Targeting HMGCS1 restores chemotherapy sensitivity in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a common hematological malignancy with overall poor prognosis. Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory (RR) AML patients. Through clinical specimens, animal models and cell-level studies, we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1) in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation, increase chemotherapy sensitivity and improve the occurrence and development of AML. Here, we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival (OS). Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity, while stable overexpression of HMGCS1 had the opposite effects. Mechanistically, we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase (MAPK) pathway activity, while overexpression of HMGCS1 could remarkably enhance the pathway. U0126, a MEK1 inhibitor, offset the effects of HMGCS1 overexpression, indicating that HMGCS1 promotes RR AML through the MAPK pathway. Further, we verified that hymeglusin, a specific inhibitor of HMGCS1, decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients. Furthermore, combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin (ADR) had synergistic toxic effects on AML cells. Our study demonstrates the important role of HMGCS1 in AML, and targeting this protein is promising for the treatment of RR AML.

Lipid metabolism dynamics in cancer stem cells: potential targets for cancers.

Cancer stem cells (CSCs) represent a small subset of heterogeneous cells within tumors that possess the ability to self-renew and initiate tumorigenesis. They serve as potential drivers for tumor initiation, metastasis, recurrence, and drug resistance. Recent research has demonstrated that the stemness preservation of CSCs is heavily reliant on their unique lipid metabolism alterations, enabling them to maintain their own environmental homeostasis through various mechanisms. The primary objectives involve augmenting intracellular fatty acid (FA) content to bolster energy supply, promoting ß-oxidation of FA to optimize energy utilization, and elevating the mevalonate (MVA) pathway for efficient cholesterol synthesis. Additionally, lipid droplets (LDs) can serve as alternative energy sources in the presence of glycolysis blockade in CSCs, thereby safeguarding FA from peroxidation. Furthermore, the interplay between autophagy and lipid metabolism facilitates rapid adaptation of CSCs to the harsh microenvironment induced by chemotherapy. In this review, we comprehensively review recent studies pertaining to lipid metabolism in CSCs and provide a concise overview of the indispensable role played by LDs, FA, cholesterol metabolism, and autophagy in maintaining the stemness of CSCs.

DSG2 and c-MYC Interact to Regulate the Expression of ADAM17 and Promote the Development of Cervical Cancer.

Purpose: To explore the effect of DSG2 on the growth of cervical cancer cells and its possible regulatory mechanism. Methods: The expression levels and survival prognosis of DSG2 and ADAM17 in cervical squamous cell carcinoma tissues and adjacent normal tissues were analyzed by bioinformatics. CCK-8 assay, colony formation assay and Transwell assay were used to detect the effects of DSG2 on the proliferative activity, colony formation ability and migration ability of SiHa and Hela cells. The effect of DSG 2 on the level of ADAM17 transcription and translation was detected by qPCR and Western blot experiments. The interaction between DSG2 and c-MYC was detected by immunocoprecipitation. c-MYC inhibitors were used in HeLa cells overexpressing DSG2 to analyze the effects of DSG2 and c-MYC on proliferation, colony formation and migration of Hela cells, as well as the regulation of ADAM17 expression. Results: DSG2 was highly expressed in cervical squamous cell carcinoma compared with normal tissues (P<0.05), and high DSG2 expression suggested poor overall survival (P<0.05). After DSG2 knockdown, the proliferative activity, colony formation and migration ability of SiHa and Hela cells were significantly decreased (P<0.05). Compared with adjacent normal tissues, ADAM17 was highly expressed in cervical squamous cell carcinoma (P<0.05), and high ADAM17 expression suggested poor overall survival in cervical cancer patients (P<0.05). The results of immunocoprecipitation showed the interaction between DSG2 and c-MYC. Compared with DSG2 overexpression group, DSG2 overexpression combined with c-MYC inhibition group significantly decreased cell proliferation, migration and ADAM17 expression (P < 0.05). Conclusion: DSG2 is highly expressed in cervical cancer, and inhibition of DSG2 expression can reduce the proliferation and migration ability of cervical cancer cells, which may be related to the regulation of ADAM17 expression through c-MYC interaction.

Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function.

