Podocyte-Specific Silencing of Acid Sphingomyelinase Gene to Abrogate Hyperhomocysteinemia-Induced NLRP3 Inflammasome Activation and Glomerular Inflammation.

Acid Sphingomyelinase has been reported to increase tissue ceramide and thereby mediate hHcy-induced glomerular NLRP3 inflammasome activation, inflammation, and sclerosis. In the present study, we tested whether somatic podocyte-specific silencing of Smpd1 gene attenuates hHcy-induced NLRP3 inflammasome activation and associated exosome release in podocytes and thereby suppresses glomerular inflammatory response and injury. In vivo, somatic podocyte-specific Smpd1 gene silencing almost blocked hHcy-induced glomerular NLRP3 inflammasome activation in Podocre mice compared to control littermates. By nanoparticle tracking analysis, floxed Smpd1 shRNA transfection was found to abrogate hHcy-induced elevation of urinary exosome excretion in Podocre mice. In addition, Smpd1 gene silencing in podocytes prevented hHcy-induced immune cell infiltration into glomeruli, proteinuria, and glomerular sclerosis in Podocre mice. In cell studies, we also confirmed that Smpd1 gene knockout or silencing prevented Hcy-induced elevation of exosome release in the primary cultures of podocyte isolated from Smpd1-/- mice or podocytes of Podocre mice transfected with floxed Smpd1 shRNA compared to WT/WT podocytes. Smpd1 gene overexpression amplified Hcy-induced exosome secretion from podocytes of Smpd1trg/Podocre mice, which was remarkably attenuated by transfection of floxed Smpd1 shRNA. Mechanistically, Hcy-induced elevation of exosome release from podocytes was blocked by ASM inhibitor, but not by NLRP3 inflammasome inhibitors. Super-resolution microscopy also showed that ASM inhibitor, but not NLRP3 inflammasome inhibitors, prevented the inhibition of lysosome-multivesicular body interaction by Hcy in podocytes. In conclusion, our findings suggest that ASM in podocytes plays a crucial role in the control of NLRP3 inflammasome activation and exosome release.

Ox-LDL-induced CD80+ macrophages expand pro-atherosclerotic NKT cells via CD1d in atherosclerotic mice and hyperlipidemic patients.

Atherosclerosis is an inflammatory disease of blood vessels involving the immune system. Natural killer T (NKT) cells, as crucial components of the innate and acquired immune systems, play critical roles in the development of atherosclerosis. However, the mechanism and clinical relevance of NKT cells in early atherosclerosis are largely unclear. Our findings demonstrated that there were higher populations of NKT cells and interferon gamma (IFN-γ)-producing NKT cells in the peripheral blood of patients with hyperlipidemia and in the aorta, blood, spleen, and bone marrow of early atherosclerotic mice compared to control groups. Moreover, we discovered that the infiltration of M1 macrophages and CD1d expression on M1 macrophages in atherosclerotic mice climbed remarkably. CD1d expression increased in M1 macrophages stimulated by oxidized low-density lipoprotein (ox-LDL) ex vivo and in vitro. Ex vivo co-culture of macrophages with NKT cells revealed that ox-LDL-induced M1 macrophages presented lipid antigen alpha-galactosylceramide (α-Galcer) to NKT cells via CD1d, enabling NKT cells to express more IFN-γ. Furthermore, a greater proportion of CD1d+monocytes and CD1d+M1 monocytes were found in peripheral blood of hyperlipidemic patients compared with that of healthy donors. Positive correlations were found between CD1d+ M1 monocytes and NKT cells or IFN-γ+ NKT cells in hyperlipidemic patients. Our findings illustrate that M1 macrophages stimulate NKT cells to secret IFN-γ via CD1d presenting α-Galcer, which may accelerate the progression of early atherosclerosis. Inhibiting lipid antigen presentation by M1 macrophages to NKT cells may be a promising immune target for the treatment of early atherosclerosis.

Association of serum concentrations of remnant cholesterol with incident cardiovascular disease in patients with rheumatoid arthritis: A real-world data from 2001 to 2022.

