did not cause significant pathological changes of gastrocnemius muscle in young rats. In addition, arsenite could inhibit serum MT levels, and promote serum EPO levels but inhibit EPO receptor (EPOR) expression in gastrocnemius muscle in middle-aged rats, while serum MT levels and EPOR expression in gastrocnemius muscle showed an opposite effect in young rats. Importantly, exogenous MT antagonized the arsenite-induced skeletal muscle toxic effect and restored serum EPO and gastrocnemius muscle EPOR expression levels in middle-aged rats. There was a positive correlation among gastrocnemius muscle index, serum MT level, and gastrocnemius muscle EPOR protein level in arsenite-exposed rats. This study demonstrated that inorganic arsenic could accelerate skeletal muscle mass loss and type II fiber reduction in middle-aged rats, which may be related to decreased MT secretion and declined EPO sensitivity in skeletal muscle.

ARID1A deficiency associated with MMR deficiency and a high abundance of tumor-infiltrating lymphocytes predicts a good prognosis of endometrial carcinoma.

BACKGROUND: ARID1A alterations have been detected in 40% of endometrial carcinomas (ECs) and are associated with loss of its expression. The role of ARID1A in tumorigenesis and development is complex, and the prognostic role in EC remains controversial. Hence, it is of great significance to confirm the role of ARID1A in EC. METHODS: A total of 549 EC patients (cohort A) from TCGA were evaluated to explore the prognostic role of ARID1A. NGS was performed for 13 EC patients (cohort B), and expression of ARID1A, CD3, CD8 and mismatch repair (MMR) proteins in 52 patients (cohort C) from our center was determined by immunohistochemistry (IHC). The Kaplan-Meier method was used to perform survival analyses. RESULTS: ARID1A alterations were detected in 32% of EC patients and correlated with good disease-free survival (DFS, P = 0.004) and overall survival (OS, P = 0.0353). ARID1A alterations were found to co-occur with MMR-related gene mutations and correlated with higher PD-L1 expression. Patients concomitantly harboring ARID1A alterations and MMR-related gene mutations had the best prognosis (DFS: P = 0.0488; OS: P = 0.0024). A cohort from our center showed that ARID1A deficiency was an independent prognostic factor and predicted longer recurrence-free survival (P = 0.0476). ARID1A loss was associated with a tendency toward MSI-H (P = 0.0060). ARID1A alterations and expression loss were associated with a higher abundance of CD3+ (P = 0.0406) and CD8+ (P = 0.0387) T cells. CONCLUSION: ARID1A alterations and expression loss are tightly associated with MMR deficiency and a high abundance of tumor-infiltrating lymphocytes, which might contribute to the good prognosis of EC.

Subchronic Low-Dose Methylmercury Exposure Accelerated Cerebral Telomere Shortening in Relevant with Declined Urinary aMT6s Level in Rats.

Methylmercury (MeHg) is a global pollutant with established toxic effects on the central nervous system (CNS). However, early events and early-warning biomarkers of CNS damage following exposure to low-dose MeHg are still lacking. This study aimed to investigate whether subchronic low-dose MeHg exposure had adverse effects on the cerebral telomere length, as well as serum melatonin and its urinary metabolite 6-sulfatoxymelatonin (aMT6s) in rats. Sixteen male Sprague Dawley rats were divided into two groups. Group I was the control group. In group II, rats were exposed to MeHg by gavage at a dose of 0.1 mg/kg/day for 3 months. This study revealed that MeHg exposure resulted in impairment of learning and memory ability, a slightly reduced number of neurons and an irregular arrangement of neurons in the hippocampus. It also significantly accelerated telomere shortening in the cerebral cortex, hippocampus and hypothalamus. Moreover, MeHg exposure decreased the levels of melatonin in serum and aMT6s in urine, partly by suppressing the synthesis of 5-hydroxytryptamine (5-HT) in the brain but promoted the expression of melatonin-catalyzing AANAT and ASMT. Importantly, cerebral telomere length was positively correlated with MT and aMT6s after MeHg exposure. These results suggested that the shortened telomere length in the brain may be an early event in MeHg-induced CNS toxicity, and the level of aMT6s in urine may serve as an early-warning biomarker for MeHg-induced CNS damage.

Embryonic benzophenone-3 exposure inhibited fertility in later-life female zebrafish and altered developmental morphology in offspring embryos.

