Cancer-associated fibroblasts-derived exosomal ZNF250 promotes the proliferation, migration, invasion, and immune escape of hepatocellular carcinoma cells by transcriptionally activating PD-L1.

Hepatocellular carcinoma (HCC) is a lethal form of liver cancer, and the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), plays a critical role in its progression. This study aimed to elucidate the mechanism by which CAF-derived exosomes regulate the development of HCC. The study employed quantitative real-time polymerase chain reaction for mRNA expression analysis and western blot analysis for protein expression detection. Chromatin immunoprecipitation assay and dual-luciferase reporter assay were performed to investigate the relationship between zinc finger protein 250 (ZNF250) and programmed cell death 1 ligand 1 (PD-L1). Transmission electron microscopy and western blot analysis were used to characterize the isolated exosomes. The transferability of CAF-derived exosomes and normal fibroblasts (NFs)-derived exosomes into HCC cells was analyzed using a green fluorescent labeling dye PKH67. Cell proliferation was assessed via a 5-Ethynyl-2'-deoxyuridine assay, while Transwell assays were conducted to evaluate cell migration and invasion. Flow cytometry was performed to measure cell apoptosis, while enzyme-linked immunosorbent assays were used to assess the levels of tumor necrosis factor-α and perforin. Finally, a xenograft mouse model was constructed to examine the effects of exosomes derived from ZNF250-deficient CAFs on the tumor properties of HCC cells. The study revealed increased expression of ZNF250 in HCC tissues and cells, with ZNF250 transcriptionally activating PD-L1 in HCC cells. ZNF250 expression was associated with HbsAg, clinical stage and tumor size of HCC patients. CAF-derived exosomal ZNF250 can regulate PD-L1 expression in HCC cells. Furthermore, exosomes derived from ZNF250-deficient CAFs inhibited the proliferation, migration, invasion, and immune escape of HCC cells by downregulating PD-L1 expression. Moreover, CAF-derived exosomal ZNF250 promoted tumor formation in vivo. These findings provide insights into the role of CAF-derived exosomes in the suppression of HCC development, highlighting the significance of ZNF250 and PD-L1 regulation in tumor progression.

The Role of Fe(III) in Selective Adsorption of Pullulan on Calcite Surfaces: Experimental Investigation and Molecular Dynamics Simulation.

The floatability of fluorite and calcite exhibit similar properties, rendering their flotation separation challenging. Macromolecular polysaccharide reagents containing the polyhydroxyl group have shown broad promising application. The selectivity of polysaccharide is relatively low. In this study, the introduction of Fe3+ was employed to enhance the selective adsorption capacity of Pullulan polysaccharide towards fluorite and calcite minerals, thereby achieving effective flotation separation. Furthermore, the mechanism underlying intramolecular interactions was elucidated. The DFT calculation and XPS analysis revealed that the adsorption of Fe3+ on the calcite surface was more favorable, leading to the formation of a Ca-O-Fe structure. The MD simulation, XPS analysis, and Zeta potential analysis revealed that the Fe-OH groups on the surface of calcite reacted with the -OH groups in Pullulan and formed bonds, resulting in the formation of a Calcite-Fe-Pullulan structure. This facilitated the attachment of a significant number of Pullulan molecules to the calcite surface. The formation of a hydrophilic layer on the outer surface of calcite by Pullulan, in contrast to the absence of such layer on fluorite's surface, results in an increased disparity in surface floatability between these two minerals, thereby enhancing the efficiency of flotation separation.

Early-life ozone exposure and childhood otitis media: Unveiling critical windows of risk.

