A multi-omics study to monitor senescence-associated secretory phenotypes of Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD) is characterized by the progressive degeneration and damage of neurons in the brain. However, developing an accurate diagnostic assay using blood samples remains a challenge in clinic practice. The aim of this study was to explore senescence-associated secretory phenotypes (SASPs) in peripheral blood using mass spectrometry based multi-omics approach and to establish diagnostic assays for AD. METHODS: This retrospective study included 88 participants, consisting of 29 AD patients and 59 cognitively normal (CN) individuals. Plasma and serum samples were examined using high-resolution mass spectrometry to identify proteomic and metabolomic profiles. Receiver operating characteristic (ROC) analysis was employed to screen biomarkers with diagnostic potential. K-nearest neighbors (KNN) algorithm was utilized to construct a multi-dimensional model for distinguishing AD from CN. RESULTS: Proteomics analysis revealed upregulation of five plasma proteins in AD, including RNA helicase aquarius (AQR), zinc finger protein 587B (ZNF587B), C-reactive protein (CRP), fibronectin (FN1), and serum amyloid A-1 protein (SAA1), indicating their potential for AD classification. Interestingly, KNN-based three-dimensional model, comprising AQR, ZNF587B, and CRP, demonstrated its high accuracy in AD recognition, with evaluation possibilities of 0.941, 1.000, and 1.000 for the training, testing, and validation datasets, respectively. Besides, metabolomics analysis suggested elevated levels of serum phenylacetylglutamine (PAGIn) in AD. INTERPRETATION: The multi-omics outcomes highlighted the significance of the SASPs, specifically AQR, ZNF587B, CRP, and PAGIn, in terms of their potential for diagnosing AD and suggested neuronal aging-associated pathophysiology.

Association of liver function and prognosis in patients with severe fever with thrombocytopenia syndrome.

OBJECTIVES: Severe fever with thrombocytopenia syndrome (SFTS) is an epidemic emerging infectious disease with high mortality rate. We investigated the association between liver injury and clinical outcomes in patients with SFTS. METHODS: A total of 291 hospitalized SFTS patients were retrospectively included. Cox proportional hazards model was adopted to identify risk factors of fatal outcome and Kaplan-Meier curves were used to estimate cumulative risks. RESULTS: 60.1% of patients had liver injury at admission, and the median alanine transaminase, aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBil) levels were 76.4 U/L, 152.3 U/L, 69.8 U/L and 9.9 µmol/L, respectively. Compared to survivors, non-survivors had higher levels of AST (253.0 U/L vs. 131.1 U/L, P < 0.001) and ALP (86.2 U/L vs. 67.9 U/L, P = 0.006), higher proportion of elevated ALP (20.0% vs. 4.4%, P < 0.001) and liver injury (78.5% vs. 54.9%, P = 0.001) at admission. The presence of liver injury (HR 2.049, P = 0.033) at admission was an independent risk factor of fatal outcome. CONCLUSIONS: Liver injury was a common complication and was strongly associated with poor prognosis in SFTS patients. Liver function indicators should be closely monitored for SFTS patients.

Study on the Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactone Derivatives.

With the emergence of drug-resistant strains, the treatment of tuberculosis (TB) is becoming more difficult and there is an urgent need to find new anti-TB drugs. Mycobacterium marinum, as a model organism of Mycobacterium tuberculosis, can be used for the rapid and efficient screening of bioactive compounds. The 14-membered resorcylic acid lactones (RALs) have a wide range of bioactivities such as antibacterial, antifouling and antimalarial activity. In order to further study their bioactivities, we initially constructed a 14-membered RALs library, which contains 16 new derivatives. The anti-M. marinum activity was evaluated in vitro. Derivatives 12, 19, 20 and 22 exhibited promising activity with MIC90 values of 80, 90, 80 and 80 µM, respectively. The preliminary structure-activity relationships showed that the presence of a chlorine atom at C-5 was a key factor to improve activity. Further studies showed that 12 markedly inhibited the survival of M. marinum and significantly reduced the dosage of positive drugs isoniazid and rifampicin when combined with them. These results suggest that 12 is a bioactive compound capable of enhancing the potency of existing positive drugs, and its effective properties make it a very useful leads for future drug development in combating TB resistance.

