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Abstract Sex is a fundamental biological variable that influences immune system function, with sex chromosomes (X and Y) playing a central role in these differences. Despite substantial evidence of disparities in immune responses between males and females, biomedical research has historically overlooked sex as a critical factor. This oversight has contributed to the observed disparities in susceptibility to autoimmune diseases, infectious diseases, and malignancies between the sexes. In this review, we address the phenomena and mechanisms through which aberrant expression of sex chromosome-linked genes contributes to sex-based differences in immune responses. We specifically focus on the implications of X chromosome inactivation (XCI) escape and loss of Y chromosome (LOY). Our review aims to elucidate the molecular mechanisms driving these sex-based differences, with particular emphasis on the interactions between sex chromosome genes and immune cells in both males and females. Additionally, we discuss the potential impact of these differences on disease susceptibility and identify prospective therapeutic targets. As personalized and precision medicine advances, it is crucial to integrate sex differences into immunological research and clinical trials. We advocate for an increased focus on sex-based considerations in fundamental, translational, and clinical research to promote personalized, sex-specific healthcare.

Abstract Objective Acute myeloid leukemia (AML) is a malignant clonal proliferative disease with a high mortality rate. The combination therapy of BCL-2 inhibitor Venetoclax (VEN) and hypomethylating agents (HMAs) has significant anti-leukemia activity. Methods We analyzed the efficacy, safety and immune response characteristics of AML patients who were unfit for high-dose chemotherapy and accepted the medication of VEN + HMAs. Results After VEN + HMAs treatment, 31 newly diagnosed AML patients had the morphologic leukemia-free state rate (MLFS%) of 80.6% (25/31), complete response rate (CR%) of 54.8% (17/31), the minimal residual disease negative rate (MRD-%) of 51.6% (16/31), and the median progression-free survival (PFS) of 14 months. After treatment, the proportion of bone marrow primitive cells, the MRD level, white blood cell (WBC) count, fibrinogen (FIB) level and the proportion of B cells were significantly decreased. The red blood cell (RBC) count, hemoglobin (HGB) level, platelet count (PLT) count, activated partial thromboplastin time (APTT), the proportion of total T cells, CD8 + T cells and the IFN-γ level were significantly increased. After VEN + HMAs treatment, 12 relapsed AML patients had a MLFS% of 50% (6/12), CR% of 33.3% (4/12), MRD-% of 25% (3/12), and a median PFS of 7 months. After treatment, the proportion of bone marrow primitive cells and MRD level were slightly decreased, the proportions of CD8 + T cells and NK cells were significantly increased, the proportion of B cells and IL-10 level were significantly decreased. 12 AML patients who receive microtransplantation (MST) treatment using VEN + HMAs as a pretreatment regimen had a PFS of 20.5 months, which was much greater than VEN + HMAs group alone. Hematological recovery was better in the MST group with significantly increased RBC count, HGB level and PLT count. The most common adverse events were myelosuppression, agranulocytosis, infection and cardiovascular toxicity. No fatal adverse events were reported. Conclusion The combination of BCL-2 inhibitors and HMAs had good efficacy and safety in AML patients who were unfit for high-dose chemotherapy, which may improve the immune microenvironment and enhance anti-leukemia immune response.

Abstract DARS, encoding for aspartyl-tRNA synthetase, is implicated in the pathogenesis of various cancers, including renal cell carcinoma, glioblastoma, colon cancer, and gastric cancer. Its role in BCR/ABL1-negative myeloproliferative neoplasms (MPNs), however, remains unexplored. This study aimed to elucidate the expression of DARS in patients with MPNs (PV 23, ET 19, PMF 16) through immunohistochemical analysis and to examine the profiles of circulating immune cells and cytokines using flow cytometry. Our findings indicate a significant overexpression of DARS in all MPNs subtypes at the protein level compared to controls (P

Abstract The rapid development of high-throughput sequencing in recent years has facilitated great progress in the molecular-targeted therapy of hematological malignancies, including leukemia, lymphoma, and multiple myeloma. BCL-2 inhibitors are among the most important molecular-targeted agents. Immunotherapy for hematologic malignancy has rapidly increased in popularity in recent years and has been proven to improve the overall survival rate. However, few clinical studies have investigated combination therapy with BCL-2 inhibitors and immunotherapies, such as immune molecule-targeted drugs or immune cell adoptive therapy. In this review, we discuss the drug discovery process, current clinical application status, and resistance and tolerance issues associated with BCL-2 inhibitors. We emphasize their important role in regulating the immune system and propose that the combination of BCL-2 inhibitors with immunotherapy may be one of the most promising treatment methods for hematologic malignancies.

