Material-driven immunomodulation and ECM remodeling reverse pulmonary fibrosis by local delivery of stem cell-laden microcapsules.

Recent progress in stem cell therapy has demonstrated the therapeutic potential of intravenous stem cell infusions for treating the life-threatening lung disease of pulmonary fibrosis (PF). However, it is confronted with limitations, such as a lack of control over cellular function and rapid clearance by the host after implantation. In this study, we developed an innovative PF therapy through tracheal administration of microfluidic-templated stem cell-laden microcapsules, which effectively reversed the progression of inflammation and fibrotic injury. Our findings highlight that hydrogel microencapsulation can enhance the persistence of donor mesenchymal stem cells (MSCs) in the host while driving MSCs to substantially augment their therapeutic functions, including immunoregulation and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) remodeling. We revealed that microencapsulation activates the MAPK signaling pathway in MSCs to increase MMP expression, thereby degrading overexpressed collagen accumulated in fibrotic lungs. Our research demonstrates the potential of hydrogel microcapsules to enhance the therapeutic efficacy of MSCs through cell-material interactions, presenting a promising yet straightforward strategy for designing advanced stem cell therapies for fibrotic diseases.

A comparative study on the lipid layer thickness analysis of medical staff before and after work.

Background & Aims: To study the change of the lipid layer thickness analysis in medical staff (MS) before and after work, and to explore the significance of measuring lipid layer thickness (LLT) respectively in four quadrants. Methods: Ocular Surface Disease Index (OSDI) questionnaire and video display terminal using time for 55 MS were collected (the informed consent was obtained from all patients). Noninvasive tear break-up time, LLT, tear meniscus height (TMH), meibomian glands (MG) dropout, and blink pattern before and after work (worked for more than 4 h) of 110 eyes were measured by Gaush iDea Ocular surface analyzer. Lid margin abnormalities were evaluated by the slit-lamp microscopy. Results: The average OSDI score of 55 MS was 25.68 ± 14.91. The average LLT of 110 eyes after work (65.12 ± 3.63 nm) was significantly reduced compared to before work (66.54 ± 4.16 nm), p < 0.05. The LLT in the superior quadrant was significantly thinner than that in the other three quadrants, p < 0.01. The average LLT was positively correlated with the LLT in the inferior (r = 0.822, p < 0.001), nasal (r = 0.261, p < 0.001), and temporal quadrant (r = 0.372, p < 0.001), while was negatively correlated with the MG dropout in lower lid (r = -0.209, p = 0.002). There was a significant correlation between the LLT in the inferior quadrant and the VDTt (r = -0.173, p = 0.01). The LLT of inferior quadrant were positively related to the TMH (r = 0.149, p = 0.027) and negatively related to MG dropout in lower lid (r = -0.162, p = 0.017). Conclusion: The LLT significantly decreases after work in MS. The distribution of the lipid layer on the ocular surface is uneven. It is unreasonable for current detection instruments to measure the inferior quadrant LLT alone to represent average LLT.

Electrochemically Driven α,ß-Dehydrogenation of Flavanones, Azaflavanones, and Thioflavanones.

α,ß-Dehydrogenation of flavanones represents an ideal strategy to synthesize various flavones but remains challenging because of the requirements for rigorous conditions. Herein, a straightforward and efficient route for the synthesis of flavones via electrocatalysis is disclosed. This electro-oxidative approach shows a broad substrate scope, including azaflavanones and thioflavanones, which could be performed in an undivided cell without the removal of air or water and in the absence of metal catalysts, ligands, or external oxidants. Moreover, the combination of cyclic voltammetry, square wave voltammetry experiments, and density functional theory (DFT) calculations revealed the plausible mechanism.

Prolonged Omicron-specific B cell maturation alleviates immune imprinting induced by SARS-CoV-2 inactivated vaccine.

