Microglia lactylation in relation to central nervous system diseases.

The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis. Microglia, as innate immune cells, play important roles in the maintenance of central nervous system homeostasis, injury response, and neurodegenerative diseases. Lactate has been considered a metabolic waste product, but recent studies are revealing ever more of the physiological functions of lactate. Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions, macrophage polarization, neuromodulation, and angiogenesis and has also been implicated in the development of various diseases. This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation, histone versus non-histone lactylation, and therapeutic approaches targeting lactate. Finally, we summarize the current research on microglia lactylation in central nervous system diseases. A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.

Effect of interpregnancy interval on the risk of gestational diabetes mellitus during a second pregnancy.

BACKGROUND: Interpregnancy interval (IPI) is associated with the risk of GDM in a second pregnancy. However, an optimal IPI is still need to be determined based on the characteristics of the population. This study aimed to analyze the effect of interpregnancy interval (IPI) on the risk of gestational diabetes mellitus (GDM) in the Chinese population. METHODS: We conducted a retrospective cohort study on female participants who had consecutive deliveries at Peking University Shenzhen Hospital from 2013 to 2021. The IPI was categorized into 7 groups and included into the multivariate logistic regression model with other confound factors. Analysis was also stratified based on age of first pregnancy, BMI, and history of GDM. Adjusted OR values (aOR) and 95% confidence intervals (CI) calculated. The regression coefficient of IPI months on GDM prediction risk was analyzed using a linear regression model. RESULTS: A total of 2,392 participants were enrolled. The IPI of the GDM group was significantly greater than that of the non-GDM group (P < 0.05). Compared with the 18-24 months IPI category, participants with longer IPIs (24-36 months, 36-48 months, 48-60 months, and ≥ 60 months) had a higher risk of GDM (aOR:1.585, 2.381, 2.488, and 2.565; 95% CI: 1.021-2.462, 1.489-3.809, 1.441-4.298, and 1.294-5.087, respectively). For participants aged < 30 years or ≥ 30 years or without GDM history, all longer IPIs (≥ 36 months) were all significantly associated with the GDM risk in the second pregnancy (P < 0.05), while any shorter IPIs (< 18 months) was not significantly associated with GDM risk (P > 0.05). For participants with GDM history, IPI 12-18 months, 24-36 months, 36-48 months, and ≥ 60 months were all significantly associated with the GDM risk (aOR: 2.619, 3.747, 4.356, and 5.373; 95% CI: 1.074-6.386, 1.652-8.499, 1.724-11.005, and 1.078-26.793, respectively), and the slope value of linear regression (0.5161) was significantly higher compared to participants without a history of GDM (0.1891) (F = 284.168, P < 0.001). CONCLUSIONS: Long IPI increases the risk of GDM in a second pregnancy, but this risk is independent of maternal age. The risk of developing GDM in a second pregnancy for women with GDM history is more significantly affected by IPI.

Effects of mobile Internet use on the health of middle-aged and older adults: evidences from China health and retirement longitudinal study.

The rapid development of digital technology has radically changed people's lives. Simultaneously, as the population is rapidly aging, academic research is focusing on the use of Internet technology to improve middle-aged and older people's health, particularly owing to the popularity of mobile networks, which has further increased the population's accessibility to the Internet. However, related studies have not yet reached a consensus. Herein, empirical analysis of the influence of mobile Internet use on the subjective health and chronic disease status of individuals in their Middle Ages and above was conducted utilizing ordered logit, propensity score matching (PSM), and ordered probit models with data from the 2020 China Health and Retirement Longitudinal Study. The study aimed to provide a theoretical basis and reference for exploring technological advances to empower the development of a healthy Chinese population and to advance the process of healthy aging. The health of middle-aged and older adults mobile Internet users was greatly improved, according to our findings. Further, the use of mobile Internet by these persons resulted in improvements to both their self-assessed health and the state of their chronic diseases. As per the findings of the heterogeneity analysis, the impact of mobile Internet use was shown to be more pronounced on the well-being of middle-aged persons aged 45-60 years compared to those aged ≥ 60 years. Further, the endogeneity test revealed that the PSM model could better eliminate bias in sample selection. The results suggest that the estimates are more robust after eliminating endogeneity, and that failure to disentangle sample selectivity bias would overestimate not only the facilitating effect of mobile Internet use on the self-assessed health impacts of middle-aged and older adults, but also the ameliorating effect of mobile Internet use on the chronic diseases of middle-aged and older adults. The results of the mechanistic analysis suggest that social engagement is an important mediating mechanism between mobile Internet use and the health of middle-aged and older adults. This implies that mobile Internet use increases opportunities for social participation among middle-aged and older adults, thereby improving their health.