BACKGROUND: Remnant cholesterol (RC) promotes cardiovascular disease (CVD) in the general population, but its role among rheumatoid arthritis (RA) patients remains unknown. We aimed to investigate circulating RC levels associated with incident CVD among Chinese patients with RA. METHODS: A total of 1018 RA patients free of baseline CVD were included and followed up in a prospective RA CVD cohort from 2001 to 2022. Fasting serum levels of triglycerides, total cholesterol (TC), low-density (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured, while RC and Non-HDL-C levels were calculated. The primary exposure was RC levels. A LASSO Cox model was used to select covariates. The Fine-Gray competing risk model was used to estimate hazard ratios (HRs). RESULTS: RA patients had a mean age of 53.9 years, and 802 (78.8%) were females. After a median follow-up of 5.54 years, 131 patients developed CVD with an incidence rate of 21.6 per 1000 person-years. Continuous and quartile-categorized RC levels were associated with incident CVD before and after multivariate adjustment and Bonferroni correction (all P < 0.001). There were no robust associations of other lipids with incident CVD. The fully adjusted HRs for RC were 2.30 (95% CI 1.58-3.35) per 1 mmol/L increase, and 2.40 (1.36-4.25) and 2.81 (1.60-4.94) for patients in the 3rd and 4th versus the 1st quartile, respectively. CONCLUSIONS: Circulating RC levels are positively associated with incident CVD among Chinese RA patients independent of known risk factors, implying its clinically preferable use for improving the stratification of CVD risk in RA patients.

SIRT1 activation ameliorates rhesus monkey liver fibrosis by inhibiting the TGF-ß/smad signaling pathway.

TGF-ß/Smad signaling pathway plays an important role in the pathogenesis and progression of liver fibrosis. Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+) dependent enzyme and responsible for deacetylating the proteins. Increasing numbers of reports have shown that the molecular mechanism of SIRT1 as an effective therapeutic target for liver fibrosis but the transformation is not very clear. In the present study, liver fibrotic tissues were screened by staining with Masson, hematoxylin-eosin staining (H&E) and Immunohistochemistry (IHC) for histopathological observation from the liver biopsy of seventy-seven rhesus monkey, which fixed with 4% paraformaldehyde (PFA) after treatment with high-fat diet (HFD) for two years. And the liver function was further determined by serum biochemical tests. The mRNA levels and protein expression of rat hepatic stellate (HSC-T6) cells were determined after treatment with Resveratrol (RSV) and Nicotinamide (NAM), respectively. The results showed that with the increasing of hepatic fibrosis in rhesus monkeys, the liver function impaired, and the transforming growth factor-ß1 (TGF-ß1), p-Smad3 (p-Smad3) and alpha-smooth muscle actin (α-SMA) was up-regulated, while SIRT1 and Smad7 were down-regulated. Moreover, when stimulated the HSC-T6 with RSV to activate SIRT1 for 6, 12, and 24 h, the results showed that RSV promoted the expression of smad7, while the expression of TGF-ß1, p-Smad3 and α-SMA were inhibited. In contrast, when the cells stimulated with NAM to inhibit SIRT1 for 6, 12, and 24 h, the Smad7 expression was decreased, while TGF-ß1, p-Smad3, and α-SMA expressions were increased. These results indicate that SIRT1 acts as an important protective factor for liver fibrosis, which may be attributed to inhibiting the signaling pathway of TGF-ß/Smad in hepatic fibrosis of the rhesus monkey.

Geriatric nutrition risk index: a more powerful index identifying muscle mass loss in patients with rheumatoid arthritis.

