scRNA+ TCR-seq revealed dual TCR T cells antitumor response in the TME of NSCLC.

The intricate origins, subsets, and characteristics of TCR (T Cell Receptor) s, along with the mechanisms underpinning the antitumor response of tumor-infiltrating T lymphocytes within the tumor microenvironment (TME) remain enigmatic. Recently, the advent of single-cell RNA+TCR-sequencing (scRNA+TCR seq) has revolutionized TME analysis, providing unprecedented insight into the origins, cell subsets, TCR CDR3 compositions, and the expression patterns of response/depletion factors within individual tumor-infiltrating T lymphocytes. Our analysis of the shared scRNA+TCR seq dataset revealed a substantial presence of dual TCR T cells, characterized by clonal hyperplasia and remarkable migratory prowess across various tissues, including blood, normal, peritumoral, and tumor tissues in non-small cell lung cancer patients. Notably, dual TCR CD8+T cells predominantly fell within the CXCL13+subset, displaying potent antitumor activity and a strong preference for tumor tissue residency. Conversely, dual TCR CD4+T cells were predominantly classified as CD5+ or LMNA+subsets, exhibiting a more even distribution across diverse tissue types. By harnessing scRNA+TCR seq and other cutting-edge technologies, we can delve deeper into the effects and mechanisms that regulate the antitumor response or tolerance of dual TCR T cells. This innovative approach holds immense promise in offering fresh perspectives and avenues for advancing research on TIL (Tumor infiltrating lymphocyte)s within the TME.

Combining molecular transmission network analysis and spatial epidemiology to reveal HIV-1 transmission pattern among the older people in Nanjing, China.

BACKGROUND: In China, the problem of HIV infection among the older people has become increasingly prominent. This study aimed to analyze the pattern and influencing factors of HIV transmission based on a genomic and spatial epidemiological analysis among this population. METHODS: A total of 432 older people who were aged ≥ 50 years, newly diagnosed with HIV-1 between January 2018 and December 2021 and without a history of ART were enrolled. HIV-1 pol gene sequence was obtained by viral RNA extraction and nested PCR. The molecular transmission network was constructed using HIV-TRACE and the spatial distribution analyses were performed in ArcGIS. The multivariate logistic regression analysis was performed to analyze the factors associated with clustering. RESULTS: A total of 382 sequences were successfully sequenced, of which CRF07_BC (52.3%), CRF01_AE (32.5%), and CRF08_BC (6.8%) were the main HIV-1 strains. A total of 176 sequences entered the molecular network, with a clustering rate of 46.1%. Impressively, the clustering rate among older people infected through commercial heterosexual contact was as high as 61.7% and three female sex workers (FSWs) were observed in the network. The individuals who were aged ≥ 60 years and transmitted the virus by commercial heterosexual contact had a higher clustering rate, while those who were retirees or engaged other occupations and with higher education degree were less likely to cluster. There was a positive spatial correlation of clustering rate (Global Moran I = 0.206, P < 0.001) at the town level and the highly aggregated regions were mainly distributed in rural area. We determined three large clusters which mainly spread in the intra-region of certain towns in rural areas. Notably, 54.5% of cases in large clusters were transmitted through commercial heterosexual contact. CONCLUSIONS: Our joint analysis of molecular and spatial epidemiology effectively revealed the spatial aggregation of HIV transmission and highlighted that towns of high aggregation were mainly located in rural area. Also, we found vital role of commercial heterosexual contact in HIV transmission among older people. Therefore, health resources should be directed towards highly aggregated rural areas and prevention strategy should take critical persons as entry points.

Highly sensitive blood-based biomarkers detection of beta-amyloid and phosphorylated-tau181 for Alzheimer's disease.