SARS-CoV-2 ancestral strain-induced immune imprinting poses great challenges to updating vaccines for new variants. Studies showed that repeated Omicron exposures could override immune imprinting induced by inactivated vaccines but not mRNA vaccines, a disparity yet to be understood. Here, we analyzed the immune imprinting alleviation in inactivated vaccine (CoronaVac) cohorts after a long-term period following breakthrough infections (BTI). We observed in CoronaVac-vaccinated individuals who experienced BA.5/BF.7 BTI, the proportion of Omicron-specific memory B cells (MBCs) substantially increased after an extended period post-Omicron BTI, with their antibodies displaying enhanced somatic hypermutation and neutralizing potency. Consequently, the neutralizing antibody epitope distribution encoded by MBCs post-BA.5/BF.7 BTI after prolonged maturation closely mirrors that in BA.5/BF.7-infected unvaccinated individuals. Together, these results indicate the activation and expansion of Omicron-specific naïve B cells generated by first-time Omicron exposure helped to alleviate CoronaVac-induced immune imprinting, and the absence of this process should have caused the persistent immune imprinting seen in mRNA vaccine recipients.

IL-1 receptor-associated kinase 3 (IRAK3) in lung adenocarcinoma predicts prognosis and immunotherapy resistance: involvement of multiple inflammation-related pathways.

Background: Lung cancer is a globally prevailing malignancy, and the predominant histological subtype is lung adenocarcinoma (LUAD). IL-1 receptor-associated kinase 3 (IRAK3) has been identified in connection with innate immune and inflammatory response. The aim of this study is to investigate the impact of IRAK3 on prognosis and immunotherapy efficacy in LUAD, which remains incompletely elucidated. Methods: Our study delved into multiple online databases to find out expression, methylation and prognostic potentials of IRAK3 in LUAD and other malignancies. We employed tissue microarrays to assess IRAK3 protein levels in our LUAD cohort [National Cancer Center (NCC), China] and explore prognostic values. The correlations between IRAK3 and immune infiltration based on The Cancer Genome Atlas (TCGA) data were analyzed by corresponding algorithms. The contribution of IRAK3 to immunotherapy response was explored through the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Both LinkedOmics database and gene set enrichment analysis (GSEA) were applied to investigate how IRAK3 influences the tumor immune microenvironment and regulates immunotherapy response. We applied single-cell RNA sequencing datasets for the investigation of IRAK3 expression across diverse immune cells. Moreover, we employed genomics of drug sensitivity in cancer (GDSC) databases to examine how IRKA3 expression correlates with different drug responses. Results: Compared with normal tissues, various tumor tissues had lower IRAK3 expression which could be regulated by its high methylation level. Reduced IRAK3 protein level was observed to correlate with advanced tumor stages and unfavorable prognosis among patients with LUAD, especially individuals with lymph node metastasis. Gene set enrichment analysis (GSEA) and tumor infiltration analysis proved that IRAK3 provoked immune infiltration. Macrophages/monocytes, CD4+ T cells, CD8+ T cells and neutrophils correlated significantly with IRAK3 expression. With TIDE algorithm, IRAK3 was verified to be related to poor immune checkpoint blockade (ICB) response. IRAK3 demonstrated positive associations with T-cell dysfunction score and immune checkpoint markers. Conversely, it exhibited negative correlations with microsatellite instability (MSI) and tumor mutation burden (TMB). High IRAK3 expression exacerbated cytotoxic T lymphocyte (CTL) dysfunction and predicted immunotherapy resistance by involvement of multiple inflammation-related pathways including IL-6/JAK/STAT3 signaling, inflammatory response and interferon-gamma (IFN-γ) response pathways. Additionally, elevated IRAK3 expression was predicted to be related with better responses to chemotherapeutic and molecular targeted drugs. Conclusions: Our findings indicated that IRAK3 could function as an independent prognostic predictor and an immunotherapeutic indicator in LUAD through involvement of multiple inflammation-related pathways.

Plasma fatty acid levels and risk of non-small cell lung cancer: a large-scale prospective cohort study.

Background: Non-small cell lung cancer (NSCLC) ranks among the most prevalent and lethal malignancies globally. Fatty acids (FAs) play a significant role in diverse physiological and pathological mechanisms, yet their precise involvement in NSCLC remains poorly understood. Methods: This study utilized a large-scale prospective cohort of 249,132 participants, observed over an average of 12 years, to investigate the relationship between different FAs and NSCLC risk. Analytical approaches included Cox proportional hazards regression, Kaplan-Meier survival analysis, accelerated failure time (AFT) modeling, and restricted cubic spline (RCS) analysis. Results: During the follow-up period, 1,460 participants were diagnosed with NSCLC. Cox regression analysis demonstrated that elevated levels of docosahexaenoic acid (DHA), linoleic acid (LA), and omega-3 were inversely associated with NSCLC risk. Kaplan-Meier curves, along with AFT models, corroborated that elevated concentrations of DHA and LA significantly delayed NSCLC onset. Additionally, RCS analysis uncovered nuanced dose-response relationships between these FAs and NSCLC. Stratified analyses highlighted variability based on smoking status, gender, and body mass index subgroups. Conclusion: The concentration of specific FAs exhibits a significant association with NSCLC risk. These results offer a foundation for devising dietary FA composition adjustments aimed at reducing NSCLC risk.