OBJECTIVE: To explore the association of geriatric nutrition risk index (GNRI), a traditional albumin-body weight calculation, with myopenia in patients with rheumatoid arthritis (RA) and compare its ability to identify myopenia with protein indicators. METHODS: This cross-sectional study was carried out based on a Chinese RA cohort. Clinical data and protein indicators (including albumin, globulin, albumin to globulin ratio, prealbumin, hemoglobin) were collected. GNRI was estimated by serum albumin and body weight. Myopenia was indicated as muscle mass loss measured by bioelectric impedance analysis. RESULTS: There were 789 RA patients included with mean age 52.6 ± 12.6 years and 77.6% female. There were 41.3%, 18.0%, 27.5%, 13.2% patients with no (GNRI > 98), low (GNRI 92 to ≤ 98), moderate (GNRI 82 to < 92), and major nutrition-related risk (GNRI < 82). There were 406 (51.5%) RA patients with myopenia, RA patients with major nutrition-related risk had the highest prevalence of myopenia (87.5% vs. 73.3% vs. 50.0% vs. 26.1%). Multivariate logistic analysis showed that compared with no risk, RA patients with low (OR = 3.23, 95% CI: 1.86-5.61), moderate (OR = 9.56, 95% CI: 5.70-16.01), and major nutrition-related risk (OR = 28.91, 95% CI: 13.54-61.71) were associated with higher prevalence of myopenia. Receiver operating characteristic curves showed that GNRI (AUC = 0.79) performed a better identifiable ability toward myopenia than serum albumin (AUC = 0.66) or others indicators (AUC range 0.59 to 0.65), respectively. CONCLUSION: GNRI, an objective and convenient albumin-weight index, may be preferable for identifying myopenia in RA patients. Key Points • We firstly elucidated the association of GNRI with muscle mass loss among RA patients, and compared its ability to identify muscle mass loss with serum albumin or other protein indicators. • Major nutrition-related risk identified by GNRI showed the highest risk of muscle mass loss, GNRI demonstrated a greater ability to identify myopenia in RA patients. which indicated GNRI was an objective and convenient albumin-weight index to identify myopenia in RA patients.

Hydrophobic Surface Array Structure Based on Laser-Induced Graphene for Deicing and Anti-Icing Applications.

The exceptional performance of graphene has driven the advancement of its preparation techniques and applications. Laser-induced graphene (LIG), as a novel graphene preparation technique, has been applied in various fields. Graphene periodic structures created by the LIG technique exhibit superhydrophobic characteristics and can be used for deicing and anti-icing applications, which are significantly influenced by the laser parameters. The laser surface treatment process was simulated by a finite element software analysis (COMSOL Multiphysics) to optimize the scanning parameter range, and the linear array surface structure was subsequently fabricated by the LIG technique. The generation of graphene was confirmed by Raman spectroscopy and energy-dispersive X-ray spectroscopy. The periodic linear array structure was observed by scanning electron microscopy (SEM) and confocal laser imaging (CLSM). In addition, CLSM testings, contact angle measurements, and delayed icing experiments were systematically performed to investigate the effect of scanning speed on surface hydrophobicity. The results show that high-quality and uniform graphene can be achieved using the laser scanning speed of 125 mm/s. The periodic linear array structures can obviously increase the contact angle and suppress delayed icing. Furthermore, these structures have the enhanced ability of the electric heating deicing, which can reach 100 °C and 240 °C within 15 s and within 60 s under the DC voltage power supply ranging from 3 to 7 V, respectively. These results indicate that the LIG technique can be developed to provide an efficient, economical, and convenient approach for preparing graphene and that the hydrophobic surface array structure based on LIG has considerable potential for deicing and anti-icing applications.

A Flexible Wearable Sensor Based on Laser-Induced Graphene for High-Precision Fine Motion Capture for Pilots.

There has been a significant shift in research focus in recent years toward laser-induced graphene (LIG), which is a high-performance material with immense potential for use in energy storage, ultrahydrophobic water applications, and electronic devices. In particular, LIG has demonstrated considerable potential in the field of high-precision human motion posture capture using flexible sensing materials. In this study, we investigated the surface morphology evolution and performance of LIG formed by varying the laser energy accumulation times. Further, to capture human motion posture, we evaluated the performance of highly accurate flexible wearable sensors based on LIG. The experimental results showed that the sensors prepared using LIG exhibited exceptional flexibility and mechanical performance when the laser energy accumulation was optimized three times. They exhibited remarkable attributes, such as high sensitivity (~41.4), a low detection limit (0.05%), a rapid time response (response time of ~150 ms; relaxation time of ~100 ms), and excellent response stability even after 2000 s at a strain of 1.0% or 8.0%. These findings unequivocally show that flexible wearable sensors based on LIG have significant potential for capturing human motion posture, wrist pulse rates, and eye blinking patterns. Moreover, the sensors can capture various physiological signals for pilots to provide real-time capturing.

Early Detection of Molecular Residual Disease and Risk Stratification for Children with Acute Myeloid Leukemia via Circulating Tumor DNA.