Abstract Background Tyrosine kinase inhibitor (TKI) resistance is a significant factor exacerbating the burden on chronic myeloid leukemia (CML) patients and impacting clinical efficacy. The main goal is to offer new insights into overcoming drug resistance in treating CML. Methods Imatinib (IM) resistant K562/IM cells were generated using gradient induction. Responses to IM, lycorine, and autophagy modulators were assessed using CCK-8. Protein expression of Beclin-1, Atg5, LC3, Caspase-3, P62, Bax, Bcl-2, and P-gp was detected using Western blot. Lycorine-induced apoptosis and cell cycle changes were evaluated through flow cytometry, while autophagy alterations were detected using monodansylcadaverine (MDC) staining. In the K562/IM mice model, non-obese diabetic severe combined immunodeficent (NOD-SCID) mice were subcutaneously inoculated with K562/IM cells. After 17 days of lycorine injection, assessments included tumor size, hematoxylin–eosin (HE) staining, and Ki67 expression. Results After 72 h of IM treatment, K562/IM cells showed a 55.86-fold increase in drug resistance compared to K562 cells. Lycorine treatment for 24 h inhibited cell proliferation and induced G0/G1 phase cell cycle arrest and apoptosis in both K562 and K562/IM cells. MDC staining indicated reduced autophagy in K562/IM cells, mitigated by lycorine. In vivo experiments demonstrated reduced tumor size and Ki67 proliferation index in the lycorine treatment group (K562+L, K562/IM+L) compared to the control group, particularly in the drug-resistant group. However, no significant change in Ki67 was observed in the K562 group after lycorine treatment. Conclusion In summary, K562/IM cells displayed heightened autophagy levels compared to K562 cells. Lycorine effectively impeded the proliferation of K562/IM cells through diverse mechanisms, including reduced autophagy, enhanced apoptosis, and induced cell cycle arrest.

Abstract Background The definitive establishment of a causal relationship between gut microbiota and myelodysplastic syndrome (MDS) has not been achieved. Furthermore, the involvement of immune cells in mediating the connection between gut microbiota and MDS is presently unclear. Methods To elucidate the bidirectional correlation between gut microbiota and MDS, as well as to investigate the mediating role of immune cells, a bidirectional two-sample, two-step Mendelian randomization (MR) study was conducted. Summary statistics were obtained from genome-wide association studies (GWAS), including MDS (456,348 individuals), gut microbiota (18,340 individuals), and 731 immune cells signatures (3757 individuals). Results Genetically predicted eight gut microbiota traits were significantly associated with MDS risk, but not vice versa. Through biological annotation of host-microbiome shared genes, we found that immune regulation may mediate the impact of gut microbiota on MDS. Subsequently, twenty-three immunophenotypes that exhibited significant associations with MDS risk and five of these immunophenotypes were under the causal influence of gut microbiota. Importantly, the causal effects of gut microbiota on MDS were significantly mediated by five immunophenotypes, including CD4 +T cell %leukocyte, CD127 on CD45RA − CD4 not regulatory T cell, CD45 on CD33 + HLA DR + WHR, CD33 on basophil, and Monocyte AC. Conclusions Gut microbiota was causally associated with MDS risk, and five specific immunophenotypes served as potential causal mediators of the effect of gut microbiota on MDS. Understanding the causality among gut microbiota, immune cells and MDS is critical in identifying potential targets for diagnosis and treatment.