Background: Plasma biomarker has the potential to be the reliable and propagable approach in the early stage diagnosis of Alzheimer's disease (AD). However, conventional methods appear powerless in the detection of these biomarkers at low concentrations in plasma. Here, we determined plasma biomarker concentrations of patients across the AD spectrum by an improved digital enzyme-linked immunosorbent assay (ELISA) technique. Confirms the predictive and diagnostic value of this method for AD patients and study the relationships between these biomarkers and cognitive status. Methods: Plasma concentrations of amyloid-beta 40 (Aß40), amyloid-beta 42 (Aß42) and plasma phosphorylated tau at threonine 181 (p-tau181) were determined in 43 AD patients, 33 mild cognitive impairment (MCI) patients and 40 normal cognition (NC) subjects as healthy controls using the improved digital ELISA technique. In addition, all subjects were required to receive neuropsychological assessments. Results: Plasma p-tau181 level showed certain discrepancies between NC and MCI (p < 0.05), AD (p < 0.01) groups. The level of plasma Aß42 (p < 0.05) and Aß40 (p < 0.01) was significantly different between AD and NC group. The p-tau181 level was able to distinguish AD (AUC = 0.8768) and MCI (AUC = 0.7932) from NC with higher accuracy than Aß42/Aß40 ratio (AUC = 0.8343, AUC = 0.6569). Both p-tau181 (CDR: r = 0.388 p < 0.001; MMSE: r = -0.394 p < 0.001) and Aß42/Aß40 ratio (CDR: r = -0.413 p < 0.001; MMSE: r = 0.358 p < 0.001) showed stronger positive correlation with clinical dementia rating (CDR) and mini mental state examination (MMSE) scores than Aß42 (CDR: r = -0.280 p = 0.003; MMSE: r = 0.266 p = 0.005) or Aß40 (CDR: r = 0.373 p < 0.001; MMSE: r = -0.288 p = 0.002) alone. Conclusion: Plasma p-tau181 level and Aß42/Aß40 ratio showed promising values in diagnosis of AD and MCI. Our results indicate that this improved digital ELISA diagnosis approach can facilitate early recognition and management of AD and pre-AD patients.

Air pollution, sustainable development, and corporate R&D: Evidence from emerging countries.

This paper studies the adverse effect of air pollution on corporate research and development (R&D) and how sustainable development moderates this negative impact in emerging market economies (EMEs). Using a sample of 18 EMEs' firm-level data, the empirical results show that firms substantially reduce R&D expenses in the face of increasing air pollution, and this adverse effect becomes less pronounced with higher levels of sustainable development. Our analyses suggest that air pollution negatively affects R&D by increasing firms' difficulties in hiring highly skilled people or raising operation and production costs. Furthermore, we divide our sample firms into two groups according to some institutional quality factors related to sustainable development. The negative impact of air pollution on R&D is lower in countries with higher levels of institutional quality. Based on our research, to attract more R&D investment, EMEs should not only make an effort to manage air pollution but also invest more in human capital and improve their institutional quality to amplify the impact of their efforts.

A novel prognosis evaluation indicator of patients with sepsis created by integrating six microfluidic-based neutrophil chemotactic migration parameters.

Impaired neutrophil migration in sepsis is associated with a poor prognosis. The potential of utilizing neutrophil chemotaxis to assess immune function, disease severity, and patient prognosis in sepsis remains underexplored. This study employed an innovative approach by integrating a multi-tip pipette with a Six-Unit microfluidic chip (SU6-chip) to establish gradients in six microchannels, thereby analyzing neutrophil chemotaxis in sepsis patients. We compared chemotactic parameters between healthy controls (NH = 20) and sepsis patients (NS1 = 25), observing significant differences in gradient perception time (GP), migration distance (MD), peak velocity (Vmax), chemotactic index (CI), reverse migration rate (RM), and stop migration number (SM). A novel composite indicator, the Sepsis Neutrophil Migration Evaluation (SNME) index, was developed by integrating these six chemotactic migration parameters. The SNME index and individual chemotaxis parameters showed significant correlations with the Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation (APACHE II) score, hypersensitivity C-reactive protein (hs-CRP), and heparin-binding protein (HBP). Moreover, the SNME index demonstrated potential for monitoring sepsis progression, with ROC analysis confirming its predictive accuracy (area under the curve [AUC] = 0.895, cutoff value = 31.5, specificity = 86.73 %, sensitivity = 86.71 %), outperforming individual neutrophil chemotactic parameters. In conclusion, the SNME index represents a promising new tool for adjunctive diagnosis and prognosis assessment in patients with sepsis.

