TBHP Mediated C-N Bond Cleavage of Tertiary Amines toward the Synthesis of Oxalamides and α,ß-Epoxy Amides.

An efficient and convenient method for the synthesis of oxalamides by the reaction of ß-ketoamides with tertiary amines and TBHP was developed. A variety of ß-ketoamides and tertiary amines substrates were well-tolerated in this transformation. Based on the control experiments, a plausible mechanism for this reaction was proposed that involved the tandem oxidation/amination process. In addition, α,ß-epoxy amides could be obtained by adjusting the reaction conditions.

In situ monitoring of toxic effects of algal toxin on cells by a novel microfluidic flow cytometry instrument.

Algal toxins produced by microalgae, such as domoic acid (DA)1, have toxic effects on humans. However, toxicity tests using mice only yield lethal doses of algal toxins without providing insights into the mechanism of action on cells. In this study, a fast segmentation of microfluidic flow cytometry cell images based on the bidirectional background subtraction (BBS)2 method was developed to get the visual evidence of apoptosis in both bright-field and fluorescence images. This approach enables mapping of changes in cell morphology and activity under algal toxins, allowing for fast (within 60 s) and automated biological detection. By combining microfluidics with flow cytometry, the intricate cellular-level reaction process can be observed in micro samples of 293 T cells and mouse spleen cells, offering potential for future in vitro experiments.

Efficacy of OLIF combined with pedicle screw internal fixation for lumbar spinal stenosis on spinal canal changes before and after surgery.

PURPOSE: The purpose of the study was to evaluate the efficacy of OLIF combined with pedicle screw internal fixation in the treatment of lumbar spinal stenosis by assessing the changes in spinal canal before and after surgery. METHODS: In this retrospective study, we included sixteen patients who underwent a combination of single-segment OLIF and pedicle screw internal fixation for the treatment of lumbar spinal stenosis at the Affiliated Hospital of Jiangxi University of Chinese Medicine between February 2018 and August 2022. The patients' pre- and post-operative data were compared. Intraoperative bleeding, duration of surgery, visual analogue score (VAS), Oswestry Disability Index (ODI), disc height (DH), cross-sectional area of vertebral canal (CSAVC), cross-sectional area of dural sac (CSADS), cross-sectional area of intervertebral foramen (CSAIF), spinal canal volume (SCV), spinal canal volume expansion rate, lumbar lordosis, and sagittal vertical axis were observed and recorded. The efficacy of OLIF combined with pedicle screw internal fixation for lumbar spinal stenosis on spinal canal changes before and after surgery was summarized. RESULTS: The results showed that OLIF combined with pedicle screw internal fixation effectively restored disc height and increased the cross-sectional area of the spinal canal. It also had an indirect decompression effect. The intraoperative bleeding and duration of surgery were within acceptable ranges. The VAS and ODI scores significantly improved after surgery, indicating a reduction in pain and improvement in functional disability. The CSAVC, CSADS, CSAIF, SCV, and spinal canal volume expansion rate were all increased postoperatively. Additionally, there was improvement in lumbar lordosis and sagittal vertical axis. We conducted a follow-up of all patients at 1 year after the surgery. The results revealed that the parameter values at 1 year post-surgery showed varying degrees of decrease or increase compared to the immediate postoperative values. However, these values remained statistically significant when compared to the preoperative parameter values (P < 0.05). CONCLUSIONS: OLIF combined with pedicle screw internal fixation effectively restores disc height and increases the cross-sectional area of the vertebral canal in patients with LSS, reflecting the indirect decompression effect. Measuring parameters such as DH, CSAVC, CSADS, CSAIF, SCV, and SCV expansion rate before and after surgery provides valuable information for evaluating the efficacy and functional recovery of the lumbar spine in LSS patients treated with OLIF surgery.

Remodeling metabolism of Corynebacterium glutamicum for high-level dencichine production.

