Curcumin activates the Wnt/ß-catenin signaling pathway to alleviate hippocampal neurogenesis abnormalities caused by intermittent hypoxia: A study based on network pharmacology and experimental verification.

The purpose of this work was to investigate how curcumin (Cur) might enhance cognitive function and to gain a better understanding of the molecular mechanisms behind Cur's impacts on neurogenesis deficits brought on by intermittent hypoxia (IH). Using network pharmacology, we explored possible targets for Cur's obstructive sleep apnea (OSA) therapy. We established an IH model using C57BL/6 mice and c17.2 cells, and we assessed the influence of Cur on treatment outcomes as well as the effect of IH on cognitive function. Hippocampal damage and neurogenesis, as well as expression of core targets, were then examined. Network pharmacology analysis revealed that Cur has the potential for multi-target, multi-pathway therapy, with CTNNB1 and MYC as core target genes. The Morris water maze test showed that Cur (100 mg/kg, intragastrically) significantly improved cognitive dysfunction induced by IH. The hematoxylin and eosin (H&E) and Nissl staining indicated that Cur could alleviate damage to the hippocampus caused by IH. Immunohistochemistry, immunofluorescence, and western blotting results showed that Cur might promote neurogenesis and upregulate the expression of ß-catenin and c-myc. In vitro, Cur (0.5 µM) has a protective effect on IH-induced neural stem cells (NSCs) injury and apoptosis and can restore the Wnt/ß-catenin. Cur significantly increased the neurogenesis via the Wnt/ß-catenin pathway, providing the scientific groundwork for the development of new treatment strategies for neurological damage linked to OSA.

A comprehensive review of antibiotic resistance gene contamination in agriculture: Challenges and AI-driven solutions.

Since their discovery, the prolonged and widespread use of antibiotics in veterinary and agricultural production has led to numerous problems, particularly the emergence and spread of antibiotic-resistant bacteria (ARB). In addition, other anthropogenic factors accelerate the horizontal transfer of antibiotic resistance genes (ARGs) and amplify their impact. In agricultural environments, animals, manure, and wastewater are the vectors of ARGs that facilitate their spread to the environment and humans via animal products, water, and other environmental pathways. Therefore, this review comprehensively analyzed the current status, removal methods, and future directions of ARGs on farms. This article 1) investigates the origins of ARGs on farms, the pathways and mechanisms of their spread to surrounding environments, and various strategies to mitigate their spread; 2) determines the multiple factors influencing the abundance of ARGs on farms, the pathways through which ARGs spread from farms to the environment, and the effects and mechanisms of non-antibiotic factors on the spread of ARGs; 3) explores methods for controlling ARGs in farm wastes; and 4) provides a comprehensive summary and integration of research across various fields, proposing that in modern smart farms, emerging technologies can be integrated through artificial intelligence to control or even eliminate ARGs. Moreover, challenges and future research directions for controlling ARGs on farms are suggested.

GLP-1 analogue liraglutide attenuates CIH-induced cognitive deficits by inhibiting oxidative stress, neuroinflammation, and apoptosis via the Nrf2/HO-1 and MAPK/NF-κB signaling pathways.

Obstructive sleep apnea (OSA) is a common clinical condition linked to cognitive impairment, mainly characterized by chronic intermittent hypoxia (CIH). GLP-1 receptor agonist, known for promoting insulin secretion and reducing glucose levels, has demonstrated neuroprotective effects in various experimental models such as stroke, Alzheimer's disease, and Parkinson's disease. This study aims to investigate the potential role and mechanisms of the GLP-1 receptor agonist liraglutide in ameliorating OSA-induced cognitive deficits. CIH exposure, a well-established and mature OSA pathological model, was used both in vitro and in vivo. In vitro, CIH significantly activated oxidative stress, inflammation, and apoptosis in SH-SY5Y cells. Liraglutide enhanced the nuclear translocation of Nrf2, activating its downstream pathways, thereby mitigating CIH-induced injury in SH-SY5Y cells. Additionally, liraglutide modulated the MAPK/NF-κB signaling pathway, reducing the expression of inflammatory factors and proteins. In vivo, we subjected mice to an intermittent hypoxia incubator to mimic the pathogenesis of human OSA. The Morris water maze test revealed that CIH exposure substantially impaired spatial memory. Subsequent western blot analyses and histopathological examinations indicated that liraglutide could activate the Nrf2/HO-1 axis and inhibit the MAPK/NF-κB signaling pathway, thereby alleviating OSA-associated cognitive dysfunction in mice. These findings suggest that GLP-1 receptor agonists may offer a promising preventive strategy for OSA-associated cognitive impairment. By refining these findings, we provide new insights into GLP-1's protective mechanisms in combating cognitive deficits associated with CIH, underscoring its potential as a therapeutic agent for conditions linked to OSA.