Morphological Innovation Drives Sperm Release in Bryophytes.

Plant movements for survival are nontrivial. Antheridia in the moss Physcomitrium patens (P. patens) use motion to eject sperm in the presence of water. However, the biological and mechanical mechanisms that actuate the process are unknown. Here, the burst of the antheridium of P. patens, triggered by water, results from elastic instability and is determined by an asymmetric change in cell geometry. The tension generated in jacket cell walls of antheridium arises from turgor pressure, and is further promoted when the inner walls of apex burst in hydration, causing water and cellular contents of apex quickly influx into sperm chamber. The outer walls of the jacket cells are strengthened by NAC transcription factor VNS4 and serve as key morphomechanical innovations to store hydrostatic energy in a confined space in P. patens. However, the antheridium in liverwort Marchantia polymorpha (M. polymorpha) adopts a different strategy for sperm release; like jacket cell outer walls of P. patens, the cells surrounding the antheridium of M. polymorpha appear to play a similar role in the storage of energy. Collectively, the work shows that plants have evolved different ingenious devices for sperm discharge and that morphological innovations can differ.

Proton Sponge Nanocomposites for Synergistic Tumor Elimination via Autophagy Inhibition-Promoted Cell Apoptosis and Macrophage Repolarization-Enhanced Immune Response.

Cytoprotective autophagy and an immunosuppressive tumor microenvironment (TME) are two positive promoters for tumor proliferation and metastasis that severely hinder therapeutic efficacy. Inhibiting autophagy and reconstructing TME toward macrophage activation simultaneously are of great promise for effective tumor elimination, yet are still a huge challenge. Herein, a kind of dendrimer-based proton sponge nanocomposites was designed and constructed for tumor chemo/chemodynamic/immunotherapy through autophagy inhibition-promoted cell apoptosis and macrophage repolarization-enhanced immune response. These obtained nanocomposites contain a proton sponge G5AcP dendrimer, a Fenton-like agent Cu(II), and chemical drug doxorubicin (DOX). When accumulated in tumor regions, G5AcP can act as an immunomodulator to realize deacidification-promoted macrophage repolarization toward antitumoral type, which then secretes inflammatory cytokines to activate T cells. They also regulate intracellular lysosomal pH to inhibit cytoprotective autophagy. The released Cu(II) and DOX can induce aggravated damage through a Fenton-like reaction and chemotherapeutic effect in this autophagy-inhibition condition. Tumor-associated antigens are released from these dying tumor cells to promote the maturity of dendritic cells, further activating T cells. Effective tumor elimination can be achieved by this dendrimer-based therapeutic strategy, providing significant guidance for the design of a promising antitumor nanomedicine.

High-frequency repetitive transcranial magnetic stimulation promotes ipsilesional functional hyperemia and motor recovery in mice with ischemic stroke.