Dencichine, a sought-after compound in the medical industry, requires a more efficient and sustainable production method than the current plant extraction process. This study successfully remodeled the metabolic pathway of Corynebacterium glutamicum to produce dencichine from the precursors of L-2,3-diaminopropionate (L-DAP) and oxalyl-coenzyme A. Firstly, a synthetic pathway for L-DAP was established by introducing exogenous enzymes ZmaU/ZmaV. This resulted in a production of 628 mg/L by overexpressing key genes and reducing the endogenous competitive pathway. Secondly, an oxalyl-CoA synthetic pathway was created through the enzymatic conversion of glyoxylate by introducing heterologous enzymes. Finally, with the integration of the exogenous enzyme BAHD, de novo synthesis of dencichine in C. glutamicum was achieved, and production reached 31.75 mg/L within 48-hour fermentation. This achievement represents the first successful biosynthesis of dencichine in C. glutamicum, offering a promising approach for natural product through microbial fermentation.

Base-tuned selective 1,2-dichloromethylhydroxylation and 1,2-peroxyhydroxylation of 1,3-dienes via a tandem radical process.

A catalyst-free 1,2-difunctionalization of 1,3-dienes with CHCl3 and TBHP in the presence of NEt3 to give the dichloromethylhydroxylation products was developed. Various substituents on the aryl ring of the dienes tolerated the reactions and gave the corresponding products in moderate to good yields. When Na2CO3 was employed as the base, the key intermediate α-amino radical could not be formed; therefore, 1,2-peroxyhydroxylation products were obtained instead. This protocol provides an effective and functional group tolerant strategy for diene 1,2-difunctionalization, thus providing great potential for further functionalization and modification of synthetic molecules.

ApoC1 promotes glioma metastasis by enhancing epithelial-mesenchymal transition and activating the STAT3 pathway.

OBJECTIVE: One of the apolipoprotein's members, apolipoprotein C1 (ApoC1), is critical in the metabolism of both very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) cholesterols. Multiple studies have recently revealed that ApoC1 may be a viable therapeutic target in solid malignancies. However, the motor protein ApoC1's specific role and mechanism in glioblastoma remain unknown. METHODS: In this study, the Cancer Genome Atlas (TCGA) database was used to look at the level of ApoC1 in glioma tissues and normal tissues, as well as how it related to the prognosis of glioma. Glioma cell lines (U87 and U251) were subjected to a wide range of experiments to determine the involvement of ApoC1 in cell proliferation, migration, and invasion. RESULTS: Cell proliferation, migration, and invasion decreased in glioma cell lines when ApoC1 was silenced. Furthermore, ApoC1 increased glioma cell metastasis through the epithelial-mesenchymal transition (EMT), while ApoC1 deletion reduced this impact. Additionally, APOC1 influenced the evolution of glioma by affecting the STAT3 pathway. In addition, APOC1 knockdown reduced the activation of the phosphorylated-total signal transducer and activator of transcription (STAT3) in the glioma cells. ApoC1-induced glioma cell metastatic ability was prevented by niclosamide (a STAT3 inhibitor). CONCLUSIONS: These results uncover that ApoC1 may serve as a biomarker or therapeutic target for future fundamental study or clinical treatment of glioma.

Interbacterial Chemical Communication-Triggered Nascent Proteomics.

Metabolic labeling with clickable noncanonical amino acids has enabled nascent proteome profiling, which can be performed in a cell-type-specific manner. However, nascent proteomics in an intercellular communication-dependent manner remains challenging. Here we develop communication-activated profiling of protein expression (CAPPEX), which integrates the LuxI/LuxR quorum sensing circuit with the cell-type-specific nascent proteomics method to enable selective click-labeling of newly synthesized proteins in a specific bacterium upon receiving chemical signals from another reporter bacterium. CAPPEX reveals that E. coli competes with Salmonella for tryptophan as the precursor for indole, and the resulting indole suppressed the expression of virulence factors in Salmonella. This tryptophan-indole axis confers attenuation of Salmonella invasion in host cells and living mice. The CAPPEX strategy should be widely applicable for investigating various interbacterial communication processes.

Tetramethylpyrazine Inhibits the Proliferation and Invasion of Glioma Cells by Regulating the UBL7-AS1/miR-144-3p Pathway.