Genome-Wide Identification of Pentatricopeptide Repeat (PPR) Gene Family and Multi-Omics Analysis Provide New Insights Into the Albinism Mechanism of Kandelia obovata Propagule Leaves.

Pentatricopeptide repeat (PPR) gene family constitutes one of the largest gene families in plants, which mainly participate in RNA editing and RNA splicing of organellar RNAs, thereby affecting the organellar development. Recently, some evidence elucidated the important roles of PPR proteins in the albino process of plant leaves. However, the functions of PPR genes in the woody mangrove species have not been investigated. In this study, using a typical true mangrove Kandelia obovata, we systematically identified 298 PPR genes and characterized their general features and physicochemical properties, including evolutionary relationships, the subcellular localization, PPR motif type, the number of introns and PPR motifs, and isoelectric point, and so forth. Furthermore, we combined genome-wide association studies (GWAS) and transcriptome analysis to identify the genetic architecture and potential PPR genes associated with propagule leaves colour variations of K. obovata. As a result, we prioritized 16 PPR genes related to the albino phenotype using different strategies, including differentially expressed genes analysis and genetic diversity analysis. Further analysis discovered two genes of interest, namely Maker00002998 (PLS-type) and Maker00003187 (P-type), which were differentially expressed genes and causal genes detected by GWAS analysis. Moreover, we successfully predicted downstream target chloroplast genes (rps14, rpoC1 and rpoC2) bound by Maker00002998 PPR proteins. The experimental verification of RNA editing sites of rps14, rpoC1, and rpoC2 in our previous study and the verification of interaction between Maker00002998 and rps14 transcript using in vitro RNA pull-down assays revealed that Maker00002998 PPR protein might be involved in the post-transcriptional process of chloroplast genes. Our result provides new insights into the roles of PPR genes in the albinism mechanism of K. obovata propagule leaves.

Proteasome inhibition induces apoptosis through simultaneous inactivation of MCL-1/BCL-XL by NOXA independent of CHOP and JNK pathways.

Proteasome inhibitors have been employed in the treatment of relapsed multiple myeloma and mantle cell lymphoma. The observed toxicity caused by proteasome inhibitors is a universal phenotype in numerous cancer cells with different sensitivity. In this study, we investigate the conserved mechanisms underlying the toxicity of the proteasome inhibitor bortezomib using gene editing approaches. Our findings utilizing different caspase knocking out cells reveal that bortezomib induces classic intrinsic apoptosis by activating caspase-9 and caspase-3/7, leading to pore-forming protein GSDME cleavage and subsequent lytic cell death or called secondary necrosis, a phenotype also observed in many apoptosis triggers like TNFα plus CHX, DTT and tunicamycin treatment in HeLa cells. Furthermore, through knocking out of nearly all BH3-only proteins including BIM, BAD, BID, BMF and PUMA, we demonstrate that NOXA is the sole BH3-only protein responsible for bortezomib-induced apoptosis. Of note, NOXA is well known for selectively binding to MCL-1 and A1, but our studies utilizing different BH3 mimetics as well as immunoprecipitation assays indicate that, except for the constitutive interaction of NOXA with MCL-1, the accumulation of NOXA after bortezomib treatment allows it to interact with BCL-XL, then simultaneous relieving suppression on apoptosis by both anti-apoptotic proteins BCL-XL and MCL-1. In addition, though bortezomib-induced significant ER stress and JNK activation were observed in the study, further genetic depletion experiments prove that bortezomib-induced apoptosis occurs independently of ER stress-related apoptosis factor CHOP and JNK. In summary, these results provide a solid conclusion about the critical role of NOXA in inactivation of BCL-XL except MCL-1 in bortezomib-induced apoptosis.

