Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma.

Dysregulation of the aldehyde dehydrogenase (ALDH) family has been implicated in various pathological conditions, including cancer. However, a systematic evaluation of ALDH alterations and their therapeutic relevance in hepatocellular carcinoma (HCC) remains lacking. Herein, we found that 15 of 19 ALDHs were transcriptionally dysregulated in HCC tissues compared to normal liver tissues. A four gene signature, including ALDH2, ALDH5A1, ALDH6A1, and ALDH8A1, robustly predicted prognosis and defined a high-risk subgroup exhibiting immunosuppressive features like regulatory T cell (Tregs) infiltration. Single-cell profiling revealed selective overexpression of tumor necrosis factor receptor superfamily member 18 (TNFRSF18) on Tregs, upregulated in high-risk HCC patients. We identified ALDH2 as a tumor suppressor in HCC, with three novel phosphorylation sites mediated by protein kinase C zeta that enhanced enzymatic activity. Mechanistically, ALDH2 suppressed Tregs differentiation by inhibiting ß-catenin/TGF-ß1 signaling in HCC. Collectively, our integrated multi-omics analysis defines an ALDH-Tregs-TNFRSF18 axis that contributes to HCC pathogenesis and represents potential therapeutic targets for this aggressive malignancy.

On the correlation among the students' epistemic cognition, academic emotions, and academic achievement in higher education.

Students' academic achievement relies on a variety of pedagogical, affective, and individual factors. The investigation of academic emotions and epistemic cognition has been a focal point in existing research. Previous studies have predominantly delved into the essence of students' epistemic cognition and academic emotions. Nonetheless, the correlation between the epistemic cognition, academic emotions, and academic success of Chinese undergraduate students remains inadequately explored. This research delves into the interconnectedness of these variables and examines which facets of epistemic cognition and academic emotions can forecast students' academic performance. A total of three hundred and eighty (380) Chinese undergraduate students were chosen via random sampling for this study. Their self-reported academic achievements were taken into account. Additionally, they completed questionnaires tailored to evaluate their epistemic cognition and academic emotions. The participants' scores underwent Pearson correlation and multiple regression analyses. The findings indicate that positive emotions correlate positively, while negative emotions correlate negatively with students' academic success. Furthermore, positive emotions and three categories of epistemic cognition were found to be predictors of students' academic accomplishments. In conclusion, it is deduced that both epistemic cognition and positive emotions play a role in enhancing students' academic success. The implications of these findings extend to educational psychologists, educators, and students, both theoretically and practically.

Case reports on uniparental disomy of chromosomes 6 and 3 in paternity testing.

In paternity testing, when there are Mendelian errors in the alleles between the child and the parents, a slippage mutation, or silent allele may not fully explain the phenomenon. Sometimes, it is attributed to chromosomal abnormalities, such as uniparental disomy (UPD). Here, we present the investigation of two cases of suspected UPD in paternity testing based on short tandem repeat (STR) detection (capillary electrophoresis platform). Case 1 involves a trio, where all genotypes detected on chromosome 6 in the child are homozygous and found in the father. Case 2 is a duo (mother and child), where all genotypes on chromosome 3 in the child are homozygous and not always found in the mother. At the same time, Mendelian error alleles were also observed at specific loci in these two chromosomes. Furthermore, we used the MGIEasy Signature Identification Library Prep Kit for sequencing on the massively parallel sequencing platform, which included common autosomal, X and Y chromosomes, and mitochondrial genetic markers used in forensic practice. The results showed that the genotypes of shared STRs on the two platforms were consistent, and STRs and single nucleotide polymorphisms (SNPs) on these two chromosomes were homozygous. All other genetic markers followed the laws of inheritance. A comprehensive analysis supported the parent-child relationship between the child and the alleged parent, and the observed genetic anomalies can be attributed to UPD. UPD occurrences are rare, and ignoring its presence can lead to erroneous exclusions in paternity testing, particularly when multiple loci on a chromosome exhibit homozygosity.