PURPOSE: Patient-tailored minimal residual disease (MRD) monitoring based on circulating tumor DNA (ctDNA) sequencing of leukemia-specific mutations enables early detection of relapse for pre-emptive treatment, but its utilization in pediatric acute myelogenous leukemia (AML) is scarce. Thus, we aim to examine the role of ctDNA as a prognostic biomarker in monitoring response to the treatment of pediatric AML. EXPERIMENTAL DESIGN: A prospective longitudinal study with 50 children with AML was launched, and sequential bone marrow (BM) and matched plasma samples were collected. The concordance of mutations by next-generation sequencing-based BM-DNA and ctDNA was evaluated. In addition, progression-free survival (PFS) and overall survival (OS) were estimated. RESULTS: In 195 sample pairs from 50 patients, the concordance of leukemia-specific mutations between ctDNA and BM-DNA was 92.8%. Patients with undetectable ctDNA were linked to improved OS and PFS versus detectable ctDNA in the last sampling (both P < 0.001). Patients who cleared their ctDNA post three cycles of treatment had similar PFS compared with persistently negative ctDNA (P = 0.728). In addition, patients with >3 log reduction but without clearance in ctDNA were associated with an improved PFS as were patients with ctDNA clearance (P = 0.564). CONCLUSIONS: Thus, ctDNA-based MRD monitoring appears to be a promising option to complement the overall assessment of pediatric patients with AML, wherein patients with continuous ctDNA negativity have the option for treatment de-escalation in subsequent therapy. Importantly, patients with >3 log reduction but without clearance in ctDNA may not require an aggressive treatment plan due to improved survival, but this needs further study to delineate.

Performance of 99mTc-PYP scintigraphy in the diagnosis of hereditary transthyretin cardiac amyloidosis.

OBJECTIVE: Most reported research has primarily investigated wild-type transthyretin cardiac amyloidosis (ATTRwt-CA). However, the application of bone scintigraphy for hereditary transthyretin cardiac amyloidosis (ATTRv-CA) has not been systematically investigated. Therefore, in this study, we aimed to evaluate the diagnostic value of 99mTc-PYP scintigraphy in ATTRv-CA. METHODS: Fifty-four patients were enrolled in a highly suspected cardiac amyloidosis cohort. Transthyretin (TTR) gene characteristics were summarized in the ATTRv-CA group. In 99mTc-PYP scintigraphy, the diagnostic efficiency of the visual score (VGS) and heart-to-contralateral chest (H/CL) ratio were evaluated. Furthermore, the interobserver consistency among the diagnosticians was investigated. RESULTS: Twenty-eight patients were diagnosed with ATTRv-CA with eight genotypes. The Ala97Ser genotype accounts for 46% (n = 13) with a mean age of disease onset, definite diagnosis, and interval of 61.6 ± 1.9, 66.5 ± 1.3, and 4.0 (3.0, 6.2) years, respectively. Their VGS is Grade 3, and their H/CL ratio is higher than that of the non-Ala97Ser group, but no statistical significance exists (mean H/CL: 1.95 ± 0.06 vs. 1.87 ± 0.02, p = 0.844). Additionally, ATTRv-CA patients showed VGS ≥ 2, and mean H/CL ratio of 2.09 ± 0.06. The sensitivity and specificity of VGS were 100% and 65%, respectively. And the interobserver consistency analysis of VGS showed the intraclass correlation coefficient is 0.522. The best cutoff value of H/CL ratio was 1.51 (AUC = 0.996), and the diagnostic consistency of H/CL (bias: 0.018) was high. CONCLUSIONS: Ala97Ser is the most common genotype in ATTRv-CA in our cohort, with characteristics of later onset and rapid progression, but delayed diagnosis and extensive 99mTc-PYP uptake. Overall, ATTRv-CA patients showed moderate-to-extensive myocardial 99mTc-PYP uptake. Additionally, VGS carries subjectivity, low specialty and interobserver consistency. But H/CL exhibit high diagnostic efficacy and interobserver consistency. The H/CL ratio is more useful than VGS.

Human umbilical cord mesenchymal stem cells improve disease characterization of Sjogren's syndrome in NOD mice through regulation of gut microbiota and Treg/Th17 cellular immunity.

