Repetitive Transcranial Magnetic Stimulation Reversing Abnormal Brain Function in Mood Disorders with Early Life Stress: from preclinical models to clinical applications.

BACKGROUND: Early life stress (ELS) significantly increases the risk of mood disorders and affects the neurodevelopment of the primary cortex. HYPOTHESIS: Modulating the primary cortex through neural intervention can ameliorate the impact of ELS on brain development and consequently alleviate its effects on mood disorders. METHOD: We induced the chronic unpredictable mild stress (CUMS) model in adolescent rats, followed by applying repetitive transcranial magnetic stimulation (rTMS) to their primary cortex in early adulthood. To assess the applicability of primary cortex rTMS in humans, we recruited individuals aged 17-25 with mood disorders who had experienced ELS and performed primary cortex rTMS on them. Functional magnetic resonance imaging (fMRI) and depression-related behavioral and clinical symptoms were conducted in both rats and human subjects before and after the rTMS. RESULTS: In animals, fMRI analysis revealed increased activation in the primary cortex of CUMS rats and decrease subcortical activation. Following the intervention of primary cortex rTMS, the abnormal functional activity was reversed. Similarly, in mood disorders patients with ELS, increased activation in the primary cortex and decreased activation in the frontal cortex were observed. During rTMS intervention, similar neuroimaging improvements were noted, particularly decreased activation in the primary cortex. This suggests that targeted rTMS in the primary cortex can reverse the abnormal neuroimaging. CONCLUSION: This cross-species translational study has identified the primary cortex as a key region in mood disorders patients with ELS. Targeting the primary cortex with rTMS can correct abnormal functional activity while improving symptoms. Our study provides translational evidence for therapeutics targeting the ELS factor of mood disorders patients.

TRPV3-activated PARP1/AIFM1/MIF axis through oxidative stress contributes to atopic dermatitis.

TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3+/G568V mice, both of which carry gain-of-function mutations in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. Herein, we showed that gain-of-function mutation or pharmacological activation of TRPV3 resulted in PARP1/AIFM1/MIF axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging reactive oxygen species or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3+/G568V mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis (AD), while inhibiting PARP1 largely alleviated the MC903-induced dermatitis. Additionally, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of AD. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/MIF axis is a critical contributor to the pathogenesis of Olmsted syndrome and AD, suggesting that modulating the PARP1/AIFM1/MIF axis is a promising therapy for these conditions.

Operando Spectroscopic Elucidation of the Bubble Sunshade Effect in Inorganic-Biological Hybrids for Photosynthetic Hydrogen Production.

Hydrogen production by photosynthetic hybrid systems (PBSs) offers a promising avenue for renewable energy. However, the light-harvesting efficiency of PBSs remains constrained due to unclear intracellular kinetic factors. Here, we present an operando elucidation of the sluggish light-harvesting behavior for existing PBSs and strategies to circumvent them. By quantifying the spectral shift in the structural color scattering of individual PBSs during the photosynthetic process, we observe the accumulation of product hydrogen bubbles on their outer membrane. These bubbles act as a sunshade and inhibit light absorption. This phenomenon elucidates the intrinsic constraints on the light-harvesting efficiency of PBSs. The introduction of a tension eliminator into the PBSs effectively improves the bubble sunshade effect and results in a 4.5-fold increase in the light-harvesting efficiency. This work provides valuable insights into the dynamics of transmembrane transport gas products and holds the potential to inspire innovative designs for improving the light-harvesting efficiency of PBSs.

Pancreatic mucinous adenocarcinoma has different clinical characteristics and better prognosis compared to non-specific PDAC: A retrospective observational study.