BACKGROUND: Despite increasing evidence of a strong correlation between air pollution and otitis media (OM), the impact of early-life ozone (O3) exposure on the development of OM in children remains uncertain. OBJECTIVES: To explore the connection between early-life O3 exposure and OM, and to identify the critical time period(s) during which O3 exposure significantly influences the development of OM in children. METHODS: We conducted a study involving 8689 children living in Changsha, China. Information regarding personal factors, health conditions, and the indoor environment was gathered using questionnaires. Personal exposure to outdoor O3 and other major pollutants at the place of residence during the periods before conception, prenatal periods, and after birth was calculated by applying the inverse distance weighted (IDW) method with data gathered from ten air quality monitoring stations. Multiple logistic regression analyses were employed to investigate the associations between O3 exposure and children's OM. RESULTS: After controlling for covariates and ambient temperature, exposure to O3 during the year preceding pregnancy was correlated with childhood lifetime OM, showing ORs (95 % CI) of 1.28 (1.01-1.64). O3 exposures in the 10th-12th, 7th-9th, and 4th-6th months before pregnancy were all linked to children's lifetime OM. Within the multi-window model, we detected that O3 exposure in the 10th to 12th month prior to pregnancy was significantly related to lifetime OM, showing ORs (95 % CI) of 1.28 (1.05-1.55). A significant link was discovered between childhood OM and O3 exposure after controlling for six other pollutants (SO2, PM2.5, NO2, PM2.5-10, CO, and PM10) during the 10th to 12th month prior to conception. Exposure to O3 during the 36th gestational week significantly raised the likelihood of childhood lifetime OM. There is a significant interaction between O3 and temperature exposure during the first trimester of pregnancy and one year before pregnancy on childhood lifetime OM. CONCLUSIONS: Preconceptional O3 exposure and its interaction with low temperature played critical roles in children's OM development, backing the hypothesis of "(pre) fetal origins of childhood OM".

The tomato WRKY-B transcription factor modulates lateral branching by targeting BLIND, PIN4, and IAA15.

Lateral branching is a crucial agronomic trait that impacts crop yield. In tomato ( Solanum lycopersicum ), excessive lateral branching is unfavorable and results in substantial labor and management costs. Therefore, optimizing lateral branching is a primary objective in tomato breeding. Although many genes related to lateral branching have been reported in tomato, the molecular mechanism underlying their network remains elusive. In this study, we found that the expression profile of a WRKY gene, WRKY-B (for WRKY-BRANCING), was associated with the auxin-dependent axillary bud development process. Wrky-b mutants generated by the CRISPR/Cas9 editing system presented fewer lateral branches, while WRKY-B overexpression lines presented more lateral branches than did wild-type plants. Furthermore, WRKY-B can directly target the well-known branching gene BLIND (BL) and the auxin efflux carrier gene PIN4 to activate their expression. Both the bl and pin4 mutants exhibited reduced lateral branching, similar to the wrky-b mutant. The IAA contents in the axillary buds of the wrky-b, bl, and pin4 mutant plants were significantly higher than those in the wild-type plants. In addition, WRKY-B can also directly target the AUX/IAA gene IAA15 and repress its expression. In summary, WRKY-B works upstream of BL, PIN4, and IAA15 to regulate the development of lateral branches in tomato.

Highlighting immune features of the tumor ecosystem and prognostic value of Tfh and Th17 cell infiltration in head and neck squamous cell carcinoma by single-cell RNA-seq.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) typically present with a complex anatomical distribution, often accompanied by insidious symptoms. This combination contributes to its high incidence and poor prognosis. It is now understood that the immune features of cellular components within the tumor ecosystem and their complex interactions are critical factors influencing both tumor progression and the effective immune response. METHODS: We obtained single-cell RNA sequencing data of 26,496 cells from three tumor tissues and five normal tissues and performed subsequent analyses. Immunohistochemical staining on tumor sections was used to validate the presence of malignant cells. Additionally, we included bulk RNA sequencing data from 502 HNSCC patients. Kaplan-Meier analysis and the log-rank test were employed to assess predictors of patient outcomes. RESULTS: We identified three epithelial subclusters exhibiting immune-related features. These subclusters promoted the infiltration of T cells, dendritic cells, and monocytes into the tumor microenvironment. Additionally, cancer-associated fibroblasts displayed tumor-promoting and angiogenesis characteristics, contrasting with the predominant antigen-presenting and inflammatory roles observed in fibroblasts from normal tissues. Furthermore, tumor endothelial subsets exhibited a double-sided effect, promoting tumor progression and enhancing the effectiveness of immune response. Finally, follicular helper T cells and T helper 17 cells were found to be significantly correlated with improved outcomes in HNSCC patients. These CD4+ T cell subpopulations could promote the anti-tumor immune response by recruiting and activating B and T cells. CONCLUSION: Our findings provide deeper insights into the immune features of the tumor ecosystem and reveal the prognostic significance of follicular helper T cells and T helper 17 cells. These findings may pave the way for the development of therapeutic approaches.