Abstract Objective In the pathogenesis of myeloproliferative neoplasms (MPN), inflammation plays an important role. However, it is unclear whether there is a causal link between inflammation and MPNs. We used a bidirectional, two-sample Mendelian randomization (MR) approach to investigate the causal relationship between systemic inflammatory cytokines and myeloproliferative neoplasms. Methods A genome-wide association study (GWAS) of 8293 European participants identified genetic instrumental variables for circulating cytokines and growth factors. Summary statistics of MPN were obtained from a GWAS including 1086 cases and 407,155 controls of European ancestry. The inverse-variance-weighted method was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl). Results Our results showed that higher Interleukin-2 receptor, alpha subunit (IL-2rα) levels, and higher Interferon gamma-induced protein 10 (IP-10) levels were associated with an increased risk of MPN (OR = 1.36,95%CI = 1.03–1.81, P = 0.032; OR = 1.55,95%CI = 1.09–2.22, P = 0.015; respectively).In addition, Genetically predicted MPN promotes expression of the inflammatory cytokines interleukin-10 (IL-10) (BETA = 0.033, 95% CI = 0.003 ~ 0.064, P = 0.032) and monokine induced by interferon-gamma (MIG) (BETA = 0.052, 95% CI = 0.002–0.102, P = 0.043) and, on activation, normal T cells express and secrete RANTES (BETA = 0.055, 95% CI = 0.0090.1, P = 0.018). Conclusion Our findings suggest that cytokines are essential to the pathophysiology of MPN. More research is required if these biomarkers can be used to prevent and treat MPN.

Abstract By introducing some concepts such as multiple integral inner product (MIIP) and multiple integral inner product space (MIIPS), new series of single/multiple integral inequalities are developed in a systematic way, which produce more accurate bounds on the cross terms from the direct Lyapunov method than those in the literature. Some previous integral inequalities including both single and multiple integral inequalities can be regarded as special cases of the proposed inequalities. Accordingly, such integral inequalities are less conservative in comparison with the existing integral inequalities.

IntroductionThe microbial genome-wide association studies (mbGWAS) have highlighted significant host-microbiome interactions based on microbiome heritability. However, establishing causal relationships between particular microbiota and multiple myeloma (MM) remains challenging due to limited sample sizes.MethodsGut microbiota data from a GWAS with 18,340 participants and MM summary statistics from 456,348 individuals. The inverse variance-weighted (IVW) method was used as the main bidirectional Mendelian randomization (MR) analysis. To assess the robustness of our results, we further performed supplementary analyses, including MR pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger, Weighted median, Simple mode, and Weighted mode. Moreover, a backward MR analysis was conducted to investigate the potential for reverse causation. Finally, gene and gene-set-based analyses were then conducted to explore the common biological factors connecting gut microbiota and MM.ResultsWe discovered that 10 gut microbial taxa were causally related to MM risk. Among them, family Acidaminococcaceae, Bacteroidales family S24-7, family Porphyromonadaceae, genus Eubacterium ruminantium group, genus Parabacteroides, and genus Turicibacter were positively correlated with MM. Conversely, class Verrucomicrobia, family Verrucomicrobiaceae, genus Akkermansia, and order Verrucomicrobiales were negatively correlated with MM. The heterogeneity test revealed no Heterogeneity. MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy. Importantly, leave-one-out analysis confirmed the robustness of MR results. In the backward MR analysis, no statistically significant associations were discovered between MM and 10 gut microbiota taxa. Lastly, we identified novel host-microbiome shared genes (AUTS2, CDK2, ERBB3, IKZF4, PMEL, SUOX, and RAB5B) that are associated with immunoregulation and prognosis in MM through biological annotation.DiscussionOverall, this study provides evidence supporting a potential causal relationship between gut microbiota and MM risk, while also revealing novel host-microbiome shared genes relevant to MM immunoregulation and clinical prognosis.

Multiple myeloma (MM), a stage-developed plasma cell malignancy, evolves from monoclonal gammopathy of undetermined significance (MGUS) or smoldering MM (SMM). Emerging therapies including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, chimeric antigen-T/natural killer (NK) cells, bispecific T-cell engagers, selective inhibitors of nuclear export, and small-molecule targeted therapy have considerably improved patient survival. However, MM remains incurable owing to inevitable drug resistance and post-relapse rapid progression. NK cells with germline-encoded receptors are involved in the natural evolution of MGUS/SMM to active MM. NK cells actively recognize aberrant plasma cells undergoing malignant transformation but are yet to proliferate during the elimination phase, a process that has not been revealed in the immune editing theory. They are potential effector cells that have been neglected in the therapeutic process. Herein, we characterized changes in NK cells regarding disease evolution and elucidated its role in the early clinical monitoring of MM. Additionally, we systematically explored dynamic changes in NK cells from treated patients who are in remission or relapse to explore future combination therapy strategies to overcome drug resistance.