Kidney disease is highly heritable; however, the causal genetic variants, the cell types in which these variants function, and the molecular mechanisms underlying kidney disease remain largely unknown. To identify genetic loci affecting kidney function, we performed a GWAS using multiple kidney function biomarkers and identified 462 loci. To begin to investigate how these loci affect kidney function, we generated single-cell chromatin accessibility (scATAC-seq) maps of the human kidney and identified candidate cis -regulatory elements (cCREs) for kidney podocytes, tubule epithelial cells, and kidney endothelial, stromal, and immune cells. Kidney tubule epithelial cCREs explained 58% of kidney function SNP-heritability and kidney podocyte cCREs explained an additional 6.5% of SNP-heritability. In contrast, little kidney function heritability was explained by kidney endothelial, stromal, or immune cell-specific cCREs. Through functionally informed fine-mapping, we identified putative causal kidney function variants and their corresponding cCREs. Using kidney scATAC-seq data, we created a deep learning model (which we named ChromKid) to predict kidney cell type-specific chromatin accessibility from sequence. ChromKid and allele specific kidney scATAC-seq revealed that many fine-mapped kidney function variants locally change chromatin accessibility in tubule epithelial cells. Enhancer assays confirmed that fine-mapped kidney function variants alter tubule epithelial regulatory element function. To map the genes which these regulatory elements control, we used CRISPR interference (CRISPRi) to target these regulatory elements in tubule epithelial cells and assessed changes in gene expression. CRISPRi of enhancers harboring kidney function variants regulated NDRG1 and RBPMS expression. Thus, inherited differences in tubule epithelial NDRG1 and RBPMS expression may predispose to kidney disease in humans. We conclude that genetic variants affecting tubule epithelial regulatory element function account for most SNP-heritability of human kidney function. This work provides an experimental approach to identify the variants, regulatory elements, and genes involved in polygenic disease.

Next-Generation Green Hydrogen: Progress and Perspective from Electricity, Catalyst to Electrolyte in Electrocatalytic Water Splitting.

Green hydrogen from electrolysis of water has attracted widespread attention as a renewable power source. Among several hydrogen production methods, it has become the most promising technology. However, there is no large-scale renewable hydrogen production system currently that can compete with conventional fossil fuel hydrogen production. Renewable energy electrocatalytic water splitting is an ideal production technology with environmental cleanliness protection and good hydrogen purity, which meet the requirements of future development. This review summarizes and introduces the current status of hydrogen production by water splitting from three aspects: electricity, catalyst and electrolyte. In particular, the present situation and the latest progress of the key sources of power, catalytic materials and electrolyzers for electrocatalytic water splitting are introduced. Finally, the problems of hydrogen generation from electrolytic water splitting and directions of next-generation green hydrogen in the future are discussed and outlooked. It is expected that this review will have an important impact on the field of hydrogen production from water.

An open-label, prospective trial to evaluate the efficacy and safety of ixazomib in combination with cyclophosphamide and dexamethasone in patients with newly diagnosed POEMS syndrome.

This open-label, prospective trial evaluated the combination of ixazomib, cyclophosphamide and dexamethasone (ICD) in 12 newly diagnosed POEMS syndrome patients. The study is registered with the Chinese Clinical Trials Registry (ChiCTR2000030072). The treatment protocol consisted of 12 cycles of the ICD regimen compromising ixazomib (4 mg on Days 1, 8 and 15), oral cyclophosphamide (300 mg on Days 1, 8 and 15) and dexamethasone (20 mg weekly). A total of 12 patients received a median of 10 (range: 3-23) cycles of the ICD regimen. The haematological response could be evaluated in 10 patients. The overall haematological response rate was 80% (8/10), with 30% (3/10) achieving complete haematological response, and the overall serum VEGF response rate and neurological response were 100% and 83.3% respectively. Two patients experienced grade 3/4 AEs, including diarrhoea (n = 1) and leukopenia (n = 1). The combination of ixazomib, cyclophosphamide and dexamethasone demonstrated both efficacy and safety in newly diagnosed POEMS syndrome, making it a viable treatment option.

The CoREST complex regulates multiple histone modifications temporal-specifically in clock neurons.

Epigenetic regulation is important for circadian rhythm. In previous studies, multiple histone modifications were found at the Period (Per) locus. However, most of these studies were not conducted in clock neurons. In our screen, we found that a CoREST mutation resulted in defects in circadian rhythm by affecting Per transcription. Based on previous studies, we hypothesized that CoREST regulates circadian rhythm by regulating multiple histone modifiers at the Per locus. Genetic and physical interaction experiments supported these regulatory relationships. Moreover, through tissue-specific chromatin immunoprecipitation assays in clock neurons, we found that the CoREST mutation led to time-dependent changes in corresponding histone modifications at the Per locus. Finally, we proposed a model indicating the role of the CoREST complex in the regulation of circadian rhythm. This study revealed the dynamic changes of histone modifications at the Per locus specifically in clock neurons. Importantly, it provides insights into the role of epigenetic factors in the regulation of dynamic gene expression changes in circadian rhythm.