This work aims to investigate the effects of tetramethylpyrazine (TMP) on the proliferation, migration, and invasion of glioma cells and to analyze the regulation mechanism of TMP on the long noncoding RNA UBL7-AS1/miR-144-3p pathway. Glioma cell line and normal astrocytes were collected. The expression of UBL7-AS1 was detected by real-time PCR. The glioma cells were overexpressed with UBL7-AS1. CCK-8 and Transwell assays were used to detect cell proliferation and cell invasion ability, respectively. Bioinformatics was adopted to predict the possible regulatory mechanisms of UBL7-AS1. The dual luciferase reporter gene was applied to verify the regulatory effect of RNA UBL7-AS1 with miR-144-3p. TMP inhibited the proliferation and invasion of glioma cells. UBL7-AS1 was highly expressed in glioma tissues and cells. The overexpression of UBL7-AS1 promotes the cell proliferation and invasion of glioma. UBL7-AS1 can act as a sponge for miR-144-3p in glioma cells. The overexpression of UBL7-AS1 can reverse the inhibition of TMP on proliferation, migration, and invasion of glioma cells. TMP inhibits the proliferation, migration, and invasion of glioma cells by regulating the UBL7-AS1/miR-144-3p pathway.

Efficient biodegradation of di-(2-ethylhexyl) phthalate by a novel strain Nocardia asteroides LMB-7 isolated from electronic waste soil.

The di-2-ethylhexyl phthalate (DEHP) degrading strain LMB-7 was isolated from electronic waste soil. According to its biophysical/biochemical characteristics and 16S rRNA gene analysis, the strain was identified as Nocardia asteroides. Optimal pH and temperature for DEHP degradation were 8.0 and 30 °C, respectively, and DEHP removal reached 97.11% after cultivation for 24 h at an initial concentration of 400 mg/L. As degradation intermediates, di-butyl phthalates, mono-2-ethylhexyl phthalate and 2-ethylhexanol could be identified, and it could be confirmed that DEHP was completely degraded by strain LMB-7. To our knowledge, this is a new report of DEHP degradation by a strain of Nocardia asteroides, at rates higher than those reported to date. This finding provides a new way for DEHP elimination from environment.

Low-Temperature (≤500 °C) Complementary Schottky Source/Drain FinFETs for 3D Sequential Integration.

In this work, low-temperature Schottky source/drain (S/D) MOSFETs are investigated as the top-tier devices for 3D sequential integration. Complementary Schottky S/D FinFETs are successfully fabricated with a maximum processing temperature of 500 °C. Through source/drain extension (SDE) engineering, competitive driving capability and switching properties are achieved in comparison to the conventional devices fabricated with a standard high-temperature (≥1000 °C) process flow. Schottky S/D PMOS exhibits an ON-state current (ION) of 76.07 µA/µm and ON-state to OFF-state current ratio (ION/IOFF) of 7 × 105, and those for NMOS are 48.57 µA/µm and 1 × 106. The CMOS inverter shows a voltage gain of 18V/V, a noise margin for high (NMH) of 0.17 V and for low (NML) of 0.43 V, with power consumption less than 0.9 µW at VDD of 0.8 V. Full functionality of CMOS ring oscillators (RO) are further demonstrated.

The Efficacy of Nitrates for Bone Health: A Systematic Review and Meta-Analysis of Observational and Randomized Controlled Studies.

Background: Although some studies have found that nitrates were beneficial for bone health, the findings are inconsistent. To assess the efficacy of nitrates for bone health, we conducted a meta-analysis. Methods: PubMed, EMBASE databases, Cochrane Library for relevant articles published before December 2021 were searched. All observational and randomized controlled studies that reporting bone mineral density (BMD), fractures with nitrates use were included. A meta-analysis was performed to calculate risk ratios (RRs) for fractures, change differences for bone mineral density. Results: Four cohort studies and two case-control studies examining the association between nitrates use and fractures were identified. The nitrates use was not associated with any fracture risk (RR = 0.97; 95% CI, 0.94-1.01; I2 = 31.5%) and hip fracture (RR = 0.88; 95% CI, 0.76-1.02; I2 = 74.5%). Subgroup analyses revealed no differences in fracture risk, whereas two cohort studies revealed a reduced risk of hip fracture (RR = 0.71, 95% CI, 0.58-0.86, I2 = 0.0%). There were no statistically significant differences in BMD percent changes at lumbar spine (WMD = -0.07, 95% CI,-0.78-0.65; I2 = 0.0%), total hip (WMD = -0.42, 95% CI,-0.88-0.04; I2 = 0.0%), femoral neck (WMD = -0.38, 95% CI,-1.02-0.25; I2 = 0.0%), or total body (WMD = -0.17, 95% CI,-0.51-0.17; I2 = 0.0%) in two randomized controlled trials (RCTs) compared with a placebo. Another two RCTs compared nitrates with alendronate. Nitrates were comparable to alendronate in increasing bone mineral density at lumbar spine (WMD = 0.00, 95% CI,-0.01-0.02; I2 = 0.0%). Besides, the most common adverse effect was headache, contributing to low adherence to therapy. Conclusion: Our meta-analysis showed no association between nitrates use and fractures in observational studies. The results of RCTs on the usage of nitrates and their effects on BMD were inconsistent. High-quality, long-term studies are needed to clarify the efficacy of nitrates for bone health.

