Cerebrospinal Fluid Neutrophil Gelatinase-Associated Lipocalin as a Novel Biomarker for Postneurosurgical Bacterial Meningitis: A Prospective Observational Cohort Study.

BACKGROUND AND OBJECTIVES: Postneurosurgical bacterial meningitis (PNBM) was a significant clinical challenge, as early identification remains difficult. This study aimed to explore the potential of neutrophil gelatinase-associated lipocalin (NGAL) as a novel biomarker for the early diagnosis of PNBM in patients who have undergone neurosurgery. METHODS: A total of 436 postneurosurgical adult patients were enrolled in this study. Clinical information, cerebrospinal fluid (CSF), and blood samples were collected. After the screening, the remaining 267 patients were divided into the PNBM and non-PNBM groups, and measured CSF and serum NGAL levels to determine the diagnostic utility of PNBM. Subsequently, patients with PNBM were categorized into gram-positive and gram-negative bacterial infection groups to assess the effectiveness of CSF NGAL in differentiating between these types of infections. We analyzed the changes in CSF NGAL expression before and after anti-infection treatment in PNBM. Finally, an additional 60 patients were included as an independent validation cohort to further validate the diagnostic performance of CSF NGAL. RESULTS: Compared with the non-PNBM group, CSF NGAL was significantly higher in the PNBM group (305.1 [151.6-596.5] vs 58.5 [30.7-105.8] ng/mL; P < .0001). The area under the curve of CSF NGAL for diagnosing PNBM was 0.928 (95% CI: 0.897-0.960), at a threshold of 119.7 ng/mL. However, there was no significant difference in serum NGAL between the 2 groups (142.5 [105.0-248.6] vs 161.9 [126.6-246.6] ng/mL, P = .201). Furthermore, CSF NGAL levels were significantly higher in patients with gram-negative bacterial infections than those with gram-positive bacteria (P = .023). In addition, CSF NGAL levels decrease after treatment compared with the initial stage of infection (P < .0001). Finally, in this validation cohort, the threshold of 119.7 ng/mL CSF NGAL shows good diagnostic performance with a sensitivity and specificity of 90% and 80%, respectively. CONCLUSION: CSF NGAL holds promise as a potential biomarker for the diagnosis, early drug selection, and efficacy monitoring of PNBM.

CsRAXs negatively regulate leaf size and fruiting ability through auxin glycosylation in cucumber.

Leaves are the main photosynthesis organ that directly determines crop yield and biomass. Dissecting the regulatory mechanism of leaf development is crucial for food security and ecosystem turn-over. Here, we identified the novel function of R2R3-MYB transcription factors CsRAXs in regulating cucumber leaf size and fruiting ability. Csrax5 single mutant exhibited enlarged leaf size and stem diameter, and Csrax1/2/5 triple mutant displayed further enlargement phenotype. Overexpression of CsRAX1 or CsRAX5 gave rise to smaller leaf and thinner stem. The fruiting ability of Csrax1/2/5 plants was significantly enhanced, while that of CsRAX5 overexpression lines was greatly weakened. Similarly, cell number and free auxin level were elevated in mutant plants while decreased in overexpression lines. Biochemical data indicated that CsRAX1/5 directly promoted the expression of auxin glucosyltransferase gene CsUGT74E2. Therefore, our data suggested that CsRAXs function as repressors for leaf size development by promoting auxin glycosylation to decrease free auxin level and cell division in cucumber. Our findings provide new gene targets for cucumber breeding with increased leaf size and crop yield.

SIRT1 and miR-34a-5p Expression in PBMCs as Potential Biomarkers for Patients With Type 2 Diabetes With Cognitive Impairments.