A mild deprotection of isopropylidene ketals from 2-deoxyglycosides using AcOH/H2O/DME: An efficient regioselective deprotection of terminal isopropylidene ketals.

This paper describes a mild and efficient catalytic deprotection method for isopropylidene ketals and benzylidene acetals using AcOH/H2O/DME(1,2-Dimethoxyethane). The method effectively removes ketal and acetal protecting groups from 2-deoxyglycosides which are prone to hydrolysis under acidic conditions. Moreover, it enables the selective removal of the terminal ketal over an internal one.

Prognostic awareness and willingness to explore prognosis in older adults with cancer.

INTRODUCTION: Prognostic awareness varies widely among older adults with cancer. Accurate prognostic awareness helps to ensure delivery of care that is aligned with the patient's goals. Understanding factors associated with poor prognostic awareness in older adults with cancer may help identify which patients may need interventions to improve prognostic awareness. In this study, we assessed factors associated with poor prognostic awareness in older adults with cancer. MATERIALS AND METHODS: We conducted a cross-sectional analysis of older patients with cancer referred to a geriatric oncology clinic at the University of Rochester. We provided paper questionnaires for patients to complete prior to their clinic assessment. Questionnaires asked patients to estimate their overall life expectancy and the life expectancy of a person of the same age with normal health. Prognostic awareness was considered poor if patients estimated living at least as long as a person of the same age with normal health. We assessed independent demographic and clinical variables (age, sex, race, income, religion, living situation, education, marital status, and cancer type and stage), aging-related factors (comorbidities, cognition, depression, social support, nutritional status, and physical function), and willingness to discuss prognosis. Factors significant at p ≤ 0.15 on bivariate analyses were included in the multivariable logistic regression model. RESULTS: We included 257 patients; the mean age was 80 years (standard deviation [SD] 6.8, range 55-97), 37% were female, 71% were White, and 44% were married. Nearly two-thirds of patients (62%) had poor prognostic awareness: 7% estimated they would live longer than and 55% estimated they would live as long as a person of the same age with normal health. Half (49%) were willing to discuss prognosis, 29% were not, and 22% did not answer. On multivariable analysis, factors associated with poor prognostic awareness were older age [one-year increase; adjusted odds ratio (AOR) 1.07, 95% confidence interval (CI) 1.02-1.12], race other than White (AOR 2.35, 95% CI 1.09-5.06), unwillingness to discuss prognosis (AOR 3.33, 95% CI 1.54-7.18), and stage I-III cancer (vs. stage IV, AOR 3.83, 95% CI 1.8-8.17). DISCUSSION: In a cohort of older patients with cancer, approximately two-thirds had poor prognostic awareness. Older age, race other than White, stage I-III cancer, and unwillingness to discuss prognosis were associated with higher odds of poor prognostic awareness. Interventions aiming to improve patients' prognostic awareness may need to gauge patients' willingness to discuss prognosis.

Cryo-electron tomography reveals the packaging pattern of RuBisCOs in Synechococcus ß-carboxysome.

Carboxysomes are large self-assembled microcompartments that serve as the central machinery of a CO2-concentrating mechanism (CCM). Biogenesis of carboxysome requires the fine organization of thousands of individual proteins; however, the packaging pattern of internal RuBisCOs remains largely unknown. Here we purified the intact ß-carboxysomes from Synechococcus elongatus PCC 7942 and identified the protein components by mass spectrometry. Cryo-electron tomography combined with subtomogram averaging revealed the general organization pattern of internal RuBisCOs, in which the adjacent RuBisCOs are mainly arranged in three distinct manners: head-to-head, head-to-side, and side-by-side. The RuBisCOs in the outermost layer are regularly aligned along the shell, the majority of which directly interact with the shell. Moreover, statistical analysis enabled us to propose an ideal packaging model of RuBisCOs in the ß-carboxysome. These results provide new insights into the biogenesis of ß-carboxysomes and also advance our understanding of the efficient carbon fixation functionality of carboxysomes.