Interfacial energy conversion mechanism between 3003 aluminum alloy and 321 stainless steel in vaporizing foil actuator welding process.

Conventional welding methods encounter significant challenges, including poor weldability, low joint strength, and the formation of brittle intermetallic compounds, primarily due to the substantial disparities in the physical and chemical properties of aluminum and iron. To mitigate these issues, the vaporizing foil actuator welding (VFAW) process has emerged as a highly promising solid-phase welding technology, particularly suitable for joining dissimilar metals with pronounced differences in properties, such as aluminum alloys and stainless steels. The present study provides an innovative quantitative analysis of the interfacial impact energy conversion mechanisms within the VFAW process. The analysis reveals that the energy responsible for accelerating the flyer workpiece comprises burst vaporization energy ( E d ) and continuous vaporization energy ( E p ), with E d identified as the primary energy source, contributing approximately 65-80% of the total energy required for acceleration. Further examination elucidates the mechanisms underlying heat generation and transfer during the interface collision. The investigation identifies the formation of an overheating zone at the interface, attributed to the combined effects of plastic deformation energy and adiabatic shear energy within the flyer workpiece. Consequently, the interface temperature can rise significantly, reaching up to 1394 K, with impact velocities as high as 925 m/s. The analyses contribute to establishing a theoretical foundation for understanding the interface bonding mechanisms characteristic of the vaporizing foil actuator welding method.

Droplet Impact on the Superhydrophobic Surface with Singularities.

Reducing the contact time of an impacting droplet is highly desirable in various industrial fields including anti-icing. With the straightforward upscaling advantage, singularities on superhydrophobic surfaces can induce an annular rebound with a limited reduction in contact time. To break this limitation and further reduce contact time, this study focuses on optimizing the singularity number and arrangement. The effects of the singularity number and dimensionless spacing (l* scaled by the droplet diameter) on the dynamic and contact time characteristics of a droplet impacting the superhydrophobic surface are experimentally studied under varying Weber numbers (We). The experimental results indicate that in comparison to the single singularity, two singularities with l* < 1.0 can generate two liquid rings with four lateral liquid subunits due to the impalement at the high We region. Owing to the reduced equivalent diameter of the subunit, increasing We results in a gradually decreased contact time and accordingly breaks the limitation. However, the liquid film cannot be pierced at l* > 1.0 with a limited reduction. Considering the further reducing potential at l* < 1.0, four singularities are explored without a further reduced contact time due to the formed central liquid film. Using an additional central singularity, the central liquid film is pierced promoting its annular rebound. In consequence, five singularities significantly break the limitation in contact time, particularly a 61.7% reduction to the superhydrophobic flat surface at l* < 1.0.

Catalytic Asymmetric Diastereodivergent Synthesis of 2-Alkenylindoles Bearing both Axial and Central Chirality.

The catalytic asymmetric diastereodivergent synthesis of axially chiral 2-alkenylindoles was established via chiral phosphoric acid-catalyzed addition reactions of C3-unsubstituted 2-alkenylindoles with o-hydroxybenzyl alcohols under different reaction conditions. Using this strategy, two series of 2-alkenylindoles bearing both axial and central chirality were synthesized in a diastereodivergent fashion with moderate to high yields and good stereoselectivities (up to 99% yield, 95:5 er, >95:5 dr). Moreover, theoretical calculations were performed on the key transition states leading to different stereoisomers, which provided an in-depth understanding of the origin of the observed stereoselectivity and diastereodivergence of the products under different reaction conditions. More importantly, these 2-alkenylindoles were utilized in asymmetric catalysis as chiral organocatalysts and in medicinal chemistry for evaluation of their cytotoxicity, which demonstrated their potential applications. This study has not only established the catalytic atroposelective synthesis of axially chiral 2-alkenylindoles, but also provided an efficient strategy for catalytic asymmetric diastereodivergent construction of indole-based scaffolds bearing both axial and central chirality.