Salivary-secreted vitellogenin suppresses H2O2 burst of plants facilitating Recilia dorsalis leafhopper feeding.

BACKGROUND: Vitellogenin (Vg), known as the yolk protein precursor for oocyte development in female insects, can be secreted to plant host from salivary glands of hemipterans, including rice leafhopper Recilia dorsalis. The aim of this study was to investigate the function of salivary-secreted Vg of R. dorsalis (RdVg) in rice host. We propose that RdVg possibly regulates the rice defense against insects, benefiting R. dorsalis feeding. RESULTS: RdVg was released into rice phloem along with saliva during R. dorsalis feeding. Knocking down RdVg increased the level of H2O2 and improved H2O2 metabolism in rice plants, making it difficult for R. dorsalis to feed. The transient expression or overexpression of the lipoprotein N-terminal domain of RdVg (RdVg2) significantly reduced hydrogen peroxide (H2O2) metabolism in plants. This suggests that salivary-secreted RdVg acts as an effector suppressing the H2O2 burst in rice plants, and RdVg2 is the key domain. RdVg2 could interact with rice sulfite oxidase (OsSO), which catalyzes the oxidation of SO3 2- and produces H2O2. Exposure of rice plants to R. dorsalis, overexpression of RdVg2 or knocking out OsSO reduced OsSO accumulation and SO3 2- oxidation, benefiting R. dorsalis feeding. However overexpression of OsSO increased SO3 2- oxidation and H2O2 metabolism, inhibiting R. dorsalis feeding. CONCLUSION: RdVg inhibits H2O2 generation via suppressing OsSO accumulation, ultimately benefiting R. dorsalis feeding. These findings identify RdVg as an effector that suppresses plant defense to insects, and provide insights into the function of salivary-secreted Vg in other Hemiptera insects. © 2024 Society of Chemical Industry.

A comparative evaluation of bioequivalence of Gan & Lee glargine U300 and Toujeo® in Chinese healthy male participants.

Background: To assess the bioequivalence between Gan & Lee (GL) glargine U300 and Toujeo® regarding pharmacokinetics (PK), pharmacodynamics (PD), and safety in Chinese healthy male participants. Methods: A single-center, randomized, double-blind, single-dose, two-preparation, two-sequence, four-cycle repeated crossover design study was performed to compare GL glargine U300 and Toujeo® in 40 healthy participants. The primary PK endpoints were the area under the curve of glargine metabolites, M1 concentration from 0 to 24 hours (AUC0-24h), and the maximum glargine concentration within 24 hours post-dose (Cmax). The primary PD endpoints were the area under the glucose infusion rate (GIR) curve from 0 to 24 hours (AUCGIR.0-24h) and the maximum GIR within 24 hours post-dose (GIRmax). Results: GL Glargine U300 demonstrated comparable PK parameters (AUC0-24h, Cmax, AUC0-12h, and AUC12-24h of M1) and PD responses [AUCGIR.0-24h, GIRmax, AUCGIR.0-12h, and AUCGIR.12-24h] to those of Toujeo®, as indicated by 90% confidence intervals ranging from 80% to 125%. No significant disparities in safety profiles were observed between the two treatment groups, and there were no reported instances of serious adverse events. Conclusion: The PK, PD, and safety of GL glargine U300 were bioequivalent to that of Toujeo®. Clinical trial registration: https://www.chinadrugtrials.org.cn/, identifier CTR20212419.

Biomedical application of TiO2NPs can cause arterial thrombotic risks through triggering procoagulant activity, activation and aggregation of platelets.