The effects of empiric antibiotic regimens in adults with non-ventilator-associated hospital-acquired pneumonia: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: The optimal empiric antibiotic regimen for non-ventilator-associated hospital-acquired pneumonia (HAP) is uncertain. OBJECTIVES: To compare alternative empiric antibiotic regimens in HAP using a network meta-analysis (NMA). METHODS: Data sources: Medline, EMBASE, Cochrane CENTRAL, Web of Science, and CINAHL from database inception to July 06, 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials (RCT). PARTICIPANTS: Adults with clinical suspicion of HAP. INTERVENTION: Any empiric antibiotic regimen versus another, placebo, or no treatment. ASSESSMENT OF RISK OF BIAS: Paired reviewers independently assessed risk of bias using a modified Cochrane tool for assessing risk of bias in randomized trials. METHODS OF DATA ANALYSIS: Paired reviewers independently extracted data on trial and patient characteristics, antibiotic regimens, and outcomes of interest. We conducted frequentist random-effects NMAs for treatment failure and all-cause mortality and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: 39 trials proved eligible. 30 RCTs involving 4,807 participants found low certainty evidence that piperacillin-tazobactam (RR compared to all cephalosporins: 0.65; 95% CI: 0.42, 1.01) and carbapenems (RR compared to all cephalosporins: 0.77; 95% CI: 0.53, 1.11) might be among the most effective in reducing treatment failure. The findings were robust to the secondary analysis comparing piperacillin-tazobactam vs antipseudomonal cephalosporins or antipseudomonal carbapenems vs antipseudomonal cephalosporins. 11 RCTs involving 2,531 participants found low certainty evidence that ceftazidime and linezolid combination may not be convincingly different from cephalosporin alone in reducing all-cause mortality. Evidence on other antibiotic regimens is very uncertain. Data on other patient-important outcomes including adverse events was sparse, and we did not perform network or pairwise meta-analysis. CONCLUSIONS: For empiric antibiotic therapy of adults with HAP, piperacillin-tazobactam might be among the most effective in reducing treatment failure in HAP. Empiric MRSA coverage may not exert additional benefit in reducing mortality in HAP. REGISTRATION: PROSPERO (CRD 42022297224).

Thawed drip and its membrane-separated components: Role in retarding myofibrillar protein gel deterioration during freezing-thawing cycles.

Myofibrillar proteins are crucial for gel formation in processed meat products such as sausages and meat patties. Freeze-thaw cycles can alter protein properties, impacting gel stability and product quality. This study aims to investigate the potential of thawed drip and its membrane-separated components as potential antifreeze agents to retard denaturation, oxidation and gel deterioration of myofibrillar proteins during freezing-thawing cycles of pork patties. The thawed drip and its membrane-separated components of > 10 kDa and < 10 kDa, along with deionized water, were added to minced pork at 10 % mass fraction and subjected to increasing freeze-thaw cycles. Results showed that the addition of thawed drip and its membrane separation components inhibited denaturation and structural changes of myofibrillar proteins, evidenced by reduced surface hydrophobicity and carbonyl content, increased free sulfhydryl groups, protein solubility and α-helix, as compared to the deionized water group. Correspondingly, improved gel properties including water-holding capacity, textural parameters and denser network structure were observed with the addition of thawed drip and its membrane separation components. Denaturation and oxidation of myofibrillar proteins were positively correlated with gel deterioration during freezing-thawing cycles. We here propose a role of thawed drip and its membrane separation components as cryoprotectants against myofibrillar protein gel deterioration during freeze-thawing cycles.

Constructing myosin/high-density lipoprotein composite emulsions: Roles of pH on emulsification stability, rheological and structural properties.

