Advancing intrauterine adhesion severity prediction: Integrative machine learning approach with hysteroscopic cold knife system, clinical characteristics and hematological parameters.

Intrauterine Adhesion (IUA) constitute a significant determinant impacting female fertility, potentially leading to infertility, miscarriage, menstrual irregularities, and placental complications. The precise assessment of the severity of IUA is pivotal for the customization of personalized treatment plans, aimed at enhancing the success rate of treatments and mitigating reproductive health risks. This study proposes bTLSMA-SVM-FS, a novel feature selection machine learning model that integrates an enhanced slime mould algorithm (SMA), termed TLSMA, with support vector machines (SVM), aiming to develop a predictive model for assessing the severity of IUA. Initially, a series of optimization comparative experiments were conducted on the TLSMA using the CEC 2017 benchmark functions. By comparing it with eleven meta-heuristic algorithms as well as eleven SOTA algorithms, the experimental outcomes corroborated the superior performance of the TLSMA. Subsequently, the developed bTLSMA-SVM-FS model was employed to conduct a thorough analysis of the clinical features of 107 IUA patients from Wenzhou People's Hospital, comprising 61 cases of moderate IUA and 46 cases of severe IUA. The evaluation results of the model demonstrated exceptional performance in predicting the severity of IUA, achieving an accuracy of 86.700 % and a specificity of 87.609 %. Moreover, the model successfully identified critical factors influencing the prediction of IUA severity, including the preoperative Chinese IUA score, production times, thrombin time, preoperative endometrial thickness, and menstruation. The identification of these key factors not only further validated the efficacy of the proposed model but also provided vital scientific evidence for a deeper understanding of the pathogenesis of IUA and the enhancement of targeted treatment strategies.

Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii.

Ribose-5-phosphate (R5P) is a precursor for nucleic acid biogenesis; however, the importance and homeostasis of R5P in the intracellular parasite Toxoplasma gondii remain enigmatic. Here, we show that the cytoplasmic sedoheptulose-1,7-bisphosphatase (SBPase) is dispensable. Still, its co-deletion with transaldolase (TAL) impairs the double mutant's growth and increases 13C-glucose-derived flux into pentose sugars via the transketolase (TKT) enzyme. Deletion of the latter protein affects the parasite's fitness but is not lethal and is correlated with an increased carbon flux via the oxidative pentose phosphate pathway. Further, loss of TKT leads to a decline in 13C incorporation into glycolysis and the TCA cycle, resulting in a decrease in ATP levels and the inability of phosphoribosyl-pyrophosphate synthetase (PRPS) to convert R5P into 5'-phosphoribosyl-pyrophosphate and thereby contribute to the production of AMP and IMP. Likewise, PRPS is essential for the lytic cycle. Not least, we show that RuPE-mediated metabolic compensation is imperative for the survival of the ΔsbpaseΔtal strain. In conclusion, we demonstrate that multiple routes can flexibly supply R5P to enable parasite growth and identify catalysis by TKT and PRPS as critical enzymatic steps. Our work provides novel biological and therapeutic insights into the network design principles of intracellular parasitism in a clinically-relevant pathogen.

Association between sleep traits and sarcopenia-related traits: A two-sample bidirectional Mendelian randomization study.

AIM: Despite limited evidence regarding the impact of sleep quality on sarcopenia, it is widely recognized as being associated with various diseases. This study aimed to explore the causal relationship between sleep traits and sarcopenia-related traits. METHODS: This study utilized a two-sample bidirectional Mendelian randomization analysis. Genetic genome-wide summary data of sleep quality indicators, including chronotype, morning wake-up time, sleep duration, daytime napping, insomnia and daytime dozing, were used. Data on sarcopenia-related traits, such as appendicular lean mass, grip strength of both hands, walking pace and waist circumference, were collected from a large cohort study. The primary method used was the inverse-variance weighted analysis. RESULTS: A causal association was found between chronotype and appendicular lean mass (odds ratio [OR] 1.019, 95% confidence interval [CI] 1.016-1.211, P = 0.021). Napping during the day was connected with walking pace (OR 0.879, 95% CI 0.834-0.928, P = 2.289 × 10-6) and waist circumference (OR 1.234, 95% CI 1.081-1.408, P = 0.002). Insomnia was related to lower grip strength of the right hand (OR 0.844, 95% CI 0.747-0.954, P = 0.007), left hand (OR 0.836, 95% CI 0.742-0.943, P = 0.003), as well as walking pace (OR 0.871, 95% CI 0.798-0.951, P = 0.002). Furthermore, the reverse Mendelian randomization analysis showed associations between certain sarcopenia-related traits and poor sleep quality. CONCLUSIONS: Some sleep traits were associated with the occurrence of sarcopenia. These findings emphasized the significance of prioritizing sleep quality as a preventive measure against sarcopenia. Geriatr Gerontol Int 2024; ••: ••-••.