Background: Pancreatic mucinous adenocarcinoma (PMAC) is a rare malignant tumour, and there is limited understanding of its epidemiology and prognosis. Initially, PMAC was considered a metastatic manifestation of other cancers; however, instances of non-metastatic PMAC have been documented through monitoring, epidemiological studies, and data from the Surveillance, Epidemiology, and End Results (SEER) database. Therefore, it is crucial to investigate the epidemiological characteristics of PMAC and discern the prognostic differences between PMAC and the more prevalent pancreatic ductal adenocarcinoma (PDAC). Methods: The study used data from the SEER database from 2000 to 2018 to identify patients diagnosed with PMAC or PDAC. To ensure comparable demographic characteristics between PDAC and PMAC, propensity score matching was employed. Kaplan-Meier analysis was used to analyse overall survival (OS) and cancer-specific survival (CSS). Univariate and multivariate Cox regression analyses were used to determine independent risk factors influencing OS and CSS. Additionally, the construction and validation of risk-scoring models for OS and CSS were achieved through the least absolute shrinkage and selection operator-Cox regression technique. Results: The SEER database included 84,857 patients with PDAC and 3345 patients with PMAC. Notably, significant distinctions were observed in the distribution of tumour sites, diagnosis time, use of radiotherapy and chemotherapy, tumour size, grading, and staging between the two groups. The prognosis exhibited notable improvement among married individuals, those receiving acceptable chemotherapy, and those with focal PMAC (p < 0.05). Conversely, patients with elevated log odds of positive lymph node scores or higher pathological grades in the pancreatic tail exhibited a more unfavourable prognosis (p < 0.05). The risk-scoring models for OS or CSS based on prognostic factors indicated a significantly lower prognosis for high-risk patients compared to their low-risk counterparts (area under the curve OS: 0.81-0.82, CSS: 0.80-0.82). Conclusion: PMAC exhibits distinct clinical characteristics compared to non-specific PDAC. Leveraging these features and pathological classifications allows for accurate prognostication of PMAC or PDAC.

Chromosome-scale reference genome of broccoli (Brassica oleracea var. italica Plenck) provides insights into glucosinolate biosynthesis.

Broccoli (Brassica oleracea var. italica Plenck) is an important vegetable crop, as it is rich in health-beneficial glucosinolates (GSLs). However, the genetic basis of the GSL diversity in Brassicaceae remains unclear. Here we report a chromosome-level genome assembly of broccoli generated using PacBio HiFi reads and Hi-C technology. The final genome assembly is 613.79 Mb in size, with a contig N50 of 14.70 Mb. The GSL profile and content analysis of different B. oleracea varieties, combined with a phylogenetic tree analysis, sequence alignment, and the construction of a 3D model of the methylthioalkylmalate synthase 1 (MAM1) protein, revealed that the gene copy number and amino acid sequence variation both contributed to the diversity of GSL biosynthesis in B. oleracea. The overexpression of BoMAM1 (BolI0108790) in broccoli resulted in high accumulation and a high ratio of C4-GSLs, demonstrating that BoMAM1 is the key enzyme in C4-GSL biosynthesis. These results provide valuable insights for future genetic studies and nutritive component applications of Brassica crops.

Anti-inflammatory and uric acid lowering effects of Euodiae fructus on hyperuricemia and gout mice.

The metabolic disease hyperuricemia (HUA) is caused by presence of excessive serum uric acid (UA), which leads to an increased risk of chronic kidney disease and gout. As a widely used traditional Chinese medicine, Euodiae fructus (ER) has strong anti-inflammatory and analgesic effects, however, its therapeutic effects on HUA and gout have not been investigated. To investigate the potential effects and underlying mechanisms, the effect of ER on proinflammatory cytokines and NLRP3 inflammasome activation was studied in mouse bone marrow macrophages. Moreover, a mouse model of HUA and gouty arthritis was established by coadministration of potassium oxonate (PO) and monosodium urate crystals to mice fed a high-fat diet (HFD) for 37 consecutive days. Oral administration of ER aqueous extract was given 1 hour later after the injection of PO for 10 days. Our study showed that ER is a powerful NLRP3 inhibitor in mouse macrophages. Most importantly, ER (0.75 g/kg) treatment substantially decreased the ankle joint thickness ratio, serum UA, creatinine and blood urea nitrogen levels (p < 0.05). Additionally, ER (0.75 g/kg) dramatically reversed the increases in renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) as well as the decreases in organic anion transporter 1 (OAT1) and ATP binding cassette subfamily G member 2 (ABCG2) levels (p < 0.05). Moreover, ER (0.75 g/kg) markedly ameliorated the production of the serum inflammatory cytokines IL-1ß and TNF-α (p < 0.01), and improved the activation of NLRP3 inflammasome signaling in the kidneys. Taken together, these data indicate that ER, a powerful and specific NLRP3 inhibitor, has multiple anti-HUA, anti-gout and anti-inflammatory effects. Our investigation is designed to experimentally support the conventional use of ER-containing classical herbal formulas in the treatment of HUA-related disorders and may add a new dimension to the clinical application of ER.

