ZnO NPs induce miR-342-5p mediated ferroptosis of spermatocytes through the NF-κB pathway in mice.

BACKGROUND: Zinc oxide nanoparticle (ZnO NP) is one of the metal nanomaterials with extensive use in many fields such as feed additive and textile, which is an emerging threat to human health due to widely distributed in the environment. Thus, there is an urgent need to understand the toxic effects associated with ZnO NPs. Although previous studies have found accumulation of ZnO NPs in testis, the molecular mechanism of ZnO NPs dominated a decline in male fertility have not been elucidated. RESULTS: We reported that ZnO NPs exposure caused testicular dysfunction and identified spermatocytes as the primary damaged site induced by ZnO NPs. ZnO NPs led to the dysfunction of spermatocytes, including impaired cell proliferation and mitochondrial damage. In addition, we found that ZnO NPs induced ferroptosis of spermatocytes through the increase of intracellular chelatable iron content and lipid peroxidation level. Moreover, the transcriptome analysis of testis indicated that ZnO NPs weakened the expression of miR-342-5p, which can target Erc1 to block the NF-κB pathway. Eventually, ferroptosis of spermatocytes was ameliorated by suppressing the expression of Erc1. CONCLUSIONS: The present study reveals a novel mechanism in that miR-342-5p targeted Erc1 to activate NF-κB signaling pathway is required for ZnO NPs-induced ferroptosis, and provide potential targets for further research on the prevention and treatment of male reproductive disorders related to ZnO NPs.

Anisotropic Electron-Phonon Interactions in 2D Lead-Halide Perovskites.

Two-dimensional (2D) hybrid organic-inorganic metal halide perovskites offer enhanced stability for perovskite-based applications. Their crystal structure's soft and ionic nature gives rise to strong interaction between charge carriers and ionic rearrangements. Here, we investigate the interaction of photogenerated electrons and ionic polarizations in single-crystal 2D perovskite butylammonium lead iodide (BAPI), varying the inorganic lamellae thickness in the 2D single crystals. We determine the directionality of the transition dipole moments (TDMs) of the relevant phonon modes (in the 0.3-3 THz range) by the angle- and polarization-dependent THz transmission measurements. We find a clear anisotropy of the in-plane photoconductivity, with a ∼10% reduction along the axis parallel with the transition dipole moment of the most strongly coupled phonon. Detailed calculations, based on Feynman polaron theory, indicate that the anisotropy originates from directional electron-phonon interactions.

Therapeutic effect and mechanisms of traditional Chinese medicine compound (Qilong capsule) in the treatment of ischemic stroke.