Naringenin protects against septic cardiomyopathy in mice by targeting HIF-1α.

Myocardial dysfunction is a prevalent complication of sepsis (septic cardiomyopathy) with a high mortality rate and limited therapeutic options. Naringenin, a natural flavonoid compound with anti-inflammatory and antioxidant properties, holds promise as a potential treatment for sepsis-induced myocardial dysfunction. This study investigated the pharmacological effects of naringenin on septic cardiomyopathy. In vivo and in vitro experiments demonstrated that naringenin improved cardiomyocyte damage. Network pharmacology and database analysis revealed that HIF-1α is a key target protein of naringenin. Elevated expression of HIF-1α was observed in damaged cardiomyocytes, and the HIF-1α inhibitor effectively protected against LPS-induced cardiomyocyte damage. Molecular docking studies confirmed the direct binding between naringenin and HIF-1α protein. Importantly, our findings demonstrated that naringenin did not provide additional attenuation of cardiomyocyte injury on the biases of HIF-1α inhibitor treatment. In conclusion, this study proves that naringenin protects against septic cardiomyopathy through HIF-1α signaling. Naringenin is a promising therapeutic candidate for treating septic cardiomyopathy.

Soat2 inhibitor avasimibe alleviates acute pancreatitis by suppressing acinar cell ferroptosis.

Ferroptosis, characterized by lipid peroxidation, plays a significant role in the pathogenesis of acute pancreatitis (AP). While sterol O-acyltransferase 2 (Soat2) is known for its crucial regulatory role in cholesterol homeostasis, its involvement in the development of AP remains unreported. We conducted this study to identify the pivotal role of Soat2 in AP using transcriptomic databases. Subsequently, we confirmed its alterations through both in vitro and in vivo experimental models. Furthermore, we performed intervention with the Soat2 inhibitor avasimibe to evaluate pancreatic tissue pathology and serum enzymatic levels and observe inflammatory cell infiltration through immunohistochemistry. Additionally, changes in indicators related to ferroptosis were also observed. The results showed that in the AP mouse model, the protein and mRNA levels of Soat2 were significantly increased. Following avasimibe administration, there was a decrease in serum amylase levels, reduction in pancreatic tissue pathological damage, and attenuation of inflammatory cell infiltration. Furthermore, avasimibe administration resulted in downregulation of ferroptosis-related indicators. In conclusion, our findings suggest that the Soat2 inhibitor avasimibe protects against AP in mice through inhibition of the ferroptosis.

High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response.

Previous evidence has confirmed that branched-chain aminotransferase-1 (BCAT1), a key enzyme governing branched-chain amino acid (BCAA) metabolism, has a role in cancer aggression partly by restricting αKG levels and inhibiting the activities of the αKG-dependent enzyme family. The oncogenic role of BCAT1, however, was not fully elucidated in acute myeloid leukemia (AML). In this study, we investigated the clinical significance and biological insight of BCAT1 in AML. Using q-PCR, we analyzed BCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. High BCAT1 expression independently predicts poor prognosis in patients with AML. We also established BCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found that BCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated that BCAT1 regulates histone methylation by reducing intracellular αKG levels in AML cells. Moreover, high expression of BCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression. KEY MESSAGES: High expression of BCAT1 is an independent risk factor for poor prognosis in patients with CN-AML. High BCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels. H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.

THADA inhibits autophagy and increases 5-FU sensitivity in gastric cancer cells via the PI3K/AKT/mTOR signaling pathway.