A case report of right-sided heart failure secondary to JAK2-mutation Loeffler endocarditis.

Loeffler's endocarditis (LE) is the cardiac manifestation of hypereosinophilic syndrome. We present a case of LE in a 45-year-old female, resulting in diffuse endothelial fibrosis and severe right-sided heart failure. The patient was admitted with dyspnoea and oedema, with haematology revealing an absolute eosinophil count of 20.9 × 109. Imaging showed near-complete obliteration of the right ventricular apical and formation of thromboses. Endomyocardial biopsy indicated diffuse fibrous hyperplasia of the endocardium with fibrinous thrombi rich in eosinophils. Molecular and cytogenetic analyses of bone marrow cells showed no signs of FIP1L1-PDGFRA fusion, PDGFRB mutation, abnormal myeloid maturation, or a lymphoproliferative disorder. Flow cytometry indicated no clonality, ruling out chronic eosinophilic leukaemia. Gene mutation screening discovered a p.L583_A586delinesS mutation in the JAK2 gene. Following treatment with ruxolitinib, the patient's eosinophil levels normalized, but unfortunately, the damage to the heart was irreversible. The patient was hospitalized multiple times due to right heart failure and resistance to diuretics. After thorough discussions with the medical team, it was determined that a heart transplantation would be the most effective treatment. Following the surgery, the patient successfully navigated the postoperative critical period with the support of an intra-aortic balloon pump (IABP), continuous renal replacement therapy (CRRT), and ventilator-assisted ventilation but subsequently developed an acquired Intensive care unit-acquired weakness (ICU-AW) and a depressive state. Fortunately, the patient gradually recovered from these complications.

HPV integration: a precise biomarker for detection of residual/recurrent disease after treatment of CIN2-3.

BACKGROUND: This study aimed to investigate whether persistent human papillomavirus integration at the same loci (PHISL) before and after treatment can predict recurrent/residual disease in women with CIN2-3. METHODS: A total of 151 CIN2-3 women treated with conization between August 2020 and September 2021 were included. To investigate the precision of HPV integration, we further analyzed HPV integration-positive patients. Sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively), and the Youden index for predicting recurrence/residual disease were calculated. RESULTS: Among the 151 enrolled CIN2-3 women, 56 were HPV integration-positive and 95 had HPV integration-negative results. Six (10.7%) experienced recurrence among 56 HPV integration-positive patients, which was more than those in HPV integration-negative patients (one patient, 1.1%). In the 56 HPV integration-positive patients, 12 had positive HPV results after treatment, seven had PHISL, and two had positive cone margin. Among the seven patients who tested with PHISL, six (85.7%) had residual/recurrent disease. PHISL was a prominent predictor of persistent/recurrent disease. The HPV test, the HPV integration test, and PHISL all had a sensitivity of 100% and a NPV of 100% for residual/recurrent disease. PHISL showed better specificity (98.0% vs. 82.0%, p = 0.005) and PPV (85.7% vs. 40.0%, p = 0.001) than the HPV test for predicting recurrence. CONCLUSIONS: The HPV-integration-positive CIN2-3 women had much higher relapse rates than HPV-integration-negative CIN2-3 women. The findings indicate that PHISL derived from preoperative and postoperative HPV integration tests may be a precise biomarker for the identification of residual/recurrent CIN 2/3.