Background Qilong capsule (QLC) is a well-known traditional Chinese medicine compound extensively used in clinical practice. It has been approved by the China's FDA for the treatment of ischemic stroke (IS). In our clinical trial involving QLC (ClinicalTrials.gov identifier: NCT03174535), we observed the potential of QLC to improve neurological function in IS patients at the 24th week, while ensuring their safety. However, the effectiveness of QLC beyond the initial 12-week period remains uncertain, and the precise mechanisms underlying its action in IS have not been fully elucidated. Purpose In order to further explore the clinical efficacy of QLC in treating IS beyond the initial 12-week period and systematically elucidate its underlying mechanisms. Study Design This study employed an interdisciplinary integration strategy that combines post hoc analysis of clinical trials, transcriptome sequencing, integrated bioinformatics analysis, and animal experiments. Methods In this study, we conducted a post-hoc analysis with 2302 participants to evaluate the effectiveness of QLC at the 12th week. The primary outcome was the proportion of patients achieving functional independence at the 12th week, defined as a score of 0-2 on the modified Rankin Scale (mRS), which ranges from 0 (no symptoms) to 6 (death). Subsequently, we employed RNA sequencing (RNA-Seq) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) techniques in the QLC trial to investigate the potential molecular mechanisms underlying the therapeutic effect of QLC in IS. Simultaneously, we utilized integrated bioinformatics analyses driven by external multi-source data and algorithms to further supplement the exploration and validation of QLC's therapeutic mechanism in treating IS. This encompassed network pharmacology analysis and analyses at the mRNA, cellular, and pathway levels focusing on core targets. Additionally, we developed a disease risk prediction model using machine learning. By identifying differentially expressed core genes (DECGs) between the normal and IS groups, we quantitatively predicted IS occurrence. Furthermore, to assess its protective effects and determine the key regulated pathway, we conducted experiments using a middle cerebral artery occlusion and reperfusion (MACO/R) rat model. Results Our findings demonstrated that the combination of QLC and conventional treatment (CT) significantly improved the proportion of patients achieving functional independence (mRS score 0-2) at the 12th week compared to CT alone (n = 2,302, 88.65 % vs 87.33 %, p = 0.3337; n = 600, 91.33 % vs 84.67 %, p = 0.0165). Transcriptome data revealed that the potential underlying mechanism of QLC for IS is related to the regulation of the NF-κB inflammatory pathway. The RT-qPCR results demonstrated that the regulatory trends of key genes, such as MD-2, were consistent with those observed in the RNA-Seq analysis. Integrated bioinformatics analysis elucidated that QLC regulates the NF-κB signaling pathway by identifying core targets, and machine learning was utilized to forecast the risk of IS onset. The MACO/R rat model experiment confirmed that QLC exerts its anti-CIRI effects by inhibiting the MD-2/TLR-4/NF-κB signaling axis. Conclusion: Our interdisciplinary integration study has demonstrated that the combination of QLC with CT exhibits significant superiority over CT alone in improving functional independence in patients at the 12th week. The potential mechanism underlying QLC's therapeutic effect in IS involves the inhibition of the MD-2/TLR4/NF-κB inflammatory signaling pathway, thereby attenuating cerebral ischemia/reperfusion inflammatory injury and facilitating neurofunctional recovery. The novelty and innovative potential of this study primarily lie in the novel finding that QLC significantly enhances the proportion of patients achieving functional independence (mRS score 0-2) at the 12th week. Furthermore, employing a "multilevel-multimethod" integrated research approach, we elucidated the potential mechanism underlying QLC's therapeutic effect in IS.

Unveiling the potential of breast MRI: a game changer for BI-RADS 4A microcalcifications.

PURPOSE: To assess the diagnostic performance of breast MRI for BI-RADS 4A microcalcifications on mammography and propose a potential clinical pathway to avoid unnecessary biopsies. METHODS: Bibliometrics analysis of breast MRI and BI-RADS 4 was provided. A retrospective analysis was conducted on 139 women and 142 cases of BI-RADS 4A microcalcifications on mammography from Fudan University Shanghai Cancer Center. The mammographic BI-RADS level and the MRI reports were compared with the final pathological diagnosis. RESULTS: Much attention has been given to breast MRI and BI-RADS 4 in the literature. However, studies on BI-RADS 4A are limited. Pathological results showed 117 cases (82.4%) were benign lesions, malignant cases of 25 (17.6%) in our study. The positive predictive values (PPV), specificity, sensitivity and negative predictive values (NPV) of MRI were 44.2% (23/52), 75.2% (88/117), 92.0% (23/25), and 97.8% (88/90), respectively. Therefore, 75.2% (88/117) of biopsies for benign lesions could potentially be avoided. There were 2.2% (2/90) malignant lesions missed. Logistic regression indicated that patients who are postmenopausal (HR = 2.655, p = 0.012), have a history of breast cancer (family history) (HR = 2.833, p = 0.029), and exhibit clustered microcalcifications (HR = 2.179, p = 0.046) are more likely to have a higher MRI BI-RADS level. CONCLUSIONS: Breast MRI has the potential to improve the diagnosis of BI-RADS 4A microcalcifications on mammography. We propose a potential clinical pathway that patients with BI-RADS 4A on mammography who are premenopausal, have no personal history of breast cancer (family history) or have non-clustered distribution of calcifications can undergo MRI to avoid unnecessary biopsies.

Solar-driven sugar production directly from CO2 via a customizable electrocatalytic-biocatalytic flow system.