Objectives: 5-Fluorouracil (5-FU) is currently the main drug used in chemotherapy for gastric cancer (GC). The main clinical problems of 5-FU therapy are insensitivity and acquired resistance to 5-FU. The mechanism of GC cell resistance to 5-FU is currently unknown. Materials and Methods: This study employed next-generation sequencing (NGS) to analyze the differentially expressed genes (DEGs) in chemotherapy-sensitive and non-sensitive GC tissues. In addition, a bioinformatics analysis was conducted using the GC dataset of GEO, and further validated and explored through in vitro experiments. Results: Thyroid adenoma-associated gene (THADA) was highly expressed in GC tissues from chemotherapy-sensitive patients and was an independent prognostic factor in GC patients receiving postoperative 5-FU adjuvant chemotherapy. Notably, heightened THADA expression in GC cells was associated with the down-regulation of autophagy-related proteins (LC-3, ATG13, ULK1, and TFEB). Furthermore, the PI3K/AKT/mTOR signaling pathway and mTORC1 signaling pathway were remarkably increased in patients with elevated THADA expression. THADA expression was associated with mTOR, the core protein of the mTOR signaling pathway, and related proteins involved in regulating the mTORC1 signaling pathway (mLST8, RHEB, and TSC2). THADA exhibited inhibitory effects on autophagy and augmented the sensitivity of GC cells to 5-FU through the PI3K/AKT/mTOR signaling pathway. Conclusion: The findings suggest that THADA may be involved in the regulatory mechanism of GC cell sensitivity to 5-FU. Consequently, the detection of THADA in tumor tissues may bring clinical benefits, specifically for 5-FU-related chemotherapy administered to GC patients with elevated THADA expression.

Gilteritinib-based combination therapy in adult relapsed/refractory FLT3-mutated acute myeloid leukaemia.

Gilteritinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor, was approved for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukaemia (AML) patients but still showed limited efficacy. Here, we retrospectively analysed the efficacy and safety of different gilteritinib-based combination therapies (gilteritinib plus hypomethylating agent and venetoclax, G + HMA + VEN; gilteritinib plus HMA, G + HMA; gilteritinib plus venetoclax, G + VEN) in 33 R/R FLT3-mutated AML patients. The composite complete response (CRc) and modified CRc (mCRc) rates were 66.7% (12/18) and 88.9% (16/18) in patients received G + HMA + VEN, which was higher compared with that in G + HMA (CRc: 18.2%, 2/11; mCRc: 45.5%, 5/11) or G + VEN (CRc: 50.0%, 2/4; mCRc: 50.0%, 2/4). The median overall survival (OS) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 160.0 days and 231.0 days. The median duration of remission (DOR) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 82.0 days and 77.0 days. Four patients in the G + HMA + VEN group received alloHSCT after remission exhibited prolonged median DOR. The most common grade 3/4 adverse events were cytopenia, febrile neutropenia and pulmonary infection; there were no differences among the three groups. In conclusion, our data demonstrated promising response of G + HMA + VEN combination therapy in R/R FLT3-mutated AML, and it may be considered an effective therapy bridge to transplantation.

RhoA suppresses pseudorabies virus replication in vitro.

The porcine pseudorabies virus (PRV) is one of the most devastating pathogens and brings great economic losses to the swine industry worldwide. Viruses are intracellular parasites that have evolved numerous strategies to subvert and utilize different host processes for their life cycle. Among the different systems of the host cell, the cytoskeleton is one of the most important which not only facilitate viral invasion and spread into neighboring cells, but also help viruses to evade the host immune system. RhoA is a key regulator of cytoskeleton system that may participate in virus infection. In this study, we characterized the function of RhoA in the PRV replication by chemical drugs treatment, gene knockdown and gene over-expression strategy. Inhibition of RhoA by specific inhibitor and gene knockdown promoted PRV proliferation. On the contrary, overexpression of RhoA or activation of RhoA by chemical drug inhibited PRV infection. Besides, our data demonstrated that PRV infection induced the disruption of actin stress fiber, which was consistent with previous report. In turn, the actin specific inhibitor cytochalasin D markedly disrupted the normal fibrous structure of intracellular actin cytoskeleton and decreased the PRV replication, suggesting that actin cytoskeleton polymerization contributed to PRV replication in vitro. In summary, our data displayed that RhoA was a host restriction factor that inhibited PRV replication, which may deepen our understanding the pathogenesis of PRV and provide further insight into the prevention of PRV infection and the development of anti-viral drugs.

