Targeting treatment resistance: unveiling the potential of RNA methylation regulators and TG-101,209 in pan-cancer neoadjuvant therapy.

BACKGROUND: Tumor recurrence and mortality rates remain challenging in cancer patients despite comprehensive treatment. Neoadjuvant chemotherapy and immunotherapy aim to eliminate residual tumor cells, reducing the risk of recurrence. However, drug resistance during neoadjuvant therapy is a significant hurdle. Recent studies suggest a correlation between RNA methylation regulators (RMRs) and response to neoadjuvant therapy. METHODS: Using a multi-center approach, we integrated advanced techniques such as single-cell transcriptomics, whole-genome sequencing, RNA sequencing, proteomics, machine learning, and in vivo/in vitro experiments. Analyzing pan-cancer cohorts, the association between neoadjuvant chemotherapy/immunotherapy effectiveness and RNA methylation using single-cell sequencing was investigated. Multi-omics analysis and machine learning algorithms identified genomic variations, transcriptional dysregulation, and prognostic relevance of RMRs, revealing distinct molecular subtypes guiding pan-cancer neoadjuvant therapy stratification. RESULTS: Our analysis unveiled a strong link between neoadjuvant therapy efficacy and RNA methylation dynamics, supported by pan-cancer single-cell sequencing data. Integration of omics data and machine learning algorithms identified RMR genomic variations, transcriptional dysregulation, and prognostic implications in pan-cancer. High-RMR-expressing tumors displayed increased genomic alterations, an immunosuppressive microenvironment, poorer prognosis, and resistance to neoadjuvant therapy. Molecular investigations and in vivo/in vitro experiments have substantiated that the JAK inhibitor TG-101,209 exerts notable effects on the immune microenvironment of tumors, rendering high-RMR-expressing pan-cancer tumors, particularly in pancreatic cancer, more susceptible to chemotherapy and immunotherapy. CONCLUSIONS: This study emphasizes the pivotal role of RMRs in pan-cancer neoadjuvant therapy, serving as predictive biomarkers for monitoring the tumor microenvironment, patient prognosis, and therapeutic response. Distinct molecular subtypes of RMRs aid individualized stratification in neoadjuvant therapy. Combining TG-101,209 adjuvant therapy presents a promising strategy to enhance the sensitivity of high-RMR-expressing tumors to chemotherapy and immunotherapy. However, further validation studies are necessary to fully understand the clinical utility of RNA methylation regulators and their impact on patient outcomes.

Association between obesity and systemic immune inflammation index, systemic inflammation response index among US adults: a population-based analysis.

BACKGROUND: Obesity is characterized by a chronic low-grade inflammatory condition. Two emerging inflammatory biomarkers, the systemic immune-inflammation index (SII) and the systemic inflammation response index (SIRI), have gained attention. However, the relationships between obesity and SII/SRI remain unclear. METHODS: In this study, we analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018 among adults. SII-SIRI/SII/SIRI were categorized into three groups based on tertiles. The association between obesity and SII-SIRI/SII/SIRI was assessed by multivariable logistic regression models. Restricted cubic spline (RCS) plots were used to examine the nonlinear association between obesity and SII/SIRI. Finally, potential independent associations between obesity and SII/SIRI were further explored using subgroup analyses. RESULTS: The study included 20,011 adults, of whom 7,890 (39.32%) were obesity. In model 1, participants in the high (Q3) level of SII-SIRI had a significantly association with obesity than those in the low (Q1) level group. The high level of SII and SIRI were positively associated with obesity as compared to low levels. Model 2 revealed a positive association between obesity and high levels of SII-SIRI/SII/SIRI. Model 3 demonstrated a similar trend. RCS curves revealed a nonlinear association linking obesity to SII/SIRI. Subgroup analysis showed an interaction between SII/SIRI and age. CONCLUSIONS: Our research suggested that obesity was positively associated with SII-SIRI/SII/SIRI in U.S. adults. SII/SIRI may represent a cost-effective and direct approach to assessing obesity.

Tropical cyclone FANTALA's three turnbacks in the northeast of Madagascar Island.