AbstractObjective To compare CO2 laser resection and laryngeal microsurgery for vocal cord polyps and provide evidence for the optimal surgical method.Methods This was a retrospective cohort study that included 74 patients with vocal cord polyps who underwent either CO2 laser resection or laryngeal microsurgery in our hospital from August 2018 to December 2021. According to their preference, 77 patients were divided into two groups: a CO2 laser resection group (n = 35) and a laryngeal microsurgery group (n = 39). Patients were evaluated two days before surgery, and follow-ups were conducted one, two and four weeks after surgery. The voice handicap index (VHI-10) score, voice acoustic analysis results and electronic laryngoscopy results were collected for each patient, and the differences between the two groups were evaluated.Results The basic demographic characteristics of the 74 patients were comparable, and all patients completed postoperative follow-up observations. A total of 30 (85.71%) patients in the CO2 laser resection group and 22 (56.41%) patients in the laryngeal microsurgery group were healed. The total effectiveness rate of the CO2 laser resection group (94.29%) was significantly higher than that of the laryngeal microsurgery group (82.05%), and the difference between the two groups was statistically significant (p = .037). Both surgical methods had a positive effect on reducing VHI-10 scores with the effect of CO2 laser resection being more obvious. The difference between the two groups in this regard was statistically significant (p .05).Conclusion CO2 laser resection and laryngeal microsurgery have similar effects on voice quality, but CO2 laser resection has higher clinical efficacy.

Multiple myeloma (MM) is a hematologic disorder characterized by the accumulation of malignant plasma cells in the bone marrow. Genetic and environmental factors are contributed to the etiology of MM. Notably, studies have shown that obesity increases the risk of MM and worsens outcomes for MM patients. Adipokines play an important role in mediating the close association between MM and metabolic derangements. In this review, we summarize the epidemiologic studies to show that the risk of MM is increased in obese. Accumulating clinical evidence suggests that adipokines could display a correlation with MM. In vitro and in vivo studies have shown that adipokines are linked to MM, including roles in the biological behavior of MM cells, cancer-associated bone loss, the progression of MM, and drug resistance. Current and potential therapeutic strategies targeted to adipokines are discussed, proposing that adipokines can guide early patient diagnosis and treatment.

Abstract This study prospectively compared the efficacy and safety between matched related donor-hematopoietic stem cell transplantation (MRD-HSCT) (n = 108) and immunosuppressive therapy (IST) plus eltrombopag (EPAG) (IST + EPAG) (n = 104) to determine whether MRD-HSCT was still superior as a front-line treatment for patients with severe aplastic anemia (SAA). Compared with IST + EPAG group, patients in the MRD-HSCT achieved faster transfusion independence, absolute neutrophil count ≥ 1.0 × 109/L (P

Abstract Engineered extracellular vesicles (EVs) are considered excellent delivery vehicles for a variety of therapeutic agents, including nucleic acids, proteins, drugs, and nanomaterials. Recently, several studies have indicated that clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated 9 (Cas9) delivered by EVs enable efficient DNA editing. However, an RNA editing tool delivered by EVs is still unavailable. Here, a signal peptide‐optimized and EVs‐delivered guide RNA (gRNA) and CRISPR/CasRx (Cas13d) system capable of rapidly inhibiting the expression of targeted genes with quick catabolism after performing their functions is developed. EVs with CRISPR/CasRx and tandem gRNAs targeting pivotal cytokines are further packed whose levels increase substantially over the course of acute inflammatory diseases and find that these engineered EVs inhibit macrophage activation in vitro. More importantly, this system attenuates lipopolysaccharide (LPS)‐triggered acute lung injury and sepsis in the acute phase, mitigating organ damage and improving the prognosis in vivo. In summary, a potent tool is provided for short‐acting RNA editing, which could be a powerful therapeutic platform for the treatment of acute diseases.