Colossal Barocaloric Effect near Ambient Temperature in 1-Dodecanol under a Low Pressure.

Solid-state refrigeration based on the barocaloric effect is an effective alternative to traditional vapor compression refrigeration. Here 1-dodecanol has been studied due to its large latent heat at a solid-liquid phase transition point around room temperature. The transition temperature will vary with the applied hydrostatic pressure, exhibiting with a sensitivity of 0.14 K MPa-1, which indicates its potential for refrigeration. A pressure of 40 MPa can result in a large isothermal entropy change of 520 J kg-1 K-1 (equivalent to that obtained in vapor compression refrigeration) at 297 K. A large adiabatic temperature change of >20 K in 1-dodecanol was acquired by direct measurement. A wide temperature window of ∼50 K (288-337 K) can be obtained in 1-dodecanol, which demonstrates broad application prospects. These discoveries offer promising prospects for barocaloric cooling and high-efficiency refrigeration technologies relying on solid-liquid phase transitions.

Identification of Matrine as a Kirsten rats Arcomaviral oncogene homolog inhibitor alleviating chemotherapy-induced neuropathic pain.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) represents a prevailing and severe clinical concern, characterized by limited availability of clinically effective treatment strategies. Current evidence endorses matrine's potential as a neuroprotective and analgesic agent for CIPN. Nevertheless, the precise targets and mechanisms of action of matrine remain insufficiently explored, impeding comprehensive pharmacological investigation and clinical application. OBJECTIVE: This study endeavors to elucidate the analgesic and neuroprotective effects of matrine in mice with vincristine-induced neuropathic pain. A focal point is the identification of matrine's specific target and the underlying molecular mechanisms governing its analgesic and neuroprotective actions. METHODS: To discern matrine's analgesic effects in CIPN mice, we conducted behavioral experiments encompassing the Von Frey filament test and Hargreaves Test. Furthermore, we conducted electrophysiological and histopathological assessments involving HE staining, Nissl staining, and Fluoro-Jade B staining to evaluate matrine's effects on neuroprotection within dorsal root ganglia and the spinal cord of CIPN mice. Sequentially, thermal shift assay, GTP hydrolysis assay, and nucleotide exchange assay were executed to validate matrine's inhibitory effects on KRAS. Molecular docking and site-directed mutagenesis experiments were implemented to identify the precise binding pocket of matrine on KRAS. Lastly, matrine's inhibitory effects on downstream signaling pathways of KRAS were confirmed through experiments conducted at animal model. RESULTS: Matrine exhibited a notable increase in mechanical withdrawal threshold and thermal withdrawal latency in vincristine-treated mice. This compound substantially ameliorated the neurofunctional blockade associated with sensory and motor functions induced by vincristine. Moreover, matrine mitigated pathological damage within DRG and the L4-L5 spinal cord regions. The study's MST experiments indicated matrine's substantial elevation of KRAS's melting temperature. The GTP hydrolysis and nucleotide exchange assays revealed concentration-dependent inhibition of KRAS activity by matrine. Molecular docking provided insight into the binding mode of matrine with KRAS, while site-directed mutagenesis verified the specific binding site of matrine on KRAS. Lastly, matrine's inhibition of downstream Raf/Erk1/2 and PI3K/Akt/mTOR signaling pathways of KRAS was confirmed in VCR mice. CONCLUSION: Compared to previous studies, our research has identified matrine as a natural inhibitor of the elusive protein KRAS, often considered "undruggable." Furthermore, this study has revealed that matrine exerts its therapeutic effects on chemotherapy-induced peripheral neuropathy (CIPN) by inhibiting KRAS activation, subsequently suppressing downstream signaling pathways such as Raf/Erk1/2 and PI3K/Akt/mTOR. This investigation signifies the discovery of a novel target for matrine, thus expanding the potential scope of its involvement in KRAS-related biological functions and diseases. These findings hold the promise of providing a crucial experimental foundation for forthcoming drug development initiatives centered around matrine, thereby advancing the field of pharmaceutical research.