Photoactivated disinfection procedure for denture stomatitis in diabetic rats.

Objective: To study the efficacy of PADTM Plus-based photoactivated disinfection (PAD) for treating denture stomatitis (DS) in diabetic rats by establishing a diabetic rat DS model. Methods: The diabetic rat DS model was developed by randomly selecting 2-month-old male Sprague-Dawley rats and dividing them into four groups. The palate and denture surfaces of rats in the PAD groups were incubated with 1 mg/mL toluidine blue O for 1 min each, followed by a 1-min exposure to 750-mW light-emitting diode light. The PAD-1 group received one radiation treatment, and the PAD-2 group received three radiation treatments over 5 days with a 1-day interval. The nystatin (NYS) group received treatment for 5 days with a suspension of NYS of 100,000 IU. The infection group did not receive any treatment. In each group, assessments included an inflammation score of the palate, tests for fungal load, histological evaluation, and immunohistochemical detection of interleukin-17 (IL-17) and tumor necrosis factor (TNF-α) conducted 1 and 7 days following the conclusion of treatment. Results: One day after treatment, the fungal load on the palate and dentures, as well as the mean optical density values of IL-17 and TNF-α, were found to be greater in the infection group than in the other three treatment groups (P < 0.05). On the 7th day after treatment, these values were significantly higher in the infection group than in the PAD-2 and NYS groups (P < 0.05). Importantly, there were no differences between the infection and PAD-1 groups nor between the PAD-2 and NYS groups (P > 0.05). Conclusions: PAD effectively reduced the fungal load and the expressions of IL-17 and TNF-α in the palate and denture of diabetic DS rats. The efficacy of multiple-light treatments was superior to that of single-light treatments and similar to that of NYS.

Revealing the Sources of Cadmium in Rice Plants under Pot and Field Conditions from Its Isotopic Fractionation.

The highly excessive uptake of cadmium (Cd) by rice plants is well known, but the transfer pathway and mechanism of Cd in the paddy system remain poorly understood. Herein, pot experiments and field investigation were systematically carried out for the first time to assess the phytoavailability of Cd and fingerprint its transfer pathway in the paddy system under different treatments (slaked lime and biochar amendments), with the aid of a pioneering Cd isotopic technique. Results unveiled that no obvious differences were displayed in the δ114/110Cd of Ca(NO3)2-extractable and acid-soluble fractions among different treatments in pot experiments, while the δ114/110Cd of the water-soluble fraction varied considerably from -0.88 to -0.27%, similar to those observed in whole rice plant [Δ114/110Cdplant-water ≈ 0 (-0.06 to -0.03%)]. It indicates that the water-soluble fraction is likely the main source of phytoavailable Cd, which further contributes to its bioaccumulation in paddy systems. However, Δ114/110Cdplant-water found in field conditions (-0.39 ± 0.05%) was quite different from those observed in pot experiments, mostly owing to additional contribution derived from atmospheric deposition. All these findings demonstrate that the precise Cd isotopic compositions can provide robust and reliable evidence to reveal different transfer pathways of Cd and its phytoavailability in paddy systems.