Recent studies have shown that microtransplant (MST) could improve outcome of patients with elderly acute myeloid leukemia (EAML). To further standardize the MST therapy and improve outcomes in EAML patients, based on analysis of the literature on MST, especially MST with EAML from January 1st, 2011 to November 30th, 2022, the International Microtransplant Interest Group provides recommendations and considerations for MST in the treatment of EAML. Four major issues related to MST for treating EAML were addressed: therapeutic principle of MST (1), candidates for MST (2), induction chemotherapy regimens (3), and post-remission therapy based on MST (4). Others included donor screening, infusion of donor cells, laboratory examinations, and complications of treatment.

Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid clonal diseases with diverse clinical courses, and immune dysregulation plays an important role in the pathogenesis of MDS. However, immune dysregulation is complex and heterogeneous in the development of MDS. Lower-risk MDS (LR-MDS) is mainly characterized by immune hyperfunction and increased apoptosis, and the immunosuppressive therapy shows a good response. Instead, higher-risk MDS (HR-MDS) is characterized by immune suppression and immune escape, and the immune activation therapy may improve the survival of HR-MDS. Furthermore, the immune dysregulation of some MDS changes dynamically which is characterized by the coexistence and mutual transformation of immune hyperfunction and immune suppression. Taken together, the authors think that the immune dysregulation in MDS with different risk stratification can be summarized by an advanced philosophical thought “Yin-Yang theory” in ancient China, meaning that the opposing forces may actually be interdependent and interconvertible. Clarifying the mechanism of immune dysregulation in MDS with different risk stratification can provide the new basis for diagnosis and clinical treatment. This review focuses on the manifestations and roles of immune dysregulation in the different risk MDS, and summarizes the latest progress of immunotherapy in MDS.

Background and aimsHow to select the treatment is a challenge for the management of acquired patients with infections. This study aimed at comparing the outcomes of SAA with infections who had an allogeneic hematopoietic stem cell transplantation (allo-HSCT)with that of patients who had an infection and received non-HSCT therapy.MethodsWe retrospectively compared the outcomes of patients with acquired SAA and infections who had an allo-HSCT (n = 141) with that of patients who had an infection and received non-HSCT therapy (n = 186) between July 2004 and January 2020.ResultsThe treatment-related mortality (TRM) of grade 1-2 infections in the HSCT and non-HSCT groups was 24.99% and 13.68%, respectively (P = 0.206), while the TRM of grade 3-4 infections was lower in the HSCT group than that observed in the non-HSCT group (18.54% vs. 33.33%, P = 0.036). At 6 months post-treatment, 91.30% patients in the HSCT group and 8.78% patients in the non-HSCT group had achieved a normal blood profile (P < 0.0001). The time required to discontinue transfusions of red blood cells and platelets in the non-HSCT group was longer than in the HSCT group (P < 0.0001). Estimated overall survival (OS) at 6 years was similar in the two groups (75.5% ± 3.9% vs. 76.3% ± 3.1%, P = 0.996), while the estimated failure-free survival (FFS) at 6 years was 75.2% ± 3.8% in the HSCT group and 48.9% ± 3.7% in the non-HSCT group (P < 0.0001). Multivariate analysis showed that younger age, lower grade of infection (grade 1-2), and SAA (vs. very SAA) were favorable factors for OS (P < 0.05), and that the choice of HSCT and younger age were favorable factors for FFS (P < 0.0001).ConclusionThese results suggest that allo-HSCT has a better chance of a successful outcome than non-HSCT in SAA patients with an infection.