Deletion of Nrf2 induced severe oxidative stress and apoptosis in mice model of diabetic bladder dysfunction.

The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway has been confirmed as a therapeutic target for type 2 diabetes mellitus (T2DM), however few studies revealed its effect in diabetic bladder dysfunction (DBD). Herein, we reported a Nrf2 deletion diabetic mouse model induced by 8-week high-fat diet feeding combined with streptozocin (STZ) injection in Nrf2 knockout mice. Besides, wild-type mice (WT) were used as control group, wild-type mice with high-fat diet feeding and STZ injection as diabetic group (WT-T2DM), and Nrf2 knockout mice as Nrf2 deletion group (KO). The pathophysiological indexes and bladder morphology showed typical pathological features of diabetic bladder dysfunction in Nrf2 knockout diabetic mouse mice (KO-T2DM). ELISA results showed that advanced glycation end products (AGEs), ROS and malondialdehyde (MDA) levels in bladder was were up-regulated in both WT-T2DM and KO-T2DM group, while superoxide dismutase (SOD) and glutathione (GSH) levels decreased in these two groups. Compared with WT-T2DM group, western blot analysis of the bladder showed down-regulated expression of NQO1 and HO-1 in KO-T2DM group. However, apoptosis, marked by Caspase3 and bax/bcl-2 ratio, was increased in KO-T2DM group. Neurotrophic factor (NGF) was significantly decreased in DBD model, and even much lower in KO-T2DM group. Collectively, our findings demonstrated that deletion of Nrf2 lead to severe oxidative stress, apoptosis, and lower level of neurotrophic factor, and provided the first set of experimental evidence, in a mouse model, to support Nrf2 as a promising target for DBD.

ECG-surv: A deep learning-based model to predict time to 1-year mortality from 12-lead electrocardiogram.

BACKGROUND: Electrocardiogram (ECG) abnormalities have demonstrated potential as prognostic indicators of patient survival. However, the traditional statistical approach is constrained by structured data input, limiting its ability to fully leverage the predictive value of ECG data in prognostic modeling. METHODS: This study aims to introduce and evaluate a deep-learning model to simultaneously handle censored data and unstructured ECG data for survival analysis. We herein introduce a novel deep neural network called ECG-surv, which includes a feature extraction neural network and a time-to-event analysis neural network. The proposed model is specifically designed to predict the time to 1-year mortality by extracting and analyzing unique features from 12-lead ECG data. ECG-surv was evaluated using both an independent test set and an external set, which were collected using different ECG devices. RESULTS: The performance of ECG-surv surpassed that of the Cox proportional model, which included demographics and ECG waveform parameters, in predicting 1-year all-cause mortality, with a significantly higher concordance index (C-index) in ECG-surv than in the Cox model using both the independent test set (0.860 [95% CI: 0.859- 0.861] vs. 0.796 [95% CI: 0.791- 0.800]) and the external test set (0.813 [95% CI: 0.807- 0.814] vs. 0.764 [95% CI: 0.755- 0.770]). ECG-surv also demonstrated exceptional predictive ability for cardiovascular death (C-index of 0.891 [95% CI: 0.890- 0.893]), outperforming the Framingham risk Cox model (C-index of 0.734 [95% CI: 0.715-0.752]). CONCLUSION: ECG-surv effectively utilized unstructured ECG data in a survival analysis. It outperformed traditional statistical approaches in predicting 1-year all-cause mortality and cardiovascular death, which makes it a valuable tool for predicting patient survival.

DNAJC24 acts directly with PCNA and promotes malignant progression of LUAD by activating phosphorylation of AKT.