Trehalose along with ABA promotes the salt tolerance of Avicennia marina by regulating Na+ transport.

Mangroves grow in tropical/subtropical intertidal habitats with extremely high salt tolerance. Trehalose and trehalose-6-phosphate (T6P) have an alleviating function against abiotic stress. However, the roles of trehalose in the salt tolerance of salt-secreting mangrove Avicennia marina is not documented. Here, we found that trehalose was significantly accumulated in A. marina under salt treatment. Furthermore, exogenous trehalose can enhance salt tolerance by promoting the Na+ efflux from leaf salt gland and root to reduce the Na+ content in root and leaf. Subsequently, eighteen trehalose-6-phosphate synthase (AmTPS) and 11 trehalose-6-phosphate phosphatase (AmTPP) genes were identified from A. marina genome. Abscisic acid (ABA) responsive elements were predicted in AmTPS and AmTPP promoters by cis-acting elements analysis. We further identified AmTPS9A, as an important positive regulator, that increased the salt tolerance of AmTPS9A-overexpressing Arabidopsis thaliana by altering the expressions of ion transport genes and mediating Na+ efflux from the roots of transgenic A. thaliana under NaCl treatments. In addition, we also found that ABA could promote the accumulation of trehalose, and the application of exogenous trehalose significantly promoted the biosynthesis of ABA in both roots and leaves of A. marina. Ultimately, we confirmed that AmABF2 directly binds to the AmTPS9A promoter in vitro and in vivo. Taken together, we speculated that there was a positive feedback loop between trehalose and ABA in regulating the salt tolerance of A. marina. These findings provide new understanding to the salt tolerance of A. marina in adapting to high saline environment at trehalose and ABA aspects.

Plasma Deoxycholic Acid Levels are Associated with Hemodynamic and Clinical Outcomes in Acute Pulmonary Embolism Patients.

This study aimed to evaluate the correlation of plasma deoxycholic acid (DCA) levels with clinical and hemodynamic parameters in acute pulmonary embolism (APE) patients. Total 149 APE adult patients were prospectively recruited. Plasma DCA levels were measured using rapid resolution liquid chromatography-quadrupole time-of-flight mass spectrometry. Baseline clinical and hemodynamic parameters were evaluated according to plasma DCA levels. The plasma DCA levels were significantly lower in APE patients than in those without APE (P < 0.001). APE patients with adverse events had lower plasma DCA levels (P < 0.001). Low DCA group patients presented more adverse cardiac function, higher NT-proBNP levels (P = 0.010), and higher WHO functional class levels (P = 0.023). Low DCA group also presented with an adverse hemodynamic status, with higher pulmonary vascular resistance levels (P = 0.027) and lower cardiac index levels (P = 0.024). Both cardiac function and hemodynamic parameters correlated well with plasma DCA levels. Kaplan-Meier survival analysis demonstrated that APE patients with lower plasma DCA levels had a significantly higher event rate (P = 0.009). In the univariate and multivariate Cox regression analyses, the plasma DCA level was an independent predictor of clinical worsening events after adjusting for age, sex, WHO functional class, NT-proBNP level, pulmonary vascular resistance, and cardiac index (HR 0.370, 95% CI 0.161, 0.852; P = 0.019). Low plasma DCA levels predicted adverse cardiac function and hemodynamic collapse. A low DCA level was correlated with a higher clinical worsening event rate and could be an independent predictor of clinical outcomes in multivariate analysis.

Integrative multi-omics analysis reveals the underlying toxicological mechanisms of enrofloxacin on the growth of wheat seedling roots.