Tumor suppressor FRMD3 controls mammary epithelial cell fate determination via notch signaling pathway.

The luminal-to-basal transition in mammary epithelial cells (MECs) is accompanied by changes in epithelial cell lineage plasticity; however, the underlying mechanism remains elusive. Here, we report that deficiency of Frmd3 inhibits mammary gland lineage development and induces stemness of MECs, subsequently leading to the occurrence of triple-negative breast cancer. Loss of Frmd3 in PyMT mice results in a luminal-to-basal transition phenotype. Single-cell RNA sequencing of MECs indicated that knockout of Frmd3 inhibits the Notch signaling pathway. Mechanistically, FERM domain-containing protein 3 (FRMD3) promotes the degradation of Disheveled-2 by disrupting its interaction with deubiquitinase USP9x. FRMD3 also interrupts the interaction of Disheveled-2 with CK1, FOXK1/2, and NICD and decreases Disheveled-2 phosphorylation and nuclear localization, thereby impairing Notch-dependent luminal epithelial lineage plasticity in MECs. A low level of FRMD3 predicts poor outcomes for breast cancer patients. Together, we demonstrated that FRMD3 is a tumor suppressor that functions as an endogenous activator of the Notch signaling pathway, facilitating the basal-to-luminal transformation in MECs.

Clinical diagnostic value of targeted next­generation sequencing for infectious diseases (Review).

As sequencing technology transitions from research to clinical settings, due to technological maturity and cost reductions, metagenomic next­generation sequencing (mNGS) is increasingly used. This shift underscores the growing need for more cost­effective and universally accessible sequencing assays to improve patient care and public health. Therefore, targeted NGS (tNGS) is gaining prominence. tNGS involves enrichment of target pathogens in patient samples based on multiplex PCR amplification or probe capture with excellent sensitivity. It is increasingly used in clinical diagnostics due to its practicality and efficiency. The present review compares the principles of different enrichment methods. The high positivity rate of tNGS in the detection of pathogens was found in respiratory samples with specific instances. tNGS maintains high sensitivity (70.8­95.0%) in samples with low pathogen loads, including blood and cerebrospinal fluid. Furthermore, tNGS is effective in detecting drug­resistant strains of Mycobacterium tuberculosis, allowing identification of resistance genes and guiding clinical treatment decisions, which is difficult to achieve with mNGS. In the present review, the application of tNGS in clinical settings and its current limitations are assessed. The continued development of tNGS has the potential to refine diagnostic accuracy and treatment efficacy and improving infectious disease management. However, further research to overcome technical challenges such as workflow time and cost is required.

Immunogenic cell death inducers for cancer therapy: An emerging focus on natural products.

BACKGROUND: Immunogenic cell death (ICD) is a specific form of regulated cell death induced by a variety of stressors. During ICD, the dying cancer cells release damage-associated molecular patterns (DAMPs), which promote dendritic cell maturation and tumor antigen presentation, subsequently triggering a T-cell-mediated anti-tumor immune response. In recent years, a growing number of studies have demonstrated the potential of natural products to induce ICD and enhance tumor cell immunogenicity. Moreover, there is an increasing interest in identifying new ICD inducers from natural products. PURPOSE: This study aimed to emphasize the potential of natural products and their derivatives as ICD inducers to promote research on using natural products in cancer therapy and provide ideas for future novel immunotherapies based on ICD induction. METHOD: This review included a thorough search of the PubMed, Web of Science, Scopus, and Google Scholar databases to identify natural products with ICD-inducing capabilities. A comprehensive search for clinical trials on natural ICD inducers was also conducted using ClinicalTrials.gov, as well as the approved patents using the Espacenet and CNKI Patent Database. RESULTS: Natural compounds that induce ICD can be categorized into several groups, such as polyphenols, flavonoids, terpenoids, and alkaloids. Natural products can induce the release of DAMPs by triggering endoplasmic reticulum stress, activation of autophagy-related pathways, and reactive oxygen species generation, etc. Ultimately, they activate anti-tumor immune response and improve the efficacy of cancer treatments. CONCLUSION: A growing number of ICD inducers from natural products with promising anti-cancer potential have been identified. The detailed information presented in this review will contribute to the further development of natural ICD inducers and cancer treatment strategies based on ICD-induced responses.

Triglyceride Glucose Index for the Detection of Diabetic Kidney Disease and Diabetic Peripheral Neuropathy in Hospitalized Patients with Type 2 Diabetes.