VPA0198, a GGDEF domain-containing protein, affects the motility and biofilm formation of Vibrio parahaemolyticus and is regulated by quorum sensing associated regulators.

Cyclic di-GMP (c-di-GMP), a ubiquitous secondary messenger in bacteria, affects multiple bacterial behaviors including motility and biofilm formation. c-di-GMP is synthesized by diguanylate cyclase harboring a GGDEF domain and degraded by phosphodiesterase harboring an either EAL or HD-GYP domain. Vibrio parahaemolyticus, the leading cause of seafood-associated gastroenteritis, harbors more than 60 genes involved in c-di-GMP metabolism. However, roles of most of these genes including vpa0198, which encodes a GGDEF-domain containing protein, are still completely unknown. AphA and OpaR are the master quorum sensing (QS) regulators operating at low (LCD) and high cell density (HCD), respectively. QsvR integrates into QS to control gene expression via direct regulation of AphA and OpaR. In this study, we showed that deletion of vpa0198 remarkably reduced c-di-GMP production and biofilm formation, whereas promoted the swimming motility of V. parahaemolyticus. Overexpression of VPA0198 in the vpa0198 mutant strain significantly reduced the swimming and swarming motility and enhanced the biofilm formation ability of V. parahaemolyticus. In addition, transcription of vpa0198 was under the collective regulation of AphA, OpaR and QsvR. AphA activated the transcription of vpa0198 at LCD, whereas QsvR and OpaR coordinately and directly repressed vpa0198 transcription at HCD, thereby leading to a cell density-dependent expression of vpa0198. Therefore, this work expanded the knowledge of synthetic regulatory mechanism of c-di-GMP in V. parahaemolyticus.

Childhood Helicobacter pylori infection: Impacts of environmental exposures and parental stress.

BACKGROUND: Helicobacter pylori infection (HPI) is extremely common in the world, particularly in less developed areas, but the primary causes of childhood HPI are unspecified. OBJECTIVES: To determine the influences of exposure to home environmental factors (HEFs), outdoor air pollutants (OAPs), and parental stress (PS), as well as their interactions on children's HPI. METHODS: We implemented a retrospective cohort study with 8689 preschoolers from nine districts at Changsha, China, was conducted using questionnaires to collect data of health and HEFs. Temperature and OAPs data were collected from ten and eight monitoring stations, individually. Temperature and OAPs exposures were calculated for all home addresses using the inversed distance weighted (IDW) model. Multiple logistic regression analysis was carried out to determine the separate and combined impacts of HEFs, OAPs, and PS on HPI. RESULTS: Children's HPI was significantly associated with exposure to moisture-specific indoor allergens in one-year preceding conception, gestation, and first year, smoke-specific air pollution throughout life, and plant-specific allergens in previous year. Outdoor exposures to CO in the 7th-9th month before conception, as well as PM2.5 in the second trimester and previous year, were associated with HPI, with ORs (95 % CIs) of 1.22 (1.05-1.41), 1.23 (1.03-1.46), and 1.33 (1.14-1.55). Parents' socioeconomic and psychological stress indicators were positively related to HPI. High socioeconomic indicators and psychological stresses increased the roles of indoor renovation and moisture indicators as well as outdoor SO2, PM2.5 and O3 on children's HPI over their entire lives. Parental psychological stress interacts with indoor renovation-specific air pollution, moisture- and plant-specific allergens, as well as outdoor traffic-related air pollution on HPI, during a critical time window in early life. CONCLUSIONS: Indoor and outdoor air pollutants, as well as allergens, separately and interactively exert important effects on childhood HPI, lending support to the "(pre-) fetal origin of HPI" hypothesis.

Biomimetic nanomedicine cocktail enables selective cell targeting to enhance ovarian Cancer chemo- and immunotherapy.