Associations of sarcopenia, obesity, and metabolic health with the risk of urinary incontinence in U.S. adult women: a population-based cross-sectional study.

Introduction: Urinary incontinence (UI) significantly impairs women's quality of life. Identifying its risk factors is essential for developing effective interventions. Sarcopenia, characterized by the accelerated loss of muscle mass and function, is an emerging concern often linked to obesity and abnormal metabolic status, exacerbating various adverse health outcomes. This population-based study aimed to explore the independent and joint associations of sarcopenia, obesity, and metabolic health with UI risk, as well as to evaluate the mediating role of metabolic indicators in these associations. Methods: A total of 3,557 women aged ≥20 years from the National Health and Nutrition Examination Survey were included. Sarcopenia was assessed using the appendicular lean mass index (ALMI), and obesity was defined by body mass index and waist circumference. Metabolic health was evaluated using revised criteria from the National Cholesterol Education Program-Adult Treatment Panel III. UI was identified through responses to the "Kidney Conditions-Urology" questionnaire and classified into stress UI (SUI), urgency UI (UUI), and mixed UI (MUI). Multivariable logistic regression and restricted cubic spline models were used to evaluate the associations and visualize the relationship between ALMI and UI. Mediation models were constructed to assess the mediating role of metabolic indicators. Results: We found that sarcopenia was significantly associated with an increased risk of MUI in the general population. Age-specific analysis revealed that sarcopenia is an independent risk factor for SUI in women aged ≥60, and for MUI in women aged 40-59 years. Sarcopenic obesity, particularly under central obesity criteria, further elevated the risk of UI. Notably, women with the metabolically unhealthy obese phenotype with sarcopenia were at the highest risk for both SUI and MUI. Metabolically unhealthy status, glycohemoglobin, vitamin D, and serum albumin levels were partial mediators of these associations. Conclusion: Our findings elucidated the complex interactions between sarcopenia, obesity, and metabolic health, underscoring the critical need for integrated therapeutic strategies that address both metabolic health and targeted nutritional interventions, aiming to enhance muscular health and effectively manage and prevent UI.

Omicron-specific ultra-potent SARS-CoV-2 neutralizing antibodies targeting the N1/N2 loop of Spike N-terminal domain.

A multitude of functional mutations continue to emerge on the N-terminal domain (NTD) of the spike protein in SARS-CoV-2 Omicron subvariants. Understanding the immunogenicity of Omicron NTD and the properties of antibodies elicited by it is crucial for comprehending the impact of NTD mutations on viral fitness and guiding vaccine design. In this study, we find that most of NTD-targeting antibodies isolated from individuals with BA.5/BF.7 breakthrough infection (BTI) are ancestral (wild-type or WT)-reactive and non-neutralizing. Surprisingly, we identified five ultra-potent neutralizing antibodies (NAbs) that can only bind to Omicron but not WT NTD. Structural analysis revealed that they bind to a unique epitope on the N1/N2 loop of NTD and interact with the receptor-binding domain (RBD) via the light chain. These Omicron-specific NAbs achieve neutralization through ACE2 competition and blockage of ACE2-mediated S1 shedding. However, BA.2.86 and BA.2.87.1, which carry insertions or deletions on the N1/N2 loop, can evade these antibodies. Together, we provided a detailed map of the NTD-targeting antibody repertoire in the post-Omicron era, demonstrating their vulnerability to NTD mutations enabled by its evolutionary flexibility, despite their potent neutralization. These results revealed the function of the indels in the NTD of BA.2.86/JN.1 sublineage in evading neutralizing antibodies and highlighted the importance of considering the immunogenicity of NTD in vaccine design.

The neutrophil-to-lymphocyte ratio levels over time correlate to all-cause hospital mortality in sepsis.