Conventional food production is restricted by energy conversion efficiency of natural photosynthesis and demand for natural resources. Solar-driven artificial food synthesis from CO2 provides an intriguing approach to overcome the limitations of natural photosynthesis while promoting carbon-neutral economy, however, it remains very challenging. Here, we report the design of a hybrid electrocatalytic-biocatalytic flow system, coupling photovoltaics-powered electrocatalysis (CO2 to formate) with five-enzyme cascade platform (formate to sugar) engineered via genetic mutation and bioinformatics, which achieves conversion of CO2 to C6 sugar (L-sorbose) with a solar-to-food energy conversion efficiency of 3.5%, outperforming natural photosynthesis by over three-fold. This flow system can in principle be programmed by coupling with diverse enzymes toward production of multifarious food from CO2. This work opens a promising avenue for artificial food synthesis from CO2 under confined environments.

An Intelligent Customer-Driven Digital Solution to Improve Perioperative Health Outcomes Among Children Undergoing Circumcision and Their Parents: Development and Evaluation.

BACKGROUND: Circumcision as a common elective pediatric surgery worldwide is a stressful and anxiety-inducing experience for parents and children. Although current perioperative interventions proved effective, such as reducing preoperative anxiety, there are limited holistic solutions using mobile apps. OBJECTIVE: This paper aims to describe the development and primary evaluation of an intelligent customer-driven smartphone-based app program (ICory-Circumcision) to enhance health outcomes among children undergoing circumcision and their family caregivers. METHODS: Based on the review of the literature and previous studies, Bandura's self-efficacy theory was adopted as the conceptual framework. A multidisciplinary team was built to identify the content and develop the apps. Semistructured interviews were conducted to evaluate the ICory-Circumcision. RESULTS: The ICory-Circumcision study was carried out from March 2019 to January 2020 and comprised 2 mobile apps, BuddyCare app and Triumf Health mobile game app. The former provides a day-by-day perioperative guide for parents whose children are undergoing circumcision, while the latter provides emotional support and distraction to children. In total, 6 participants were recruited to use the apps and interviewed to evaluate the program. In total, 4 main categories and 10 subcategories were generated from content analysis. CONCLUSIONS: ICory-Circumcision seemed to lean toward being useful. Revisions to ICory-Circumcision are necessary to enhance its contents and features before advancing to the randomized controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04174404; https://clinicaltrials.gov/ct2/show/NCT04174404.

TPN10475 Constrains Effector T Lymphocytes Activation and Attenuates Experimental Autoimmune Encephalomyelitis Pathogenesis by Facilitating TGF-ß Signal Transduction.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) mediated by immune cells, in which auto-reactive CD4+ T cells have been implicated as a major driver in the pathogenesis of the disease. In this study, we aimed to investigate whether the artemisinin derivative TPN10475 could alleviate experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of MS and its possible mechanisms. TPN10475 effectively resisted the reduction of TGF-ß signal transduction induced by TCR stimulation, suppressed the activation and function of effector CD4+ T cells in vitro, and restricted the differentiation of pathogenic Th1 and Th17 cells. It was also found to negatively regulate the inflammatory response in EAE by reducing the peripheral activation drive of auto-reactive helper T lymphocytes, inhibiting the migration of inflammatory cells into the CNS to attenuate EAE. The above results suggested that the upregulation of TGF-ß signal transduction may provide new ideas for the study of MS pathogenesis and have positive implications for the development of drugs for the treatment of autoimmune diseases.

Rational and trial design of FASCINATE-N: a prospective, randomized, precision-based umbrella trial.