Heat shock proteins (HSPs) are a group of highly conserved proteins found in a wide range of organisms. In recent years, members of the HSP family were overexpressed in various tumors and widely involved in oncogenesis, tumor development, and therapeutic resistance. In our previous study, DNAJC24, a member of the DNAJ/HSP40 family of HSPs, was found to be closely associated with the malignant phenotype of hepatocellular carcinoma. However, its relationship with other malignancies needs to be further explored. Herein, we demonstrated that DNAJC24 exhibited upregulated expression in LUAD tissue samples and predicted poor survival in LUAD patients. The upregulation of DNAJC24 expression promoted proliferation and invasion of LUAD cells in A549 and NCI-H1299 cell lines. Further studies revealed that DNAJC24 could regulate the PI3K/AKT signaling pathway by affecting AKT phosphorylation. In addition, a series of experiments such as Co-IP and mass spectrometry confirmed that DNAJC24 could directly interact with PCNA and promoted the malignant phenotypic transformation of LUAD. In conclusion, our results suggested that DNAJC24 played an important role in the progression of LUAD and may serve as a specific prognostic biomarker for LUAD patients. The DNAJC24/PCNA/AKT axis may be a potential target for future individualized and precise treatment of LUAD patients.

Clinical Analysis of 76 Cases of Second Branchial Cleft Fistula.

Objective: To provide the experience of diagnosis and treatment of second branchial cleft fistula in children. Methods: The clinical data of 76 children with second branchial cleft fistulas admitted to Beijing Children's Hospital affiliated with Capital Medical University from January 2016 to December 2020 were retrospectively analyzed. All patients underwent cervical ultrasonography and resection of the second branchial cleft fistula, and their clinical manifestations, surgical methods, complications, recurrence condition, and lesion appearance of the patients were analyzed. Results: Among the 76 cases, the lesions of 43 cases were on the right side, 20 were on the left side, and 13 were bilateral, for a total of 89 lesions. There were 49 type I lesions, 28 type II lesions, 8 type III lesions, and 4 type IV lesions. Type I and type II cases underwent complete excision of the fistula through a small incision in the neck; 2 cases of type III branchial cleft fistulas were treated with trapezoidal incision; 2 cases of type III branchial cleft fistulas underwent single transverse incisions; single small incision-assisted endoscopic resection was adopted in 4 cases of type III and 4 cases of type IV branchial cleft fistulas. During the follow-up period of 6 to 60 months, only 3 cases developed postoperative infection, the others had no postoperative complications, and no cases had recurrence during postoperative follow-up. Conclusion: The incision of the second branchial fistula should be selected according to imaging examination to achieve removal of the fistula while maintaining esthetics.

Boosting tetracycline degradation of BaTiO3-based piezo-catalysts via modulating phase boundary and band structure.

Piezoelectric catalysis, which converts mechanical energy into chemical activity, has important applications in environmental remediation. However, the piezo-catalytic activity of various piezoelectric materials is limited by the weak piezoelectricity as well as the mismatched band-gap, leading to inefficient electron-hole pair generation and difficult carrier migration. Here, a simple strategy combining phase boundary and energy band structure modulation was innovatively proposed to enhance the piezo-catalytic activity of BaTiO3 ferroelectric by Ce ions selecting different doping sites. Thanks to the coexistence of tetragonal (P4mm) and orthorhombic (Amm2) phases effectively flattened the Gibbs free-energy and thus enhanced the piezoelectric activity, as well as suitable energy bandwidth facilitating the carrier migration were realized in the B-sites doped Ba(Ti0.95Ce0.05)O3. The degradation rate constant k of tetracycline (TC) was high to 30.56 × 10-3 min-1, which was 2.03 times higher than that of pure BaTiO3 and superior to most representative lead-free perovskite piezoelectric materials. Theoretical calculations validated that the charge density and high O2 and OH- adsorption energy on the Ba(Ti0.95Ce0.05)O3 surface promoted more efficient •O2- and •OH radicals conversion and bettered response to piezo-catalytic reaction. This work is important to design high-performance piezo-catalysts by synergistic regulation of phase boundary and energy band structure in perovskite materials for long-term antibiotic tetracycline removal.