Application of metagenomic next-generation sequencing in optimizing the diagnosis of ascitic infection in patients with liver cirrhosis.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) is an emerging technique for the clinical diagnosis of infectious disease that has rarely been used for the diagnosis of ascites infection in patients with cirrhosis. This study compared mNGS detection with conventional culture methods for the on etiological diagnosis of cirrhotic ascites and evaluated the clinical effect of mNGS. METHODS: A total of 109 patients with ascites due to cirrhosis were included in the study. We compared mNGS with conventional culture detection by analyzing the diagnostic results, pathogen species and clinical effects. The influence of mNGS on the diagnosis and management of ascites infection in patients with cirrhosis was also evaluated. RESULTS: Ascites cases were classified into three types: spontaneous bacterial peritonitis (SBP) (16/109, 14.7%), bacterascites (21/109, 19.3%) and sterile ascites (72/109, 66.1%). In addition, 109 patients were assigned to the ascites mNGS-positive group (80/109, 73.4%) or ascites mNGS-negative group (29/109, 26.6%). The percentage of positive mNGS results was significantly greater than that of traditional methods (73.4% vs. 28.4%, P < 0.001). mNGS detected 43 strains of bacteria, 9 strains of fungi and 8 strains of viruses. Fourteen bacterial strains and 3 fungal strains were detected via culture methods. Mycobacteria, viruses, and pneumocystis were detected only by the mNGS method. The mNGS assay produced a greater polymicrobial infection rate than the culture method (55% vs. 16%). Considering the polymorphonuclear neutrophil (PMN) counts, the overall percentage of pathogens detected by the two methods was comparable, with 87.5% (14/16) in the PMN ≥ 250/mm3 group and 72.0% (67/93) in the PMN < 250/mm3 group (P > 0.05). Based on the ascites PMN counts combined with the mNGS assay, 72 patients (66.1%) were diagnosed with ascitic fluid infection (AFI) (including SBP and bacterascites), whereas based on the ascites PMN counts combined with the culture assay, 37 patients (33.9%) were diagnosed with AFI (P < 0.05). In 60 (55.0%) patients, the mNGS assay produced positive clinical effects; 40 (85.7%) patients had their treatment regimen adjusted, and 48 patients were improved. The coincidence rate of the mNGS results and clinical findings was 75.0% (60/80). CONCLUSIONS: Compared with conventional culture methods, mNGS can improve the detection rate of ascites pathogens, including bacteria, viruses, and fungi, and has significant advantages in the diagnosis of rare pathogens and pathogens that are difficult to culture; moreover, mNGS may be an effective method for improving the diagnosis of ascites infection in patients with cirrhosis, guiding early antibiotic therapy, and for reducing complications related to abdominal infection. In addition, explaining mNGS results will be challenging, especially for guiding the treatment of infectious diseases.

CD4+CD57+ senescent T cells as promoters of systemic lupus erythematosus pathogenesis and the therapeutic potential of senolytic BCL-2 inhibitor.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by persistent activation of immune cells and overproduction of autoantibodies. The accumulation of senescent T and B cells has been observed in SLE and other immune-mediated diseases. However, the exact mechanistic pathways contributing to this process in SLE remain incompletely understood. In this study, we found that in SLE patients: (1) the frequency of CD4+CD57+ senescent T cells was significantly elevated and positively correlated with disease activity; (2) the expression levels of B-lymphoma-2 (BCL-2) family and interferon-induced genes (ISGs) were significantly upregulated; and (3) in vitro, the cytokine IL-15 stimulation increased the frequency of senescent CD4+ T cells and upregulated the expression of BCL-2 family and ISGs. Further, treatment with ABT-263 (a senolytic BCL-2 inhibitor) in MRL/lpr mice resulted in decreased: (1) frequency of CD4+CD44hiCD62L-PD-1+CD153+ senescent CD4+ T cells; (2) frequency of CD19+CD11c+T-bet+ age-related B cells; (3) level of serum antinuclear antibody; (4) proteinuria; (5) frequency of Tfh cells; and (6) renal histopathological abnormalities. Collectively, these results indicated a dominant role for CD4+CD57+ senescent CD4+ T cells in the pathogenesis of SLE and senolytic BCL-2 inhibitor ABT-263 may be the potential treatment in ameliorating lupus phenotypes.

Genome-wide analysis of UDP-glycosyltransferases family and identification of UGT genes involved in drought stress of Platycodon grandiflorus.