Background: With our growing insight into the molecular heterogeneity and biological characteristics of breast cancer, individualized treatment is the future of cancer treatment. In this prospective Fudan University Shanghai Cancer Center Breast Cancer Precision Platform Series study - neoadjuvant therapy (FASCINATE-N) trial, we classify breast cancer patients using multiomic characteristics into different subtypes to evaluate the efficacy of precision-based targeted therapies compared to standard neoadjuvant chemotherapy. Methods and design: The FASCINATE-N trial is a prospective, randomized, precision-based umbrella trial that plans to enroll 716 women with early breast cancer. After enrollment, patients will first be divided into three groups: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-, HER2+, and HR-/HER2-. The HR+/HER2- patients are further stratified using fusion and clustering of similarity network fusion (SNF) algorithm into four subtypes; HER2+ patients are divided into HR+/HER2+ and HR-/HER2+ subtypes; and HR-/HER2- patients are stratified using the Fudan University Shanghai Cancer Center classification. For the assignment of drugs to patients, Bayesian methods of adaptive randomization will be used. The primary endpoint is pathological complete response rate; secondary endpoints include 3-year invasive disease-free survival, overall response rate, and toxicities according to common terminology criteria for adverse events (CTCAE) scale version 4.0 and the ratio of patients with complete cell cycle arrest (Ki67 < 2.7%) in HR+/HER2+ breast cancer. Discussion: The goal of our trial is to test the efficacy of our subtyping-based treatment in a neoadjuvant setting and to conduct a pilot study into the efficacy of targeted therapies within each precision-based subtype. The precision-based treatment arm can be updated with the refinement of our subtyping method, the discovery of new targets, and the development of novel targeted drugs. Our trial offers a unique opportunity to provide patients with individualized neoadjuvant therapy and test promising novel treatments that may further benefit patients. Trial registration: ClinicalTrials.gov identifier: NCT05582499 (https://classic.clinicaltrials.gov/ct2/show/NCT05582499).

Rational and trial design of FASCINATE-N (Fudan University Shanghai Cancer Center Breast Cancer Precision Platform Series study- neoadjuvant therapy): a prospective, randomized, precision-based umbrella trial Our FASCINATE-N trial is a prospective, randomized, precision-based umbrella trial that plans to enroll 716 women with early breast cancer. We will first divide patients into three groups: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)−, HER2+, and HR−/HER2−. Then, we will further classify patients using multiomic characteristics into different subtypes to evaluate the efficacy of precision-based targeted therapies compared to standard neoadjuvant chemotherapy. The goal of our trial is to test the efficacy of our subtyping-based treatment in a neoadjuvant setting and to conduct a pilot study into the efficacy of targeted therapies within each precision-based subtype. The precision-based treatment arm can be updated with the refinement of our subtyping method, the discovery of new targets and the development of novel targeted drugs. Our trial offers a unique opportunity to provide patients with individualized neoadjuvant therapy and test promising novel treatments that may further benefit patients.

Antimicrobial resistance crisis: could artificial intelligence be the solution?

Antimicrobial resistance is a global public health threat, and the World Health Organization (WHO) has announced a priority list of the most threatening pathogens against which novel antibiotics need to be developed. The discovery and introduction of novel antibiotics are time-consuming and expensive. According to WHO's report of antibacterial agents in clinical development, only 18 novel antibiotics have been approved since 2014. Therefore, novel antibiotics are critically needed. Artificial intelligence (AI) has been rapidly applied to drug development since its recent technical breakthrough and has dramatically improved the efficiency of the discovery of novel antibiotics. Here, we first summarized recently marketed novel antibiotics, and antibiotic candidates in clinical development. In addition, we systematically reviewed the involvement of AI in antibacterial drug development and utilization, including small molecules, antimicrobial peptides, phage therapy, essential oils, as well as resistance mechanism prediction, and antibiotic stewardship.