INTRODUCTION: The triglyceride-glucose index (TyG) has been identified as a dependable and simple indicator marker of insulin resistance (IR). Research has demonstrated a correlation between macrovascular complications and TyG. However, limited research exists regarding the relationship between TyG and diabetic microvascular complications. Consequently, the objective of this study is to investigate the association between TyG and diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN). METHODS: This is a cross-sectional, observational study. A total of 2048 patients from Tongren Hospital, Shanghai Jiao Tong University School of Medicine were enrolled. The primary outcomes are DKD and DPN. Quantile regression analysis was employed to investigate the implicit factors of TyG quartiles. Subsequently, based on implicit factors, logistic regression models were constructed to further examine the relationship between TyG and DKD and DPN. RESULTS: In the baseline, TyG exhibited higher values across patients with DKD, DPN, and co-existence of DKD and DPN (DKD + DPN) in type 2 diabetes (T2D). Univariate logistic regressions demonstrated a significant association between an elevated TyG and an increased risk of DKD (OR = 1.842, [95% CI] 1.317-2.578, P for trend < 0.01), DPN (OR = 1.516, [95% CI] 1.114-2.288, P for trend < 0.05), DKD + DPN (OR = 2.088, [95% CI] 1.429-3.052, P for trend < 0.05). Multivariable logistic regression models suggested a statistically significant increase in the risk of DKD (OR = 1.581, [95% CI] 1.031-2.424, p < 0.05), DKD + DPN (OR = 1.779, [95% CI] 1.091-2.903, p < 0.05) after adjusting the implicit factors of TyG quartiles. However, no significant relationship was observed between TyG and DPN in the multivariable regression analysis. CONCLUSIONS: Elevated TyG was significantly associated with an increased risk of DKD in T2D, but no significant relationship was shown with DPN. This finding provided further evidence for the clinical significance of integrating TyG into the initial assessment of diabetic microvascular complications.

Integrating Network Pharmacology and Experimental Validation to Decipher the Mechanism of Action of Astragalus-Atractylodes Herb Pair in Treating Hepatocellular Carcinoma.

Purpose: Traditional Chinese medicine (TCM) therapy is an important means to treat hepatocellular carcinoma (HCC), Astragalus (Latin name: Hedysarum Multijugum Maxim; Chinese name: Huangqi, HQ) and Atractylodes (Latin name: Atractylodes Macrocephala Koidz; Chinese name: Baizhu, BZ) (HQBZ), a classic herb pair, is often used in combination to HCC. However, the main components and potential mechanisms of HQBZ therapy in HCC remain unclear. This study aimed to identify the potential active ingredients and molecular mechanisms of action of HQBZ in HCC treatment. Methods: The HQBZ-Compound-Target-HCC network and HQBZ-HCC transcriptional regulatory network were constructed to screen the core active compound components and targets of HQBZ therapy for HCC. Molecular docking techniques are used to verify the stability of binding core active compound components to targets. GO and KEGG enrichment analysis were used to explore the signaling pathway of HQBZ in HCC treatment, the mechanism of HQBZ treatment of HCC was verified based on in vivo H22 tumor bearing mice and in vitro cell experiments. Results: Network pharmacology and molecular docking studies showed that HQBZ treatment of HCC was related to the targeted regulation of IL-6 and STAT3 by the active compound biatractylolide, KEGG pathway enrichment analysis suggest that HQBZ may play a role in the treatment of HCC through IL-6/STAT3 signaling pathway. In vitro experiment results proved that HQBZ could regulate IL-6/STAT3 signaling pathway transduction on CD8+T cells, inhibit CD8+T cell exhaustion and restore the function of exhausted CD8+T cells. In vivo experiment results proved that HQBZ can regulate IL-6/STAT3 signaling pathway transduction in H22 liver cancer model mouse tumor tissue, increased the proportion of tumor infiltrating CD8+T cells. Conclusion: This study found that HQBZ may play a therapeutic role in HCC by targeting IL-6 and STAT3 through biatractylolide, its mechanism of action is related to regulating IL-6/STAT3 signaling pathway, reversing T cell failure and increasing tumor infiltration CD8+T cells.

Gender inequality in workloads explained by operational sex ratio.