The unique Tropical cyclone (TC) Fantala appeared in the central Indian Ocean (12.4°S, 73.5°E) at 00Z on April 11 in 2016 and moved northwestward along the northeast of Madagascar at 18 Z on April 15. Then, two incomprehensible turnbacks formed a unique TC track. The dynamic mechanisms of the three turnbacks were first studied based on remote sensing and multisource reanalysis data. The results reveal that the wind field with upper divergence and lower convergence promotes the development of Fantala. The anticyclone high pressure on the middle level atmosphere is an important factor for TC turnbacks. On 15 April, the TC made the first turnback to turn northwest due to the southward anticyclone weakened to moving northwest. On 18 April, the TC made the second turnback along the anticyclone edge due to the northern high-pressure and southern low-pressure trough. On 22 April, the TC made the third turnback because the anticyclonic high press center broke into two small independent anticyclonic centers in the southwest and northeast, which created a barrier band and pushed the northern TC to move to the northwest. Meanwhile, the vertical wind shear (VWS) also provides favorable conditions for TC turnbacks. On April 18, the middle atmosphere of the TC was affected by strong easterly shear and weak southerly shear, and the second turnback was completed. On April 22, the middle level environment was affected by strong westerly shear and weak north shear, and the third turnback was completed. Additionally, heat transport from the ocean to the atmosphere provides favorable conditions for TC development. On April 18, The maximum mean latent heat flux over northeastern Madagascar was 112.94 W/m2, Tropical Cyclone Heat Potential was 39.05 kJ/cm2, and the maximum wind speed at the center of the TC was 155 kts. On April 22, The heat transfer from the equator increased by 18.08 W/m2 compared with the latent heat on 21 April, the Tropical Cyclone Heat Potential was 33.30 kJ/cm2, the maximum wind speed in the TC center was 90 kts, the high PV centerspread down from 850 mb to 900 mb. This study deepens the understanding of track forecasting during the development of a TC.

The aminophospholipid transporter, ATP8B3, as a potential biomarker and target for enhancing the therapeutic effect of PD-L1 blockade in colon adenocarcinoma.

BACKGROUND: Colon adenocarcinoma (COAD) is a prevalent malignant tumor globally, contributing significantly to cancer-related mortality. COAD guidelines label MSI (Microsatellite instability) and MSS (Microsatellite stability) subtypes as global classification criteria and treatment strategy selection criteria for COAD. Various combination therapies involving PD-L1 inhibitors and adjuvant therapy to enhance anti-tumor efficacy. METHODS: Datasets from single-cell RNA sequencing and bulk RNA sequencing in the TCGA and GEO databases were utilized to identify differentially expressed genes (DEGs). Furthermore, the correlation between ATP8B3 and PD-L1 was validated using siRNA, shRNA, and western blot analysis. Additionally, the association between ATP8B3 and immune checkpoint blockade (ICB) therapy was investigated through immune infiltration analysis and flow cytometry in both in vivo and in vitro assays. RESULTS: In the COAD patient group, ATP8B3 significantly contributed to the establishment of an immunosuppressive microenvironment. Inhibiting ATP8B3 led to a reduction in PD-L1 expression in colon cancer cell lines. Additionally, ATP8B3 expression levels could serve as a potential guide for PD-L1 treatment in MSI-H COAD patients, with higher ATP8B3 expression associated with increased sensitivity to PD-L1 therapy. However, due to the lack of immuno-killer cells in the microenvironment of MSS subtypes, elevated ATP8B3 expression couldn't increase the sensitivity of MSS COAD patients to PD-L1 inhibitors. CONCLUSION: Our research results support that Inhibiting ATP8B3 could enhance TIL (tumor-infiltrating lymphocyte) infiltration by reducing PD-L1 expression in MSI-H COAD, thereby serving as an effective strategy to improve PD-L1 blocker efficacy. The treatment strategy of combining ATP8B3 inhibitors and immunotherapy for MSI/MSS COAD patients will be the best choice.