Spermatid perinuclear RNA-binding protein promotes UBR5-mediated proteolysis of Dicer to accelerate triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer with no targeted therapy. Spermatid perinuclear RNA binding protein (STRBP), a poorly characterized RNA-binding protein (RBP), has an essential role in normal spermatogenesis and sperm function, but whether and how its dysregulation contributing to cancer progression has not yet been explored. Here, we report that STRBP functions as a novel oncogene to drive TNBC progression. STRBP expression was upregulated in TNBC tissues and correlated with poor disease prognosis. Functionally, STRBP promoted TNBC cell proliferation, migration, and invasion in vitro, and enhanced xenograft tumor growth and lung colonization in mice. Mechanistically, STRBP interacted with Dicer, a core component of the microRNA biogenesis machinery, and promoted its proteasomal degradation through enhancing its interaction with E3 ubiquitin ligase UBR5. MicroRNA-sequencing analysis identified miR-200a-3p as a downstream effector of STRBP, which was regulated by Dicer and affected epithelial-mesenchymal transition. Importantly, the impaired malignant phenotypes of TNBC cells caused by STRBP depletion were largely rescued by knockdown of Dicer, and these effects were compromised by transfection of miR-200a-3p mimics. Collectively, these findings revealed a previously unrecognized oncogenic role of STRBP in TNBC progression and identified STRBP as a promising target against TNBC.

Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial.

BACKGROUND: Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer. METHODS: FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18-70 years, with an Eastern Cooperative Oncology Group performance status of 0-1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKTmut and MES-PI3K/AKTmut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKTWT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989). FINDINGS: Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2-29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6-15·2]) than in the control group (5·8 months [4·0-6·7]; hazard ratio 0·44 [95% CI 0·30-0·65]; p<0·0001). The most common grade 3-4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group. INTERPRETATION: These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway. FUNDING: National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Manganese Exacerbates ConA-Induced Liver Inflammation via the cGAS-STING Signaling Pathway.

There is a potential association between the dysregulation of trace elements and impaired liver function. Elevated levels of manganese, an essential metal ion, have been observed in liver-related diseases, and excessive intake of manganese can worsen liver damage. However, the specific mechanisms underlying manganese-induced liver injury are not well understood. The aim of our study was to investigate the effects of excess manganese on autoimmune hepatitis (AIH) and elucidate its mechanisms. Our findings revealed that manganese exacerbates liver damage under ConA-induced inflammatory conditions. Transcriptomic and experimental data suggested that manganese enhances inflammatory signaling and contributes to the inflammatory microenvironment in the liver of AIH mice. Further investigations demonstrated that manganese exacerbates liver injury by activating the cGAS-STING signaling pathway and its downstream pro-inflammatory factors such as IFN[Formula: see text], IFN[Formula: see text], TNF[Formula: see text], and IL-6 in the liver of AIH mice. These results suggest that manganese overload promotes the progression of AIH by activating cGAS-STING-mediated inflammation, providing a new perspective for the treatment and prognosis of AIH.

A gait stability evaluation method based on wearable acceleration sensors.

In this study, an accurate tool is provided for the evaluation of the effect of joint motion effect on gait stability. This quantitative gait evaluation method relies exclusively on the analysis of data acquired using acceleration sensors. First, the acceleration signal of lower limb motion is collected dynamically in real-time through the acceleration sensor. Second, an algorithm based on improved dynamic time warping (DTW) is proposed and used to calculate the gait stability index of the lower limbs. Finally, the effects of different joint braces on gait stability are analyzed. The experimental results show that the joint brace at the ankle and the knee reduces the range of motions of both ankle and knee joints, and a certain impact is exerted on the gait stability. In comparison to the ankle joint brace, the knee joint brace inflicts increased disturbance on the gait stability. Compared to the joint motion of the braced side, which showed a large deviation, the joint motion of the unbraced side was more similar to that of the normal walking process. In this paper, the quantitative evaluation algorithm based on DTW makes the results more intuitive and has potential application value in the evaluation of lower limb dysfunction, clinical training and rehabilitation.

[Baicalin improves inflammatory response of human microglia by regulating cAMP-PKA-NF-κB/CREB pathway].