CONTEXT: Patients with type 2 diabetes mellitus (T2DM) are at significantly increased risk of Alzheimer disease (AD). However, no biomarkers are available for early identification of patients with T2DM with cognitive impairment (T2DM-CI). Mitochondrial dysfunction is linked to AD. Silent Information Regulator 1 (SIRT1), which is responsible for regulating mitochondrial biogenesis, and its related miRNAs were also altered in AD. OBJECTIVE: This study aimed to determine whether mitochondrial function in peripheral blood mononuclear cells (PBMCs) of patients with T2DM-CI was altered and if these alterations could be used as biomarkers. METHODS: A total of 374 subjects were enrolled, including AD, T2DM-CI, T2DM-nCI (T2DM without cognitive impairment), and healthy controls. The mitochondrial function was determined using a commercial assay kit. The mitochondrial DNA (mtDNA) content, the expression of SIRT1, and selected miRNAs in PBMCs were measured by quantitative polymerase chain reaction. The correlations and diagnostic accuracy were assessed using the Spearman correlation coefficient or receiver operating characteristics analysis, respectively. RESULTS: We found significant changes in mitochondrial function in PBMCs of patients with AD compared with controls (all P < .05), which were not found in T2DM-CI. However, mtDNA content and SIRT1 mRNA expression were lower in PBMCs of patients with T2DM-CI, while miR-34a-5p expression was higher than in patients with T2DM-nCI (all P < .05). A combination of SIRT1 and miR-34a-5p demonstrated excellent discrimination between T2DM-CI and T2DM-nCI (area under the curve = 0.793; sensitivity: 80.01%; specificity: 78.46%). Furthermore, correlation analysis revealed a link between miR-34a-5p expression and hyperglycemia in T2DM-CI. CONCLUSION: Our findings revealed that there was an alteration of mitochondria at the peripheral level in patients with T2DM-CI. SIRT1 combined with miR-34a-5p in PBMCs performed well in identifying patients with T2DM-CI and may be a promising biomarker.

Diagnostic value of cerebrospinal fluid Neutrophil Gelatinase-Associated Lipocalin for differentiation of bacterial meningitis from tuberculous meningitis or cryptococcal meningitis: a prospective cohort study.

BACKGROUND: The early differential diagnosis between bacterial meningitis (BM) and tuberculous meningitis (TBM) or cryptococcal meningitis (CM) remains a significant clinical challenge. Neutrophil Gelatinase-Associated Lipocalin (NGAL) has been reported as a novel inflammatory biomarker in the early stages of infection. This study aimed to investigate whether cerebrospinal fluid (CSF) NGAL can serve as a potential biomarker for distinguishing between BM and TBM or CM. METHODS: We prospectively enrolled the patients with suspected CNS infections at admission and divided them into three case groups: BM (n = 67), TBM (n = 55), CM (n = 51), and an age- and sex-matched hospitalized control (HC, n = 58). Detected the CSF NGAL and assessed its diagnostic accuracy in distinguishing between BM and TBM or CM. Additionally, longitudinally measured the CSF NGAL levels in patients with BM to evaluate its potential as a monitoring tool for antibacterial treatment. RESULTS: The concentration of CSF NGAL in BM was significantly higher than in TBM, CM, and HC (all P < 0.05), while the serum NGAL did not show significant differences among the three case groups. The ROC analysis demonstrated that CSF NGAL presented a good diagnostic performance with an AUC of 0.834 (0.770-0.886) and at the optimal cutoff value of 74.27 ng/mL with 70.15% sensitivity and 77.36% specificity for discriminating BM with TBM and CM. Additionally, the CSF NGAL in the convalescent period of BM was significantly lower than in the acute period (P < 0.05). CONCLUSIONS: CSF NGAL may serve as a potential biomarker for distinguishing between acute BM and TBM or CM. Additionally, it holds clinical significance in monitoring the effectiveness of antibiotic therapy for BM.

Carbon cloth supporting spinel CuMn0.5Co2O4 nanoneedles with the regulated electronic structure by multiple metal elements as catalysts for efficient oxygen evolution reaction.