Neurovascular decoupling plays a significant role in dysfunction following an ischemic stroke. This study aimed to explore the effect of low- and high-frequency repetitive transcranial magnetic stimulation on neurovascular remodeling after ischemic stroke. To achieve this goal, we compared functional hyperemia, cerebral blood flow regulatory factors, and neurochemical transmitters in the peri-infract cortex 21 days after a photothrombotic stroke. Our findings revealed that low- and high-frequency repetitive transcranial magnetic stimulation increased the real-time cerebral blood flow in healthy mice and improved neurobehavioral outcomes after stroke. Furthermore, high-frequency (5-Hz) repetitive transcranial magnetic stimulation revealed stronger functional hyperemia recovery and increased the levels of post-synaptic density 95, neuronal nitric oxide synthase, phosphorylated-endothelial nitric oxide synthase, and vascular endothelial growth factor in the peri-infract cortex compared with low-frequency (1-Hz) repetitive transcranial magnetic stimulation. The magnetic resonance spectroscopy data showed that low- and high-frequency repetitive transcranial magnetic stimulation reduced neuronal injury and maintained excitation/inhibition balance. However, 5-Hz repetitive transcranial magnetic stimulation showed more significant regulation of excitatory and inhibitory neurotransmitters after stroke than 1-Hz repetitive transcranial magnetic stimulation. These results indicated that high-frequency repetitive transcranial magnetic stimulation could more effectively promote neurovascular remodeling after stroke, and specific repetitive transcranial magnetic stimulation frequencies might be used to selectively regulate the neurovascular unit.

Clinical characteristics and risk factors for Klebsiella pneumoniae bloodstream infection in 152 immunocompetent patients.

OBJECTIVE: To investigate the clinical characteristics and prognostic risk factors for Klebsiella pneumoniae bloodstream infections in immunocompetent patients. METHODS: The study included patients with K. pneumoniae bloodstream infection treated in Zhongda Hospital from June 2016 to June 2021. Clinical data and antibiotic susceptibility test results were retrospectively collected and analyzed. Independent risk factors for mortality were screened using the chi-square test and multivariate logistic regression. RESULTS: A total of 152 patients were included in the analysis. In our cohort, 77.6% of patients were older than 60 years, and 80.9% of them had community-acquired infections. The most common complications were type 2 diabetes, hypertension, and stroke sequelae. The proportion of patients with septic shock or abscesses was 34.9% and 25.7%, respectively. There were significant differences in the site of infection, septic shock, and serum levels of procalcitonin, hypersensitive C-reactive protein, D-dimer, creatinine, and lactic acid between survivors and non-survivors (p < 0.05). Multivariate regression analysis showed that hospital-acquired infections, septic shock, length of hospital stay, and creatinine levels were independent risk factors for mortality. Antibiotic susceptibility test results indicated that clinical outcomes varied depending on bacterial sensitivity to ampicillin/sulbactam. DISCUSSION: Klebsiella pneumoniae is a common community-acquired and hospital-acquired bacteria and usually infects older people with complications such as diabetes. Nosocomial infections, length of stay, septic shock, and renal insufficiency are potentially associated with poor prognosis. Bacterial susceptibility to ampicillin/sulbactam affects prognosis.

Nonspecific phospholipases C3 and C4 interact with PIN-FORMED2 to regulate growth and tropic responses in Arabidopsis.

The dynamic changes in membrane phospholipids affect membrane biophysical properties and cell signaling, thereby influencing numerous biological processes. Nonspecific phospholipase C (NPC) enzymes hydrolyze common phospholipids to release diacylglycerol (DAG), which is converted to phosphatidic acid (PA) and other lipids. In this study, two Arabidopsis (Arabidopsis thaliana) tandemly arrayed genes, NPC3 and NPC4, were identified as critical factors modulating auxin-controlled plant growth and tropic responses. Moreover, NPC3 and NPC4 were shown to interact with the auxin efflux transporter PIN-FORMED2 (PIN2). The loss of NPC3 and NPC4 enhanced the endocytosis and vacuolar degradation of PIN2, which disrupted auxin gradients and slowed gravitropic and halotropic responses. Furthermore, auxin-triggered activation of NPC3 and NPC4 is required for the asymmetric PA distribution that controls PIN2 trafficking dynamics and auxin-dependent tropic responses. Collectively, our study reveals an NPC-derived PA signaling pathway in Arabidopsis auxin fluxes that is essential for fine-tuning the balance between root growth and environmental responses.

HMGA2 overexpression activates IGF2BP2 to stabilize APLP2 via m6A modification and promote pancreatic cancer progression.