BACKGROUND: Titanium dioxide nanoparticles (TiO2NPs) are widely used in medical application. However, the relevant health risk has not been completely assessed, the potential of inducing arterial thrombosis (AT) in particular. METHODS: Alterations in platelet function and susceptibility to arterial thrombosis induced by TiO2NPs were examined using peripheral blood samples from healthy adult males and an in vivo mouse model, respectively. RESULTS: Here, using human platelets (hPLTs) freshly isolated from health volunteers, we demonstrated TiO2NP treatment triggered the procoagulant activity of hPLTs through phosphatidylserine exposure and microvesicles generation. In addition, TiO2NP treatment increased the levels of glycoprotein IIb/IIIa and P-selectin leading to aggregation and activation of hPLTs, which were exacerbated by providing physiology-mimicking conditions, including introduction of thrombin, collagen, and high shear stress. Interestingly, intracellular calcium levels in hPLTs were increased upon TiO2NP treatment, which were crucial in TiO2NP-induced hPLT procoagulant activity, activation and aggregation. Moreover, using mice in vivo models, we further confirmed that TiO2NP treatment a reduction in mouse platelet (mPLT) counts, disrupted blood flow, and exacerbated carotid arterial thrombosis with enhanced deposition of mPLT. CONCLUSIONS: Together, our study provides evidence for an ignored health risk caused by TiO2NPs, specifically TiO2NP treatment augments procoagulant activity, activation and aggregation of PLTs via calcium-dependent mechanism and thus increases the risk of AT.

Bispecific CAR-T cells targeting CD19/20 in patients with relapsed or refractory B cell non-Hodgkin lymphoma: a phase I/II trial.

Non-Hodgkin lymphoma (NHL) is a common malignancy in the hematologic system, and traditional therapy has limited efficacy for people with recurrent/refractory NHL (R/R NHL), especially for patients with diffuse large B cell lymphoma (DLBCL). Chimeric antigen receptor (CAR) T-cell therapy is a novel and effective immunotherapy strategy for R/R hematopoietic malignancies, but relapses can occur due to the loss of CAR-T cells in vivo or the loss of antigen. One strategy to avoid antigen loss after CAR-T cell therapy is to target one more antigen simultaneously. Tandem CAR targeting CD19 and CD22 has demonstrated the reliability of tandem CAR-T cell therapy for R/R B-ALL. This study explores the therapeutic potential of tandem CD19/20 CAR-T in the treatment of R/R B cell NHL. The efficacy and safety of autologous CD19/20 CAR-T cells in eleven R/R B cell NHL adult patients were evaluated in an open-label, single-arm trial. Most patients achieved complete response, exhibiting the efficacy and safety of tandem CD19/20 CAR-T cells. The TCR repertoire diversity of CAR-T cells decreased after infusion. The expanded TCR clones in vivo were mainly derived from TCR clones that had increased expression of genes associated with immune-related signaling pathways from the infusion product (IP). The kinetics of CAR-T cells in vivo were linked to an increase in the expression of genes related to immune response and cytolysis/cytotoxicity.

Sublobar resection for lung adenocarcinoma less than 2 cm containing solid or micropapillary components radiologically presented as consolidation-to-tumor ratio (CTR) ≤0.25 [ground-glass opacity (GGO)].

Background: The suitability of sublobar resection as a surgical approach for early-stage non-small cell lung cancer (NSCLC) remains unclear. This study investigated the feasibility of sublobar resection in patients with pathological-stage IA adenocarcinoma less than 2 cm characterized by a high-risk pathological subtype but exhibiting radiologically noninvasive features. Methods: We conducted a retrospective review of patients diagnosed with pathological stage IA lung adenocarcinoma who underwent surgical intervention between 2013 and 2017. The inclusion criteria included a maximum tumor diameter of 2.0 cm or less, a consolidation-to-tumor ratio (CTR) of 0.25 or less, and a histopathological confirmation of a solid or micropapillary component. Patients were categorized into sublobar resection and lobectomy groups, and propensity score matching was employed to mitigate potential confounders. The primary endpoints were lung cancer-specific survival (LCSS) and overall survival (OS). Results: The study comprised 149 patients, with 84 in the lobectomy group and 65 in the limited resection group. In the overall cohort, the 5-year LCSS was 100% for both groups, while the 5-year OS was 97.6% (95% CI: 94.41-100.00%) in the lobectomy group and 100% in the sublobar resection group (P=0.21). After propensity score matching, the LCSS remained at 100% for both groups, and the 5-year OS was 97.14% in the lobectomy group and 100% in the sublobar resection group (P=0.32). Conclusions: Based on our experience, for lung adenocarcinoma containing solid/micropapillary subtype, a size less than 2 cm, and a CTR ≤0.25, the oncological outcomes appeared to be comparable between sublobar resection and lobectomy, suggesting that sublobar resection might serve as an equivalent alternative to lobectomy for such lesions.