The continuous release of antibiotics into agroecosystems has raised concerns about the potential negative effects of antibiotic residues on crops. In this study, the toxicological effects of enrofloxacin (ENR) on wheat seedlings were analyzed using a combination of morpho-physiological, transcriptomic, proteomic, and metabolomic approaches. ENR inhibited the growth of wheat (Triticum aestivum L.) roots and induced oxidative stress. In particular, ENR downregulated the oxidative phosphorylation pathway, while it enhanced glycolysis and the tricarboxylic acid cycle, thereby regulating the balance of intracellular energy metabolism. In addition, sustained exposure to excessive reactive oxygen species (ROS) resulted in an increase in reduced glutathione (GSH), a slight decrease in ascorbic acid (AsA), and a significant decrease in the ratio of GSH to oxidized glutathione (GSSG), which imbalanced the AsA-GSH cycle. In addition, the resulting increase in abnormal proteins triggered ubiquitin-independent proteasomal degradation pathways. Further, an increase in abscisic acid (ABA) and a decrease in jasmonic acid (JA) and its derivatives alleviated the inhibitory effect of ENR on the growth of wheat roots. In conclusion, direct damage and signaling by ROS, hormonal regulation, a decrease in the GSH to GSSG ratio, and insufficient energy supply were identified as key factors for the significant inhibition of wheat root growth under ENR stress.

Light-Driven Electrochemical Biosensing with DNA Origami-Assisted Hybrid Nanoantenna for Fumonisin B1 Monitoring.

The electrochemical detection of biosensors is largely governed by the changes in physical properties of redox probes, which are susceptible to electrode substrate effects, inhibiting sensor sensitivity. In this work, a light-driven electrochemical biosensor based on a hybrid nanoantenna was developed for the sensitive detection of fumonisin B1 (FB1). The hybrid nanoantenna sensing interface was constructed by coupling CdSe quantum dots (QDs)-DNA nanowire and graphdiyne oxide composites loaded with methylene blue and gold nanorods (GDYO-MB-Au NRs) using a tetrahedral DNA nanostructure, which acted as a light-driven unit and an amplification unit, respectively. The hybrid nanoantenna with light-driven properties facilitated the alteration in the chemical properties of MB at the sensing interface; that is, MB was degraded under light illumination. The stripping of the CdSe QDs-DNA nanowire triggered by the binding of FB1 could degrade the light-driven capability, thereby improving the electrochemical signal through depressing MB degradation. Taking advantage of the photodegradation of MB by the hybrid nanoantenna, the developed biosensor reduced the background signal and increased the detection sensitivity. The developed biosensor exhibited a linear detection range from 0.5 fg mL-1 to 10 pg mL-1 and a detection limit down to 0.45 fg mL-1. This strategy shows great promise for the fabrication of highly sensitive electrochemical biosensors.

Genome Editing of Mammalian Cells Through RNA Transcript-Mediated Homologous Recombination Repair.

Double-stranded break (DSB) repair of eukaryotic DNA is mainly accomplished by nonhomologous end joining and homologous recombination (HR). Providing exogenous templates during HR repair can result in the editing of target genes, which is the central mechanism of the well-established clustered regularly interspaced short palindromic repeats (CRISPR) gene editing system. Currently, exogenous templates are mainly DNA molecules, which can provoke a cellular immune response within the cell. In order to verify the feasibility of RNA molecules as repair templates for HR in mammalian cell genome editing, we fused RNA template molecules to the 3'-end of single guide RNA (sgRNA), so that the sgRNA and the homologous template RNA form a single RNA molecule. The results show this construct can be used as a repair template to achieve target gene editing in mammalian cells. In addition, the factors influencing HR mediated by RNA template molecules were investigated, and it was found that increasing the length of homologous arms and inducing an R-loop near the DSBcan effectively promote HR repair. Furthermore, intracellular homologous chromosomes may compete with exogenous RNA templates. The findings in this article provide a reference for the utilization of RNA template molecules to mediate target gene editing in eukaryotic cells, as well as a basis for the study of the mechanism by which RNA molecules mediate the repair of DSBs.