Pancreatic cancer is a highly aggressive malignancy of the digestive system, with occult onset, rapid progression, and poor prognosis. The genetic heterogeneity of pancreatic cancer contributes to its highly malignant biological behavior. HMGA2 is overexpressed in tumors and is known to regulate tumor progression in various cancers through the HMGA2-IGF2BP2 axis, but its role and mechanism in pancreatic cancer remain unclear. In this study, we demonstrated that HMGA2 promotes pancreatic cancer progression. We further revealed that HMGA2 upregulates IGF2BP2, which stabilizes APLP2 mRNA via m6A modification, thereby promoting pancreatic cancer progression. These results indicate that HMGA2/IGF2BP2/APLP2 signaling axis regulates the progression of pancreatic cancer.

Genotype diversity enhances invasion resistance of native plants via soil biotic feedbacks.

Although native species diversity is frequently reported to enhance invasion resistance, within-species diversity of native plants can also moderate invasions. While the positive diversity-invasion resistance relationship is often attributed to competition, indirect effects mediated through plant-soil feedbacks can also influence the relationship. We manipulated the genotypic diversity of an endemic species, Scirpus mariqueter, and evaluated the effects of abiotic versus biotic feedbacks on the performance of a global invader, Spartina alterniflora. We found that invader performance on live soils decreased non-additively with genotypic diversity of the native plant that trained the soils, but this reversed when soils were sterilized to eliminate feedbacks through soil biota. The influence of soil biota on the feedback was primarily associated with increased levels of microbial biomass and fungal diversity in soils trained by multiple-genotype populations. Our findings highlight the importance of plant-soil feedbacks mediating the positive relationship between genotypic diversity and invasion resistance.

An increase in SNHG5 expression is associated with poor cancer prognosis, according to a meta-analysis.

BACKGROUND: He long noncoding RNA small nucleolar host RNA 5 (SNHG5) is highly expressed in many cancers, and there is a notable correlation between the elevated expression of SNHG5 and survival outcome in cancer patients. The objective of this study was to conduct a meta-analysis to evaluate the correlation between SNHG5 expression and the clinical outcome of cancer patients. METHODS: Six relevant electronic databases were exhaustively searched, and, depending on the inclusion and exclusion criteria, appropriate literature was obtained. The Newcastle-Ottawa Scale (NOS) score was utilized to evaluate the quality of the research for every article included, and pertinent data from each study were carefully extracted. Hazard ratios (HRs), odds ratios (ORs) and 95% confidence intervals (CIs) were combined to explore the association of SNHG5 expression levels with cancer prognosis, and sensitivity analyses and assessments of publication bias were also conducted to investigate any possibility in the publication of the studies. RESULTS: Eleven studies encompassing 721 patients were ultimately collected. When combined, the hazard ratios (HRs) revealed a substantial direct correlation between elevated SNHG5 expression and an unfavourable prognosis for cancer patients (HR = 1.90, 95% CI 0.87-4.15); however, the correlation did not reach statistical significance. Furthermore, high SNHG5 expression was predictive of advanced TNM stage (OR: 1.988, 95% CI 1.205-3.278) and larger tumour size (OR: 1.571, 95% CI 1.090-2.264); moreover, there were nonsignificant relationships between SNHG5 expression and DM (OR: 0.449, 95% CI 0.077-2.630), lymph node metastasis (OR: 1.443, 95% CI 0.709-2.939), histological grade (OR: 2.098, 95% CI 0.910-4.838), depth of invasion (OR: 1.106, 95% CI 0.376-3.248), age (OR: 0.946, 95% CI 0.718-1.247) and sex (OR: 0.762, 95% CI 0.521-1.115). CONCLUSION: SNHG5 expression is typically increased in the majority of tumour tissues. Elevated SNHG5 expression may indicate poor prognosis in cancer patients. Therefore, SNHG5 is a promising potential therapeutic target for tumours and a reliable prognostic biomarker.