Case Report: Amiodarone-induced multi-organ toxicity.

Background: Amiodarone is a class III antiarrhythmic drug that is commonly used in the clinic to treat ventricular arrhythmias and atrial fibrillation. We present a case report of the adverse effects of amiodarone and review its characteristics. Case report: A 73-year-old Asian female with a history of paroxysmal atrial fibrillation managed with amiodarone, well-controlled hypertension, and no substance abuse presented with gastrointestinal distress and dizziness, without chest pain or palpitations. Despite normal annual check-ups, she developed abnormal liver and thyroid function tests, and imaging revealed lung and liver changes suggestive of amiodarone toxicity. Discontinuation of amiodarone for sotalol led to symptom improvement and normalization of thyroid and liver functions, with imaging indicating recovery from interstitial fibrosis and reduced liver density. Discussion: Amiodarone, a widely used for treating ventricular and atrial arrhythmias, and with significant benefits in improving patient survival in cases of ventricular fibrillation. However, its long-term use is associated with serious adverse effects, including thyroid dysfunction, liver injury, and pulmonary toxicity, necessitating careful monitoring and management. Despite its efficacy, the need for research on early detection and management of amiodarone's side effects is crucial, highlighting the importance of regular monitoring and possibly adjusting therapy to mitigate these risks.

An additional proofreader contributes to DNA replication fidelity in mycobacteria.

The removal of mis-incorporated nucleotides by proofreading activity ensures DNA replication fidelity. Whereas the ε-exonuclease DnaQ is a well-established proofreader in the model organism Escherichia coli, it has been shown that proofreading in a majority of bacteria relies on the polymerase and histidinol phosphatase (PHP) domain of replicative polymerase, despite the presence of a DnaQ homolog that is structurally and functionally distinct from E. coli DnaQ. However, the biological functions of this type of noncanonical DnaQ remain unclear. Here, we provide independent evidence that noncanonical DnaQ functions as an additional proofreader for mycobacteria. Using the mutation accumulation assay in combination with whole-genome sequencing, we showed that depletion of DnaQ in Mycolicibacterium smegmatis leads to an increased mutation rate, resulting in AT-biased mutagenesis and increased insertions/deletions in the homopolymer tract. Our results showed that mycobacterial DnaQ binds to the ß clamp and functions synergistically with the PHP domain proofreader to correct replication errors. Furthermore, the loss of dnaQ results in replication fork dysfunction, leading to attenuated growth and increased mutagenesis on subinhibitory fluoroquinolones potentially due to increased vulnerability to fork collapse. By analyzing the sequence polymorphism of dnaQ in clinical isolates of Mycobacterium tuberculosis (Mtb), we demonstrated that a naturally evolved DnaQ variant prevalent in Mtb lineage 4.3 may enable hypermutability and is associated with drug resistance. These results establish a coproofreading model and suggest a division of labor between DnaQ and PHP domain proofreader. This study also provides real-world evidence that a mutator-driven evolutionary pathway may exist during the adaptation of Mtb.

Vanadium-Based Metal-Organic Frameworks with Peroxidase-like Activity as a Colorimetric Sensing Platform for Direct Detection of Organophosphorus Pesticides.

Colorimetry based on the bioenzyme inhibition strategy holds promising application prospects in the field of organophosphorus pesticide (OPs) detection. However, overcoming the challenges of the high cost and low stability of bioenzymes remains crucial. In this study, we successfully synthesized a peroxidase vanadium-based metal-organic framework (MOF) nanozyme named MIL-88B(V) and employed its mediated bioenzyme-free colorimetric strategy for direct OPs detection. The experimental results demonstrated that MIL-88B(V) exhibited a remarkable affinity and a remarkable catalytic rate. When the OPs target is added, it can be anchored on the MOF surface through a V-O-P bond, effectively inhibiting the MOF's activity. Subsequently, leveraging the advantages of smartphones such as convenience, speed, and sensitivity, we developed a paper sensor integrated into a smartphone for efficient OPs detection. The as-designed nanozyme-based colorimetric assay and paper sensor presented herein offer notable advantages, including affordability, speed, stability, wide adaptability, low cost, and accuracy in detecting OPs, thus providing a versatile and promising analytical approach for real sample analysis and allowing new applications of V-based MOF nanozymes.