Objective: This research aims to investigate the prognosis value using the time-weighted average neutrophil-to-lymphocyte ratio (TWA-NLR) for predicting all-cause hospital mortality among sepsis patients. Data were analyzed through the use of the eICU Collaborative Research Database (eICU-CRD 2.0) as well as Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV 2.2). Methods: Septic patients from both eICU-CRD 2.0 as well as MIMIC-IV 2.2 databases were included. The neutrophil-to-lymphocyte ratios (NLR) were available for analysis, utilizing complete blood counts obtained on days one, four, and seven following ICU admission. The TWA-NLR was computed at the end of the seven days, and patients were then stratified based on TWA-NLR thresholds. 90-day all-cause mortality during hospitalization was the primary objective, with 60-day all-cause hospital mortality as a secondary objective. The correlation between TWA-NLR and sepsis patients' primary outcome was analyzed using univariable and multivariable Cox proportional hazard regressions. A restricted cubic spline (RCS) analysis was conducted in an attempt to confirm this association further, and subgroup analyses were employed to evaluate the correlation across various comorbidity groups. Results: 3921 patients were included from the eICU-CRD 2.0, and the hospital mortality rate was 20.8 %. Both multivariable as well as univariable Cox proportional hazard regression analyses revealed that TWA-NLR was independently correlated with 90-day all-cause hospital mortality, yielding a hazard ratio (HR) of 1.02 (95 % CI 1.01-1.02, P-value<0.01) as well as 1.12 (95 % CI 1.01-1.15, P-value<0.01), respectively. The RCS analysis demonstrated a significant nonlinear relationship between TWA-NLR and 90-day all-cause hospital mortality risk. The study subjects were divided into higher (>10.5) and lower (≤10.5) TWA-NLR cohorts. A significantly decreased incidence of 90-day all-cause hospital mortality (HR = 0.56, 95 % CI 0.48-0.64, P-value<0.01) and longer median survival time (40 days vs 24 days, P-value<0.05) were observed in the lower TWA-NLR cohort. However, septic patients with chronic pulmonary (interaction of P-value = 0.009) or renal disease (interaction of P-value = 0.008) exhibited significant interactive associations between TWA-NLR and 90-day all-cause hospital mortality, suggesting the predictive power of TWA-NLR may be limited in these subgroups. The MIMIC-IV 2.2 was utilized as a validation cohort and exhibited a similar pattern. Conclusion: Our findings suggest that TWA-NLR is a powerful and independent prognostic indicator for 90-day all-cause hospital mortality among septic patients, and the TWA-NLR cutoff value may prove a useful method for identifying high-risk septic patients.

3D Leaf-Like Copper-Zinc Alloy Enables Dendrite-Free Zinc Anode for Ultra-Long Life Aqueous Zinc Batteries.

Metallic zinc exhibits immense potential as an anode material for aqueous rechargeable zinc batteries due to its high theoretical capacity, low redox potential, and inherent safety. However, practical applications are hindered by dendrite formation and poor cycling stability. Herein, a facile substitution reaction method is presented to fabricate a 3D leaf-like Cu@Zn composite anode. This unique architecture, featuring a 3D network of leaf-like Cu on a Zn foil surface, significantly reduces nucleation overpotential and facilitates uniform Zn plating/stripping, effectively suppressing dendrite growth. Notably, an alloy layer of CuZn5 forms in situ on the 3D Cu layer during cycling. DFT calculations reveal that this CuZn5 alloy possesses a lower Zn binding energy compared to both Cu and Zn metal, further promoting Zn plating/stripping and enhancing electrochemical kinetics. Consequently, the symmetric Cu@Zn electrode exhibits remarkable cycling stability, surpassing 1300 h at 0.5 mA cm-2 with negligible dendrite formation. Furthermore, full cells comprising Cu@Zn||VO2 exhibit superior capacity and rate performance compared to bare Zn anodes. This work provides a promising strategy for constructing highly stable and efficient Zn anodes for next-generation aqueous zinc batteries.

Association of pre-pregnancy body mass index and gestational weight gain on postpartum pelvic floor muscle morphology and function in Chinese primiparous women: A retrospective cohort study.