Genomic and transcriptomic profiling of peripheral T cell lymphoma reveals distinct molecular and microenvironment subtypes.

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin's lymphomas varying in clinical, phenotypic, and genetic features. The molecular pathogenesis and the role of the tumor microenvironment in PTCL are poorly understood, with limited biomarkers available for genetic subtyping and targeted therapies. Through an integrated genomic and transcriptomic study of 221 PTCL patients, we delineate the genetic landscape of PTCL, enabling molecular and microenvironment classification. According to the mutational status of RHOA, TET2, histone-modifying, and immune-related genes, PTCL is divided into 4 molecular subtypes with discrete patterns of gene expression, biological aberrations, and vulnerabilities to targeted agents. We also perform an unsupervised clustering on the microenvironment transcriptional signatures and categorize PTCL into 4 lymphoma microenvironment subtypes based on characteristic activation of oncogenic pathways and composition of immune communities. Our findings highlight the potential clinical rationale of future precision medicine strategies that target both molecular and microenvironment alterations in PTCL.

A Sustainable Retinal Drug Co-Delivery for Boosting Therapeutic Efficacy in wAMD: Unveiling Multifaceted Evidence and Synergistic Mechanisms.

Sustainable retinal codelivery poses significant challenges technically, although it is imperative for synergistic treatment of wet age-related macular degeneration (wAMD). Here, a microemulsion-doped hydrogel (Bor/PT-M@TRG) is engineered as an intravitreal depot composing of temperature-responsive hydrogel (TRG) and borneol-decorated paeoniflorin (PF) & tetramethylpyrazine (TMP)-coloaded microemulsions (Bor/PT-M). Bor/PT-M@TRG, functioning as the "ammunition depot", resides in the vitreous and continuously releases Bor/PT-M as the therapeutic "bullet", enabling deep penetration into the retina for 21 days. A single intravitreal injection of Bor/PT-M@TRG yields substantial reductions in choroidal neovascularization (CNV, a hallmark feature of wAMD) progression and mitigates oxidative stress-induced damage in vivo. Combinational PF&TMP regulates the "reactive oxygen species/nuclear factor erythroid-2-related factor 2/heme oxygenase-1" pathway and blocks the "hypoxia inducible factor-1α/vascular endothelial growth factor" signaling in retina, synergistically cutting off the loop of CNV formation. Utilizing fluorescence resonance energy transfer and liquid chromatography-mass spectrometry techniques, they present compelling multifaceted evidence of sustainable retinal codelivery spanning formulations, ARPE-19 cells, in vivo eye balls, and ex vivo section/retina-choroid complex cell levels. Such codelivery approach is elucidated as the key driving force behind the exceptional therapeutic outcomes of Bor/PT-M@TRG. These findings highlight the significance of sustainable retinal drug codelivery and rational combination for effective treatment of wAMD.

Creation of Interfacial S4 -Sn-N2 Electron Pathways for Efficient Light-Driven Hydrogen Evolution.

Establishing effective charge transfer channels between two semiconductors is key to improving photocatalytic activity. However, controlling hetero-structures in situ and designing binding modes pose significant challenges. Herein, hydrolytic SnCl2 ·2H2 O is selected as the metal source and loaded in situ onto a layered carbon nitriden supramolecular precursor. A composite photocatalyst, S4 -Sn-N2 , with electron pathways of SnS2 and tubular carbon nitriden (TCN) is prepared through pyrolysis and vulcanization processes. The contact interface of SnS2 -TCN is increased significantly, promoting the formation of S4 -Sn-N2 micro-structure in a Z-scheme charge transfer channel. This structure accelerates the separation and transport of photogenerated carriers, maintains the stronger redox ability, and improves the stability of SnS2 in this series of heterojunctions. Therefore, the catalyst demonstrated exceptional photocatalytic hydrogen production efficiency, achieving a reaction rate of 86.4 µmol h-1 , which is 3.15 times greater than that of bare TCN.