Uterine tumors mimicking ovarian sex cord tumors with rhabdoid differentiation: a clinicopathologic study of 4 cases: A case series analysis.

RATIONALE: Uterine tumors resembling ovarian sex cord tumors (UTROSCT) with rhabdoid features are uncommon mesenchymal neoplasms exhibiting diverse histological patterns, including significant rhabdoid morphology. A thorough comprehension of their clinicopathologic features is crucial for precise diagnosis and effective management. PATIENT CONCERNS: This study presents 4 cases of UTROSCT with rhabdoid features, diagnosed in patients aged 31 to 58. Varied recurrence patterns were observed, including similar recurrent lesions to the primary tumors with subsequent mortality, initial invasion and lymph node metastasis, and presence of only primary tumor. DIAGNOSES: Histopathological examination revealed diverse morphological patterns, prominently featuring rhabdoid differentiation. Immunohistochemical analysis showed expression of hormone receptors, sex cord, smooth muscle, and epithelial markers, notably WT1, CD56, and CD99. Molecular analysis identified ESR1-NCOA2 fusions and ESR1 and NCOA2/3 rearrangements, indicating a potential association between these genetic alterations and extensive rhabdoid differentiation. INTERVENTIONS: Various treatments were administered post-recurrence, including chemotherapy and targeted therapies. However, poor clinical outcomes were observed in all cases. OUTCOMES: Despite aggressive treatments, including chemotherapy and targeted therapies, poor clinical outcomes were observed, highlighting the aggressive nature of UTROSCT with significant rhabdoid differentiation. LESSONS: This case series emphasizes the importance of detailed pathological reporting, comprehensive molecular testing, and thorough tumor staging in UTROSCT cases with rhabdoid features. Enhanced understanding of the clinicopathologic characteristics of UTROSCT with rhabdoid differentiation is crucial for accurate diagnosis, prognostication, and management strategies.

Transformation of p-arsanilic acid by dissolved Mn(III) and enhanced arsenic removal: Mechanism, toxicity and performance in complicated water matrices.

Dissolved Mn(III), as a potent one-electron transfer oxidant, is ubiquitous in natural waters and sediments and actively involved in the transformation of organics in biogeochemical processes and water treatment. However, the important role of Mn(III) has long been overlooked because of its short life. This study was the first to investigate the performance of Mn(III) in organoarsenic transformation and to highlight the environmental implications. Both homogeneous and heterogeneous Mn(III)-based systems were effective to remove p-arsanilic acid (p-ASA, 15 µM) with degradation efficiency approaching 40.4 %-98.3 %. Two degradation pathways of p-ASA were proposed, in which As-C bond and amino group were vulnerable sites to Mn(III) attack, leading to the formation of more toxic arsenate (As(V)) and nitarsone. Through transforming organoarsenic to inorganic arsenic species, the removal efficiency of total arsenic and dissolved organics were enhanced to 65.1 %-95.5 % and 16.6 %-36.6 %, respectively, by post-treatment of coagulation or adsorption, accompanied with significant reduction of cytotoxicity and environmental risks. Particularly, polymeric ferric sulfate and granular activated alumina showed superior performance in the total As removal. Moreover, oxidation efficiency of Mn(III) was hardly affected by common cations and anions (e.g., Ca2+, Mg2+, NH4+, NO3-, SO4-), halide ions (e.g., Cl-, Br-) and natural organic matter, showing high robustness for organoarsenic removal under complicated water matrices. Overall, this study shed light on the significance of Mn(III) to the fate of organoarsenics in manganese-rich environments, and demonstrated the promising potential of Mn(III)-based strategies to achieve targeted decontamination in water/wastewater purification.