A membrane associated tandem kinase from wild emmer wheat confers broad-spectrum resistance to powdery mildew.

Crop wild relatives offer natural variations of disease resistance for crop improvement. Here, we report the isolation of broad-spectrum powdery mildew resistance gene Pm36, originated from wild emmer wheat, that encodes a tandem kinase with a transmembrane domain (WTK7-TM) through the combination of map-based cloning, PacBio SMRT long-read genome sequencing, mutagenesis, and transformation. Mutagenesis assay reveals that the two kinase domains and the transmembrane domain of WTK7-TM are critical for the powdery mildew resistance function. Consistently, in vitro phosphorylation assay shows that two kinase domains are indispensable for the kinase activity of WTK7-TM. Haplotype analysis uncovers that Pm36 is an orphan gene only present in a few wild emmer wheat, indicating its single ancient origin and potential contribution to the current wheat gene pool. Overall, our findings not only provide a powdery mildew resistance gene with great potential in wheat breeding but also sheds light into the mechanism underlying broad-spectrum resistance.

A novel framework for urban flood risk assessment: Multiple perspectives and causal analysis.

Risk assessment and adaptation have become key focuses in the examination of urban flooding risk. In recent decades, global climate change has resulted in a high incidence of extreme weather events, notably flooding. This study introduces a spatial multi-indicator model developed for assessing flood risk at the urban agglomeration scale. A crucial addition to the model is the incorporation of an adaptive capacity within the IPCC risk framework. The model systematically considers various flood risk indicators related to the economic, social, and geographic environments of the central and southern Liaoning urban agglomeration (CSLN). It generates a spatial distribution map of integrated flood risk for multiple scenario combinations. Furthermore, the intricate relationship between different risk indicators and flood risk was analyzed using correlation analysis and the Light Gradient Boosting Machine model (Light GBM). The findings reveal notable variations in flood risk under different scenarios. The inclusion of vulnerability indicators increased flood risk by 33 %, while the subsequent inclusion of adaptive indicators decreased flood risk by 45 %. Dense populations and assets contribute to high flood risk, while adaptive capacity significantly mitigates urban flood risk. The framework adopted in this paper can be applied to other areas where urban agglomeration-scale flood risk assessment is needed, and can contribute to advancing scientific research on flood forecasting and mitigation.

Effect of Ba2+ on the biomineralization of Ca2+ and Mg2+ ions induced by Bacillus licheniformis.

The effect of barium ions on the biomineralization of calcium and magnesium ions is often overlooked when utilizing microbial-induced carbonate precipitation technology for removing barium, calcium, and magnesium ions from oilfield wastewater. In this study, Bacillus licheniformis was used to bio-precipitate calcium, magnesium, and barium ions. The effects of barium ions on the physiological and biochemical characteristics of bacteria, as well as the components of extracellular polymers and mineral characteristics, were also studied in systems containing coexisting barium, calcium, and magnesium ions. The results show that the increasing concentrations of barium ions decreased pH, carbonic anhydrase activity, and concentrations of bicarbonate and carbonate ions, while it increased the contents of humic acids, proteins, polysaccharides, and DNA in extracellular polymers in the systems containing all three types of ions. With increasing concentrations of barium ions, the content of magnesium within magnesium-rich calcite and the size of minerals precipitated decreased, while the full width at half maximum of magnesium-rich calcite, the content of O-C=O and N-C=O, and the diversity of protein secondary structures in the minerals increased in systems containing all three coexisting ions. Barium ions does inhibit the precipitation of calcium and magnesium ions, but the immobilized bacteria can mitigate the inhibitory effect. The precipitation ratios of calcium, magnesium, and barium ions reached 81-94%, 68-82%, and 90-97%. This research provides insights into the formation of barium-enriched carbonate minerals and offers improvements for treating oilfield wastewater.