The emulsification activity of myosin plays a significant role in affecting quality of emulsified meat products. High-density lipoprotein (HDL) possesses strong emulsification activity and stability due to its structural characteristics, suggesting potential for its utilization in developing functional emulsified meat products. In order to explore the effect of HDL addition on emulsification stability, rheological properties and structural features of myosin (MS) emulsions, HDL-MS emulsion was prepared by mixing soybean oil with isolated HDL and MS, with pH adjustments ranging from 3.0 to 11.0. The results found that emulsification activity and stability in two emulsion groups consistently improved as pH increased. Under identical pH, HDL-MS emulsion exhibited superior emulsification behavior as compared to MS emulsion. The HDL-MS emulsion under pH of 7.0-11.0 formed a viscoelastic protein layer at the interface, adsorbing more proteins and retarding oil droplet diffusion, leading to enhanced oxidative stability, compared to the MS emulsion. Raman spectroscopy analysis showed more flexible conformational changes in the HDL-MS emulsion. Microstructural observations corroborated these findings, showing a more uniform distribution of droplet sizes in the HDL-MS emulsion with smaller particle sizes. Overall, these determinations suggested that the addition of HDL enhanced the emulsification behavior of MS emulsions, and the composite emulsions demonstrated heightened responsiveness under alkaline conditions. This establishes a theoretical basis for the practical utilization of HDL in emulsified meat products.

Epidemiologic features and therapeutic strategies of kerion: A nationwide multicentre study.

BACKGROUND: Kerion is a severe type of tinea capitis that is difficult to treat and remains a public health problem. OBJECTIVES: To evaluate the epidemiologic features and efficacy of different treatment schemes from real-world experience. METHODS: From 2019 to 2021, 316 patients diagnosed with kerion at 32 tertiary Chinese hospitals were enrolled. We analysed the data of each patient, including clinical characteristics, causative pathogens, treatments and outcomes. RESULTS: Preschool children were predominantly affected and were more likely to have zoophilic infection. The most common pathogen in China was Microsporum canis. Atopic dermatitis (AD), animal contact, endothrix infection and geophilic pathogens were linked with kerion occurrence. In terms of treatment, itraconazole was the most applied antifungal agent and reduced the time to mycological cure. A total of 22.5% of patients received systemic glucocorticoids simultaneously, which reduced the time to complete symptom relief. Furthermore, glucocorticoids combined with itraconazole had better treatment efficacy, with a higher rate and shorter time to achieving mycological cure. CONCLUSIONS: Kerion often affects preschoolers and leads to serious sequelae, with AD, animal contact, and endothrix infection as potential risk factors. Glucocorticoids, especially those combined with itraconazole, had better treatment efficacy.

Metagenomic and flavoromic profiling reveals the correlation between the microorganisms and volatile flavor compounds in Monascus-fermented cheese.

The Monascus-fermented cheese (MC) is a unique cheese product that undergoes multi-strain fermentation, imparting it with distinct flavor qualities. To clarify the role of microorganisms in the formation of flavor in MC, this study employed SPME (arrow)-GC-MS, GC-O integrated with PLS-DA to investigate variations in cheese flavors represented by volatile flavor compounds across 90-day ripening periods. Metagenomic datasets were utilized to identify taxonomic and functional changes in the microorganisms. The results showed a total of 26 characteristic flavor compounds in MC at different ripening periods (VIP＞1, p < 0.05), including butanoic acid, hexanoic acid, butanoic acid ethyl ester, hexanoic acid butyl ester, 2-heptanone and 2-octanone. According to NR database annotation, the genera Monascus, Lactococcus, Aspergillus, Lactiplantibacillus, Staphylococcus, Flavobacterium, Bacillus, Clostridium, Meyerozyma, and Enterobacter were closely associated with flavor formation in MC. Ester compounds were linked to Monascus, Meyerozyma, Staphylococcus, Lactiplantibacillus, and Bacillus. Acid compounds were linked to Lactococcus, Lactobacillus, Staphylococcus, and Bacillus. The production of methyl ketones was closely related to the genera Monascus, Staphylococcus, Lactiplantibacillus, Lactococcus, Bacillus, and Flavobacterium. This study offers insights into the microorganisms of MC and its contribution to flavor development, thereby enriching our understanding of this fascinating dairy product.

N-glycan signatures identified in the serum from biliary tract cancer patients: Association with clinical diagnosis and prognosis.