Serum Cys C predicts acute kidney injury in patients with acute pancreatitis: A retrospective study.

BACKGROUND AND STUDY AIMS: We investigated the value of the serum cystatin C level as a potential predictor of acute kidney injury (AKI) in patients with acute pancreatitis (AP). PATIENTS AND METHODS: We retrospectively examined patients diagnosed with AP between January 2013 and December 2018. Patients were categorized into two groups based on their serum cystatin C levels after admission: the normal (n-Cys C group) and high serum cystatin C levels groups (h-Cys C group). Patients in the h-Cys C group demonstrated serum cystatin C levels ≥1.05 mg/L. Demographic parameters, laboratory data, and AP severity were compared between the two groups. Receiver operating curve (ROC) analysis was used to evaluate the efficacy of serum cystatin C in predicting persistent AKI. RESULTS: A total of 379 patients with AP were enrolled: 319 in the n-Cys C group and 60 in the h-Cys C group. Serum cystatin C levels were significantly higher in patients with severe acute pancreatitis (SAP) compared to moderate acute pancreatitis (MAP) (P< 0.05). The h-Cys C group had a higher BISAP score (P < 0.001). Incidences of organ failure and SAP were significantly higher in the h-Cys C group (P < 0.05). ROC analysis indicated that a serum cystatin C cutoff point of 1.055 mg/L optimally predicted persistent AKI (AUC = 0.711). For internal validation, we selected 545 AP patients, treated at our center from 2019 to 2022, including 54 AKI patients. ROC analysis in this validation group yielded a sensitivity of 100% and specificity of 90.9% (AUC = 0.916, 95% CI: 0.894-0.937). CONCLUSION: Elevated serum cystatin C levels are sensitive indicators of adverse AKI prognosis in AP patients. The cystatin C level at admission can reflect a patient's initial renal function status.

Depression score mediate the association between a body shape index and infertility in overweight and obesity females, NHANES 2013-2018.

BACKGROUND: Overweight and obese females demonstrate a significantly increased risk of anovulatory infertility. This study aims to investigate whether depression score could mediate the association between a body shape index (ABSI) and infertility, especially in overweight and obese population. METHODS: We included 5431 adult female Americans from the National Health and Nutrition Examination Survey (NHANES, 2013-2018) database. ABSI manifested the body shape using waist circumference, weight, and height. Infertility or fertility status was defined by interviewing female participants aged ≥ 18 through the reproductive health questionnaires. Depression symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9) with total scores between 0 and 27. To investigate the association of infertility with ABSI and other individual components, survey-weighted multivariable logistic regression was performed. Mediation analysis of PHQ-9 score was conducted to disentangle the pathways that link ABSI to infertility among the NHANES participants. RESULTS: 596 (10.97%) females were categorized with having infertility among 5431 participants. Participants with infertility showed higher ABSI and PHQ-9 score, appearing greater population proportion with depression symptoms. In the multivariable logistic regression model, ABSI (adjusted odds ratio = 0.14, 95% CI: 0.04 to 0.50) and PHQ-9 (adjusted odds ratio = 1.04, 95% CI: 1.01 to 1.07) were positively associated with infertility. PHQ-9 score was estimated to mediate 0.2% (P = 0.03) of the link between ABSI and infertility in all individuals, but to mediate 13.5% (P < 0.01) of the ABSI-infertility association in overweight and obese adult females. CONCLUSION: The association between ABSI and infertility seems to be mediated by depression symptoms scored by PHQ-9, especially in those adult females with overweigh and obesity. Future studies should be implemented to further explore this mediator in ABSI-infertility link.

Exploring a high-urease activity Bacillus cereus for self-healing concrete via induced CaCO3 precipitation.