Comparative metabolic profiling of different pakchoi cultivars reveals nutritional diversity via widely targeted metabolomics.

Pakchoi (Brassica rapa ssp. chinensis) is cultivated for its high nutritional value; however, the nutritional diversity of different pakchoi cultivars is rarely investigated. Herein, we performed widely targeted metabolic profiling analyses of five popular pakchois. A total of 670 metabolites were detected, which could be divided into 13 categories. The accumulation patterns of main nutritional metabolites among the five pakchois were significantly different and complementary. Moreover, the pakchoi cultivar 'QYC' showed quite different metabolomic profiles compared with other pakchois. The Venn diagram showed that the 75 differential metabolites were shared among the comparison groups ('QYC' vs. 'MET'/ 'NBC'/ 'PPQ'/ 'XQC'), of which 52 metabolites were upregulated in 'QYC'. The phenolic acids had the largest variations between 'QYC' and the other pakchoi cultivars. These findings expand metabolomic information on different pakchoi cultivars and further provide new insights into the selection and breeding of excellent pakchoi cultivars.

Prediction of Hydration Heat for Diverse Cementitious Composites through a Machine Learning-Based Approach.

Hydration plays a crucial role in cement composites, but the traditional methods for measuring hydration heat face several limitations. In this study, we propose a machine learning-based approach to predict hydration heat at specific time points for three types of cement composites: ordinary Portland cement pastes, fly ash cement pastes, and fly ash-metakaolin cement composites. By adjusting the model architecture and analyzing the datasets, we demonstrate that the optimized artificial neural network model not only performs well during the learning process but also accurately predicts hydration heat for various cement composites from an extra dataset. This approach offers a more efficient way to measure hydration heat for cement composites, reducing the need for labor- and time-intensive sample preparation and testing. Furthermore, it opens up possibilities for applying similar machine learning approaches to predict other properties of cement composites, contributing to efficient cement research and production.

Preparation of nano-silver containing black phosphorus based on quaternized chitosan hydrogel and evaluating its effect on skin wound healing.

Hydrogels with favorable biocompatibility and antibacterial properties are essential in postoperative wound hemorrhage care, facilitating rapid wound healing. The present investigation employed electrostatic adsorption of black phosphorus nanosheets (BPNPs) and nano­silver (AgNPs) to cross-link the protonated amino group NH3+ of quaternized chitosan (QCS) with the hydroxyl group of hyaluronic acid (HA). The electrostatic interaction between the two groups resulted in the formation of a three-dimensional gel network structure. Additionally, the hydrogel containing AgNPs deposited onto BPNPs was assessed for its antibacterial properties and effects on wound healing. Hydrogel demonstrated an outstanding drug-loading capacity and could be employed for wound closure. AgNPs loaded on the BPNPs released silver ions and exhibited potent antibacterial properties when exposed to 808 nm near-infrared (NIR) radiation. The ability of the hydrogel to promote wound healing in an acute wound model was further evaluated. The BPNPs were combined with HA and QCS in the aforementioned hydrogel system to improve adhesion, combine the photothermal and antibacterial properties of the BPNPs, and promote wound healing. Therefore, the reported hydrogels displayed excellent biocompatibility and hold significant potential for application in the field of tissue engineering for skin wound treatment.

RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses.

BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. METHODS: We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities. FINDINGS: Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71. INTERPRETATION: RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling. FUNDING: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

Revisiting the potency of Tbx2 expression in transforming outer hair cells into inner hair cells at multiple ages in vivo.