OBJECTIVE: Our study aimed to investigate the association between maternal pre-pregnancy body mass index (BMI), gestational weight gain (GWG), and impaired pelvic floor muscle (PFM) morphology and function during the early postpartum period. METHODS: This retrospective cohort study was conducted at Shanghai First Maternity and Infant Hospital from December 2020 to December 2022. A total of 1118 primiparous women with singleton pregnancies who underwent vaginal deliveries and participated in postpartum PFM assessments were included. Maternal pre-pregnancy BMI and GWG were considered as exposures. PFM morphology and function impairment were the primary outcomes. PFM morphology impairment, defined as levator ani muscle avulsion, was assessed using transperineal ultrasound. PFM function impairment, manifested as diminished PFM fiber strength, was assessed through vaginal manometry. Multivariable logistic regression analysis was employed to calculate adjusted odds ratios (aOR) with 95% confidence intervals (CI). Restricted cubic spline models were used to validate and visualize the relationship. RESULTS: Women with lower pre-pregnancy BMI were at an increased risk of levator ani muscle avulsion (aOR = 1.73, 95% CI: 1.10-2.70, P = 0.017), particularly when combined with excessive GWG during pregnancy (aOR = 3.20, 95% CI: 1.15-8.97, P = 0.027). Lower pre-pregnancy BMI was also identified as an independent predictor of PFM weakness (aOR = 1.53, 95% CI: 1.08-2.16, P = 0.017 for type I fiber injuries). Notably, regardless of the avulsion status, both underweight and overweight/obese women faced an elevated risk of reduced PFM strength (aOR = 1.74, 95% CI: 1.17-2.59, P = 0.006 for underweight women with type I fiber injuries; aOR = 1.67, 95% CI: 1.06-2.64, P = 0.027; and aOR = 1.73, 95% CI: 1.09-2.76, P = 0.021 for overweight/obese women with type I and type II fibers injuries, respectively). CONCLUSIONS: Both lower and higher pre-pregnancy BMI, as well as excessive GWG, were strongly associated with PFM impairments. These findings highlighted the critical importance of comprehensive weight management throughout pregnancy to effectively promote women's pelvic health.

Association between BMI and success of transaxillary venous port implantation: A retrospective cohort study.

PURPOSE: Totally implanted venous access device are widely used for long-term chemotherapy in cancer patients. Previous studies have only focused on the analysis of complications associated with infusion port implantation, ignoring the causes of unsuccessful infusion port implantation. The purpose of this study was to investigate the association between body mass index (BMI) and the success rate of transaxillary intravenous port implantation in breast cancer patients. MATERIALS AND METHODS: To review 361 breast cancer patients who underwent intravenous port implantation from January 2021 to September 2021. Baseline data, and surgical data were collected from the patients, and the success rate of puncture of the axillary vein was recorded. The logistic regression analysis and smoothed curve fitting were used to assess the relationship between BMI and the success rate of axillary venipuncture. In addition, subgroup analyses were performed to explore potential interactions. RESULTS: Under ultrasound guidance, 67.3% of patients (243/361) had an infusion port implanted by axillary vein puncture. There was a roughly linear relationship between BMI and the success rate of axillary venipuncture. In the multiple regression equation, BMI was significantly and negatively associated with the success rate of axillary venipuncture (OR = 0.83; 95% CI = 0.77-0.89; p < 0.001). Stratified analysis showed that the relationship between BMI and the success rate of axillary venipuncture was stable and unaffected by other variables. CONCLUSIONS: The higher the patient's BMI, the higher the chance of difficult axillary venipuncture or failed cannulation.

OsHAK4 functions in retrieving sodium from the phloem at the reproductive stage of rice.

Soil salinity significantly limits rice productivity, but it is poorly understood how excess sodium (Na+) is delivered to the grains at the reproductive stage. Here, we functionally characterized OsHAK4, a member of the clade IV HAK/KUP/KT transporter subfamily in rice. OsHAK4 was localized to the plasma membrane and exhibited influx transport activity for Na+, but not for K+. Analysis of organ- and growth stage-dependent expression patterns showed that very low expression levels of OsHAK4 were detected at the vegetative growth stage, but its high expression in uppermost node I, peduncle, and rachis was found at the reproductive stage. Immunostaining indicated OsHAK4 localization in the phloem region of node I, peduncle, and rachis. Knockout of OsHAK4 did not affect the growth and Na+ accumulation at the vegetative stage. However, at the reproductive stage, the hak4 mutants accumulated higher Na+ in the peduncle, rachis, husk, and brown rice compared to the wild-type rice. Element imaging revealed higher Na+ accumulation at the phloem region of the peduncle in the mutants. These results indicate that OsHAK4 plays a crucial role in retrieving Na+ from the phloem in the upper nodes, peduncle, and rachis, thereby preventing Na+ distribution to the grains at the reproductive stage of rice.