BACKGROUND: For the unclear pathogenesis of Sjogren's syndrome (SS), further exploration is necessary. Mesenchymal stem cells (MSCs) and derived exosomes (MSCs-exo) have exhibited promising results in treating SS. OBJECT: This study aimed to investigate the effect and mechanism of human umbilical cord MSCs (UC-MSCs) on SS. METHODS: Nonobese Diabetic (NOD) mouse splenic T cells were co-cultured with UC-MSCs and UC-MSCs-exo, and interferon-gamma (IFN-γ), interleukin (IL)-6, IL-10, prostaglandin E2 (PGE2), and transforming growth factor-ß1 (TGF-ß1) levels in the supernatant were assessed by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Co-cultured T cells were injected into NOD mice via the tail vein. The inflammatory cell infiltration in the intestine and the submandibular gland was characterized by hematoxylin-eosin staining. Treg/Th17 homeostasis within the spleen was determined by flow cytometry. Gut microbiota was detected by 16S rRNA sequencing, and the relationship between differential microbiota and Treg/Th17 cytokines was analyzed by the Pearson correlation coefficient. RESULTS: UC-MSCs, UC-MSCs-exo, and NOD mouse splenic T cells were successfully cultured and identified. After T cells were co-cultured with UC-MSCs and UC-MSCs-exo, both IFN-γ and IL-6 were decreased while IL-10, PGE2, and TGF-ß1 were increased in transcriptional and translational levels. UC-MSCs and UC-MSCs-exo partially restored salivary secretion function, reduced Ro/SSA antibody and α-Fodrin immunoglobulin A levels, reduced inflammatory cell infiltration in the intestine and submandibular gland, raised proportion of Treg cells, decreased IFN-γ, IL-6, IL-2, IL-17, lipopolysaccharide, and tumor necrosis factor-alpha levels, and raised IL-10, Foxp3, and TGF-ß1 levels by affecting co-cultured T cells. The intervention of UC-MSCs and UC-MSCs-exo improved intestinal homeostasis in NOD mice by increasing microbiota diversity and richness. Additionally, differential microbiota was significantly associated with Treg/Th17 cytokine levels. CONCLUSION: Human UC-MSCs and UC-MSCs-exo improved disease characterization of SS in NOD mice through regulation of gut microbiota and Treg/Th17 cellular immunity.

Prognostic implications of CD9 in childhood acute lymphoblastic leukemia: insights from a nationwide multicenter study in China.

The outcomes of children with acute lymphoblastic leukemia (ALL) have been incrementally improved with risk-directed chemotherapy but therapy responses remain heterogeneous. Parameters with added prognostic values are warranted to refine the current risk stratification system and inform appropriate therapies. CD9, implicated by our prior single-center study, holds promise as one such parameter. To determine its precise prognostic significance, we analyzed a nationwide, multicenter, uniformly treated cohort of childhood ALL cases, where CD9 status was defined by flow cytometry on diagnostic samples of 3781 subjects. CD9 was expressed in 88.5% of B-ALL and 27.9% of T-ALL cases. It conferred a lower 5-year EFS and a higher CIR in B-ALL but not in T-ALL patients. The prognostic impact of CD9 was most pronounced in the intermediate/high-risk arms and those with minimal residual diseases, particularly at day 19 of remission induction. The adverse impact of CD9 was confined to specific cytogenetics, notably BCR::ABL1+ rather than KMT2A-rearranged leukemia. Multivariate analyses confirmed CD9 as an independent predictor of both events and relapse. The measurement of CD9 offers insights into patients necessitating intervention, warranting its seamless integration into the diagnostic marker panel to inform risk level and timely introduction of therapeutic intervention for childhood ALL.

Clonal evolution dissection reveals that a high MSI2 level promotes chemoresistance in T-cell acute lymphoblastic leukemia.

ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer with resistant clonal propagation in recurrence. We performed high-throughput droplet-based 5' single-cell RNA with paired T-cell receptor (TCR) sequencing of paired diagnosis-relapse (Dx_Rel) T-ALL samples to dissect the clonal diversities. Two leukemic evolutionary patterns, "clonal shift" and "clonal drift" were unveiled. Targeted single-cell DNA sequencing of paired Dx_Rel T-ALL samples further corroborated the existence of the 2 contrasting clonal evolution patterns, revealing that dynamic transcriptional variation might cause the mutationally static clones to evolve chemotherapy resistance. Analysis of commonly enriched drifted gene signatures showed expression of the RNA-binding protein MSI2 was significantly upregulated in the persistent TCR clonotypes at relapse. Integrated in vitro and in vivo functional studies suggested that MSI2 contributed to the proliferation of T-ALL and promoted chemotherapy resistance through the posttranscriptional regulation of MYC, pinpointing MSI2 as an informative biomarker and novel therapeutic target in T-ALL.

Outcome of first or second transplantation using unrelated umbilical cord blood without ATG conditioning regimen for pediatric bone marrow failure disorders.

BACKGROUND: Unrelated umbilical cord blood transplantation (UCBT) for bone marrow failure (BMF) disorders using conditioning regimens without Anti-Thymocyte Globulin (ATG) has been used as an alternative transplantation for emerging patients without matched-sibling donors. Experience with this transplant modality in children is limited, especially as a secondary treatment for transplant failure patients. PROCEDURE: We retrospectively reviewed 17 consecutive bone marrow failure patients who underwent unrelated umbilical cord blood transplantation in our center and received conditioning regimens of Total Body Irradiation (TBI) or Busulfan (BU) + Fludarabine (FLU) + Cyclophosphamide (CY). RESULTS: Among the 17 BMF patients, 15 patients were treated with first cord blood transplantation and another 2 with secondary cord blood transplantation because of graft failure after first haploidentical stem cell transplantation at days +38 and +82. All patients engrafted with a median donor cell chimerism of 50 % at days +7 (range, 16 %-99.95 %) and finally rose to 100 % at days +30. Median time to neutrophil engraftment was 19 days (range, 12-30) and time to platelet engraftment was 32 days (range, 18-61). Pre-engraftment syndrome (PES) was found in 16 patients (94.11 %, 16/17). Cumulative incidence of grades II to IV acute GVHD was 58.8 % (95 % CI: 32.7-84.9 %), and 17.6 % (95 % CI: 2.6-37.9 %) of patients developed chronic GVHD. The 3-year overall survival (OS) and failure-free survival (FFS) rates were 92.86 ± 6.88 %. CONCLUSION: UCBT is an effective alternative treatment for bone marrow failure pediatric patients. TBI/BU + FLU + CY regimen ensure a high engraftment rate for unrelated umbilical cord blood transplantation, which overcomes the difficulty of graft failure. Secondary salvage use of cord blood transplantation may still be useful for patients who have failed after other transplantation.

Integration of Transcriptomic Features to Improve Prognosis Prediction of Pediatric Acute Myeloid Leukemia With KMT2A Rearrangement.

Lysine methyltransferase 2A-rearranged acute myeloid leukemia (KMT2A-r AML) is a special entity in the 2022 World Health Organization classification of myeloid neoplasms, characterized by high relapse rate and adverse outcomes. Current risk stratification was established on the treatment response and translocation partner of KMT2A. To study the transcriptomic feature and refine the current stratification of pediatric KMT2A-r AML, we analyzed clinical and RNA sequencing data of 351 patients. By implementing least absolute shrinkage and selection operator algorithm, we identified 7 genes (KIAA1522, SKAP2, EGFL7, GAB2, HEBP1, FAM174B, and STARD8) of which the expression levels were strongly associated with outcomes. We then developed a transcriptome-based score, dividing patients into 2 groups with distinct gene expression patterns and prognosis, which was further validated in an independent cohort and outperformed the LSC17 score. We also found cell cycle, oxidative phosphorylation, and metabolism pathways were upregulated in patients with inferior outcomes. By integrating clinical characteristics, we proposed a simple-to-use prognostic scoring system with excellent discriminability, which allowed us to distinguish allogeneic hematopoietic stem cell transplantation candidates more precisely. In conclusion, pediatric KMT2A-r AML is heterogenous on transcriptomic level and the newly proposed scoring system combining clinical characteristics and transcriptomic features can be instructive in clinical routines.

Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients.