Developing transition metal oxide catalysts to replace the noble metal oxide catalysts for efficient oxygen evolution reaction (OER) is essential to promote the practical application of water splitting. Herein, we designed and constructed the carbon cloth (CC) supporting spinel CuMn0.5Co2O4 nanoneedles with regulated electronic structure by multiple metal elements with variable chemical valences in the spinel CuMn0.5Co2O4. The carbon cloth not only provided good conductivity for the catalytic reaction but also supported the well-standing spinel CuMn0.5Co2O4 nanoneedles arrays with a large special surface area. Meanwhile, the well-standing nanoneedles arrays and mesoporous structure of CuMn0.5Co2O4 nanoneedles enhanced their wettability and facilitated access for electrolyte to electrochemical catalysis. Besides, the regulated electronic structure and generated oxygen vacancies of CuMn0.5Co2O4/CC by multiple metal elements improved the intrinsic catalytic activity and the durability of OER activity. Profiting from these merits, the CuMn0.5Co2O4/CC electrode exhibited superior OER activity with an ultralow overpotential of 189 mV at the current density of 10 mA⋅cm-2 and a smaller Tafel slope of 64.1 mV⋅dec-1, which was competitive with the noble metal oxides electrode. And the CuMn0.5Co2O4/CC electrode also exhibited long-term durability for OER with 95.3% of current retention after 1000 cycles. Therefore, the competitive OER activity and excellent cycling durability suggested that the CuMn0.5Co2O4/CC electrode is a potential candidate catalyst for efficient OER.

CsTRM5 regulates fruit shape via mediating cell division direction and cell expansion in cucumber.

Fruit shape and size are important appearance and yield traits in cucumber, but the underlying genes and their regulatory mechanisms remain poorly understood. Here we identified a mutant with spherical fruits from an Ethyl Methane Sulfonate (EMS)-mutagenized library, named the qiu mutant. Compared with the cylindrical fruit shape in 32X (wild type), the fruit shape in qiu was round due to reduced fruit length and increased fruit diameter. MutMap analysis narrowed the candidate gene in the 6.47 MB range on Chr2, harboring the FS2.1 locus reported previously. A single-nucleotide polymorphism (SNP) (11359603) causing a truncated protein of CsaV3_2G013800, the homolog of tomato fruit shape gene SlTRM5, may underlie the fruit shape variation in the qiu mutant. Knockout of CsTRM5 by the CRISPR-Cas9 system confirmed that CsaV3_2G013800/CsTRM5 was the causal gene responsible for qiu. Sectioning analysis showed that the spherical fruit in qiu resulted mainly from increased and reduced cell division along the transverse and longitudinal directions, respectively. Meanwhile, the repressed cell expansion contributed to the decreased fruit length in qiu. Transcriptome profiling showed that the expression levels of cell-wall-related genes and abscisic acid (ABA) pathway genes were significantly upregulated in qiu. Hormone measurements indicated that ABA content was greatly increased in the qiu mutant. Exogenous ABA application reduced fruit elongation by inhibiting cell expansion in cucumber. Taken together, these data suggest that CsTRM5 regulates fruit shape by affecting cell division direction and cell expansion, and that ABA participates in the CsTRM5-mediated cell expansion during fruit elongation in cucumber.

Transfer RNA-derived small RNAs and their potential roles in the therapeutic heterogeneity of sacubitril/valsartan in heart failure patients after acute myocardial infarction.

Background: It has been reported that sacubitril/valsartan can improve cardiac function in acute myocardial infarction (AMI) patients complicated by heart failure (HF). However, a number of patients cannot be treated successfully; this phenomenon is called sacubitril/valsartan resistance (SVR), and the mechanisms remain unclear. Methods: In our present research, the expression profiles of transfer RNA (tRNA)-derived small RNAs (tsRNAs) in SVR along with no sacubitril/valsartan resistance (NSVR) patients were determined by RNA sequencing. Through bioinformatics, quantitative real-time PCR (qRT-PCR), and cell-based experiments, we identified SVR-related tsRNAs and confirmed their diagnostic value, predicted their targeted genes, and explored the enriched signal pathways as well as regulatory roles of tsRNAs in SVR. Results: Our research indicated that 36 tsRNAs were upregulated and that 21 tsRNAs were downregulated in SVR. Among these tsRNAs, the expression of tRF-59:76-Tyr-GTA-2-M3 and tRF-60:76-Val-AAC-1-M5 was upregulated, while the expression of tRF-1:29-Gly-GCC-1 was downregulated in the group of SVR. Receiver operating characteristic (ROC) curve analysis demonstrated that these three tsRNAs were potential biomarkers of the therapeutic heterogeneity of sacubitril/valsartan. Moreover, tRF-60:76-Val-AAC-1-M5 might target Tnfrsf10b and Bcl2l1 to influence the observed therapeutic heterogeneity through the lipid and atherosclerosis signaling pathways. Conclusion: Hence, tsRNA might play a vital role in SVR. These discoveries provide new insights for the mechanistic investigation of responsiveness to sacubitril/valsartan.