GlnR-mediated regulation of KstR controls cholesterol catabolism in Mycobacterium smegmatis.

Tuberculosis, caused by mycobacteria, continues to pose a substantial public health threat. Mycobacteria typically use cholesterol from the membranes of host macrophages as a carbon and energy source. Most genes that control cholesterol degradation are regulated by KstR, which is highly conserved in Mycobacterium tuberculosis and Mycobacterium smegmatis. Through bioinformatic analysis, we found a typical global nitrogen regulator (GlnR)-binding motif (CCGAC-AACAGT-GACAC) in the promoter region of kstR of M. smegmatis, and we determined its binding activity in vitro using electrophoretic mobility shift assays. Using RT-qPCR, we found that nine genes involved in side-chain or sterol-ring oxidation were upregulated in a ΔglnR M. smegmatis strain compared to the WT strain and glnR-complemented strains under nitrogen limitation. ATP assays in macrophages revealed that coordinated GlnR-KstR regulation significantly reduced the viability of M. smegmatis in macrophages. Thus, we found that various genes involved in cholesterol catabolism are regulated by GlnR via KstR in response to environmental nitrogen, and that they further affect the invasive ability of M. smegmatis. These findings revealed a novel regulatory mechanism of cholesterol catabolism, which may be useful in the development of new strategies for controlling tuberculosis.

Acid-Suppressive Drugs and Risk of Fracture in Children and Young Adults: A Meta-Analysis of Observational Studies.

Background: Recent studies have suggested that proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H2RAs) may increase the risk of fracture. We performed a meta-analysis to evaluate the risk of fracture with PPIs and H2RAs use in children and young adults. Methods: PubMed, EMBASE database, Cochrane Library, and Web of Science for relevant articles published before May 2021 were searched. We included all the observational studies reporting on the risk of fracture with acid-suppressive drug (PPIs and H2RAs) use in children and young adults. We calculated pooled risk ratios (RRs) for fracture using random-effects models and conducted subgroup analyses. Results: A total of six studies were included in our analysis. Pooled analysis of PPIs use showed significant risk for fracture (RR = 1.23; 95% CI, 1.12-1.34; I 2 = 79.3), but not significant for PPIs combined with H2RAs use (RR = 1.22; 95% CI, 0.94-1.60; I 2 = 44.0%), as well as for H2RAs use alone (RR = 1.08; 95% CI, 0.94-1.24; I 2 = 84.1%). Grouping of studies by region showed a significantly increased fracture risk with PPIs use in North America (RR = 1.24; 95% CI, 1.16-1.32; I 2 =0.0%) than in Europe (RR = 1.23; 95% CI, 1.00-1.52; I 2 = 94.6%) and Asia (RR = 1.10; 95% CI, 0.96-1.25). However, there was no significant association between the H2RAs use and the fracture risk in North America (RR = 1.08; 95% CI, 1.00-1.09; I 2 = 0.0%). Moreover, PPIs use showed an increased risk of fracture in women (RR = 1.13; 95% CI, 1.07-1.19; I 2 = 0.0%), whereas there was no significant association between the PPIs use and the risk of fracture in men (RR = 0.93; 95% CI, 0.66-1.31; I 2 = 0.0%). Conclusion: PPIs use alone could increase the risk of fracture in children and young adults, but not for PPIs combined with H2RAs use or H2RAs use alone. Clinicians should exercise caution when prescribing PPIs for patients.