Toward Estimating CO2 Solubility in Pure Water and Brine Using Cascade Forward Neural Network and Generalized Regression Neural Network: Application to CO2 Dissolution Trapping in Saline Aquifers.

Predicting carbon dioxide (CO2) solubility in water and brine is crucial for understanding carbon capture and storage (CCS) processes. Accurate solubility predictions inform the feasibility and effectiveness of CO2 dissolution trapping, a key mechanism in carbon sequestration in saline aquifers. In this work, a comprehensive data set comprising 1278 experimental solubility data points for CO2-brine systems was assembled, encompassing diverse operating conditions. These data encompassed brines containing six different salts: NaCl, KCl, NaHCO3, CaCl2, MgCl2, and Na2SO4. Also, this databank encompassed temperature spanning from 273.15 to 453.15 K and a pressure range spanning 0.06-100 MPa. To model this solubility databank, cascade forward neural network (CFNN) and generalized regression neural network (GRNN) were employed. Furthermore, three optimization algorithms, namely, Bayesian Regularization (BR), Broyden-Fletcher-Goldfarb-Shanno (BFGS) quasi-Newton, and Levenberg-Marquardt (LM), were applied to enhance the performance of the CFNN models. The CFNN-LM model showcased average absolute percent relative error (AAPRE) values of 5.37% for the overall data set, 5.26% for the training subset, and 5.85% for the testing subset. Overall, the CFNN-LM model stands out as the most accurate among the models crafted in this study, boasting the highest overall R2 value of 0.9949 among the other models. Based on sensitivity analysis, pressure exerts the most significant influence and stands as the sole parameter with a positive impact on CO2 solubility in brine. Conversely, temperature and the concentration of all six salts considered in the model exhibited a negative impact. All salts exert a negative impact on CO2 solubility due to their salting-out effect, with varying degrees of influence. The salting-out effects of the salts can be ranked as follows: from the most pronounced to the least: MgCl2 > CaCl2 > NaCl > KCl > NaHCO3 > Na2SO4. By employing the leverage approach, only a few instances of potential suspected and out-of-leverage data were found. The relatively low count of identified potential suspected and out-of-leverage data, given the expansive solubility database, underscores the reliability and accuracy of both the data set and the CFNN-LM model's performance in this survey.

Genetic diversity and recombination of bovine enterovirus strains in China.

Bovine enterovirus (BEV) consisting of enterovirus species E (EV-E) and F (EV-F) is the causative agent associated with respiratory and gastrointestinal diseases in cattle. Here, we reported the characterization, genetic diversity, and recombination of novel BEV strains isolated from the major cattle-raising regions in China during 2012-2018. Twenty-seven BEV strains were successfully isolated and characterized. Molecular characterization demonstrated that the majority of these novel BEV strains (24/27) were EV-E, while only few strains (3/27) were EV-F. Sequence analysis revealed the diversity of the circulating BEV strains such as species and subtypes where different species or subtype coinfections were detected in the same regions and even in the same cattle herds. For the EV-E, two novel subtypes, designated as EV-E6 and EV-E7, were revealed in addition to the currently reported EV-E1-EV-E5. Comparative genomic analysis revealed the intraspecies and interspecies genetic exchanges among BEV isolates. The representative strain HeN-B62 was probably from AN12 (EV-F7) and PS-87-Belfast (EV-F3) strains. The interspecies recombination between EV-E and EV-F was also discovered, where the EV-F7-AN12 might be from EV-E5 and EV-F1, and EV-E5-MexKSU/5 may be recombined from EV-F7 and EV-E1. The aforementioned results revealed the genetic diversity and recombination of novel BEV strains and unveiled the different BEV species or subtype infections in the same cattle herd, which will broaden the understanding of enterovirus genetic diversity, recombination, pathogenesis, and prevention of disease outbreaks. IMPORTANCE: Bovine enterovirus (BEV) infection is an emerging disease in China that is characterized by digestive, respiratory, and reproductive disorders. In this study, we first reported two novel EV-E subtypes detected in cattle herds in China, unveiled the coinfection of two enterovirus species (EV-E/EV-F) and different subtypes (EV-E2/EV-E7, EV-E1/EV-E7, and EV-E3/EV-E6) in the same cattle herds, and revealed the enterovirus genetic exchange in intraspecies and interspecies recombination. These results provide an important update of enterovirus prevalence and epidemiological aspects and contribute to a better understanding of enterovirus genetic diversity, evolution, and pathogenesis.