Introduction: The uridine diphosphate (UDP)-glycosyltransferase (UGT) family is the largest glycosyltransferase family, which is involved in the biosynthesis of natural plant products and response to abiotic stress. UGT has been studied in many medicinal plants, but there are few reports on Platycodon grandiflorus. This study is devoted to genome-wide analysis of UGT family and identification of UGT genes involved in drought stress of Platycodon grandiflorus (PgUGTs). Methods: The genome data of Platycodon grandiflorus was used for genome-wide identification of PgUGTs, online website and bioinformatics analysis software was used to conduct bioinformatics analysis of PgUGT genes and the genes highly responsive to drought stress were screened out by qRT-PCR, these genes were cloned and conducted bioinformatics analysis. Results: A total of 75 PgUGT genes were identified in P.grandiflorus genome and clustered into 14 subgroups. The PgUGTs were distributed on nine chromosomes, containing multiple cis-acting elements and 22 pairs of duplicate genes were identified. Protein-protein interaction analysis was performed to predict the interaction between PgUGT proteins. Additionally, six genes were upregulated after 3d under drought stress and three genes (PGrchr09G0563, PGrchr06G0523, PGrchr06G1266) responded significantly to drought stress, as confirmed by qRT-PCR. This was especially true for PGrchr06G1266, the expression of which increased 16.21-fold after 3d of treatment. We cloned and conducted bioinformatics analysis of three candidate genes, both of which contained conserved motifs and several cis-acting elements related to stress response, PGrchr06G1266 contained the most elements. Discussion: PgGT1 was confirmed to catalyze the C-3 position of platycodin D and only eight amino acids showed differences between gene PGr008G1527 and PgGT1, which means PGr008G1527 may be able to catalyze the C-3 position of platycodin D in the same manner as PgGT1. Seven genes were highly expressed in the roots, stems, and leaves, these genes may play important roles in the development of the roots, stems, and leaves of P. grandiflorus. Three genes were highly responsive to drought stress, among which the expression of PGrchr06G1266 was increased 16.21-fold after 3d of drought stress treatment, indicating that PGrchr06G1266 plays an important role in drought stress tolerance. To summarize, this study laied the foundation to better understand the molecular bases of responses to drought stress and the biosynthesis of platycodin.

Combination of Creatinine with Inflammatory Biomarkers (PCT, CRP, hsCRP) for Predicting Postoperative ICU Admissions for Elderly Patients.

INTRODUCTION: The number of elderly patients who require surgery as their primary treatment has increased rapidly in recent years. Among 300 million people globally who underwent surgery every year, patients aged 65 years and over accounted for more than 30% of cases. Despite medical advances, older patients remain at higher risk of postoperative complications. Early diagnosis and effective prediction are essential requirements for preventing serious postoperative complications. In this study, we aim to provide new biomarker combinations to predict the incidence of postoperative intensive care unit (ICU) admissions > 24 h in elderly patients. METHODS: This investigation was conducted as a nested case-control study, incorporating 413 participants aged ≥ 65 years who underwent non-cardiac, non-urological elective surgeries. These individuals underwent a 30-day postoperative follow-up. Before surgery, peripheral venous blood was collected for analyzing serum creatinine (Scr), procalcitonin (PCT), C-reactive protein (CRP), and high-sensitivity CRP (hsCRP). The efficacy of these biomarkers in predicting postoperative complications was evaluated using receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) values. RESULTS: Postoperatively, 10 patients (2.42%) required ICU admission. Regarding ICU admissions, the AUCs with 95% confidence intervals (CIs) for the biomarker combinations of Scr × PCT and Scr × CRP were 0.750 (0.655-0.845, P = 0.007) and 0.724 (0.567-0.882, P = 0.015), respectively. Furthermore, cardiovascular events were observed in 14 patients (3.39%). The AUC with a 95% CI for the combination of Scr × CRP in predicting cardiovascular events was 0.688 (0.560-0.817, P = 0.017). CONCLUSION: The innovative combinations of biomarkers (Scr × PCT and Scr × CRP) demonstrated efficacy as predictors for postoperative ICU admissions in elderly patients. Additionally, the Scr × CRP also had a moderate predictive value for postoperative cardiovascular events. TRIAL REGISTRATION: China Clinical Trial Registry, ChiCTR1900026223.