Cell volume regulation modulates macrophage-related inflammatory responses via JAK/STAT signaling pathways.

Cell volume as a characteristic of changes in response to external environmental cues has been shown to control the fate of stem cells. However, its influence on macrophage behavior and macrophage-mediated inflammatory responses have rarely been explored. Herein, through mediating the volume of macrophages by adding polyethylene glycol (PEG), we demonstrated the feasibility of fine-tuning cell volume to regulate macrophage polarization towards anti-inflammatory phenotypes, thereby enabling to reverse macrophage-mediated inflammation response. Specifically, lower the volume of primary macrophages can induce both resting macrophages (M0) and stimulated pro-inflammatory macrophages (M1) to up-regulate the expression of anti-inflammatory factors and down-regulate pro-inflammatory factors. Further mechanistic investigation revealed that macrophage polarization resulting from changing cell volume might be mediated by JAK/STAT signaling pathway evidenced by the transcription sequencing analysis. We further propose to apply this strategy for the treatment of arthritis via direct introduction of PEG into the joint cavity to modulate synovial macrophage-related inflammation. Our preliminary results verified the credibility and effectiveness of this treatment evidenced by the significant inhibition of cartilage destruction and synovitis at early stage. In general, our results suggest that cell volume can be a biophysical regulatory factor to control macrophage polarization and potentially medicate inflammatory response, thereby providing a potential facile and effective therapy for modulating macrophage mediated inflammatory responses. STATEMENT OF SIGNIFICANCE: Cell volume has recently been recognized as a significantly important biophysical signal in regulating cellular functionalities and even steering cell fate. Herein, through mediating the volume of macrophages by adding polyethylene glycol (PEG), we demonstrated the feasibility of fine-tuning cell volume to induce M1 pro-inflammatory macrophages to polarize towards anti-inflammatory M2 phenotype, and this immunomodulatory effect may be mediated by the JAK/STAT signaling pathway. We also proposed the feasible applications of this PEG-induced volume regulation approach towards the treatment of osteoarthritis (OA), wherein our preliminary results implied an effective alleviation of early synovitis. Our study on macrophage polarization mediated by cell volume may open up new pathways for immune regulation through microenvironmental biophysical clues.

U-shaped correlation of lymphocyte count with all-cause hospital mortality in sepsis and septic shock patients: a MIMIC-IV and eICU-CRD database study.

BACKGROUND: In sepsis, the relationship between lymphocyte counts and patient outcomes is complex. Lymphocytopenia and lymphocytosis significantly influence survival, illustrating the dual functionality of lymphocytes in responding to infections. This study investigates this complex interaction, focusing on how variations in lymphocyte counts correlate with all-cause hospital mortality among sepsis patients. METHODS: This retrospective cohort study analyzed data from two extensive critical care databases: the Medical Information Mart for Intensive Care IV 2.0 (MIMIC-IV 2.0) from Beth Israel Deaconess Medical Center, Boston, Massachusetts, and the eICU Collaborative Research Database (eICU-CRD), which was Multi-center database from over 200 hospitals across the United States conducted by Philips eICU Research Institute. We included adult patients aged 18 years and older who met the Sepsis-3 criteria, characterized by documented or suspected infection and a Sequential Organ Failure Assessment (SOFA) score of 2 or higher. Sepsis patients were categorized into quartiles based on lymphocyte counts. The primary outcome was all-cause mortality in the hospital, with 90 and 60-day all-cause mortality as the secondary outcomes. Univariable and multivariable Cox proportional hazard regressions were utilized to assess lymphocyte counts' impact on hospital mortality. An adjusted restricted cubic spline (RCS) analysis was performed to elucidate this relationship further. Subgroup analyses were also conducted to explore the association across various comorbidity groups among sepsis and septic shock patients. RESULTS: Our study included 37,054 patients, with an observed in-hospital mortality rate of 16.6%. Univariable and multivariable Cox proportional hazard regression models showed that lymphocyte counts were independently associated with in-hospital mortality (HR = 1.04, P < 0.01; HR = 1.06, P < 0.01). RCS regression analysis revealed a U-shaped relationship between lymphocyte levels and hospital mortality risk in sepsis and septic shock patients (P for overall < 0.001, P for nonliner < 0.01; P for overall = 0.002, P for nonliner = 0.014). Subgroup analyses revealed that elevated lymphocyte counts correlated with increased hospital mortality among sepsis patients with liver disease and requiring renal replacement therapy (P for overall = 0.021, P for nonliner = 0.158; P for overall = 0.025, P for nonliner = 0.759). These findings suggest that lymphocytes may have enhanced prognostic value in specific subsets of critically ill sepsis patients. CONCLUSION: Our findings demonstrate that lymphocyte counts are a significant independent predictor of hospital mortality in sepsis and septic shock patients. We observed a U-shaped association between lymphocyte levels and mortality risk, indicating that high and low counts are linked to increased mortality. This result highlights the complex role of lymphocytes in sepsis outcomes and suggests the need for further investigation into the underlying mechanisms and potential therapeutic approaches. Integrating lymphocyte count assessment into risk stratification algorithms and clinical decision support tools could enhance the early identification of high-risk sepsis patients.