Low-dose lipopolysaccharide protects nerve cells against spinal cord injury via regulating the PI3K-AKT-Nrf2 signaling pathway.

This study explored the molecular mechanism behind the protective effects from low-dose lipopolysaccharide (LPS) on an in-vitro model of spinal cord injury (SCI). For this, PC12 cells were treated with different concentrations of LPS and the cell counting kit-8 assay was used to measure the toxicity of LPS to the cells. Next, we used immunofluorescence to measure nuclear translocation of Nrf2 in PC12 cells. PC12 cells were then treated with IGF-1 (PI3K agonist) and LY294002 (PI3K inhibitor). An in-vitro model of SCI was then established via oxygen-glucose deprivation/reoxygenation. Rates of apoptosis were measured using flow cytometry and the TUNEL assay. Low-dose LPS increased the expression levels of Nrf2, p-PI3K/PI3K, and p-AKT/AKT, and facilitated nuclear translocation of Nrf2. The activation of PI3K-AKT signaling by IGF-1 significantly increased the expression of Nrf2, whereas inhibition of PI3K-AKT signaling significantly decreased the expression of Nrf2. Low-dose LPS reduced the apoptotic ratio of PC12 cells, decreased the expression levels of caspase 3 and caspase 9, and increased the expression levels of HO-1, NQO1, and γ-GCS. Low-dose LPS also reduced the rate of apoptosis and oxidative stress by activating the PI3K-AKT-Nrf2 signaling pathway. Collectively, the results indicate that PI3K-AKT-Nrf2 signaling participates in the protective effects from low-dose LPS in an in-vitro PC12 cell model of SCI.

MicroRNAs as Biomarkers for the Diagnosis of Ankylosing Spondylitis: A Systematic Review and Meta-Analysis.

Background: Abnormal expression levels of microRNAs (miRNAs) were observed in ankylosing spondylitis (AS) in recent articles, suggesting that miRNAs may be used as biomarkers for AS diagnoses. In this paper, we conducted a meta-analysis to identify the overall diagnostic accuracy of miRNA biomarkers in AS patients. Methods: An extensive search was undertaken in PubMed, Embase, Cochrane databases, and Wan Fang database up to 30 December 2020 using the following key words: ("microRNAs" or "microRNA" or "miRNA" or "miR" or "RNA, Micro" or "Primary MicroRNA") and ("Spondylitis Ankylosing" or "Spondyloarthritis Ankylopoietica" or "Ankylosing Spondylarthritis" or "Ankylosing Spondylarthritides" or "Spondylarthritides Ankylosing" or "Ankylosing Spondylitis") and ("blood" or "serum" or "plasma"). Statistical evaluation of dysregulated miRNAs using the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the curve (AUC). Results: Twenty-nine articles reporting on the miRNAs of AS were included. A total of 42 miRNAs were observed to be up-regulated and 45 miRNAs were down-regulated in the AS cases compared with the controls. Besides, 29 studies from nine articles were included in our meta-analysis. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0. 76 (95% CI, 0.70-0.81), 0.80 (95% CI, 0.74-0.85), 3.75 (95% CI, 2.82-5.01), 0.30 (95% CI, 0.24-0.39), 12.32 (95% CI, 7.65-19.83), 0.85 (95% CI, 0.81-0.88), respectively, suggesting a good diagnostic accuracy of miRNAs for AS. Conclusions: Circulating miRNAs are deregulated in AS patients. miRNAs may be used as a relatively non-invasive biomarkers for the detection of AS.

Synthetic Route to Enaminones via Metal-Free Four-Component Sequential Reactions of Aryl Olefins with CHCl3, Et3N, and TBHP.

An efficient and modular strategy was used to obtain enaminones with a wide range of functional groups via a four-component sequential reaction. This reaction proceeded under mild conditions without a catalyst in one pot. Furthermore, the products could be transformed into thiadiazoles.

Neuropsychiatric Symptoms in Parkinson's Disease After Subthalamic Nucleus Deep Brain Stimulation.