Benzophenone-3 (BP3), an organic UV filter widely used in personal care products, is ubiquitous in aquatic environments. Previous studies have shown that BP3 can interfere with oocytes development in the ovary. The current study was conducted to evaluate the effects of embryonic BP3 exposure on reproductive outcomes in later life. Zebrafish embryos were exposed to different concentrations of BP3 (0, 1, 10, 100 µg/L) for 5 days in the developmental stage and subsequently fed for 4 months without any toxins. The body length, body weight, and ovary weight in F0 female adult zebrafish and morphology indices in F1 offspring embryos were measured. The reproductive behaviors of adult zebrafish were recorded by a digital camera. HE staining was used to estimate the development of oocytes and the proportion of different phases was calculated. qPCR was used to detect the expression levels of reproduction-related genes of the hypothalamic-pituitary-gonadal (HPG) axis. Our findings revealed that the body length and body weight were not changed with embryonic BP3 exposure, but BP3 exposure inhibited the development and maturation of ovaries in later-life female zebrafish, accompanied by an increased proportion of follicles in the primary growth and early vitellogenic stages, and a decline in the full-growth stage in ovaries. Meanwhile, reduced egg production, delayed hatching rate, altered somite count and increased mortality rate were observed at 100 µg/L in offspring embryos. Behavioral results showed that BP3 exposure reduced the frequency of chasing, touching, entering the spawning area, and the duration of fish entering the spawning area later in life, qPCR analysis showed that the expression levels of reproduction-related genes of the HPG axis were downregulated in females, following a decreasing trend in plasma E2 and 11-KT levels. These results suggested that embryonic BP3 exposure negatively affected the fertility of fish and the development of their offspring embryos, which may cause potential risks to aquatic ecosystems and human health.

Environmentally relevant concentrations of organic (benzophenone-3) and inorganic (titanium dioxide nanoparticles) UV filters co-exposure induced neurodevelopmental toxicity in zebrafish.

UV filters, widely used in personal care products, are ubiquitous environmental pollutants detected and pose a significant public health concern. Benzophenone-3 (BP3) and titanium dioxide nanoparticles (nano-TiO2) are the predominant organic and inorganic UV filters in environmental media. However, few studies have explored the combined developmental neurotoxic (DNT) effects and the underlying mechanisms when co-exposed to BP3 and nano-TiO2. In the present study, zebrafish (Danio rerio) embryos were exposed to environmentally relevant concentrations of BP3 (10 µg/L), nano-TiO2 (100 µg/L), and mixtures starting from 6 h post fertilization (hpf), respectively. Developmental indicators and motor behaviors were investigated at various developmental stages. Our results showed that BP3 alone or co-exposed with nano-TiO2 increased spontaneous movement at 24 hpf, co-exposure decreased touch response at 30 hpf and hatching rate at 60 hpf. Consistent with these motor deficits, co-exposure to BP3 and nano-TiO2 inhibited relative axon length of primary motor neuron during the early developmental stages, disturbed the expression of axonal growth-related genes at 30 and 48 hpf, increased cell apoptosis on the head region and mRNA levels of apoptosis-related genes, and also increased reactive oxygen species (ROS) levels in zebrafish, suggesting the functional relevance of structural changes. Taken together, our findings demonstrated that BP3 alone or in combination with nano-TiO2 at environmentally relevant concentrations induced evident neurotoxic effects on the developing embryos in zebrafish.

Lifetime exposure to benzophenone-3 at an environmentally relevant concentration leads to female-biased social behavior and cognition deficits in zebrafish.

Benzophenone-3 (BP3) is an organic UV filter widely used in the commercial formulations of various personal care products. It has been detected ubiquitously in the environment and human tissues. Recently, BP3-induced neurotoxicity has been identified as the main health risk to humans and aquatic organisms. However, most research has been focused on embryonic development, and few studies explore chronic lifetime exposure. In the present study, we evaluated the neurotoxicity of lifetime exposure to an environmentally relevant concentration of BP3 in zebrafish. Our findings revealed that continuous BP3 exposure at 10 µg/L (0.04 µM) from 6 h post fertilization (hpf) to adulthood at 5 months led to female-biased social behavioral deficits and learning and memory impairment. These neurobehavioral effects were characterized by decreased prosocial activities in the social preference test and mirror biting assay, and reduced learning and memory in a T-maze test. Furthermore, these effects were accompanied by female-specific decreases in brain weight and brain dopamine concentration, female-biased decrease of neurogenesis in the telencephalon as well as female-specific increases in apoptotic cells and expression levels of genes and proteins related to the apoptosis pathway in the brain. Our results suggest that BP3-induced social behavior and learning/memory deficits are correlated to the cell loss in the telencephalon region of the zebrafish brain.