Ovarian cancer is one of the deadliest cancers, and combined chemo- and immunotherapies are potential strategies to combat it. However, the anti-cancer efficacy of the combined therapies may be limited by the non-selective co-delivery of chemotherapy and immunotherapy. Herein, a combined chemo- and immunotherapy is designed to selectively target ovarian tumor (ID8) cells and dendritic cells (DCs) using ID8 cell membrane (IM) and bacterial outer membrane vesicles (OMVs), respectively. Doxorubicin (DOX) and Ovalbumin (OVA) peptide (OVA257-264) are chosen as model chemotherapy and immunotherapy agents, respectively. A DNA nanocube capable of easily loading DOX or OVA257-264 is chosen as the carrier. Firstly, the DNA nanocube is used to load DOX or OVA257-264 to prepare cube-DOX or cube-OVA. This nanocube was then encapsulated with IM to form IM@Cube-DOX and with OMV to form OMV@Cube-OVA. IM@Cube-DOX can be selectively taken up by ID8 cells, leading to effective cell killing, while OMV@Cube-OVA targets and activates DC2.4 cells in vitro. Both IM@Cube-DOX and OMV@Cube-OVA show increased accumulation at ID8 tumors in C57BL/6 mice. Combined IM@Cube-DOX + OMV@Cube-OVA therapy demonstrates better anti-tumor efficacy than non-selective delivery methods such as OMV@(Cube-DOX + Cube-OVA) or IM@(Cube-DOX + Cube-OVA) in ID8-OVA tumor-bearing mice. In conclusion, this study demonstrates a biomimetic delivery strategy that enables selective drug delivery to tumor cells and DCs, thereby enhancing the anti-tumor efficacy of combined chemo- and immunotherapy through the selective delivery strategy.

Gut microbiota mediates ambient PM2.5 exposure-induced abnormal glucose metabolism via short-chain fatty acids.

PM2.5 exposure has been found to cause gut dysbiosis and impair glucose homeostasis in human and animals, yet their underlying biological connection remain unclear. In the present study, we aim to investigate the biological significance of gut microbiota in PM2.5-induced glucose metabolic abnormalities. Our results showed that microbiota depletion by antibiotics treatment significantly alleviated PM2.5-induced glucose intolerance and insulin resistance, as indicated by the intraperitoneal glucose tolerance test, glucose-induced insulin secretion, insulin tolerance test, insulin-induced phosphorylation levels of Akt and GSK-3ß in insulin sensitive tissues. In addition, faecal microbiota transplantation (FMT) from PM2.5-exposed donor mice successfully remodeled the glucose metabolism abnormalities in recipient mice, while the transplantation of autoclaved faecal materials did not. Faecal microbiota analysis demonstrated that the composition and alpha diversity of the gut bacterial community were altered by PM2.5 exposure and in FMT recipient mice. Furthermore, short-chain fatty acids levels analysis showed that the circulating acetate was significantly decreased in PM2.5-exposed donor and FMT recipient mice, and supplementation of sodium acetate for 3 months successfully improved the glucose metabolism abnormalities induced by PM2.5 exposure. These results indicate that manipulating gut microbiota or its metabolites could be a potential strategy for preventing the adverse health effects of ambient PM2.5.

Pullulan Polysaccharide as an Eco-Friendly Depressant for Flotation Separation of Chalcopyrite and Molybdenite.

It is difficult to separate molybdenite and chalcopyrite by froth flotation due to the good floatability of the two minerals. In this paper, the separation of copper-molybdenum sulfide minerals was realized by using pullulan polysaccharide (PU) as the depressant. The flotation test results showed that the copper concentrate grade increased from 16.24 to 29.86%, and the copper concentrate recovery reached 83.55% under low alkali conditions. The selective separation mechanism of the two minerals by PU was revealed through contact angle measurements, ζ-potential measurements, Fourier transform infrared (FTIR) spectroscopy analyses, and X-ray photoelectron spectroscopy (XPS) analyses. The ζ-potential and contact angle results showed that PU is more easily adsorbed on molybdenite to strengthen the hydrophilicity of molybdenite. The FTIR and XPS results showed that PU is adsorbed on molybdenite by physical interactions, and hydrophobic interactions and hydrogen bonding play a major role.