BACKGROUND: Changes in the expression of genes related to glycosyltransferases may lead to alterations in N-glycan structure abundance, potentially acting as markers for diagnosis and prognosis in biliary tract cancer (BTC). METHODS: This study was divided into cross-sectional and longitudinal approaches. The cross-sectional study included 316 BTC and 301 non-BTC. Propensity score matching was applied to adjust for sex and age differences between BTC and non-BTC. Univariate and multivariate logistic regression identified independent risk factors for BTC and constructed the BTC-G model. The ROC curve was used to validate the diagnostic performance of BTC-G. Longitudinal follow-up studies included postoperative (N = 50) and immunotherapy (N = 43) follow-up cohorts. Cox regression analysis identified N-glycan structures impacting BTC prognosis postoperative and immunotherapy, with further confirmation through Kaplan-Meier curves. RESULTS: Univariate and multivariate analyses identified Peak3 (OR: 0.790, 95% CI: 0.658-0.949), Peak9 (OR: 1.646, 95% CI: 1.409-1.922), and Peak9p (OR: 2.467, 95% CI: 1.267-4.804) as independent BTC risk factors, leading to the creation of the BTC-G. The ROC curve confirmed that BTC-G performed well in training (AUC: 0.753, 95% CI: 0.703-0.799), validation (AUC: 0.811, 95% CI: 0.740-0.870), and CA19-9 negative cohorts (AUC: 0.717, 95% CI: 0.664-0.767). Cox regression analysis and Kaplan-Meier curves established that Peak12 (HR: 5.578, 95% CI: 1.145-27.170) and Peak11 (HR: 1.104, 95% CI: 0.611-1.994) are independent risk factors for BTC prognosis following surgery and immunotherapy, respectively. CONCLUSIONS: Our NGFP technology supplements BTC diagnostics, distinguishing survival and recurrence subtypes for postoperative and immunotherapy, thereby supporting the development of treatment strategies.

Hoffmann's sign in cervical spondylotic myelopathy patients: pathological insights from neuroimaging.

OBJECTIVE: Hoffmann's sign testing is a commonly used physical examination in clinical practice for patients with cervical spondylotic myelopathy (CSM). However, the pathophysiological mechanisms underlying its occurrence and development have not been thoroughly investigated. Therefore, the present study aimed to explore whether a positive Hoffmann's sign (PHS) in CSM patients is associated with spinal cord and brain remodeling and to identify potential neuroimaging biomarkers with diagnostic value. METHODS: Seventy-six patients with CSM and 40 sex- and age-matched healthy controls (HCs) underwent multimodal MRI. Based on the results of the Hoffmann's sign examination, patients were divided into two groups: those with a PHS (n = 38) and those with a negative Hoffmann's sign (NHS; n = 38). Quantification of spinal cord and brain structural and functional parameters of the participants was performed using various methods, including functional connectivity analysis, voxel-based morphometry, and atlas-based analysis based on functional MRI and structural MRI data. Furthermore, this study conducted a correlation analysis between neuroimaging metrics and neurological function and utilized a support vector machine (SVM) algorithm for the classification of PHS and NHS. RESULTS: In comparison with the NHS and HC groups, PHS patients exhibited significant reductions in the cross-sectional area and fractional anisotropy (FA) of the lateral corticospinal tract (CST), reticulospinal tract (RST), and fasciculus cuneatus, concomitant with bilateral reductions in the volume of the lateral pallidum. The functional connectivity analysis indicated a reduction in functional connectivity between the left lateral pallidum and the right angular gyrus in the PHS group. The correlation analysis indicated a significant positive association between the CST and RST FA and the volume of the left lateral pallidum in PHS patients. Furthermore, all three variables exhibited a positive correlation with the patients' motor function. Finally, using multimodal neuroimaging metrics in conjunction with the SVM algorithm, PHS and NHS were classified with an accuracy rate of 85.53%. CONCLUSIONS: This research revealed a correlation between structural damage to the pallidum and RST and the presence of Hoffmann's sign as well as the motor function in patients with CSM. Features based on neuroimaging indicators have the potential to serve as biomarkers for assessing the extent of neuronal damage in CSM patients.

Efficient C(sp3)-H bond oxidation on perovskite quantum dots based on Ce-oxygen affinity.