Endovascular Therapy and Outcomes Among Patients With Very Large Ischemic Core Stroke.

Importance: The association of endovascular therapy (EVT) with outcomes is unclear for patients with very low Alberta Stroke Program Early Computed Tomography Score (ASPECTS) within 24 hours of stroke onset. Objective: To explore the association of EVT with functional and safety outcomes among patients with ASPECTS of 0 to 2 scored with noncontrast computed tomography. Design, Setting, and Participants: This cohort study used data from an ongoing, prospective, observational, nationwide registry including all patients treated at 38 stroke centers in China with an occlusion in the internal carotid artery or M1 or M2 segment of the middle cerebral artery within 24 hours of witnessed symptom onset. Patients with ASPECTS of 0 to 2 between November 1, 2021, and February 8, 2023, were included in analysis. Data were analyzed October to November 2023. Exposures: EVT vs standard medical treatment (SMT). Main Outcomes and Measures: The primary outcome was favorable functional outcome, defined as modified Rankin Scale score (mRS) of 0 to 3, at 90 days. Safety outcomes included symptomatic intracerebral hemorrhage (sICH) within 48 hours and mortality at 90 days. Results: A total of 245 patients (median [IQR] age, 71 [63-78] years; 118 [48%] women) with ASPECTS of 0 to 2 were included, of whom 111 patients (45.1%) received SMT and 135 patients (54.9%) received EVT. The EVT group had significantly greater odds of favorable functional outcome at 90 days than the SMT group (30 patients [22.2%] vs 11 patients [9.9%]; P = .01; adjusted odds ratio [aOR], 3.07 [95% CI, 1.29-7.31]; P = .01). Patients in the EVT group, compared with the SMT group, had significantly greater odds of any ICH (56 patients [41.5%] vs 16 patients [11.4%]; P < .001; aOR, 4.27 [95% CI, 2.19-8.35]; P < .001) and sICH (24 patients [17.8%] vs 1 patient [0.9%]; P < .001; aOR, 23.07 [95% CI, 2.99-177.79]; P = .003) within 48 hours. There were no differences between groups for 90-day mortality (80 patients [59.3%] vs 59 patients [53.2%]; P = .34; aOR, 1.38 [95% CI, 0.77-2.47]; P = .28). The results remained robust in the propensity score-matched analysis. Conclusions and Relevance: In this cohort study of patients with very low ASPECTS based on NCCT within 24 hours of stroke onset, those treated with EVT had higher odds of a favorable functional outcome compared with those who received SMT. Randomized clinical trials are needed to assess these findings.

6PPD-quinone affects the photosynthetic carbon fixation in cyanobacteria by extracting photosynthetic electrons.

Photosynthetic carbon fixation by cyanobacteria plays a pivotal role in the global carbon cycle but is threatened by environmental pollutants. To date, the impact of quinones, with electron shuttling properties, on cyanobacterial photosynthesis is unknown. Here, we present the first study investigating the effects of an emerging quinone pollutant, i.e., 6PPD-Q (N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone), on the cyanobacterium Synechocystis sp. over a 400-generation exposure period. Synechocystis sp. exhibited distinct sequential phases, including hormesis, toxicity, and eventual recovery, throughout this exposure. Extensive evidence, including results of thylakoid membrane morphological and photosynthetic responses, carbon fixation rate, and key gene/protein analyses, strongly indicates that 6PPD-Q is a potent disruptor of photosynthesis. 6PPD-Q accepts photosynthetic electrons at the plastoquinone QB site in photosystem II (PSII) and the phylloquinone A1 site in PSI, leading to a sustained decrease in the carbon fixation of cyanobacteria after an ephemeral increase. This work revealed the specific mechanism by which 6PPD-Q interferes with photosynthetic carbon fixation in cyanobacteria, which is highly important for the global carbon cycle.

A novel multilevel iterative training strategy for the ResNet50 based mitotic cell classifier.