Abstract Background Prostate cancer is one of the malignant tumors of the urinary system and ranks second among the fatal cancers in men. And with age, the incidence of prostate cancer will increase linearly. Methods In this study, we measured the expression of Ubiquitin Conjugating Enzyme E2 V2 (UBE2V2) in prostate cancer tissues and cell lines by WB and explored the effect of UBE2V2 on the proliferation characteristics of prostate cancer by MTT and colony formation test. Results In our research, we found that the UBE2V2 protein level in prostate cancer cell lines was significantly higher than the UBE2V2 protein level in normal prostate cells, and the mRNA expression level did not change significantly compared with normal prostate tissue cells. At the same time, we found that miR-499a combined with UBE2V2 inhibited the expression of UBE2V2 in prostate cancer cells. Conclusions In conclusion, our results indicate that miR-499a inhibits the proliferation of human prostate cancer cells by targeting UBE2V2, which will provide a potential target for the treatment of prostate cancer.

Background: Emerging evidence suggests that early-life (in-utero and first-year since birth) exposure to ambient PM2.5 is a risk factor for asthma onset and exacerbation among children, while the hazards caused by PM2.5 compositions remain largely unknown. Objective: To examine potential associations of early-life exposures to PM2.5 mass and its major chemical constituents with childhood asthma and wheezing. Methods: By conducting the Phase II of the China, Children, Homes, Health study, we investigated 30,325 preschool children aged 3–6 years during 2019–2020 in mainland China. Early-life exposure to PM2.5 mass and its constituents (i.e., black carbon [BC], organic matter [OM], nitrate, ammonium, sulfate) were calculated based on monthly estimates at a 1 km × 1 km resolution from satellite-based models. We adopted a novel quantile-based g-computation approach to assess the effect of a mixture of PM2.5 constituents on childhood asthma/wheezing. Results: The average PM2.5 concentrations during in-utero and the first year since birth were 64.7 ± 10.6 and 61.8 ± 10.5 µg/m3, respectively. Early-life exposures to a mixture of major PM2.5 constituents were significantly associated with increased risks of asthma and wheezing, while no evident compositions-wheezing associations were found in the first year. Each quintile increases in all five PM2.5 components exposures in utero was accordingly associated with an odds ratio of 1.18 [95% confidence interval: 1.07–1.29] for asthma and 1.08 [1.01–1.16] for wheezing. BC, OM and SO42− contributed more to risks of asthma and wheezing than the other PM2.5 constituents during early life, wherein the effects of BC were only observed during pregnancy. Sex subgroup analyses suggested stronger associations among girls of first-year exposures to PM2.5 components with childhood asthma. Conclusion: Early-life exposures to ambient PM2.5, particularly compositions of BC, OM and SO42−, are associated with an increased risk of childhood asthma.

Multiple myeloma (MM) is the third most common malignant neoplasm of the hematological system. It often develops from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) precursor states. In this process, the immune microenvironment interacts with the MM cells to exert yin and yang effects, promoting tumor progression on the one hand and inhibiting it on the other. Despite significant therapeutic advances, MM remains incurable, and the main reason for this may be related to the complex and variable immune microenvironment. Therefore, it is crucial to investigate the dynamic relationship between the immune microenvironment and tumors, to elucidate the molecular mechanisms of different factors in the microenvironment, and to develop novel therapeutic agents targeting the immune microenvironment of MM. In this paper, we review the latest research progress and describe the dual influences of the immune microenvironment on the development and progression of MM from the perspective of immune cells and molecules.

Abstract Background Hetrombopag, a novel thrombopoietin receptor agonist, has been found in phase I studies to increase platelet counts and reduce bleeding risks in adults with immune thrombocytopenia (ITP). This phase III study aimed to evaluate the efficacy and safety of hetrombopag in ITP patients. Methods Patients who had not responded to or had relapsed after previous treatment were treated with an initial dosage of once-daily 2.5 or 5 mg hetrombopag (defined as the HETROM-2.5 or HETROM-5 group) or with matching placebo in a randomized, double-blind, 10-week treatment period. Patients who received placebo and completed 10 weeks of treatment switched to receive eltrombopag, and patients treated with hetrombopag in the double-blind period continued hetrombopag during the following open-label 14-week treatment. The primary endpoint was the proportion of responders (defined as those achieving a platelet count of ≥ 50 × 109/L) after 8 weeks of treatment. Results The primary endpoint was achieved by significantly more patients in the HETROM-2.5 (58.9%; odds ratio [OR] 25.97, 95% confidence interval [CI] 9.83–68.63; p

Summary: Neuronal loss resulting from progressive neurodegeneration is a major pathological feature of Alzheimer’s disease (AD). Here, we present a protocol to detect neurodegeneration, neuronal apoptosis, and neuronal loss in 5XFAD mouse strain, which is a well-established model for interrogating the molecular mechanism of neuronal death in AD. This protocol describes the use of the neurodegenerative marker Fluro-Jade C, cleaved caspase-3 immunofluorescent staining and Nissl staining for the analysis of neurodegeneration and neuronal loss in 5XFAD mice.For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021).