Inhibition of Heat Shock Factor 1 Signaling Decreases Hepatoblastoma Growth via Induction of Apoptosis.

Although rare compared with adult liver cancers, hepatoblastoma (HB) is the most common pediatric liver malignancy, and its incidence is increasing. Currently, the treatment includes surgical resection with or without chemotherapy, and in severe cases, liver transplantation in children. The effort to develop more targeted, HB-specific therapies has been stymied by the lack of fundamental knowledge about HB biology. Heat shock factor 1 (HSF1), a transcription factor, is a canonical inducer of heat shock proteins, which act as chaperone proteins to prevent or undo protein misfolding. Recent work has shown a role for HSF1 in cancer beyond the canonical heat shock response. The current study found increased HSF1 signaling in HB versus normal liver. It showed that less differentiated, more embryonic tumors had higher levels of HSF1 than more differentiated, more fetal-appearing tumors. Most strikingly, HSF1 expression levels correlated with mortality. This study used a mouse model of HB to test the effect of inhibiting HSF1 early in tumor development on cancer growth. HSF1 inhibition resulted in fewer and smaller tumors, suggesting HSF1 is needed for aggressive tumor growth. Moreover, HSF1 inhibition also increased apoptosis in tumor foci. These data suggest that HSF1 may be a viable pharmacologic target for HB treatment.

Optimal Treatments for NSCLC Patients Harboring Primary or Acquired MET Amplification.

Background: In non-small cell lung cancer (NSCLC) patients harboring MET mutations, MET-tyrosine kinase inhibitors (TKIs) have been proven to achieve a good response. However, the relative efficacy of different therapeutics in primary NSCLC patients with MET amplification and the treatment options for patients harboring acquired MET amplification after the failure of epidermal growth factor receptor (EGFR)-TKIs remain unclear. Methods: In total, 33 patients harboring primary MET amplification and 9 patients harboring acquired MET alterations identified by next-generation sequencing were enrolled. A retrospective analysis was conducted to compare the efficacy of different therapeutics. In addition, studies reporting various treatments for patients harboring MET alterations were included in the meta-analysis. Results: In our cohort of patients harboring primary MET amplification, crizotinib displayed better efficacy than immunotherapy and chemotherapy, as demonstrated both in first-line (P = .0378) and second-line treatment regimens (P = .0181). The disease control rates for crizotinib, immunotherapy, and chemotherapy were 81.8%, 72.7%, and 63.6%, respectively. In particular, the median progression-free survival (PFS) time after immunotherapy in patients harboring MET amplification and high programed death ligand 1 (PD-L1) expression (>50%) was only 77.5 days. The meta-analysis revealed that the median PFS times after crizotinib and immunotherapy were 4.57 and 2.94 months, respectively. In patients harboring acquired MET amplification, chemotherapy plus bevacizumab had superior efficacy (310.0 days vs 73.5 days, P = .0360) compared with MET-TKIs ± EGFR-TKIs. Conclusions: Immunotherapy showed a low response in patients harboring MET alterations, even those with concurrent high PD-L1 expression. MET-TKIs might be an optional treatment with worth-expecting efficacy. However, chemotherapy plus bevacizumab could benefit the subpopulation of patients harboring acquired MET amplification after the failure of EGFR-TKIs.

Developmental exposure to chlorpyrifos causes neuroinflammation via necroptosis in mouse hippocampus and human microglial cell line.