The structural integrity and esthetic appeal of concrete can be compromised by concrete cracks. Promise has been shown by microbe-induced calcium carbonate precipitation (MICP) as a solution for concrete cracking, with a focus on urease-producing microorganisms in research. Bacillus cereus was isolated from soil and employed for this purpose in this study due to its high urease activity. The strain exhibited strong tolerance for alkaline media and high salt levels, which grew at a pH of 13 and 4% salt concentration. The repair of concrete cracks with this strain was evaluated by assessing the effects of four different thickeners at varying concentrations. The most effective results were achieved with 10 g/L of sodium carboxymethyl cellulose (CMC-Na). The data showed that over 90% repair of cracks was achieved by this system with an initial water penetration time of 30 s. The study also assessed the quantity and sizes of crystals generated during the bacterial mineralization process over time to improve our understanding of the process. KEY POINTS: • MICP using Bacillus cereus shows potential for repairing concrete cracks. • Strain tolerates alkaline media and high salt levels, growing at pH 13 and 4% salt concentration. • Sodium carboxymethyl cellulose (CMC-Na) at 10 g/L achieved over 90% repair of cracks.

circSLC25A13 acts as a ceRNA to regulate AML progression via miR-616-3p/ADCY2 axis.

Circular RNAs (circRNAs), a type of endogenous noncoding RNA (ncRNA), exert vital roles in leukemia progression and are promising prognostic factors. Here, we report a novel circRNA, circSLC25A13 (hsa_circ_0081188), which was increased in acute myeloid leukemia (AML) patients with poor overall survival (OS) comparing to patients with good prognosis. Knockdown of circSLC25A13 in AML cells inhibited proliferation and increased cell apoptosis in vitro and in vivo. Enhanced circSLC25A13 expression promoted the survival of AML cells. Mechanistically, circSLC25A13 played as a microRNA sponge of miR-616-3p, which inhibited the expression of adenylate cyclase 2 (ADCY2). Downregulation of miR-616-3p and overexpression of ADCY2 partially rescued circSLC25A13 deficient induced cell growth arrest. In summary, through competitive absorption of miR-616-3p and thereby upregulating ADCY2 expression, circSLC25A13 promoted AML progression. Moreover, circSLC25A13 may represent a potential novel biomarker for the prognosis of AML and offer a potential therapeutic target for AML treatment.

AKBA alleviates experimental pancreatitis by inhibiting oxidative stress in Macrophages through the Nrf2/HO-1 pathway.

BACKGROUND: Acute pancreatitis (AP) is an inflammatory condition of the pancreas characterized by oxidative stress and inflammation in its pathophysiology. Acetyl-11-keto-ß-boswellic acid (AKBA) is an active triterpenoid with antioxidant activity. This article seeks to assess the impact of AKBA on AP and investigate its underlying mechanisms. METHODS: AP was induced in wild-type, Lyz2+/cre Nrf2fl/fl mice and Pdx1+/cre Nrf2fl/fl mice by caerulein. Serum amylase and lipase levels, along with histological grading, were utilized to evaluate the severity of AP. Murine bone marrow-derived macrophages (BMDMs) were isolated, cultured, and polarized to the M1 subtype. Flow cytometry and ELISA were utilized to identify the macrophage phenotype. Alterations in oxidative stress damage and intracellular ROS were observed. Nrf2/HO-1 signaling pathways were also evaluated. RESULTS: In a caerulein-induced mouse model of AP, treatment with AKBA reduced blood amylase and lipase activity and ameliorated pancreatic tissue histological and pathological features. Furthermore, AKBA significantly mitigated oxidative stress-induced damage and induced the expression of Nrf2 and HO-1 protein. Additionally, by using conditional knockout mice (Lyz2+/cre Nrf2fl/fl and Pdx1+/cre Nrf2fl/fl mice), we verified that Nrf2 primarily functions in macrophages rather than acinar cells. In vitro, AKBA inhibits pro-inflammatory M1-subtype macrophage polarization and reduces ROS generation through Nrf2/HO-1 oxidative stress pathway. Moreover, the protective effects of AKBA against AP were abolished in myeloid-specific Nrf2-deficient mice and BMDMs. Molecular docking results revealed interactions between AKBA and Nrf2. CONCLUSION: Our results confirm that AKBA exerts protective effects against AP in mice by inhibiting oxidative stress in macrophages through the Nrf2/HO-1 Pathway.