Hypoxia-inducible lipid droplet-associated protein (HILPDA) and cystathionine ß-synthase (CBS) co-contribute to protecting intestinal epithelial cells from Staphylococcus aureus via regulating lipid droplets formation.

Despite Staphylococcus aureus (S. aureus) being a highly studied zoontic bacterium, its enteropathogenicity remains elusive. Herein, our findings demonstrated that S. aureus infection led to the accumulation of lipid droplets (LDs) in intestinal epithelial cells, accompanied by marked elevation inflammatory response that ultimately decreases intracellular bacterial load. The aforestated phenomenon may be partly attributed to the up-regulation of hypoxia-inducible lipid droplet-associated protein (HILPDA) and the concomitant down-regulation of cystathionine ß-synthase (CBS) protein. Moreover, S. aureus infection up-regulated the expression of HILPDA, thereby promoting LDs accumulation, and down-regulated that of CBS, consequently inhibiting microsomal triglyceride transfer protein (MTTP) expression. This process may suppress the transport of LDs to the extracellular environment, further contributing to the formation of intracellular LDs. In summary, the results of this study provide significant insights into the intricate mechanisms through which the host organism combats pathogens and maintains the balance of sulfur and lipid metabolism. These findings not only enhance our understanding of the host's defense mechanisms but also offer promising avenues for the development of novel strategies to combat intestinal infectious diseases.

CX43 and oxidative stress are the targets of BCB staining to predict the developmental potential of buffalo oocytes.

This study used the brilliant cresyl blue (BCB) staining method to group buffalo oocytes (BCB+ and BCB-) and perform in vitro maturation, in vitro fertilization and embryo culture. At the same time, molecular biology techniques were used to detect gap junction protein expression and oxidative stress-related indicators to explore the molecular mechanism of BCB staining to predict oocyte developmental potential. The techniques of buffalo oocytes to analyse their developmental potential and used immunofluorescence staining to detect the expression level of CX43 protein, DCFH-DA probe staining to detect ROS levels and qPCR to detect the expression levels of the antioxidant-related genes SOD2 and GPX1. Our results showed that the in vitro maturation rate, embryo cleavage rate and blastocyst rate of buffalo oocytes in the BCB+ group were significantly higher than those in the BCB- group and the control group (p < .05). The expression level of CX43 protein in the BCB+ group was higher than that in the BCB- group both before and after maturation (p < .05). The intensity of ROS in the BCB+ group was significantly lower than that in the BCB- group (p < .05), and the expression levels of the antioxidant-related genes SOD2 and GPX1 in the BCB+ group were significantly higher than those in the BCB- group (p < .05). Brilliant cresyl blue staining could effectively predict the developmental potential of buffalo oocytes. The results of BCB staining were positively correlated with the expression of gap junction protein and antioxidant-related genes and negatively correlated with the reactive oxygen species level, suggesting that the mechanism of BCB staining in predicting the developmental potential of buffalo oocytes might be closely related to antioxidant activity.

SLC7A11 protects luminal A breast cancer cells against ferroptosis induced by CDK4/6 inhibitors.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) can significantly extend tumor response in patients with metastatic luminal A breast cancer, yet intrinsic and acquired resistance remains a prevalent issue. Understanding the molecular features of CDK4/6 inhibitor sensitivity and the potential efficacy of their combination with novel targeted cell death inducers may lead to improved patient outcomes. Herein, we demonstrate that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, partly underpins the efficacy of CDK4/6 inhibitors. Mechanistically, CDK4/6 inhibitors downregulate the cystine transporter SLC7A11 by inhibiting SP1 binding to the SLC7A11 promoter region. Furthermore, SLC7A11 is identified as critical for the intrinsic sensitivity of luminal A breast cancer to CDK4/6 inhibitors. Both genetic and pharmacological inhibition of SP1 or SLC7A11 enhances cell sensitivity to CDK4/6 inhibitors and synergistically inhibits luminal A breast cancer growth when combined with CDK4/6 inhibitors in vitro and in vivo. Our data highlight the potential of targeting SLC7A11 in combination with CDK4/6 inhibitors, supporting further investigation of combination therapy in luminal A breast cancer.