The effect of bright light therapy on major depressive disorder: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The increasing prevalence of major depressive disorder (MDD) has led to increased demand for psychotherapy and pharmacotherapy, yet concerns were raised regarding the cost and accessibility to these therapies. Bright light therapy (BLT) has shown promise in mitigating depressive symptoms of non-seasonal affective disorders. This meta-analysis gathered evidence from randomised controlled trials (RCTs) to assess the effectiveness of BLT on patients with non-seasonal MDD. METHODS: Five databases were systematically searched. The primary outcome of the meta-analysis was the endpoint depression score from the BLT and control treatment groups, with the remission and response rates as the secondary outcomes. Results are presented in standardised mean difference (SMD) and log odd ratio. Subgroup analyses compared the effects of trial length and the length of daily exposure. RESULTS: Results on 15 RCTs between 1996 and 2024 with 883 patients showed positive effects of BLT on alleviating depressive symptoms (SMD = 0.48, 95 % CI [0.22, 0.74], p <.001). Trials that lasted two weeks or less or those with 60 minutes or more of daily exposure were associated with higher therapeutic effectiveness. BLT was also associated with a higher response rate at the end of the trial. CONCLUSION: This meta-analysis offers positive evidence that favours BLT in alleviating depressive symptoms in MDD, suggesting that it could be a convenient and easily accessible treatment modality to augment psychotherapy and pharmacotherapy.

Determination of glucose oxidase activity by tyrosine fluorescence spectrophotometry.

A novel Fe2+/Tyr/H2O2 fluorescence reaction system has been established for the purpose of analyzing glucose oxidase activity. This system involves the catalysis of glucose oxidase on glucose to produce H2O2, which in turn oxidizes tyrosine to a highly fluorescent substance under the catalysis of Fe2+. The fluorescence intensity is subsequently employed to ascertain the enzymatic activity of glucose oxidase. The enzymatic oxidation reaction and tyrosine fluorescence reaction conditions were optimized based on the H2O2 standard curve equation. Direct fluorescence spectrophotometry was used to determine the activity range and detection limit of glucose oxidase, which were found to be 7.00 × 10-5-7.00 × 10-2 U/mL and 3.36 × 10-5 U/mL (Enzyme-like activity is 6.72 × 10-4 U/mL, The enzyme reaction time is 5 min), respectively, with a relative standard deviation of less than 3.2 %. This method has been successfully applied to determine the activity of glucose oxidase in food additives, with a recovery rate ranging from 96.00 % to 102.0 %.

Integrated Photoelectrochemical-SERS Platform Based on Plasmonic Metal-Semiconductor Heterostructures for Multidimensional Charge Transfer Analysis and Enhanced Patulin Detection.

Comprehending the charge transfer mechanism at the semiconductor interfaces is crucial for enhancing the electronic and optical performance of sensing devices. Yet, relying solely on single signal acquisition methods at the interface hinders a comprehensive understanding of the charge transfer under optical excitation. Herein, we present an integrated photoelectrochemical surface-enhanced Raman spectroscopy (PEC-SERS) platform based on quantum dots/metal-organic framework (CdTe/Yb-TCPP) nanocomposites for investigating the charge transfer mechanism under photoexcitation in multiple dimensions. This integrated platform allows simultaneous PEC and SERS measurements with a 532 nm laser. The obtained photocurrent and Raman spectra of the CdTe/Yb-TCPP nanocomposites are simultaneously influenced by variable bias voltages, and the correlation between them enables us to predict the charge transfer pathway. Moreover, we integrate gold nanorods (Au NRs) into the PEC-SERS system by using magnetic separation and DNA biometrics to construct a biosensor for patulin detection. This biosensor demonstrates the voltage-driven ON/OFF switching of PEC and SERS signals, a phenomenon attributed to the plasmon resonance effect of Au NRs at different voltages, thereby influencing charge transfer. The detection of patulin in apples verified the applicability of the biosensor. The study offers an efficient approach to understanding semiconductor-metal interfaces and presents a new avenue for designing high-performance biosensors.

CXCR2, as a key regulatory gene of HDP-PG-1, maintains intestinal mucosal homeostasis.