Fast, high-quality, and unshielded 0.2 T low-field mobile MRI using minimal hardware resources.

OBJECTIVE: To propose a deep learning-based low-field mobile MRI strategy for fast, high-quality, unshielded imaging using minimal hardware resources. METHODS: Firstly, we analyze the correlation of EMI signals between the sensing coil and the MRI coil to preliminarily verify the feasibility of active EMI shielding using a single sensing coil. Then, a powerful deep learning EMI elimination model is proposed, which can accurately predict the EMI components in the MRI coil signals using EMI signals from at least one sensing coil. Further, deep learning models with different task objectives (super-resolution and denoising) are strategically stacked for multi-level post-processing to enable fast and high-quality low-field MRI. Finally, extensive phantom and brain experiments were conducted on a home-built 0.2 T mobile brain scanner for the evaluation of the proposed strategy. RESULTS: 20 healthy volunteers were recruited to participate in the experiment. The results show that the proposed strategy enables the 0.2 T scanner to generate images with sufficient anatomical information and diagnostic value under unshielded conditions using a single sensing coil. In particular, the EMI elimination outperforms the state-of-the-art deep learning methods and numerical computation methods. In addition, 2 × super-resolution (DDSRNet) and denoising (SwinIR) techniques enable further improvements in imaging speed and quality. DISCUSSION: The proposed strategy enables low-field mobile MRI scanners to achieve fast, high-quality imaging under unshielded conditions using minimal hardware resources, which has great significance for the widespread deployment of low-field mobile MRI scanners.

The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women.

Objective: Cyproterone acetate (CPA) and spironolactone (SPL) are different antiandrogens in gender-affirming hormone therapy (GAHT) for transgender women. Few studies have evaluated their efficacy and user satisfaction, especially among East Asians. This study aimed to evaluate these aspects in Chinese transgender women. Methods: Data were collected retrospectively from transgender women visiting the Peking University Third Hospital from 2012 to 2021. From 639 people identified as transgender women, 151 of them (80 using CPA and 71 using SPL, 16 to 40-year-old) under stable GAHT ≥6 months were enrolled. Total testosterone levels and visual analogue scale (VAS)-based satisfaction scores were evaluated. Results: No difference was observed in age between the CPA and SPL groups (median [IQR], 22 [20-24] years and 23 [20-26] years, respectively). The duration of GAHT was longer in CPA group than in SPL group (18 [10-32] months vs. 12 [8-21] months, p = 0.009). Total testosterone levels were significantly lower with CPA treatment (25 mg/d) than with SPL treatment (100 mg/d) (median [IQR]: 0.7 [0.7-2.1] nmol/L vs. 13.0 [6.0-17.8] nmol/L, p < 0.001). The proportion of total testosterone levels reaching the recommended range was significantly higher in CPA group than in SPL group (75.0% vs. 11.3%, p < 0.001). VAS-based satisfaction scores for erection decreased and figure feminization were higher in CPA group than in SPL group, which remained unchanged after adjusting for age, treatment duration, estradiol dose, and comorbid mental disorders (p < 0.05). The prolactin levels were higher in CPA group than in SPL group (18.9 [11.8-28.1] ng/ml vs. 11.8 [7.9-18.4] ng/ml, p < 0.001). No severe safety events were reported in both groups. Conclusion: In Chinese transgender women, CPA was more effective than SPL in lowering testosterone levels. Additionally, VAS scores indicated greater satisfaction with erection decreased and figure feminization using CPA compared to SPL.

A Nanoreactor Based on Metal-Organic Frameworks With Triple Synergistic Therapy for Hepatocellular Carcinoma.