Allicin Mitigates Diabetic Retinopathy in Rats by Activating Phosphatase and Tensin Homolog-induced Kinase 1/Parkin-mitophagy and Inhibiting Oxidative Stress-mediated NOD-like Receptor Family Pyrin Domain Containing 3 Inflammasome.

ABSTRACT: Diabetic retinopathy (DR) is one of the significant disabling outcomes of diabetes mellitus characterized by retinal microvascular damage, inflammation, and neuronal dysfunction. Allicin (Alc), a natural compound found in garlic, has garnered attention for its antioxidant and anti-inflammatory properties, positioning it as a potential therapeutic agent for DR. The aim of the present study was to investigate the therapeutic efficacy of Alc in DR management and elucidate its underlying mechanisms of action. We established a DR model in male Sprague-Dawley rats (n = 50, 200-250 g, 12 weeks old) using a high-fat diet for 8 weeks plus a low dose of streptozotocin administered at the start of the 4th week. The diabetic (Diab) animals were administered Alc (16 mg/kg/day, orally), either alone or in combination with mitochondrial division inhibitor-1 (Mdivi-1) as a mitophagy inhibitor, starting 28 days before tissue sampling. We evaluated histopathological changes, metabolic abnormalities associated with type 2 diabetes mellitus (T2DM), the expression of proteins regulating pyroptosis (NOD-like receptor family pyrin domain containing 3, cleaved-caspase 1, and gasdermin D-N terminal) and mitophagy (phosphatase and tensin homolog-induced kinase 1 [PINK1] and Parkin), as well as the levels of oxidative stress mediators and proinflammatory cytokines. Alc treatment effectively ameliorated histopathological changes and metabolic abnormalities associated with T2DM. It downregulated pyroptosis-related proteins, upregulated mitophagy-related proteins, reduced proinflammatory cytokine levels, and attenuated oxidative stress. Treatment with Mdivi-1 suppressed the beneficial effects of Alc. Our findings highlight the therapeutic potential of Alc in managing DR by targeting multiple pathophysiological pathways, including pyroptosis, inflammation, and oxidative stress. The observed antipyroptotic effects of Alc were partially mediated by the activation of the PINK1/parkin-mediated mitophagy pathway. Additional studies are necessary to thoroughly understand the therapeutic mechanisms of Alc and its viability as a treatment choice for DR.

Alterations of pathogen transmission patterns and attenuated immune stimulation might be the cause of increased adult respiratory infections cases in 2023, results from a multi-center study in mainland China.

Background: Several respiratory infections outbreaks have been observed in mainland China after reduction of non-pharmaceutical interventions. Other countries have seen increases in respiratory infections outside typical seasons post-COVID-19, warranting investigation into underlying causes. Methods: We established monitoring networks for suspected respiratory infection in 14 tertiary hospitals nationwide. PCR for SARS-CoV-2, influenza A and B were performed on 3708 respiratory specimens and deep sequencing were conducted to identify co-infections or newly emerging microbes in 2023. Viral evolutionary analysis was completed. We retrospectively detected serum antibody level for various respiratory pathogens from 4324 adults without respiratory infections over 7 years to observe its dynamic curves. Findings: SARS-CoV-2 and influenza A were the main pathogens during outbreaks in 2023, bacterial-virus and bacterial-bacterial co-infections were most detected, but community co-infections didn't significantly increase pneumonia incidence. Different SARS-CoV-2 and influenza variants were present in different outbreaks, and no novel pathogens were found. The epidemiological patterns of influenza A, COVID-19 and etc. were altered, exhibiting characteristics of being "staggered" compared to most global regions, and potentially led to "overlapping prevalence". Binding antibody testing showed regular fluctuation, without significant decrease against common respiratory pathogens in adults. Influenza A antibody stimulation was attenuated during the 2023 outbreak. Conclusions: "Misaligned" alteration in seasonal respiratory disease patterns possibly caused combined epidemics, leading to cases spike in China, 2023. In adults, antibody levels didn't show significant decline, but reduced immune response to influenza during 2020-2023 emphasizes the need for consistent vaccination during pandemics.