The intestine defends against pathogenic microbial invasion via the secretion of host defense peptides (HDPs). Nutritional immunomodulation can stimulate the expression of endogenous HDPs and enhance the body's immune defense, representing a novel non-antibiotic strategy for disease prevention. The project aims to explore the regulatory mechanism of protegrin-1 (PG-1) expression using sodium phenylbutyrate (PBA) by omics sequencing technology and further investigate the role of key regulatory genes on intestinal health. The results showed that PBA promoted PG-1 expression in intestinal epithelial cells based on cell density through epidermal growth factor receptor (EGFR) and G protein-coupled receptor (GPR43). Transcriptome sequencing and microRNA sequencing revealed that C-X-C motif chemokine receptor 2 (CXCR2) exhibited interactions with PG-1. Pre-treatment cells with a CXCR2 inhibitor (SB225002) effectively suppressed the induction of PG-1 by PBA. Furthermore, SB225002 significantly suppressed the gene expression of HDPs in the jejunum of mice without influencing on the morphology, number of goblet cells, and proliferation of the intestine. CXCR2 inhibition significantly reduced the expression of HDPs during E. coli infection, and resulted in the edema of jejunal epithelial cells. The 16S rDNA analysis of cecal contents showed that the E. coli and SB225002 treatments changed gut microbiota diversity and composition at different taxonomic levels. Correlation analysis suggested a potential regulatory relationship between gut microbiota and HDPs. To that end, a gene involved in the HDP expression, CXCR2, has been identified in the study, which contributes to improving intestinal immune function. PBA may be used as a functional additive to regulate intestinal mucosal function, thereby enhancing the health of the intestinal and host.

Oleanolic acid improved intestinal immune function by activating and potentiating bile acids receptor signaling in E. coli-challenged piglets.

BACKGROUND: Infection with pathogenic bacteria during nonantibiotic breeding is one of the main causes of animal intestinal diseases. Oleanolic acid (OA) is a pentacyclic triterpene that is ubiquitous in plants. Our previous work demonstrated the protective effect of OA on intestinal health, but the underlying molecular mechanisms remain unclear. This study investigated whether dietary supplementation with OA can prevent diarrhea and intestinal immune dysregulation caused by enterotoxigenic Escherichia coli (ETEC) in piglets. The key molecular role of bile acid receptor signaling in this process has also been explored. RESULTS: Our results demonstrated that OA supplementation alleviated the disturbance of bile acid metabolism in ETEC-infected piglets (P < 0.05). OA supplementation stabilized the composition of the bile acid pool in piglets by regulating the enterohepatic circulation of bile acids and significantly increased the contents of UDCA and CDCA in the ileum and cecum (P < 0.05). This may also explain why OA can maintain the stability of the intestinal microbiota structure in ETEC-challenged piglets. In addition, as a natural ligand of bile acid receptors, OA can reduce the severity of intestinal inflammation and enhance the strength of intestinal epithelial cell antimicrobial programs through the bile acid receptors TGR5 and FXR (P < 0.05). Specifically, OA inhibited NF-κB-mediated intestinal inflammation by directly activating TGR5 and its downstream cAMP-PKA-CREB signaling pathway (P < 0.05). Furthermore, OA enhanced CDCA-mediated MEK-ERK signaling in intestinal epithelial cells by upregulating the expression of FXR (P < 0.05), thereby upregulating the expression of endogenous defense molecules in intestinal epithelial cells. CONCLUSIONS: In conclusion, our findings suggest that OA-mediated regulation of bile acid metabolism plays an important role in the innate immune response, which provides a new diet-based intervention for intestinal diseases caused by pathogenic bacterial infections in piglets.

Novel design of simplified ß-hairpin antimicrobial peptide as a potential food preservative based on Trp-pocket backbone.