The number of mitotic cells is an important indicator of grading invasive breast cancer. It is very challenging for pathologists to identify and count mitotic cells in pathological sections with naked eyes under the microscope. Therefore, many computational models for the automatic identification of mitotic cells based on machine learning, especially deep learning, have been proposed. However, converging to the local optimal solution is one of the main problems in model training. In this paper, we proposed a novel multilevel iterative training strategy to address the problem. To evaluate the proposed training strategy, we constructed the mitotic cell classification model with ResNet50 and trained the model with different training strategies. The results showed that the models trained with the proposed training strategy performed better than those trained with the conventional strategy in the independent test set, illustrating the effectiveness of the new training strategy. Furthermore, after training with our proposed strategy, the ResNet50 model with Adam optimizer has achieved 89.26% F1 score on the public MITOSI14 dataset, which is higher than that of the state-of-the-art methods reported in the literature.

Nanoplastics Detected in Commercial Sea Salt.

People of all ages consume salt every day, but is it really just salt? Plastic nanoparticles [nanoplastics (NPs)] pose an increasing environmental threat and have begun to contaminate everyday salt in consumer goods. Herein, we developed a combined surface enhanced Raman scattering (SERS) and stimulated Raman scattering (SRS) approach that can realize the filtration, enrichment, and detection of NPs in commercial salt. The Au-loaded (50 nm) anodic alumina oxide substrate was used as the SERS substrate to explore the potential types of NP contaminants in salts. SRS was used to conduct imaging and quantify the presence of the NPs. SRS detection was successfully established through standard plastics, and NPs were identified through the match of the hydrocarbon group of the nanoparticles. Simultaneously, the NPs were quantified based on the high spatial resolution and rapid imaging of the SRS imaging platform. NPs in sea salts produced in Asia, Australasia, Europe, and the Atlantic were studied. We estimate that, depending on the location, an average person could be ingesting as many as 6 million NPs per year through the consumption of sea salt alone. The potential health hazards associated with NP ingestion should not be underestimated.

Targeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors.

BRAFV600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRAFV600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRAFV600E-driven thyroid cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4720. Mechanistically, the blockade of ERK-dependent feedback by BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.

Clinical value of serum polyunsaturated fatty acids in patients with gastric polyps.

Polyunsaturated fatty acids (PUFAs) are vital nutrients in human physiology and are implicated in various chronic diseases. However, the relationship between PUFAs and gastric polyps remains unclear. This study employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess PUFA levels in the serum of 350 patients, along with analyzing the ω-6 to ω-3 ratio. The results revealed significant differences in the levels of C16:1, C18:1, C18:2, α-C18:3, γ-C18:3, C20:1, C20:4, C20:5, ω-3-C22:5, ω-6-C22:5, and C22:6, as well as ω-6 to ω-3 ratio between the control and gasteic polyp groups. Moreover, setting the threshold for ω-6: ω-3 at 10 revealed a close correlation between polyp occurrence and this ratio. These findings suggest that PUFAs and the ω-6 to ω-3 ratio hold promise as potential early screening markers for gastric polyps. However, further research is imperative to elucidate the underlying mechanisms and therapeutic potential of PUFAs in managing gastric polyps.

The role of the cGAS-STING signaling pathway in viral infections, inflammatory and autoimmune diseases.

Pattern recognition receptors are an essential part of the immune system, which detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and help shape both innate and adaptive immune responses. When dsDNA is present, cyclic GMP-AMP Synthase (cGAS) produces a second messenger called cyclic GMP-AMP (cGAMP), which then triggers an adaptor protein called STING, and eventually activates the expression of type I interferon (IFN) and pro-inflammatory cytokines in immune cells. The cGAS-STING signaling pathway has been receiving a lot of attention lately as a key immune-surveillance mediator. In this review, we summarize the present circumstances of the cGAS-STING signaling pathway in viral infections and inflammatory diseases, as well as autoimmune diseases. Modulation of the cGAS-STING signaling pathway provides potential strategies for treating viral infections, inflammatory diseases, and autoimmune diseases.