This study aims to investigate the effects of baicalein(BAI) on lipopolysaccharide(LPS)-induced human microglial clone 3(HMC3) cells, with a focus on suppressing inflammatory responses and elucidating the potential mechanism underlying the therapeutic effects of BAI on ischemic stroke via modulating the cAMP-PKA-NF-κB/CREB pathway. The findings have significant implications for the application of traditional Chinese medicine in treating cerebral ischemic diseases. First, the safe dosage of BAI was screened, and then an inflammation model was established with HMC3 cells by induction with LPS for 24 h. The cells were assigned into a control group, a model group, and high-, medium-, and low-dose(5, 2.5, and 1.25 µmol·L~(-1), respectively) BAI groups. The levels of superoxide dismutase(SOD) and malondialdehyde(MDA) in cell extracts, as well as the levels of interleukin-1ß(IL-1ß), IL-6, tumor necrosis factor-α(TNF-α), and cyclic adenosine monophosphate(cAMP) in the cell supernatant, were measured. Western blot was performed to determine the expression of protein kinase A(PKA), phosphorylated cAMP-response element binding protein(p-CREB), and nuclear factor-kappa B p65(NF-κB p65). Hoechst 33342/PI staining was employed to assess cell apoptosis. High and low doses of BAI were used for treatment in the research on the mechanism. The results revealed that BAI at the concentrations of 10 µmol·L~(-1) and below had no impact on normally cultured HMC3 cells. LPS induction at 200 ng·mL~(-1) for 24 h reduced the SOD activity and increased the MDA content in HMC3 cells. However, 5, 2.5, and 1.25 µmol·L~(-1) BAI significantly increased the SOD activity and 5 µmol·L~(-1) BAI significantly decreased the MDA content. In addition, BAI ameliorated the M1 polarization of HMC3 cells induced by LPS, as indicated by cellular morphology. The results of ELISA demonstrated that BAI significantly lowered the levels of TNF-α, IL-1ß, IL-6, and cAMP in the cell supernatant. Western blot revealed that BAI up-regulated the protein levels of PKA and p-CREB while down-regulating the expression of NF-κB p65. Hoechst 33342/PI staining results indicated that BAI mitigated the apoptosis of HMC3 cells. Overall, the results indicated that BAI had protective effects on the HMC3 cells induced by LPS, and could inhi-bit inflammatory response and improve cell apoptosis, which might be related to the regulation of the cAMP-PKA-NF-κB/CREB pathway.

TPN10475 alleviates concanavalin A-induced autoimmune hepatitis by limiting T cell development and function through inhibition of PI3K-AKT pathway.

Autoimmune hepatitis (AIH) is an inflammatory liver disease in which the autoimmune system instigates an attack on the liver, causing inflammation and liver injury, and its incidence has increased worldwide in recent years. The mouse model of acute hepatitis established by concanavalin A (Con A) is a typical and recognized mouse model for the study of T-cell-dependent liver injury. In this study, we aimed to investigate whether the artemisinin derivative TPN10475 could alleviate AIH and its possible mechanisms. TPN10475 effectively inhibited lymphocyte proliferation and IFN-γ+ T cells production in vitro, alleviated liver injury by decreasing infiltrating inflammatory T cells producing IFN-γ in the liver and peripheral immune tissues, and demonstrated that TPN10475 weakened the activation and function of T cells by inhibiting PI3K-AKT signaling pathway. These results suggested that TPN10475 may be a potential drug for the treatment of AIH, and the inhibition of PI3K-AKT signaling pathway may provide new ideas for the study of the pathogenesis of AIH.

Contralateral axillary lymph node metastasis in breast cancer: An oligometastatic-like disease.

BACKGROUND: Contralateral axillary lymph node metastasis (CAM) is rare. It remains controversial whether CAM should be regarded as a regional or distant metastatic disease. Our study aims to investigate the accurate clinical orientation and management of CAM. METHODS: Two hundred and ninety-nine female patients diagnosed with breast cancer from 2000 to 2014 and confirmed to develop CAM, oligometastasis (OM) or locoregional recurrence (LRR) at Fudan University Shanghai Cancer Center (FUSCC) were included in this study. Baseline information and survival outcomes were analyzed and compared among the three groups. RESULTS: Patients with CAM exhibited similar overall survival (OS) and progression-free survival (PFS) to those with OM, but worse than those with LRR (HR: 0.47 [95 % CI: 0.27-0.85], p = 0.0097; HR:0.39 [95 % CI: 0.24-0.63], p < 0.0001, respectively). Considering the patients presented with CAM or OM as a whole, we found that local treatment combined with systemic treatment did not provide a superior survival benefit over systemic treatment alone. CONCLUSION: CAM was similar to an oligometastatic-like disease, and patients with these diseases may benefit from systemic treatment. Adding local treatment failed to significantly improve OS.