Perovskite quantum dots (QDs) have shown attractive prospects in the field of visible photocatalysis, especially in the synthesis of high value-added chemicals. However, under aerobic conditions, the stable operation of QD catalysts has been limited by the reactive oxygen species (ROS) generated by photoexcitation, especially superoxide species. Here, we propose a strategy of Ce3+ doping in perovskite QDs to guide superoxide species for photocatalytic oxidation reactions. In C(sp3)-H bond oxidation of hydrocarbons, superoxide species were rapidly generated and efficiently utilized on the surface of perovskite QDs, which achieves the stable operation of the catalytic system and obtains a high product conversion rate (15.3 mmol/g/h for benzaldehydes). The mechanism studies show that the strong Ce-oxygen affinity accelerates the relaxation process of photoinduced exciton transfer to superoxide species and inhibits the radiative recombination pathway. This work provides a new idea of utilizing oxygen species on perovskite surface and broadens the design strategy of high-performance QD photocatalysts.

Suppression of GATA3 promotes epithelial-mesenchymal transition and simultaneous cellular senescence in human extravillous trophoblasts.

The regulatory mechanism of the transcription factor GATA3 in the differentiation and maturation process of extravillous trophoblasts (EVT) in early pregnancy placenta, as well as its relevance to the occurrence of pregnancy disorders, remains poorly understood. This study leveraged single-cell RNA sequencing data from placental organoid models and placental tissue to explore the dynamic changes in GATA3 expression during EVT maturation. The expression pattern exhibited an initial upregulation followed by subsequent downregulation, with aberrant GATA3 localization observed in cases of recurrent miscarriage (RM). By identifying global targets regulated by GATA3 in primary placental EVT cells, JEG3, and HTR8/SVneo cell lines, this study offered insights into its regulatory mechanisms across different EVT cell models. Shared regulatory targets among these cell types and activation of trophoblast cell marker genes emphasized the importance of GATA3 in EVT differentiation and maturation. Knockdown of GATA3 in JEG3 cells led to repression of GATA3-induced epithelial-mesenchymal transition (EMT), as evidenced by changes in marker gene expression levels and enhanced migration ability. Additionally, interference with GATA3 accelerated cellular senescence, as indicated by reduced proliferation rates and increased activity levels for senescence-associated ß-galactosidase enzyme, along with elevated expression levels for senescence-associated genes. This study provides comprehensive insights into the dual role of GATA3 in regulating EMT and cellular senescence during EVT differentiation, shedding light on the dynamic changes in GATA3 expression in normal and pathological placental conditions.

Unraveling the causal relationships between depression and brain structural imaging phenotypes: A bidirectional Mendelian Randomization study.

BACKGROUND: Previous studies have revealed structural brain abnormalities in individuals with depression, but the causal relationship between depression and brain structure remains unclear. METHODS: A genetic correlation analysis was conducted using summary statistics from the largest genome-wide association studies for depression (N = 674,452) and 1,265 brain structural imaging-derived phenotypes (IDPs, N = 33,224). Subsequently, a bidirectional two-sample Mendelian Randomization (MR) approach was employed to explore the causal relationships between depression and the IDPs that showed genetic correlations with depression. The main MR results were obtained using the inverse variance weighted (IVW) method, and other MR methods were further employed to ensure the reliability of the findings. RESULTS: Ninety structural IDPs were identified as being genetically correlated with depression and were included in the MR analyses. The IVW MR results indicated that reductions in the volume of several brain regions, including the bilateral subcallosal cortex, right medial orbitofrontal cortex, and right middle-posterior part of the cingulate cortex, were causally linked to an increased risk of depression. Additionally, decreases in surface area of the right middle temporal visual area, right middle temporal cortex, right inferior temporal cortex, and right middle-posterior part of the cingulate cortex were causally associated with a heightened risk of depression. Validation and sensitivity analyses supported the robustness of these findings. However, no evidence was found for a causal effect of depression on structural IDPs. CONCLUSIONS: Our findings reveal the causal influence of specific brain structures on depression, providing evidence to consider brain structural changes in the etiology and treatment of depression.