Considering the connection between the Fanconi anemia (FA) signaling pathway and tumor development, we aim to investigate the links between the FA gene expression and the survival prognosis of acute myeloid leukemia (AML) patients. Our study begins by identifying two distinct clusters of pediatric AML patients. Following the batch matching of the TARGET-AML, TCGA-LAML GSE71014, GSE12417, and GSE37642 cohorts, the samples were divided into a training set and an internal validation set. A Lasso regression modeling analysis was performed to identify five signatures: BRIP1, FANCC, FANCL, MAD2L2, and RFWD3. The AML samples were stratified into high- and low-risk groups by evaluating the risk scores. The AML high-risk patients showed a poorer overall survival prognosis. To predict the survival rates, we developed an FA Nomogram incorporating risk score, gender, age, and French-American-British classification. We further utilized the BEAT-AML cohort for the external validation of FA-associated prognostic models and observed good clinical validity. Additionally, we found a correlation between DNA repair, cell cycle, and peroxide-related metabolic events and FA-related high/low risk or cluster 1/2. In summary, our novel FA-associated prognostic models promise to enhance the prediction of pediatric AML prognosis.

Variations in microbial diversity and chemical components of raw dark tea under different relative humidity storage conditions.

Raw dark tea (RDT) usually needs to be stored for a long time to improve its quality under suitable relative humidity (RH). However, the impact of RH on tea quality is unclear. In this study, we investigated the metabolites and microbial diversity, and evaluated the sensory quality of RDT stored under three RH conditions (1%, 57%, and 88%). UHPLC-Q-TOF-MS analysis identified 144 metabolites, including catechins, flavonols, phenolic acids, amino acids, and organic acids. 57% RH led to higher levels of O-methylated catechin derivatives, polymerized catechins, and flavonols/flavones when compared to 1% and 88% RH. The best score in sensory evaluation was also obtained by 57% RH. Aspergillus, Gluconobacter, Kluyvera, and Pantoea were identified as the core functional microorganisms in RDT under different RH storage conditions. Overall, the findings provided new insights into the variation of microbial communities and chemical components under different RH storage conditions.

Flexible Wearable Strain Sensors Based on Laser-Induced Graphene for Monitoring Human Physiological Signals.

Flexible wearable strain sensors based on laser-induced graphene (LIG) have attracted significant interest due to their simple preparation process, three-dimensional porous structure, excellent electromechanical characteristics, and remarkable mechanical robustness. In this study, we demonstrated that LIG with various defects could be prepared on the surface of polyimide (PI) film, patterned in a single step by adjusting the scanning speed while maintaining a constant laser power of 12.4 W, and subjected to two repeated scans under ambient air conditions. The results indicated that LIG produced at a scanning speed of 70 mm/s exhibited an obvious stacked honeycomb micropore structure, and the flexible strain sensor fabricated with this material demonstrated stable resistance. The sensor exhibited high sensitivity within a low strain range of 0.4-8.0%, with the gauge factor (GF) reaching 107.8. The sensor demonstrated excellent stability and repeatable response at a strain of 2% after approximately 1000 repetitions. The flexible wearable LIG-based sensor with a serpentine bending structure could be used to detect various physiological signals, including pulse, finger bending, back of the hand relaxation and gripping, blinking eyes, smiling, drinking water, and speaking. The results of this study may serve as a reference for future applications in health monitoring, medical rehabilitation, and human-computer interactions.

Investigating the antidepressant effect of Ziyan green tea on chronic unpredictable mild stress mice through fecal metabolomics.