Genetic loss of Nrf1 and Nrf2 leads to distinct metabolism reprogramming of HepG2 cells by opposing regulation of the PI3K-AKT-mTOR signalling pathway.

As a vital hallmarker of cancer, the metabolic reprogramming has been shown to play a pivotal role in tumour occurrence, metastasis and drug resistance. Amongst a vast variety of signalling molecules and metabolic enzymes involved in the regulation of cancer metabolism, two key transcription factors Nrf1 and Nrf2 are required for redox signal transduction and metabolic homeostasis. However, the regulatory effects of Nrf1 and Nrf2 (both encoded by Nfe2l1 and Nfe2l2, respectively) on the metabolic reprogramming of hepatocellular carcinoma cells have been not well understood to date. Here, we found that the genetic deletion of Nrf1 and Nrf2 from HepG2 cells resulted in distinct metabolic reprogramming. Loss of Nrf1α led to enhanced glycolysis, reduced mitochondrial oxygen consumption, enhanced gluconeogenesis and activation of the pentose phosphate pathway in the hepatocellular carcinoma cells. By striking contrast, loss of Nrf2 attenuated the glycolysis and gluconeogenesis pathways, but with not any significant effects on the pentose phosphate pathway. Moreover, knockout of Nrf1α also caused fat deposition and increased amino acid synthesis and transport, especially serine synthesis, whilst Nrf2 deficiency did not cause fat deposition, but attenuated amino acid synthesis and transport. Further experiments revealed that such distinctive metabolic programming of between Nrf1α-/- and Nrf2-/- resulted from substantial activation of the PI3K-AKT-mTOR signalling pathway upon the loss of Nrf1, leading to increased expression of critical genes for the glucose uptake, glycolysis, the pentose phosphate pathway, and the de novo lipid synthesis, whereas deficiency of Nrf2 resulted in the opposite phenomenon by inhibiting the PI3K-AKT-mTOR pathway. Altogether, these provide a novel insight into the cancer metabolic reprogramming and guide the exploration of a new strategy for targeted cancer therapy.

Diagnostic strategy of metagenomic next-generation sequencing for gram negative bacteria in respiratory infections.

OBJECTIVE: This study aims to identify the most effective diagnostic method for distinguishing pathogenic and non-pathogenic Gram-negative bacteria (GNB) in suspected pneumonia cases using metagenomic next-generation sequencing (mNGS) on bronchoalveolar lavage fluid (BALF) samples. METHODS: The effectiveness of mNGS was assessed on BALF samples collected from 583 patients, and the results were compared with those from microbiological culture and final clinical diagnosis. Three interpretational approaches were evaluated for diagnostic accuracy. RESULTS: mNGS outperformed culture significantly. Among the interpretational approaches, Clinical Interpretation (CI) demonstrated the best diagnostic performance with a sensitivity of 87.3%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 98.3%. CI's specificity was significantly higher than Simple Interpretation (SI) at 37.9%. Additionally, CI excluded some microorganisms identified as putative pathogens by SI, including Haemophilus parainfluenzae, Haemophilus parahaemolyticus, and Klebsiella aerogenes. CONCLUSION: Proper interpretation of mNGS data is crucial for accurately diagnosing respiratory infections caused by GNB. CI is recommended for this purpose.