Antiphospholipid syndrome presenting as extensive skin ulcers on unilateral lower extremity: a case report.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by recurrent arterial and venous thrombosis, habitual fetal miscarriages, often accompanied by mild to moderate thrombocytopenia, and persistent moderate-to-high titer positivity for antiphospholipid antibodies (aPLs). However, patients with antiphospholipid antibodies may also present with several nonthrombotic clinical manifestations, such as thrombocytopenia, cardiac valve disease, nephropathy, skin ulcers, or cognitive dysfunction, which are collectively referred to as nonstandard manifestations of APS. Of these, for APS with predominantly cutaneous ulcers, previous reports have focused on APS with combined cutaneous vasculitis, and its medical treatment, rather than cutaneous ulcers with predominantly fatty inflammatory lesions, and the associated surgical treatment. Here, we admitted a relatively rare case of primary APS with extensive skin ulceration of the right lower extremity, without cutaneous vasculitis, in the presence of extensive and severe inflammatory lipoatrophy, carrying anti-ß2-glycoprotein I and lupus anticoagulant, which is reported as follows, with a view to raising awareness of this disease.

Schisandra chinensis Bee Pollen Ameliorates Colitis in Mice by Modulating Gut Microbiota and Regulating Treg/Th17 Balance.

Colitis is a chronic disease associated with alterations in the composition of gut microbiota. Schisandra chinensis bee pollen extract (SCPE) has been proved to be rich in phenolic compounds and effective in modulating gut microbiota, but its effect on colitis and the underlying mechanism remains unclear. This study investigates the relationship between colitis amelioration and the gut microbiota regulation of SCPE via fecal microbial transplantation (FMT). The results showed that administration of 20.4 g/kg BW of SCPE could primely ameliorate colitis induced by dextran sulfate sodium (DSS) in mice, showing as more integration of colon tissue structure and the colonic epithelial barrier, as well as lower oxidative stress and inflammation levels compared with colitis mice. Moreover, SCPE supplement restored the balance of T regulatory (Treg) cells and T helper 17 (Th17) cells. Gut microbiota analysis showed SCPE treatment could reshape the gut microbiota balance and improve the abundance of gut microbiota, especially the beneficial bacteria (Akkermansia and Lactobacillus) related to the production of short-chain fatty acids and the regulation of immunity. Most importantly, the protection of 20.4 g/kg BW of SCPE on colitis can be perfectly transmitted by fecal microbiota. Therefore, the gut microbiota-SCFAS-Treg/Th17 axis can be the main mechanism for SCPE to ameliorate colitis. This study suggests that SCPE can be a new promising functional food for prevention and treatment of colitis by reshaping gut microbiota and regulating gut immunity.

Correction: Mitochondria-targeting nanozyme alleviating temporomandibular joint pain by inhibiting the TNFα/NF-κB/NEAT1 pathway.

Correction for 'Mitochondria-targeting nanozyme alleviating temporomandibular joint pain by inhibiting the TNFα/NF-κB/NEAT1 pathway' by Qian Bai et al., J. Mater. Chem. B, 2023, https://doi.org/10.1039/d3tb00929g.

Mitochondria-targeting nanozyme alleviating temporomandibular joint pain by inhibiting the TNFα/NF-κB/NEAT1 pathway.

Inflammatory cytokines that are secreted into the spinal trigeminal nucleus caudalis (Sp5C) may augment inflammation and cause pain associated with temporomandibular joint disorders (TMD). In a two-step process, we attached triphenylphosphonium (TPP) to the surface of a cubic liposome metal-organic framework (MOF) loaded with ruthenium (Ru) nanozyme. The design targeted mitochondria and was designated Mito-Ru MOF. This structure scavenges free radicals and reactive oxygen species (ROS) and alleviates oxidative stress. The present study aimed to investigate the effects and mechanisms by which Mito-Ru MOF ameliorates TMD pain. Intra-temporomandibular joint (TMJ) injections of complete Freund's adjuvant (CFA) induced inflammatory pain for ≥10 d in the skin areas innervated by the trigeminal nerve. Tumor necrosis factor-alpha (TNF-α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), long non-coding RNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1), and ROS also have been proved to be significantly upregulated in the Sp5C of TMD mice. Moreover, a single Mito-Ru MOF treatment alleviated TMD pain for 3 d and downregulated TNF-α, NF-κB, lncRNA NEAT1, and ROS. NF-κB knockdown downregulated NEAT1 in the TMD mice. Hence, Mito-Ru MOF inhibited the production of ROS and alleviated CFA-induced TMD pain via the TNF-α/NF-κB/NEAT1 pathway. Therefore, Mito-Ru MOF could effectively treat the pain related to TMD and other conditions associated with severe acute inflammatory activation.