Ecological differences between human populations can affect the relative strength of sexual selection, and hence drive gender inequality. Here, we exploit the cultural diversity of southwestern China, where some village sex ratios are female-biased, in part due to a proportion of males entering monastic celibacy, to evaluate the role of sex ratio on the sexual division of labor. We used a detachable activity tracker to measure workload by step counts in both sexes among 561 individuals in 55 villages in six different areas. We show that a lower sex ratio and a higher prevalence of monasticism are associated with higher women's workloads and reduced men's workloads in the non-celibate population. As the operational sex ratio increases, gender inequality diminishes. This study offers valuable insights into the origins of gender disparities by examining the role of sex ratio on the sexual division of labor.

Association between Urine Specific Gravity as a Measure of Hydration Status and Risk of Type 2 Diabetes: The Kailuan Prospective Cohort Study.

Diabetes, especially type 2 diabetes (T2D), poses an unprecedented challenge to global public health. Hydration status also plays a fundamental role in human health, especially in people with T2D, which is often overlooked. This study aimed to explore the longitudinal associations between hydration status and the risk of T2D among the Chinese population. This study used data from the large community-based Kailuan cohort, which included adults who attended physical examinations from 2006 to 2007 and were followed until 2020. A total of 71,526 participants who eventually met the standards were divided into five hydration-status groups based on their levels of urine specific gravity (USG). Multivariable and time-dependent Cox proportional hazards models were employed to evaluate the associations of baseline and time-dependent hydration status with T2D incidence. Restricted cubic splines (RCS) analysis was used to examine the dose-response relationship between hydration status and the risk of T2D. Over a median 12.22-year follow-up time, 11,804 of the participants developed T2D. Compared with the optimal hydration-status group, participants with dehydration and severe dehydration had a significantly increased risk of diabetes, with adjusted hazard ratios (95% CI) of 1.30 (1.04-1.63) and 1.38 (1.10-1.74). Time-dependent analyses further confirmed the adverse effects of impending dehydration, dehydration, and severe dehydration on T2D incidence by 16%, 26%, and 33% compared with the reference group. Inadequate hydration is significantly associated with increased risks of T2D among Chinese adults. Our findings provided new epidemiological evidence and highlighted the potential role of adequate hydration status in the early prevention of T2D development.

A five-year follow-up clinical study of the B cell maturation antigen chimeric antigen receptor-T cell therapy HDS269B in patients with relapsed or refractory multiple myeloma.

PURPOSE: This study aimed to report the five-year clinical outcomes of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell (HDS269B) therapy in relapsed/refractory multiple myeloma (RRMM) patients, including those with poor performance status (Eastern Cooperative Oncology Group [ECOG] 3-4), and to identify factors influencing long-term outcomes. METHODS: Forty-nine RRMM patients enrolled from 2016 to 2020 received HDS269B (9×106 cells/kg) after receiving a conditioning chemotherapy consisting of cyclophosphamide and fludarabine. The overall response, long-term outcomes, and safety were assessed, as were their associations with clinical and disease characteristics. RESULTS: With a median follow-up of 59.0 months, the overall response rate was 77.55%. The median progression-free survival (PFS) and overall survival (OS) were 9.5 months (95% confidence interval [CI], 5.01-13.99) and 20.0 months (95% CI, 11.26-28.74), respectively. The 5-year PFS and OS rates were 21.3% (95% CI, 12.3%-36.7%) and 34.1% (95% CI, 22.7%-51.3%), respectively. Patients with ECOG 0-2 had marked longer survival, with a median PFS of 11.0 months and median OS of 41.8 months. Early minimal residual disease negativity, and higher and persistent CAR-T cell expansion and absence of extramedullary disease were associated with better survival outcomes. No new CAR-T cell therapy associated toxicities were observed. Importantly, ECOG 0-2, prior therapy lines <4, and CAR-T cell persistence at ≥6 months were independently associated with longer OS. CONCLUSIONS: HDS269B is effective and safe, especially for patients with ECOG 0-2. Early CAR-T cell intervention may improve prognosis in patients with RRMM.

The binding pattern of ferric iron and iron-binding protein in Botrytis cinerea.