The transformation of monotherapy into multimodal combined targeted therapy to fully exploit synergistic efficacy is of increasing interest in tumor treatment. In this work, a novel nanodrug-carrying platform based on iron-based MOFs, which is loaded with doxorubicin hydrochloride (DOX), dihydroartemisinin (DHA), and glucose oxidase (GOx), and concurrently covalently linked to the photosensitizer 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) in polydopamine (PDA)-encapsulated MIL-101(Fe) (denoted as MIL-101(Fe)-DOX-DHA@TCPP/GOx@PDA, MDDTG@P), is successfully developed. Upon entering the tumor microenvironment, MDDTG@P catalyzes the hydrogen peroxide (H2O2) into hydroxyl radicals (·OH) and depletes glutathione (GSH); thus, exerting the role of chemodynamic therapy (CDT). The reduced Fe2+ can also activate DHA, further expanding CDT and promoting tumor cell apoptosis. The introduced GOx will rapidly consume glucose and oxygen (O2) in the tumor; while, replenishing H2O2 for Fenton reaction, starving the cancer cells; and thus, realizing starvation and chemodynamic therapy. In addition, the covalent linkage of TCPP endows MDDTG@P with good photodynamic therapeutic (PDT) properties. Therefore, this study develops a nanocarrier platform for triple synergistic chemodynamic/photodynamic/starvation therapy, which has promising applications in the efficient treatment of tumors.

Silver-catalyzed P-centered anion nucleophilic addition to isocyanide: access to 2-phosphinoyl indoles/indol-3-ols.

A silver-catalyzed chemoselective cascade nucleophilic addition of a P-centered anion to isocyanides and cyclization reaction was developed for the efficient and practical synthesis of a wide range of 2-phosphinoyl indole and indol-3-ol derivatives. Unlike the well-documented synthesis of phosphorus-functionalized heterocycles via a P-centered radical, an anionic reactivity profile of phosphine oxides is most likely involved in this domino transformation.

Mice fatal pneumonia model induced by less-virulent Streptococcus pneumoniae via intratracheal aerosolization.

Aim: Animal models of fatal pneumonia caused by Streptococcus pneumoniae (Spn) have not been reliably generated using many strains of less virulent serotypes.Materials & methods: Pulmonary infection of a less virulent Spn serotype1 strain in the immunocompetent mice was established via the intratracheal aerosolization (ITA) route. The survival, local and systemic bacterial spread, pathological changes and inflammatory responses of this model were compared with those of mice challenged via the intratracheal instillation, intranasal instillation and intraperitoneal injection routes.Results: ITA and intratracheal instillation both induced fatal pneumonia; however, ITA resulted in better lung bacterial deposition and distribution, pathological homogeneity and delivery efficiency.Conclusion: ITA is an optimal route for developing animal models of severe pulmonary infections.

What is this article about? Streptococcus pneumoniae (Spn), a type of bacteria, can cause serious illness and death in otherwise healthy people. One way that we study pneumonia is using animals. However, pneumonia in animals infected with Spn in the laboratory does not mimic that in humans very well. To study this illness, we need a new way to set up a proper animal model.What were the results? This study set up a method called intratracheal aerosolization (ITA). In ITA, bacteria can form small droplets called aerosols and reach the deepest parts of a mouse's lung. ITA can cause deadly illness in mice infected with Spn, even if the mice are healthy.What do the results of the study mean? The ITA method could be a useful tool to set up animal models of serious pneumonia with less virulent bacteria.

PtbNet: Based on Local Few-Shot Classes and Small Objects to accurately detect PTB.