The mouse auditory organ cochlea contains two types of sound receptors: inner hair cells (IHCs) and outer hair cells (OHCs). Tbx2 is expressed in IHCs but repressed in OHCs, and neonatal OHCs that misexpress Tbx2 transdifferentiate into IHC-like cells. However, the extent of this switch from OHCs to IHC-like cells and the underlying molecular mechanism remain poorly understood. Furthermore, whether Tbx2 can transform fully mature adult OHCs into IHC-like cells is unknown. Here, our single-cell transcriptomic analysis revealed that in neonatal OHCs misexpressing Tbx2, 85.6% of IHC genes, including Slc17a8, are upregulated, but only 38.6% of OHC genes, including Ikzf2 and Slc26a5, are downregulated. This suggests that Tbx2 cannot fully reprogram neonatal OHCs into IHCs. Moreover, Tbx2 also failed to completely reprogram cochlear progenitors into IHCs. Lastly, restoring Ikzf2 expression alleviated the abnormalities detected in Tbx2+ OHCs, which supports the notion that Ikzf2 repression by Tbx2 contributes to the transdifferentiation of OHCs into IHC-like cells. Our study evaluates the effects of ectopic Tbx2 expression on OHC lineage development at distinct stages of either male or female mice and provides molecular insights into how Tbx2 disrupts the gene-expression profile of OHCs. This research also lays the groundwork for future studies on OHC regeneration.Significance Statement Elucidation of the molecular and genetic mechanisms governing the determination and stability of cochlear inner hair cells (IHCs) and outer hair cells (OHCs) should provide valuable insights into the regeneration of damaged IHCs and OHCs. Here, we conditionally overexpress Tbx2 in vivo in cochlear sensory progenitors, neonatal OHCs, or adult OHCs. Our results show that Tbx2 overexpression alone can partially destabilize the OHC fate but cannot fully convert OHCs into IHCs. Specifically, we demonstrate that Ikzf2 repression due to Tbx2 overexpression is one of the key pathways disrupting the OHC fate.

A framework to evaluate the impact of a hazard chain and geographical covariates on spatial extreme water levels: A case study in the Pearl River Delta.

The interactions and collective impacts of different types of hazards within a compound hazard system, along with the influence of geographical covariates on flooding are presently unclear. Understanding these relationships is crucial for comprehending the formation and dynamic processes of the hazard chain and improving the ability to identify flood warning signals in complex hazard scenarios. In this study, we presented a multivariate spatial extreme value hierarchical (MSEVH) framework to assess the spatial extreme water levels (EWL) at different return levels under the influence of a hazard chain and geographical covariates. The Pearl River Delta (PRD) was selected as a research example to assess the effectiveness of the MSEVH framework. Firstly, we identified a hazard chain (extreme streamflow from the Xijiang River (XR) - extreme streamflow from the Beijiang River (BR) - extreme sea level) and three geographical covariates influencing EWL in the PRD. Then, we compared four hazard scenarios in the MSEVH framework to evaluate the spatial EWL at different return levels under the influence of the hazard chain in the PRD. The final step involves assessing spatial EWL with the effect of the hazard chain and geographical covariates. The results indicate that when extreme streamflow from XR and BR occurs concurrently, the extreme streamflow from BR weakens the influence of extreme streamflow from XR on EWL in the PRD. However, it cannot fully offset the overall impact of extreme streamflow from XR on EWL. In addition, when extreme streamflow from XR, extreme streamflow from BR, and extreme sea level occur simultaneously, the extreme sea level enhances the influence of concurrent extreme streamflow from XR and BR on EWL in the PRD. The proposed MSEVH is not only applicable to the PRD but also shows promising potential for evaluating extreme hydrometeorological variables under the influence of other hazard chains.

Indole Propionic Acid Disturbs the Normal Function of Tryptophanyl-tRNA Synthetase in Mycobacterium tuberculosis.

Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis and the second-most contagious killer after COVID-19. The emergence of drug-resistant TB has caused a great need to identify and develop new anti-TB drugs with novel targets. Indole propionic acid (IPA), a structural analog of tryptophan (Trp), is active against M. tuberculosis in vitro and in vivo. It has been verified that IPA exerts its antimicrobial effect by mimicking Trp as an allosteric inhibitor of TrpE, which is the first enzyme in the Trp synthesis pathway of M. tuberculosis. However, other Trp structural analogs, such as indolmycin, also target tryptophanyl-tRNA synthetase (TrpRS), which has two functions in bacteria: synthesis of tryptophanyl-AMP by catalyzing ATP + Trp and producing Trp-tRNATrp by transferring Trp to tRNATrp. So, we speculate that IPA may also target TrpRS. In this study, we found that IPA can dock into the Trp binding pocket of M. tuberculosis TrpRS (TrpRSMtb), which was further confirmed by isothermal titration calorimetry (ITC) assay. The biochemical analysis proved that TrpRS can catalyze the reaction between IPA and ATP to generate pyrophosphate (PPi) without Trp as a substrate. Overexpression of wild-type trpS in M. tuberculosis increased the MIC of IPA to 32-fold, and knock-down trpS in Mycolicibacterium smegmatis made it more sensitive to IPA. The supplementation of Trp in the medium abrogated the inhibition of M. tuberculosis by IPA. We demonstrated that IPA can interfere with the function of TrpRS by mimicking Trp, thereby impeding protein synthesis and exerting its anti-TB effect.

Exploring the diagnostic value of ultrasound radiomics for neonatal respiratory distress syndrome.

BACKGROUND: Neonatal respiratory distress syndrome (NRDS) is a prevalent cause of respiratory failure and death among newborns, and prompt diagnosis is imperative. Historically, diagnosis of NRDS relied mostly on typical clinical manifestations, chest X-rays, and CT scans. However, recently, ultrasound has emerged as a valuable and preferred tool for aiding NRDS diagnosis. Nevertheless, evaluating lung ultrasound imagery necessitates rigorous training and may be subject to operator-dependent bias, limiting its widespread use. As a result, it is essential to investigate a new, reliable, and operator-independent diagnostic approach that does not require subjective factors or operator expertise. This article aims to explore the diagnostic potential of ultrasound-based radiomics in differentiating NRDS from other non-NRDS lung disease. METHODS: A total of 150 neonatal lung disease cases were consecutively collected from the department of neonatal intensive care unit of the Quanzhou Maternity and Children's Hospital, Fujian Province, from September 2021 to October 2022. Of these patients, 60 were diagnosed with NRDS, whereas 30 were diagnosed with neonatal pneumonia, meconium aspiration syndrome (MAS), and transient tachypnea (TTN). Two ultrasound images with characteristic manifestations of each lung disease were acquired and divided into training (n = 120) and validation cohorts (n = 30) based on the examination date using an 8:2 ratio. The imaging texture features were extracted using PyRadiomics and, after the screening, machine learning models such as random forest (RF), logistic regression (LR), K-nearest neighbors (KNN), support vector machine (SVM), and multilayer perceptron (MLP) were developed to construct an imaging-based diagnostic model. The diagnostic efficacy of each model was analyzed. Lastly, we randomly selected 282 lung ultrasound images and evaluated the diagnostic efficacy disparities between the optimal model and doctors across differing levels of expertise. RESULTS: Twenty-two imaging-based features with the highest weights were selected to construct a predictive model for neonatal respiratory distress syndrome. All models exhibited favorable diagnostic performances. Analysis of the Youden index demonstrated that the RF model had the highest score in both the training (0.99) and validation (0.90) cohorts. Additionally, the calibration curve indicated that the RF model had the best calibration (P = 0.98). When compared to the diagnostic performance of experienced and junior physicians, the RF model had an area under the curve (AUC) of 0.99; however, the values for experienced and junior physicians were 0.98 and 0.85, respectively. The difference in diagnostic efficacy between the RF model and experienced physicians was not statistically significant (P = 0.24), whereas that between the RF model and junior physicians was statistically significant (P < 0.0001). CONCLUSION: The RF model exhibited excellent diagnostic performance in the analysis of texture features based on ultrasound radiomics for diagnosing NRDS.