Neurodevelopmental exposure to chlorpyrifos (CPF) could increase risks for neurological disorders, such as autism spectrum disorder, cognitive impairment, or attention deficit hyperactivity disorder. The potential involvement of microglia reactive to inflammatory stimuli in these neurological disorders has been generally reported. However, the concrete effects and potential mechanisms of microglia dysfunction triggered by developmental CPF exposure remain unclear. Therefore, we established mouse and human embryonic microglial cells (HMC3 cell) models of developmental CPF exposure to evaluate the effects of developmental CPF exposure on neuroinflammation and underlying mechanisms. The results showed that developmental exposure to CPF enhanced the expression of Iba1 in hippocampus. CPF treatment increased inflammatory cytokines levels and TSPO expression in hippocampus and HMC3 cells. The levels of necroptosis and necroptosis-related signaling RIPK/MLKL were increased in hippocampus and HMC3 cells following CPF exposure. Furthermore, the expression of TLR4/TRIF signaling was increased in hippocampus and HMC3 cells subjected to CPF exposure. Notably, the increased levels of TLR4/TRIF signaling, RIPK/MLKL signaling, necroptosis and pro-inflammatory cytokines induced by CPF treatment were remarkably inhibited by TAK-242 (a specific TLR4 inhibitor). Additionally, the necroptosis and pro-inflammatory cytokines production induced by CPF treatment were significantly relieved by Nec-1 (a specific RIPK1 inhibitor). In general, the above results suggested that activated microglia in hippocampus subjected to developmental CPF exposure underwent RIPK1/MLKL-mediated necroptosis regulated by TLR4/TRIF signaling.

Polaron formation and transport in Bi2WO6 studied by DFT+U and hybrid PBE0 functional approaches.

Bi2WO6 (BWO) is considered as a promising material for photocatalytic water splitting. Its unique layered structure leads the charge separation, and transport is different from other materials. However, the charge transport mechanisms in BWO are not well understood. In this work, we investigated polaron formation and transport in BWO using the DFT+U and hybrid PBE0 functional approaches. We found that the electron will form 2-dimensional (2D)-shaped polarons among W sites in the ab plane of BWO with approximately 55% polaron density state on the central W site. This type of polaron is similar to the electron polarons in WO3. For other W-based materials, the electrons may also form a 2D-shaped polaron. We found that the W 6s orbital plays an important role in these 2D-shaped electron polarons. The calculated mobility of electron polarons in BWO was consistent with experimental findings. For the hole state, it could form a small hole polaron on the O site with O 2p in character. However, it will not form a polaron on the Bi site, which is quite different from BiVO4. This study provides insight for understanding polaron formation and transport in materials with W and Bi ions. It also provides understanding regarding charge separation and transport for materials with layered structures.

Next-generation sequencing identifies potential novel therapeutic targets in Chinese HGSOC patients.

BACKGROUND: Targeted therapy, especially the use of poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors (PARPis), has improved the outcome of patients with ovarian cancer. However, most high-grade serous ovarian cancer (HGSOC) patients have wild-type BRCA1/2, and it is necessary to disclose more potential novel targets for other available targeted drugs. So, detection of genetic alterations beyond BRCA1/2 is critical to screen HGSOC patients for personalized therapy. In this study, a broad, hybrid capture-based next-generation sequencing (NGS) assay was used to identify actionable genetic alterations from HGSOC cancer tissues. METHODS: Sixty-eight patients with HGSOC were enrolled, including 6 International Federation of Gynecology and Obstetrics (FIGO) stage I, 15 stage II, 37 stage III and 10 stage IV patients. All patients signed informed consent forms. Potentially actionable genetic alterations, including base substitutions, indels, copy number alterations, and gene fusions, were identified using targeted NGS. RESULTS: In our study, 14.7% (10/68) of the tumors harbored actionable genetic alterations in patients with BRCA1. A total of 25.0% (17/68) of patients without BRCA1 mutations harbored other actionable genetic alterations, such as homologous recombination repair (HRR) pathway-related genes (ATM, CDK12, FANCA, and FANCD2), PI3K/AKT/mTOR pathway genes (NF1, FBXW7, PIK3CA, PTEN, TSC1, and TSC2), and some other genes (ARID1A, FGFR1, KRAS, and NRAS). Furthermore, some patients harboring ARID1A or NF1 actionable genetic alterations showed good clinical efficacy to immune checkpoint inhibitors (ICIs) and everolimus, respectively. CONCLUSIONS: Our research indicates that 39.7% (27/68) of patients with HGSOC harbored at least one actionable genetic alteration. 25.0% (17/68) of patients had somatic mutations or copy number variations beyond BRCA1 mutations and might be treated with off-label therapy or to be allocated into clinical trial. NGS assays of HGSOC patients are necessary to screen actionable genetic alterations to guide personalized and precise treatment.