EPHA4 regulates vascular smooth muscle cell contractility and is a sex-specific hypertension risk gene in individuals with type 2 diabetes.

OBJECTIVE: We investigated the association of genetic variants of EPHA4, a receptor tyrosine kinase, with hypertension, and its role in vascular smooth muscle cell (VSMC) contractility. METHODS: Data from two human genetic studies, ADVANCE and HCHS/SOL, were analyzed for association of EPHA4 single nucleotide variants (SNVs) with hypertension risks. The effect of EPHA4 signalling on mouse VSMC contractility was assessed. RESULTS: We identified a SNV (rs75843691 hg19 chr2:g.222395371 C>G), located in the third intron of EPHA4 gene, being significantly associated with hypertension in human female patients (P value = 8.3 × 10, below the Bonferroni-corrected critical P value) but not male patients with type 2 diabetes from the ADVANCE clinical trial. We found that EPHA4 was expressed in VSMCs and its stimulation by anti-EPHA4 antibody led to reduced VSMC contractility. Estrogen enhanced the contractility-lowering effect of EPHA4 stimulation. Conversely, siRNA knockdown of Epha4 expression in VSMCs resulted in increased contractility of VSMCs from female mice but not from male mice. CONCLUSION: EPHA4 appears to be a sex-specific hypertension risk gene in type 2 diabetic patients. Forward EPHA4 signalling reduces VSMC contractility, and estrogen is a modifier of this effect. The effect of EPHA4 on VSMCs contractility explains the association of EPHA4 gene with hypertension risks in female patients.

Risk factors for lymph node metastasis and the impact of adjuvant chemotherapy on ductal carcinoma in situ with microinvasion: a population-based study.

BACKGROUND: Ductal carcinoma in situ with microinvasion (DCISM) represents ~1% of all breast cancer cases. Risk factors for lymph node (LN) metastasis and appropriate adjuvant therapy for DCISM are still widely debated. METHODS: We retrieved DCISM data from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry database (1998-2013). Chi-squared tests and logistic regression models were applied to investigate the potential risks of LN metastasis. Univariate and multivariate Cox proportional hazards regressions were performed to estimate the prognostic factors of DCISM. Survival outcomes were estimated using the Kaplan-Meier method. A 1:1 propensity score matching was used to minimize potential bias. RESULTS: Overall, 6,219 patients with DCISM met our inclusion criteria. Younger age and higher grade disease were identified as risk factors for LN metastasis. In the multivariable analysis, LN metastasis and chemotherapy were prognostic factors for worse overall survival and breast cancer-specific survival. Furthermore, propensity score matching and subgroup analysis showed that chemotherapy may not be effective for DCISM patients. CONCLUSION: Younger patients with high-grade disease tend to have LN involved in DCISM. Adjuvant chemotherapy might not be necessary for patients with DCISM.

Diffuse filiform polyposis of the small intestine without inflammatory bowel disease.

Filiform polyposis is a rare disease, which typically occurs in patients with inflammatory bowel disease. We report a case of filiform polyposis occurring in a 56-year-old man with no history or evidence of inflammatory bowel disease. The patient's main symptoms were melena and anemia. We performed an emergency exploratory laparotomy, in which we observed worm-like polyps spread almost along the entire small intestine, and a partial resection of the small intestine to treat bleeding in the bowel was carried out. Two days later, the patient was noted to have melena again, and we performed an abdominal angiographic embolization, successfully stopping the bleeding. Histologic evaluation of the excised specimen revealed chronic inflammatory cells within the lamina propria without hyperplastic or adenomatous epithelial changes. Although the surgery was very successful, careful management of the patient was required, owing to the great risk of re-bleeding.