Pulmonary Tuberculosis (PTB) is one of the world's most infectious illnesses, and its early detection is critical for preventing PTB. Digital Radiography (DR) has been the most common and effective technique to examine PTB. However, due to the variety and weak specificity of phenotypes on DR chest X-ray (DCR), it is difficult to make reliable diagnoses for radiologists. Although artificial intelligence technology has made considerable gains in assisting the diagnosis of PTB, it lacks methods to identify the lesions of PTB with few-shot classes and small objects. To solve these problems, geometric data augmentation was used to increase the size of the DCRs. For this purpose, a diffusion probability model was implemented for six few-shot classes. Importantly, we propose a new multi-lesion detector PtbNet based on RetinaNet, which was constructed to detect small objects of PTB lesions. The results showed that by two data augmentations, the number of DCRs increased by 80% from 570 to 2,859. In the pre-evaluation experiments with the baseline, RetinaNet, the AP improved by 9.9 for six few-shot classes. Our extensive empirical evaluation showed that the AP of PtbNet achieved 28.2, outperforming the other 9 state-of-the-art methods. In the ablation study, combined with BiFPN+ and PSPD-Conv, the AP increased by 2.1, APs increased by 5.0, and grew by an average of 9.8 in APm and APl. In summary, PtbNet not only improves the detection of small-object lesions but also enhances the ability to detect different types of PTB uniformly, which helps physicians diagnose PTB lesions accurately. The code is available at https://github.com/Wenhui-person/PtbNet/tree/master.

Dual Nickel/Photoredox-Catalyzed Arylsulfonylation of Allenes.

The nickel/photoredox dual catalysis system is an efficient conversion platform for the difunctionalization of unsaturated hydrocarbons. Herein, we disclose the first dual nickel/photoredox-catalyzed intramolecular 1,2-arylsulfonylation of allenes, which can accurately construct a C(sp2)-C(sp2) bond and a C(sp3)-S bond. The reaction exhibits excellent chemoselectivity and regioselectivity, allowing modular conformations of a diverse series of 3-sulfonylmethylbenzofuran derivatives. Control experiments showed that the bipyridine ligand is crucial for the formation of a stable σ-alkyl nickel intermediate, providing the possibility for sulfonyl radical insertion. Meanwhile, the electrophilic sulfonyl radical facilitates further oxidative addition of the σ-alkyl nickel intermediate and inhibits addition with allenes. In addition, control experiments, cyclic voltammetry tests, Stern-Volmer experiments, and density functional theory calculations afford evidence for the Ni(0)/Ni(I)/Ni(II)/Ni(III) pathway in this 1,2-arylsulfonylation.

Securinine inhibits carcinogenesis in gastric cancer by targeting AURKA-ß-catenin/Akt/STAT3 and the cell cycle pathway.

BACKGROUND: Gastric cancer (GC) is difficult to treat with currently available treatments. Securinine (SCR) has a lengthy history of use in the treatment of disorders of the nervous system, and its anticancer potential has been gaining attention in recent years. The aim of this study was to explore the repressive effect of SCR on GC and its fundamental mechanism. METHODS: The efficacy of SCR in GC cells was detected by MTT assays. Colony formation, flow cytometry and Transwell assays were used to assess the changes in the proliferation, apoptosis, cell cycle distribution, migration and invasion of GC cells after treatment. AGS (human gastric carcinoma cell)-derived xenografts were used to observe the effect of SCR on tumor growth in vivo. The molecular mechanism of action of SCR in GC was explored via RNA sequencing, bioinformatics analysis, Western blotting, molecular docking, and immunohistochemistry. RESULTS: SCR was first discovered to inhibit the proliferation, migration, and invasion of GC cells while initiating apoptosis and cell cycle arrest in vitro. It was also established that SCR has excellent anticancer effects in vivo. Interestingly, AURKA acts as a crucial target of SCR, and AURKA expression can be blocked by SCR. Moreover, this study revealed that SCR suppresses the cell cycle and the ß-catenin/Akt/STAT3 pathways, which were previously reported to be regulated by AURKA. CONCLUSION: SCR exerts a notable anticancer effect on GC by targeting AURKA and blocking the cell cycle and ß-catenin/Akt/STAT3 pathway. Thus, SCR is a promising pharmacological option for the treatment of GC.