Summary: Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease. However, the underlying molecular mechanism is incompletely understood. Here we report that the pro-apoptotic protein BAD as a key regulator for neuronal apoptosis, neuroinflammation and Aβ clearance in AD. BAD pro-apoptotic activity is significantly increased in neurons of AD patients and 5XFAD mice. Conversely, genetic disruption of Bad alleles restores spatial learning and memory deficits in 5XFAD mice. Mechanistically, phosphorylation and inactivation of BAD by neurotropic factor-activated Akt is abrogated in neurons under AD condition. Through reactive oxygen species (ROS)-oxidized mitochondrial DNA (mtDNA) axis, BAD also promotes microglial NLRP3 inflammasome activation, thereby skewing microglia toward neuroinflammatory microglia to inhibit microglial phagocytosis of Aβ in AD mice. Our results support a model in which BAD contributes to AD pathologies by driving neuronal apoptosis and neuroinflammation but suppressing microglial phagocytosis of Aβ, suggesting that BAD is a potential therapeutic target for AD.

Background: Tibetans have lived at very high altitudes for thousands of years, and have a distinctive suite of physiological traits that enable them to tolerate environmental hypoxia. Expanding awareness and knowledge of the differences in hematology, hypoxia-associated genes, immune system of people living at different altitudes and from different ethnic groups may provide evidence for the prevention of mountain sickness. Method: Ninety-five Han people at mid-altitude, ninety-five Tibetan people at high-altitude and ninety-eight Han people at high-altitude were recruited. Red blood cell parameters, immune cells, the contents of cytokines, hypoxia-associated gene single nucleotide polymorphisms (SNPs) were measured. Results: The values of Hematocrit (HCT), Mean cell volume (MCV) and Mean cell hemoglobin (MCH) in red blood cell, immune cell CD19+ B cell number, the levels of cytokines Erb-B2 receptor tyrosine kinase 3 (ErbB3) and Tumor necrosis factor receptor II (TNF-RII) and the levels of hypoxia-associated factors Hypoxia inducible factor-1α (HIF-1α), Hypoxia inducible factor-2α (HIF-2α) and HIF prolyl 4-hydroxylase 2 (PHD2) were decreased, while the frequencies of SNPs in twenty-six Endothelial PAS domain protein 1 (EPAS1) and Egl-9 family hypoxia inducible factor 1 (EGLN1) were increased in Tibetan people at high-altitude compared with that of Han peoples at high-altitude. Furthermore, compared with mid-altitude individuals, high-altitude individuals showed lower blood cell parameters including Hemoglobin concentration (HGB), HCT, MCV and MCH, higher Mean cell hemoglobin concentration (MCHC), lower immune cells including CD19+ B cells, CD4+ T cells and CD4/CD8 ratio, higher immune cells containing CD8+ T cells and CD16/56NK cells, decreased Growth regulated oncogene alpha (GROa), Macrophage inflammatory protein 1 beta (MIP-1b), Interleukin-8 (IL-8), and increased Thrombomodulin, downregulated hypoxia-associated factors including HIF1α, HIF2α and PHD2, and higher frequency of EGLN1 rs2275279. Conclusions: These results indicated that biological adaption to hypoxia at high altitude might have been mediated by changes in immune cells, cytokines, and hypoxia-associated genes during the evolutionary history of Tibetan populations. Furthermore, different responses to high altitude were observed in different ethnic groups, which may provide a useful knowledge to improve the protection of high-altitude populations from mountain sickness.