Association between trajectories in cardiac damage and clinical outcomes after transcatheter aortic valve replacement.

BACKGROUND: There is little evidence of evolution in cardiac damage after transcatheter aortic valve replacement (TAVR) in aortic stenosis (AS) patients. Less is known about the prognostic value and potential utility of different cardiac damage trajectories following TAVR. OBJECTIVES: This study aims to investigate the cardiac damage trajectories following TAVR and explore their association with subsequent clinical outcomes. METHODS: AS patients undergoing TAVR were enrolled and classified into five cardiac damage stages (0-4) based on the echocardiographic staging classification retrospectively. They were further grouped into early stage (stage 0-2) and advanced stage (stage 3-4). The cardiac damage trajectories in TAVR recipients were evaluated according to their trend between baseline and 30 days after TAVR. RESULTS: A total of 644 TAVR recipients were enrolled, with four distinct trajectories identified. Compared to patients with early-early trajectory, patients with early-advanced trajectory were at 30-fold risk of all-cause death (HR 30.99, 95% CI 13.80-69.56; p < 0.001). In multivariable analyses, early-advanced trajectory was associated with higher 2-year all-cause death (HR 24.08, 95% CI 9.07-63.90; p < 0.001), cardiac death (HR 19.34, 95% CI 3.06-122.34; p < 0.05), and cardiac rehospitalization (HR 4.19, 95% CI 1.49-11.76; p < 0.05) after TAVR. CONCLUSIONS: This investigation provided insight into four cardiac damage trajectories in TAVR recipients and confirmed the prognostic value of distinct trajectories. Early-advanced trajectory was associated with poor clinical prognosis following TAVR.

NT-proBNP trajectory after transcatheter aortic valve replacement and its association with 5-year clinical outcomes.

Background: There are only limited reports on the trends of NT-proBNP after transcatheter aortic valve replacement (TAVR) in aortic stenosis (AS) and even fewer report on the prognostic value of the NT-proBNP trajectory following TAVR. Objectives: This study aims to investigate short-term NT-proBNP trajectory following TAVR and explore its association with clinical outcomes in TAVR recipients. Methods: Aortic stenosis patients undergoing TAVR were included if they had NT-proBNP levels recorded at baseline, prior to discharge, and within 30 days after TAVR. We used latent class trajectory models to identify NT-proBNP trajectories based on their trends over time. Results: Three distinct NT-proBNP trajectories were identified from 798 TAVR recipients, which were named class 1 (N = 661), class 2 (N = 102), and class 3 (N = 35). Compared to those with trajectory class 1, patients with trajectory class 2 had a more than 2.3-fold risk of 5-year all-cause death and 3.4-fold risk of cardiac death, while patients with trajectory class 3 had a more than 6.6-fold risk of all-cause death and 8.8-fold risk of cardiac death. By contrast, the groups had no differences in 5-year hospitalization rates. In multivariable analyses, the risk of 5-year all-cause mortality was significantly higher in patients with trajectory class 2 (HR 1.90, 95% CI 1.03-3.52, P = 0.04) and class 3 (HR 5.70, 95% CI 2.45-13.23, P < 0.01). Conclusion: Our findings implied different short-term evolution of NT-proBNP levels in TAVR recipients and its prognostic value for AS patients following TAVR. NT-proBNP trajectory may have further prognostic value, in addition to its baseline level. This may aid clinicians with regards to patient selection and risk prediction in TAVR recipients.

Impact of early changes in cardiac damage following transcatheter aortic valve implantation.