Food contamination from microbial deterioration requires the development of potent antimicrobial peptides (AMPs). The deployment of approved AMPs as dietary preservatives is limited due to barriers such as instability, toxicity, and high synthetic costs. This exploration utilizes the primary structural elements of the Trp-pocket backbone to engineer a series of ß-hairpin AMPs (XWRWRPGXKXXR-NH2, X representing I, V, F, and/or L). Peptides WpLF, with Phe as X and Leu arranged at the 11th position, demonstrated exceptional selectivity index (SI = 123.08) and sterilization effects both in vitro and in vivo. WpLF consistently exhibited stable bacteriostasis, regardless of physiological salts, serum, and extreme pH. Mechanistic analysis indicated that the peptide penetrates microbial cell membranes, inducing membrane disruption, thereby impeding drug resistance evolution. Conclusively, AMPs engineered by the Trp-pocket skeleton hold substantial potential as innovative biological preservatives in food preservation, providing valuable insights for sustainable and safe peptide-based food preservatives.

Effects of bile acid metabolism on intestinal health of livestock and poultry.

Bile acids are synthesised in the liver and are essential amphiphilic steroids for maintaining the balance of cholesterol and energy metabolism in livestock and poultry. They can be used as novel feed additives to promote fat utilisation in the diet and the absorption of fat-soluble substances in the feed to improve livestock performance and enhance carcass quality. With the development of understanding of intestinal health, the balance of bile acid metabolism is closely related to the composition and growth of livestock intestinal microbiota, inflammatory response, and metabolic diseases. This paper systematically reviews the effects of bile acid metabolism on gut health and gut microbiology in livestock. In addition, our paper summarised the role of bile acid metabolism in performance and disease control.

Analysis of Imprecision for Internal Quality Control of Newborn Screening by Tandem Mass Spectrometry in China, 2015 - 2021.

BACKGROUND: This study aimed to assess the performance of the newborn screening laboratories in China through retrospective analysis of the coefficient of variation (CV) of the internal quality control (IQC) data in the national tandem mass spectrometry screening for inherited metabolic disorders in newborns. METHODS: From 2015 to 2021, the IQC data of amino acid and acylcarnitine test were collected twice each year. CVmonthly in-control was calculated by excluding outliers for the current month and its discrete distribution and changes in trend were comprehensively evaluated for both normal and high concentration levels. The proportion of laboratories meeting both 1/3 and 1/4 quality criteria of the total error allowable (TEa), based on the CVmonthly in-control for each testing item, was calculated. RESULTS: The analysis of CVmonthly in-control for the two concentration levels for the amino acids and acylcarnitine parameters showed that CVmonthly in-control for the normal concentration levels were more discrete before 2018, while CVmonthly in-control for the high concentration levels were less discrete than the normal concentration levels, but there were relatively more outliers. More than 80% of laboratories were able to meet the 1/3 TEa standard for each test at the high concentration level, while the pass rate for the 1/4 TEa standard was significantly lower than 80% (except for C2). CONCLUSIONS: According to the current status of testing in China, it is recommended to use 1/3TEa as the imprecision level standard; for laboratories with relatively high precision, the 1/4TEa standard can be used.

Histidine re-sensitizes pediatric acute lymphoblastic leukemia to 6-mercaptopurine through tetrahydrofolate consumption and SIRT5-mediated desuccinylation.

Despite progressive improvements in the survival rate of pediatric B-cell lineage acute lymphoblastic leukemia (B-ALL), chemoresistance-induced disease progression and recurrence still occur with poor prognosis, thus highlighting the urgent need to eradicate drug resistance in B-ALL. The 6-mercaptopurine (6-MP) is the backbone of ALL combination chemotherapy, and resistance to it is crucially related to relapse. The present study couples chemoresistance in pediatric B-ALL with histidine metabolism deficiency. Evidence was provided that histidine supplementation significantly shifts the 6-MP dose-response in 6-MP-resistant B-ALL. It is revealed that increased tetrahydrofolate consumption via histidine catabolism partially explains the re-sensitization ability of histidine. More importantly, this work provides fresh insights into that desuccinylation mediated by SIRT5 is an indispensable and synergistic requirement for histidine combination therapy against 6-MP resistance, which is undisclosed previously and demonstrates a rational strategy to ameliorate chemoresistance and protect pediatric patients with B-ALL from disease progression or relapse.