The resistance of synovial sublining macrophages to apoptosis has a crucial role in joint inflammation and destruction in rheumatoid arthritis (RA). However, the underlying mechanism is incompletely understood. Here we report that inactivation of the pro-apoptotic BCL-2 family protein BAD is essential for survival of synovial sublining macrophage in RA. Genetic disruption of Bad leads to more severe joint inflammation and cartilage and bone damage with reduced apoptosis of synovial sublining macrophages in collagen-induced arthritis (CIA) and TNFα transgenic (TNF-Tg) mouse models. Conversely, Bad3SA/3SA mice, in which BAD can no longer be inactivated by phosphorylation, are protected from collagen-induced arthritis. Mechanistically, phosphorylation-mediated inactivation of BAD specifically protects synovial sublining macrophages from apoptosis in highly inflammatory environment of arthritic joints in CIA and TNF-Tg mice, and in patients with RA, thereby contributing to RA pathology. Our findings put forward a model in which inactivation of BAD confers the apoptosis resistance on synovial sublining macrophages, thereby contributing to the development of arthritis, suggesting that BAD may be a potential therapeutic target for RA.

Abstract Based on the extreme value conditions of a multiple variables function, a new class of Wirtinger-type double integral inequality is established in this paper. The proposed inequality generalizes and refines the classical Wirtinger-based integral inequality and has less conservatism in comparison with Jensen’s double integral inequality and other double integral inequalities in the literature. Thus, the stability criteria for delayed control systems derived by the proposed refined Wirtinger-type integral inequality are less conservative than existing results in the literature.

With the rapid development of micromachining technology, sphericity errors have become an important factor that determines product quality; thus, it is critical to establish an algorithm to estimate sphericity errors effectively and accurately. In this paper, an asymptotic search method based on the minimum zone sphere (MZS) is proposed to estimate sphericity errors. A least square sphere center is used as the initial reference center through establishing a search sphere model to gradually approach the MZS center. Then, a quasi-MZS center is determined. According to the definition and geometric structure of the minimum zone sphere, five control points dominating the homocentric spheres are searched. As a result, the MZS center and the sphericity error are obtained. Both simulation experiments and data from the literature are utilized to verify the feasibility and performance. The results indicate that the proposed method is reliable and can estimate sphericity errors efficiently and accurately.

Background/Aims: To evaluate the prognostic significance of monocytes and monocytic myeloid-derived suppressor cells (M-MDSCs) for patients with diffuse large B-cell lymphoma (DLBCL) under R-CHOP chemotherapy. Methods: Flow cytometry (FCM) was applied to measure M-MDSCs (CD14+ HLA-DRlow/− M-MDSCs). Results: Analysis of 144 patients with DLBCL under R-CHOP treatment showed that the 5-year overall survival rate was 61.09% (95% CI: 43.72%-72.56%) and the average survival time of patients with monocytes (%) ≥ 8% was shorter than those with monocytes (%) 2) (P = 0.0397), meanwhile, there was no significant difference in survival of patients with monocytes (%) ≥ 8% compared to patients with monocytes (%) Conclusion: Our results indicated that monocytes (%) and M-MDSCs combined with R-IPI may be a simple and efficient immunological index to evaluate prognosis.

A homodyne interferometer is one of the most important tools in nanometre measurements. However, its nonlinear error seriously affects measurement accuracy at the sub-nanometre level. As one of the dominant factors that cause nonlinear error in a homodyne interferometer with a quadrature detector system, the imperfection of polarizing beam splitters (PBSs) is investigated in this paper. The nonlinear error caused by the imperfection of PBSs in the detection part can be reduced by adjusting the gains of detectors. Nevertheless, eliminating the nonlinear error caused by the polarization mixing of the PBS in the interferometer part is difficult. In this paper, the nonlinear error caused by the polarization mixing of the PBS in the interferometer part is analyzed, and an optical compensation method is proposed to correct this polarization mixing. Theoretical calculation and simulation analysis show that this method can reduce the effect of inherent polarization mixing on nonlinear error significantly. In comparison with using only gain adjustment, the nonlinear error can be reduced by two orders of magnitude when the proposed method is applied. The nonlinear error can be decreased from approximately 4.5 nm to approximately 0.045 nm using the presented method based on the simulation results.