BACKGROUND: The staging classification of aortic stenosis (AS) which characterises the extent of cardiac damage has been validated in patients undergoing transcatheter aortic valve implantation (TAVI). Short-term changes in cardiac damage after TAVI and their association with long-term prognosis remain unknown. AIMS: This study aims to investigate the early evolution of cardiac damage after TAVI and the association of residual cardiac damage with clinical outcomes in TAVI recipients. METHODS: AS patients undergoing TAVI were consecutively enrolled and classified into five stages of cardiac damage (0-4). Early change in cardiac damage was defined as any change of stage at 30 days (Δcardiac damage between baseline pre-TAVI and 30 days post-TAVI). RESULTS: Within 30 days post-TAVI, the baseline cardiac damage stage had changed in 22.2% of 644 TAVI recipients, accompanied by improvements in the degree of dyspnoea and left ventricular ejection fraction (LVEF). Two-year mortality was associated with residual cardiac damage within 30 days post-TAVI (hazard ratio [HR] 2.97, 95% confidence interval [CI]: 2.07-4.25; p<0.001). Compared to unchanged cardiac damage post-TAVI, further cardiac damage within 30 days was associated with a higher crude risk of 2-year mortality (HR 22.04, 95% CI: 9.87-49.20; p<0.001). Cardiac deterioration within 30 days post-TAVI was an independent risk factor for 2-year mortality (HR 19.564, 95% CI: 8.047-47.565; p<0.001). CONCLUSIONS: This investigation provided insight into the early evolution of cardiac damage in TAVI recipients and confirmed the predictive value of both residual and early changes in cardiac damage post-TAVI. Cardiac deterioration within 30 days is associated with poor clinical prognosis.

MicroRNA-455-3p accelerate malignant progression of tumor by targeting H2AFZ in colorectal cancer.

Colorectal cancer (CRC) becomes the second leading cause of cancer-related deaths in 2020. Emerging studies have indicated that microRNAs (miRNAs) play a key role in tumorigenesis and progression. The dysfunctions of miR-455-3p are observed in many cancers. However, its biological function in CRC remains to be confirmed. By sequencing serum sample, miR-455-3p was found to be up-regulated in CRC patients. RT-qPCR demonstrated that the miR-455-3p expression was both higher in the serum and tumor tissues of CRC patients. Furthermore, it indicated that miR-455-3p had the ability in promoting cell proliferation, suppressing cell apoptosis, and stimulating cell migration. In vivo experiments also showed that miR-455-3p promoted tumor growth. Additionally, H2AFZ was proved as the direct gene target of miR-455-3p by dual-luciferase assay. Taken together, miR-455-3p functioned as a tumor promoter in CRC development by regulating H2AFZ directly. Thus, it has enormous potential as a biomarker in the diagnosis of CRC.

Stabilization improvement of the squeezed optical fields using a high signal-to-noise ratio bootstrap photodetector.

High-precision cavity locking is crucial for squeezing optical fields. Here, a bootstrapped low-noise photodetector is utilized in the generation process of the squeezed state of light. This process is based on a combination of a modified trans-impedance amplifier (TIA) circuit and a two-stage bootstrap amplifier circuit. This not only achieves high-precision and long-term stable locking of the optical cavity, but it also improves the degree to which the light field is squeezed. The experiment results show that the detector has a high signal-to-noise ratio (SNR) of 26.7 dB at the analysis frequency of 3 MHz when measuring the shot noise with an injection optical power of 800 µW, and the equivalent optical power noise level is lower than 2.4 pW/Hz in the frequency range of 1-30 MHz. Moreover, the squeezing degree of the quadrature amplitude squeezed state light field can be improved by more than 34.9% when the detector is used for optical cavity locking. The photodetector is useful in continuous variable (CV) quantum information research.

Tortuosity of branch retinal artery is more associated with the genesis and progress of diabetic retinopathy.

Objective: The purpose of this study is to investigate the potential of using the tortuosity of branch retinal artery as a more promising indicator for early detection and accurate assessment of diabetic retinopathy (DR). Design and method: The diagnoses, consisting of whether DR or not as well as DR severity, were given by ophthalmologists upon the assessment of those fundus images from 495 diabetic patients. Meanwhile, benefiting from those good contrast and high optical resolution fundus images taken by confocal scanning laser ophthalmoscope, the branch arteries, branch veins, main arteries and main veins in retina can be segmented independently, and the tortuosity values of them were further extracted to investigate their potential correlations with DR genesis and progress based on one-way ANOVA test. Results: For both two comparisons, i.e., between non-DR group and DR group as well as among groups with different DR severity levels, larger tortuosity increments were always observed in retinal arteries and the increments in branch retinal vessels were even larger. Furthermore, it was newly found that branch arterial tortuosity was significantly associated with both DR genesis (p=0.030) and DR progress (p<0.001). Conclusion: Based on this cohort study of 495 diabetic patients without DR and with different DR severity, the branch arterial tortuosity has been found to be more closely associated with DR genesis as well as DR progress. Therefore, the branch arterial tortuosity is expected to be a more direct and specific indicator for early detection of DR as well as accurate assessment of DR severity, which can further guide timely and rational management of DR to prevent from visual impairment or even blindness resulting from DR.