Introduction: Some studies have shown the effectiveness of tea in reducing depression. Gut flora dysfunction is strongly associated with depression. The mechanism by which Ziyan green tea ameliorates depression is not clear. Methods: In this study, we examined the impact of Ziyan green tea on mice exhibiting symptoms similar to depression. We specifically focused on the role of intestinal flora and its metabolites. We first established a chronic unpredictable mild stress (CUMS) mouse model to induce depressive symptoms and conducted behavioural tests, biochemical tests, and pathological tissue analysis. We also investigated gut microbiota changes by 16S rRNA sequencing and measured faecal metabolites in mice using UHPLC-MS/MS. Results: The results showed that Ziyan green tea intervention improved depression-like behaviour, neurobiochemical factors, and reduced levels of pro-inflammatory factors in CUMS mice. Spearman's correlation analysis showed that different microbial communities (Corynebacterium, Faecalibaculum, Enterorhabdus, Desulfovibrio) correlation with differential metabolites (Cholic acid, Deoxycholic acid, etc.) and depression-related biochemical indicators (5-HT, DA, BDNF, IL-6, and TNF-α). Discussion: In conclusion, our findings suggest that both low and high-dose interventions of Ziyan green tea have positive preventive effects on CUMS mice without dose dependence, partly because they mainly affect intestinal Purine Metabolism, Bile Acid Biosynthesis and Cysteine Metabolism in CUMS mice, thus stimulating brain 5-HT, DA and BDNF, and decreasing the inflammatory factors IL-6, TNF-α, activate the composition of intestinal flora, improve the intestinal flora environment and thus promote the production of intestinal metabolites, which can be used for depression treatment. It is suggested that Ziyan green tea may achieve an antidepressant effect through the gut-microbiota-brain axis.

Pediatric acute myeloid leukemia and hyperleukocytosis with WBC count greater than 50 × 109/L.

BACKGROUND: Acute myeloid leukemia (AML) and hyperleukocytosis have an unfavorable prognosis, but the impact of hyperleukocytosis on the prognosis of pediatric AML remains uncertain. We investigated the clinical characteristics and prognosis of pediatric AML with hyperleukocytosis, defined as WBC ≥ 50 × 109/L. METHODS: A total of 132 patients with newly diagnosed childhood AML with hyperleukocytosis were consecutively enrolled at our center from September 2009 to August 2021 to investigate prognostic factors and clinical outcomes. RESULTS: Hyperleukocytosis occurred in 27.4% of AML patients. Pediatric patients with hyperleukocytosis had similar CR and OS rates to those without hyperleukocytosis, but had a lower EFS rate. In our study, rates of CR1, mortality, relapsed/refractory disease, and HSCT were comparable between AML patients with WBC counts of 50-100 × 109/L and ≥ 100 × 109/L. AML patients with a WBC count of 50-100 × 109/L had a similar 5-year OS rate to patients with a WBC count ≥ 100 × 109/L (74.6% vs. 75.4%, P = 0.921). Among all patients with hyperleukocytosis, the FAB M5 subtype was associated with significantly inferior survival, and the prognosis of CBF-AML was good. CONCLUSIONS: Pediatric AML patients with hyperleukocytosis have the similar prognosis regardless of whether their WBC count is 50-100 × 109/L or ≥ 100 × 109/L.

The glycoside hydrolase gene family profile and microbial function of Debaryomyces hansenii Y4 during South-road dark tea fermentation.

Microbes are crucial to the quality formation of Sichuan South-road Dark Tea (SSDT) during pile-fermentation, but their mechanism of action has not yet been elucidated. Here, the glycoside hydrolase (GH) gene family and microbial function of Debaryomyces hansenii Y4 during solid-state fermentation were analyzed, and the results showed that many GH genes being distributed in comparatively abundant GH17, GH18, GH76, GH31, GH47, and GH2 were discovered in D. hansenii. They encoded beta-galactosidase, alpha-D-galactoside galactohydrolase, alpha-xylosidase, mannosidase, etc., and most of the GHs were located in the exocellular space and participated in the degradation of polysaccharides and oligosaccharides. D. hansenii Y4 could develop the mellow mouthfeel and "reddish brown" factors of SSDT via increasing the levels of water extracts, soluble sugars and amino acids but decreasing the tea polyphenols and caffeine levels, combined with altering the levels of thearubiins and brown index. It may facilitate the isomerization between epicatechin gallate and catechin gallate. Moreover, the expression levels of DEHA2G24860g (Beta-galactosidase gene) and DEHA2G08602g (Mannan endo-1,6-alpha-mannosidase DFG5 gene) were sharply up-regulated in fermentative anaphase, and they were significantly and negatively correlated with epicatechin content, especially, the expression of DEHA2G08602g was significantly and negatively correlated with catechin gallate level. It was hypothesized that D. hansenii Y4 is likely to be an important functional microbe targeting carbohydrate destruction and catechin transformation during SSDT pile-fermentation, with DEHA2G08602g as a key thermotolerant functional gene.