Hippo-PKCζ-NFκB signaling axis: A druggable modulator of chondrocyte responses to mechanical stress.

Recent studies have implicated a crucial role of Hippo signaling in cell fate determination by biomechanical signals. Here we show that mechanical loading triggers the activation of a Hippo-PKCζ-NFκB pathway in chondrocytes, resulting in the expression of NFκB target genes associated with inflammation and matrix degradation. Mechanistically, mechanical loading activates an atypical PKC, PKCζ, which phosphorylates NFκB p65 at Serine 536, stimulating its transcriptional activation. This mechanosensitive activation of PKCζ and NFκB p65 is impeded in cells with gene deletion or chemical inhibition of Hippo core kinases LATS1/2, signifying an essential role of Hippo signaling in this mechanotransduction. A PKC inhibitor AEB-071 or PKCζ knockdown prevents p65 Serine 536 phosphorylation. Our study uncovers that the interplay of the Hippo signaling, PKCζ, and NFκB in response to mechanical loading serves as a therapeutic target for knee osteoarthritis and other conditions resulting from mechanical overloading or Hippo signaling deficiencies.

PD-L1 regulates tumor proliferation and T-cell function in NF2-associated meningiomas.

INTRODUCTION: Programmed death-ligand 1 (PD-L1) expression is an immune evasion mechanism that has been demonstrated in many tumors and is commonly associated with a poor prognosis. Over the years, anti-PD-L1 agents have gained attention as novel anticancer therapeutics that induce durable tumor regression in numerous malignancies. They may be a new treatment choice for neurofibromatosis type 2 (NF2) patients. AIMS: The aims of this study were to detect the expression of PD-L1 in NF2-associated meningiomas, explore the effect of PD-L1 downregulation on tumor cell characteristics and T-cell functions, and investigate the possible pathways that regulate PD-L1 expression to further dissect the possible mechanism of immune suppression in NF2 tumors and to provide new treatment options for NF2 patients. RESULTS: PD-L1 is heterogeneously expressed in NF2-associated meningiomas. After PD-L1 knockdown in NF2-associated meningioma cells, tumor cell proliferation was significantly inhibited, and the apoptosis rate was elevated. When T cells were cocultured with siPD-L1-transfected NF2-associated meningioma cells, the expression of CD69 on both CD4+ and CD8+ T cells was partly reversed, and the capacity of CD8+ T cells to kill siPD-L1-transfected tumor cells was partly restored. Results also showed that the PI3K-AKT-mTOR pathway regulates PD-L1 expression, and the mTOR inhibitor rapamycin rapidly and persistently suppresses PD-L1 expression. In vivo experimental results suggested that anti-PD-L1 antibody may have a synergetic effect with the mTOR inhibitor in reducing tumor cell proliferation and that reduced PD-L1 expression could contribute to antitumor efficacy. CONCLUSIONS: Targeting PD-L1 could be helpful for restoring the function of tumor-infiltrating lymphocytes and inducing apoptosis to inhibit tumor proliferation in NF2-associated meningiomas. Dissecting the mechanisms of the PD-L1-driven tumorigenesis of NF2-associated meningioma will help to improve our understanding of the mechanisms underlying tumor progression and could facilitate further refinement of current therapies to improve the treatment of NF2 patients.

The tumour suppressor Fat1 is dispensable for normal murine hematopoiesis.

Loss and overexpression of FAT1 occurs among different cancers with these divergent states equated with tumor suppressor and oncogene activity, respectively. Regarding the latter, FAT1 is highly expressed in a high proportion of human acute leukemias relative to normal blood cells, with evidence pointing to an oncogenic role. We hypothesized that this occurrence represents legacy expression of FAT1 in undefined hematopoietic precursor subsets that is sustained following transformation, predicating a role for FAT1 during normal hematopoiesis. We explored this concept by using the Vav-iCre strain to construct conditional knockout (cKO) mice where Fat1 expression was deleted at the hematopoietic stem cell stage. Extensive analysis of precursor and mature blood populations using multi-panel flow cytometry revealed no ostensible differences between Fat1 cKO mice and normal littermates. Further functional comparisons involving colony forming unit and competitive bone marrow transplantation assays support the conclusion that Fat1 is dispensable for normal murine hematopoiesis.