Iron-binding protein (Ibp) has protective effect on pathogen exposed to H2O2 in defense response of plants. Ibp in Botrytis cinerea (BcIbp) is related to its virulence. Bcibp mutation lead to virulence deficiencies in B. cinerea. BcIbp is involved in the Fe3+ homeostasis regulation. Recognition the binding site and binding pattern of ferric iron and iron-binding protein in B. cinerea are vital to understand its function. In this study, molecular dynamics (MD) simulations, gaussian accelerated molecular dynamics (GaMD) simulations, dynamic cross correlation analysis and quantum chemical energy calculation were used to explore binding pattern of ferric iron. MD results showed that the C-terminal region had little effect on the stability of residues in the Fe3+-binding pocket. Energy calculations suggested the most likely coordination pattern for ferric iron in iron-binding protein. These results will help to understand the binding of ferric iron to iron-binding protein and provide new ideas for regulating the virulence of B. cinerea.

Genome-wide profiles of H3K9me3, H3K27me3 modifications, and DNA methylation during diapause of Asian corn borer (Ostrinia furnacalis).

Diapause represents a crucial adaptive strategy used by insects to cope with changing environmental conditions. In North China, the Asian corn borer (Ostrinia furnacalis) enters a winter larval diapause stage. Although there is growing evidence implicating epigenetic mechanisms in diapause regulation, it remains unclear whether dynamic genome-wide profiles of epigenetic modifications exist during this process. By investigating multiple histone modifications, we have discovered the essential roles of H3K9me3 and H3K27me3 during diapause of the Asian corn borer. Building upon previous findings in vertebrates highlighting the connection between DNA methylation and repressive histone methylations, we have examined changes in the genome-wide profile of H3K9me3, H3K27me3, and DNA methylation at the nondiapause, prediapause, and diapause stages. Data analysis reveals significant alterations in these three modifications during diapause. Moreover, we observe a correlation between the H3K9me3 and H3K27me3 modification sites during diapause, whereas DNA modifications show little association with either H3K9me3 or H3K27me3. Integrative analysis of epigenome and expression data unveils the relationship between these epigenetic modifications and gene expression levels at corresponding diapause stages. Furthermore, by studying the function of histone modifications on genes known to be important in diapause, especially those involved in the juvenile pathway, we discover that the juvenile hormone pathway lies downstream from H3K9me3 and H3K27me3 histone modifications. Finally, the analysis of gene loci with modified modifications unreported in diapause uncovers novel pathways potentially crucial in diapause regulation. This study provides a valuable resource for future investigations aiming to elucidate the underlying mechanisms of diapause.

Association between indoor residual spraying and the malaria burden in Zambia and factors associated with IRS refusals: a case-control study in Vubwi District.

BACKGROUND: Indoor residual spraying (IRS) has been implemented to prevent malaria in Zambia for several decades, but its effectiveness has not been evaluated long term and in Vubwi District yet. This study aimed to assess the association between IRS and the malaria burden in Zambia and Vubwi District and to explore the factors associated with refusing IRS. METHODS: A retrospective study was used to analyze the association between IRS and malaria incidence in Zambia in 2001-2020 and in Vubwi District in 2014-2020 by Spearman correlation analysis. A case-control study was used to explore the factors associated with IRS refusals by households in Vubwi District in 2021. A logistic regression model was performed to identify factors associated with IRS refusals. RESULTS: The malaria incidence reached its peak (391/1000) in 2001 and dropped to the lowest (154/1000) in 2019. The annual percentage change in 2001-2003, 2003-2008, 2008-2014, 2014-2018 and 2018-2020 was - 6.54%, - 13.24%, 5.04%, - 10.28% and 18.61%, respectively. A significantly negative correlation between the percentage of population protected by the IRS against the total population in Zambia (coverage) and the average malaria incidence in the whole population was observed in 2005-2020 (r = - 0.685, P = 0.003) and 2005-2019 (r = - 0.818, P < 0.001). Among 264 participants (59 in the refuser group and 205 in the acceptor group), participants with specific occupations (self-employed: OR 0.089, 95% CI 0.022-0.364; gold panning: OR 0.113, 95% CI 0.022-0.574; housewives: OR 0.129, 95% CI 0.026-0.628 and farmers: OR 0.135, 95% CI 0.030-0.608 compared to employees) and no malaria case among household members (OR 0.167; 95% CI 0.071-0.394) had a lower risk of refusing IRS implementation, while those with a secondary education level (OR 3.690, 95% CI 1.245-10.989) had a higher risk of refusing IRS implementation compared to those who had never been to school. CONCLUSIONS: Increasing coverage with IRS was associated with decreasing incidence of malaria in Zambia, though this was not observed in Vubwi District, possibly because of the special geographical location of Vubwi District. Interpersonal communication and targeted health education should be implemented at full scale to ensure household awareness and gain community trust.