Background: Indications for subthalamic nucleus deep brain stimulation (STN-DBS) surgery are determined basically by preoperative motor function; however, postoperative quality of life (QOL) is not necessarily associated with improvements in motor symptoms, suggesting that neuropsychiatric symptoms might be related to QOL after surgery in patients with Parkinson's disease. Objectives: We aimed to examine temporal changes in neuropsychiatric symptoms and their associations with QOL after STN-DBS. Materials and Methods: We prospectively enrolled a total of 61 patients with Parkinson's disease (mean age = 65.3 ± 0.9 years, mean disease duration = 11.9 ± 0.4 years). Motor function, cognitive function, and neuropsychiatric symptoms were evaluated before and after DBS surgery. Postoperative evaluation was performed at 3 months, 1 year, and 3 years after surgery. Results: Of the 61 participants, 54 completed postoperative clinical evaluation after 3 months, 47 after 1 year, and 23 after 3 years. Frontal lobe functions, depression, and verbal fluency significantly worsened 3 years after STN-DBS. Non-motor symptoms such as impulsivity and the Unified PD Rating Scale (UPDRS) part I score were associated with QOL after STN-DBS. Conclusions: Frontal lobe functions, depression, and verbal fluency significantly worsened 3 years after STN-DBS. The UPDRS part I score and higher impulsivity might be associated with QOL after STN-DBS.

Overexpression of Capsular Polysaccharide Biosynthesis Protein in Lactobacillus plantarum P1 to Enhance Capsular Polysaccharide Production for Di-n-butyl Phthalate Adsorption.

Exopolysaccharides (EPSs) such as capsular polysaccharide (CPS) are important bioactive carbohydrate compounds and are often used as bioenrichment agents and bioabsorbers to remove environmental pollutants like di-n-butyl phthalate (DBP). Among the EPS-producing bacteria, lactic acid bacteria (LAB) have gained the most attention. As generally recognized as safe (GRAS) microorganisms, LAB can produce EPSs having many different structures and no health risks. However, EPS production by LAB does not meet the needs of large-scale application on an industrial scale. Here, the capA gene (encoding CPS biosynthesis protein) was overexpressed in Lactobacillus plantarum P1 to improve the production of EPSs and further enhance the DBP adsorption capability. Compared with P1, the CPS production in capA overexpressed strain was increased by 11.3 mg/l, and the EPS thickness was increased from 0.0786 ± 0.0224 µm in P1 to 0.1160 ± 0.0480 µm in P1-capA. These increases caused the DBP adsorption ratio of P1-capA to be doubled. Overall, the findings in this study provide a safe method for the adsorption and removal of DBP.

C3AR1 mRNA as a Potential Therapeutic Target Associates With Clinical Outcomes and Tumor Microenvironment in Osteosarcoma.

Objective: Targeting cancer-specific messenger RNAs (mRNAs) may offer novel insights into therapeutic strategies in osteosarcoma. This study aimed to discover possible osteosarcoma-specific mRNA and probe its biological functions. Methods: Based on mRNA-seq data from the TARGET database, stromal and immune scores were estimated for each osteosarcoma sample via the ESTIMATE algorithm. Stromal and immune mRNAs were obtained via integration of differentially expressed mRNAs between high and low stromal / immune score groups. Among hub and prognostic mRNAs, C3AR1 mRNA was focused and its prognostic value was assessed. The associations between C3AR1 mRNA and immune cells were analyzed via the CIBERSORT algorithm. Its expression was verified in osteosarcoma tissues and cells by RT-qPCR and western blot. The functions of C3AR1 were investigated by a series of experiments. Results: Low stromal and immune scores were both indicative of unfavorable outcomes for osteosarcoma patients. Eighty-eight up-regulated and seven down-regulated stromal and immune mRNAs were identified. Among 30 hub mRNAs, low expression of C3AR1 mRNA indicated worse outcomes than its high expression. There was a lower mRNA expression of C3AR1 in metastatic than non-metastatic osteosarcoma. C3AR1 mRNA was closely correlated to various immune cells such as macrophages. C3AR1 was verified to be down-regulated in osteosarcoma tissues and cells. Its overexpression suppressed proliferation, migration and invasion and induced apoptosis in osteosarcoma cells. Conclusion: C3AR1 mRNA could be a promising therapeutic target for osteosarcoma, linked with prognosis and tumor microenvironment.