Impact of clonal TP53 mutations with loss of heterozygosity on adjuvant chemotherapy and immunotherapy in gastric cancer.

BACKGROUND: This study aimed to reveal the effect of TP53 status on clinical outcomes and underlying mechanism in gastric cancer (GC) patients. METHODS: TP53 status was divided into three groups according to genome sequencing, namely clonal mutations with LOH (C-LOH), clonal diploid or subclonal mutations (CD-SC), and wild type (WT). The p53 protein activity was divided into over-expression (OE), Null and WT according to immunohistochemical staining. Four cohorts, including the TCGA, SMC, ZSHS and FUSCC cohort, were analyzed for association between TP53 mutation status and clinical outcomes and the underlying mechanism. RESULTS: In TCGA cohort, TP53 CD-SC were associated with superior overall survival compared to TP53 C-LOH cases. GC patients could benefit from ACT only in TP53 CD-SC/ p53 OE and TP53/ p53 WT subgroups, and TP53 C-LOH subgroup demonstrated the worst response to pembrolizumab among three subgroups. Genomic and immunophenotypic deconvolution revealed that TP53 C-LOH, CD-SC and WT differed for genomic and immune-related features. CONCLUSIONS: TP53 C-LOH GCs with genomic instability and immune evasion phenotype have poor clinical outcomes in patients treated with ACT or immunotherapy.

The sparing effect of ultra-high dose rate irradiation on the esophagus.

Background and purpose: Current studies have substantiated the sparing effect of ultra-high dose rate irradiation (FLASH) in various organs including the brain, lungs, and intestines. Whether this sparing effect extends to esophageal tissue remains unexplored. This study aims to compare the different responses of esophageal tissue in histological and protein expression levels following conventional dose rate irradiation (CONV) and FLASH irradiation to ascertain the presence of a sparing effect. Methods and materials: C57 female mice were randomly divided into three groups: control, CONV, and FLASH groups. The chest region of the mice in the radiation groups was exposed to a prescribed dose of 20 Gy using a modified electron linear accelerator. The CONV group received an average dose rate of 0.1 Gy/s, while the FLASH group received an average dose rate of 125 Gy/s. On the 10th day after irradiation, the mice were euthanized and their esophagi were collected for histopathological analysis. Subsequently, label-free proteomic quantification analysis was performed on esophageal tissue. The validation process involved analyzing transmission electron microscopy images and utilizing the parallel reaction monitoring method. Results: Histopathology results indicated a significantly lower extent of esophageal tissue damage in the FLASH group compared to the CONV group (p < 0.05). Label-free quantitative proteomic analysis revealed that the sparing effect observed in the FLASH group may be attributed to a reduction in radiation-induced protein damage associated with mitochondrial functions, including proteins involved in the tricarboxylic acid cycle and oxidative phosphorylation, as well as a decrease in acute inflammatory responses. Conclusions: Compared with CONV irradiation, a sparing effect on esophageal tissue can be observed after FLASH irradiation. This sparing effect is associated with alleviated mitochondria damage and acute inflammation.