Long noncoding RNA LTCONS6801 up-regulates TBK1 mediated antiviral innate immunity in miiuy croaker, Miichttys miiuy.

The development of sequencing technology has further accelerated the research of noncoding RNA (ncRNA). A large number of studies have shown that long noncoding RNA (lncRNA) in ncRNA can regulate gene expression in various ways and then affect various physiological and biochemical processes of the host. In this study, we found a novel lncRNA in Miichthys miiuy, named LTCONS6801, which is beneficial to TANK-binding kinase 1 (TBK1) and its mediated pathway to promote the host immune function. First, we found that lncRNA LTCONS6801 can enhance cell activity through cell viability detection and cell proliferation detection. Besides, after poly (I: C) stimulation, overexpression of lncRNA LTCONS6801 promoted the expression of antiviral gene and TBK1. We found that lncRNA LTCONS6801 further affects NF-κB and IRF3 signaling pathways by regulating the expression of TBK1. In short, lncRNA LTCONS6801 is an lncRNA that can positively regulate the host innate immune response by regulating the expression of TBK1. Our study enriches the theory and insight of lncRNA regulating antiviral immune pathway and clarifies the important role of lncRNA in antiviral immunity of teleost fish.

ACSL5, a prognostic factor in acute myeloid leukemia, modulates the activity of Wnt/ß-catenin signaling by palmitoylation modification.

Acyl-CoA synthetase long chain family member 5 (ACSL5), is a member of the acyl-CoA synthetases (ACSs) family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs. The dysregulation of ACSL5 has been reported in some cancers, such as glioma and colon cancers. However, little is known about the role of ACSL5 in acute myeloid leukemia (AML). We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors. ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients. In AML cells, the ACSL5 knockdown inhibited cell growth both in vitro and in vivo. Mechanistically, the knockdown of ACSL5 suppressed the activation of the Wnt/ß-catenin pathway by suppressing the palmitoylation modification of Wnt3a. Additionally, triacsin c, a pan-ACS family inhibitor, inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199, the FDA approved BCL-2 inhibitor for AML therapy. Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML.

The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer.

Heterogeneous antigen expression is a key barrier influencing the activity of chimeric antigen receptor (CAR) T cells in solid tumors. Here, we develop CAR T cells targeting glypican-1 (GPC1), an oncofetal antigen expressed in pancreatic cancer. We report the generation of dromedary camel VHH nanobody (D4)-based CAR T cells targeting GPC1 and the optimization of the hinge (H) and transmembrane domain (TM) to improve activity. We find that a structurally rigid IgG4H and CD28TM domain brings the two D4 fragments in proximity, driving CAR dimerization and leading to enhanced T-cell signaling and tumor regression in pancreatic cancer models with low antigen density in female mice. Furthermore, single-cell-based proteomic and transcriptomic analysis of D4-IgG4H-CD28TM CAR T cells reveals specific genes (e.g., HMGB1) associated with high T-cell polyfunctionality. This study demonstrates the potential of VHH-based CAR T for pancreatic cancer therapy and provides an engineering strategy for developing potent CAR T cells targeting membrane-distal epitopes.

Silencing of PpNRAMP5 improves manganese toxicity tolerance in peach (Prunus persica) seedlings.

The natural resistance-associated macrophage protein (NRAMP) gene family assists in the transport of metal ions in plants. However, the role and underlying physiological mechanism of NRAMP genes under heavy metal toxicity in perennial trees remain to be elucidated. In Prunus persica, five NRAMP family genes were identified and named according to their predicted phylogenetic relationships. The expression profiling analysis indicated that PpNRAMPs were significantly induced by excess manganese (Mn), iron, zinc, and cadmium treatments, suggesting their potential role in heavy metal uptake and transportation. Notably, the expression of PpNRAMP5 was tremendously increased under Mn toxicity stress. Heterologous expression of PpNRAMP5 in yeast cells also confirmed Mn transport. Suppression of PpNRAMP5 through virus-induced gene silencing enhanced Mn tolerance, which was compromised when PpNRAMP5 was overexpressed in peach. The silencing of PpNRAMP5 mitigated Mn toxicity by dramatically reducing Mn contents in roots, and effectively reduced the chlorophyll degradation and improved the photosynthetic apparatus under Mn toxicity stress. Therefore, PpNRAMP5-silenced plants were less damaged by oxidative stress, as signified by lowered H2O2 contents and O2•- staining intensity, also altered the reactive oxygen species (ROS) homeostasis by activating enzymatic antioxidants. Consistently, these physiological changes showed an opposite trend in the PpNRAMP5-overexpressed peach plants. Altogether, our findings suggest that downregulation of PpNRAMP5 markedly reduces the uptake and transportation of Mn, thus activating enzymatic antioxidants to strengthen ROS scavenging capacity and photosynthesis activity, thereby mitigating Mn toxicity in peach plants.