Artificial photosynthetic cells with biotic-abiotic hybrid energy modules for customized CO2 conversion.

Programmable artificial photosynthetic cell is the ultimate goal for mimicking natural photosynthesis, offering tunable product selectivity via reductase selection toward device integration. However, this concept is limited by the capacity of regenerating the multiple cofactors that hold the key to various reductases. Here, we report the design of artificial photosynthetic cells using biotic-abiotic thylakoid-CdTe as hybrid energy modules. The rational integration of thylakoid with CdTe quantum dots substantially enhances the regeneration of bioactive NADPH, NADH and ATP cofactors without external supplements by promoting proton-coupled electron transfer. Particularly, this approach turns thylakoid highly active for NADH regeneration, providing a more versatile platform for programming artificial photosynthetic cells. Such artificial photosynthetic cells can be programmed by coupling with diverse reductases, such as formate dehydrogenase and remodeled nitrogenase for highly selective production of formate or methane, respectively. This work opens an avenue for customizing artificial photosynthetic cells toward multifarious demands for CO2 conversion.

Pre-Compensation of Thermal Error for Laser-Assisted Diamond Turning.

The laser-assisted diamond turning (LADT) method can effectively improve the machinability of hard and brittle materials based on the laser heating effect, resulting in prolonged diamond tool life and better surface integrity. However, due to the incomplete absorption of laser beam energy within the workpiece cutting zone, simultaneous heating of the tool holder occurs, resulting in a structural thermal expansion that affects the workpiece form accuracy. In this article, the form accuracy of a LADT-machined workpiece was systematically studied. Accurate calculations of the tool shank and tool holder thermal fields and thermal expansion were performed using thermodynamic coupled finite element analysis. In addition, the LADT tool path was precisely pre-compensated by taking into account the structure expansion. The experimental results demonstrate that the form accuracy can be significantly improved with a pre-compensated tool path, which provides crucial technical support for achieving a high-precision finish on optical elements using the LADT method.

A novel methodology for evaluation of S2 wide split via estimated parameters.

BACKGROUND AND OBJECTIVE: Aimed at the shortcomings of using time interval ( [Formula: see text] ) between the sounds produced by the aortic valve closure (A2) and the pulmonary valve closure (P2) to detect the wide splitting of the second heart sound (S2), which are the [Formula: see text] easily influenced by the heartbeat and not easily distinguished from the fixed splitting of S2 without considering the entire respiratory phase, and from the third heart sound (S3), this study proposes a novel methodology to detect the wide splitting of S2 using an estimated split coefficient of S2 ( [Formula: see text] ) combined with an adaptive number (NAda) of S2. METHODOLOGY: The methodology is orderly summarized as follows: Stage 1 describes the segmentation-based S2 automatic location and extraction. A Gaussian mixture model (GMM)-based regression model for S2 is proposed to estimate the positions of A2 and P2, then an overlapping rate (OLR)-based [Formula: see text] and the [Formula: see text] are estimated, and finally, a NAda-S2 is automatically determined to calculate the statistics of [Formula: see text] and [Formula: see text] . In stage 3, based on the combination of estimated features, the detection of wide splitting of S2 is determined. RESULTS: The performance is evaluated using a total of 3350-period heart sounds from 72 patients, with an overall accuracy of 100%, F1=1 and a Cohen's kappa value (κ) of 1. DISCUSSION: The significant contributions are highlighted: A novel GMM-based efficient methodology is proposed for estimating the characteristics of A2 and P2. A novel OLR-based [Formula: see text] is defined to replace the current state-of-the-art criterion for evaluating the split degree of S2. Considering respiration phases combined with CR are proposed for the high-precision diagnosis of S2 wide split.