CPT1B, a metabolic molecule, is also an independent risk factor in CN-AML.

BACKGROUND: Fatty acid oxidation has been considered as an important energy source for tumorigenesis and development. Several studies have investigated the role of CPT1A, a kind of fatty acid oxidation rate-limiting enzyme, in AML. However, prognostic value and regulatory network of another subtype, CPT1B in AML remains elusive. This study aims to clarify the independent prognostic role of CPT1B in CN-AML based on clinical data and molecular level data (mRNA, miRNA and lncRNA). OBJECTIVE: The aim of this study is to investigate the prognostic value of CPT1B in AML patients. METHODS: First, we analyzed the CPT1B expression in AML cohort via the online database "GEPIA". Subsequently, miRNA-mRNA and ceRNA networks were constructed to help predict the role of CPT1B in AML. Several molecules which showed the prognostic value and metabolic function of CPT1B were identified. Finally, the expression of CPT1B in our own cohort of 324 CN-AML patients was analyzed to clarify the results. RESULTS: It was found that CPT1B was markedly higher in AML patients compared to normal people and this upregulation was associated with the poor clinical outcome. Several molecules revealed the possible regulatory mechanism of CPT1B in AML. CONCLUSION: CPT1B is a potential prognostic factor and a therapeutic target for AML treatment.

Comprehensive physio-biochemical and transcriptomic characterization to decipher the network of key genes under waterlogging stress and its recuperation in Prunus persica.

Waterlogging is a major abiotic stress that plants encounter as a result of climate change impacts. Peach is very sensitive to hypoxia during waterlogging, which causes poor tree vigor and huge economic losses. The molecular mechanism underlying the peach response to waterlogging and reoxygenation remains unclear. Here, the physiological and molecular responses of 3-week-old peach seedlings under waterlogged and recovery conditions were comprehensively analyzed. As a result, waterlogging significantly reduced plant height and biomass with inhibition of root growth when compared with control and reoxygenation. Similar results were observed for photosynthetic activities and gaseous exchange parameters. Waterlogging increased lipid peroxidation, hydrogen peroxide, proline, glutamic acid and glutathione contents, while superoxide dismutase, peroxidases and catalase activities were decreased. The glucose and fructose contents were accumulated, contrary to sucrose which was reduced remarkably throughout the stress periods. The level of endogenous indole acetic acid (IAA) was increased in waterlogging but decreased after reoxygenation. However, the change trends of jasmonic acid (JA), cytokinins and abscisic acid (ABA) levels were opposite to IAA. In transcriptomic analysis, there were 13,343 differentially expressed genes (DEGs) with higher and 16,112 genes with lower expression. These DEGs were greatly enriched in carbohydrate metabolism, anaerobic fermentation, glutathione metabolism and IAA hormone biosynthesis under waterlogging, while they were significantly enriched in photosynthesis, reactive oxygen species scavenging, ABA and JA hormones biosynthesis in reoxygenation. Moreover, several genes related to stress response, carbohydrate metabolism and hormones biosynthesis were significantly changed in waterlogging and reoxygenation, which indicated unbalanced amino acid, carbon and fatty acid pools in peach roots. Taken together, these results suggest that glutathione, primary sugars and hormone biosynthesis and signaling might play key roles in plant response to waterlogging. Our work provides a comprehensive understanding of gene regulatory networks and metabolites in waterlogging stress and its recuperation, which will facilitate peach waterlogging control.