RNA sequencing profiling of mRNAs, long noncoding RNAs, and circular RNAs in Trigeminal Ganglion following Temporomandibular Joint inflammation.

Patients with temporomandibular joint disorders (TMD) have high levels of inflammatory pain-related disability, which seriously affects their physical and mental health. However, an effective treatment is yet to be developed. Both circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) contribute to regulating pain conduction. In our current study, we report the expression profiles of circRNAs, lncRNAs, and mRNAs in the trigeminal ganglion (TG) associated with complete Freund's adjuvant (CFA)-induced TMD inflammation pain. The collected TGs from the experimental (CFA) and control (saline) groups were processed for deep RNA sequencing. Overall, 1078,909,068 clean reads were obtained. A total of 15,657 novel lncRNAs were identified, where 281 lncRNAs were differentially expressed on CFA3D and 350 lncRNAs were differentially expressed on CFA6D. In addition, a total of 55,441 mRNAs and 27,805 circRNAs were identified, where 3,914 mRNAs and 91 circRNAs were found differentially expressed, between the CFA3D and saline groups, while 4,232 mRNAs and 98 DE circRNAs were differentially expressed between the CFA6D and saline groups. Based on functional analyses, we found that the most significant enriched biological processes of the upregulated mRNAs were involved in the immunity, neuron projection, inflammatory response, MAPK signaling pathway, Ras signaling pathway, chemokine signaling pathway, and inflammatory response in TG. Further analyses of Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway suggest the involvement of dysregulated genes in the pain occurrence mechanism. Our findings provide a resource for expression patterns of gene transcripts in regions related to pain. These results suggest that apoptosis and neuroinflammation are important pathogenic mechanisms underlying TMD pain. Some of the reported differentially expressed genes might be considered promising therapeutic targets. The current research study revealed the expression profiles of circRNAs, lncRNAs, and mRNAs during TMD inflammation pain and sheds light on the roles of circRNAs and lncRNAs underlying the pain pathway in the trigeminal system of TMD inflammation pain.

Integrated analysis of genes encoding ATP-dependent chromatin remodellers identifies CHD7 as a potential target for colorectal cancer therapy.

BACKGROUND: Genes participating in chromatin organization and regulation are frequently mutated or dysregulated in cancers. ATP-dependent chromatin remodelers (ATPCRs) play a key role in organizing genomic DNA within chromatin, therefore regulating gene expression. The oncogenic role of ATPCRs and the mechanism involved remains unclear. METHODS: We analyzed the genomic and transcriptional aberrations of the genes encoding ATPCRs in The Cancer Genome Atlas (TCGA) cohort. A series of cellular experiments and mouse tumor-bearing experiments were conducted to reveal the regulatory function of CHD7 on the growth of colorectal cancer cells. RNA-seq and ATAC-seq approaches together with ChIP assays were performed to elucidate the downstream targets and the molecular mechanisms. RESULTS: Our data showed that many ATPCRs represented a high frequency of somatic copy number alterations, widespread somatic mutations, remarkable expression abnormalities, and significant correlation with overall survival, suggesting several somatic driver candidates including chromodomain helicase DNA-binding protein 7 (CHD7) in colorectal cancer. We experimentally demonstrated that CHD7 promotes the growth of colorectal cancer cells in vitro and in vivo. CHD7 can bind to the promoters of target genes to maintain chromatin accessibility and facilitate transcription. We found that CHD7 knockdown downregulates AK4 expression and activates AMPK phosphorylation, thereby promoting the phosphorylation and stability of p53 and leading to the inhibition of the colorectal cancer growth. Our muti-omics analyses of ATPCRs across large-scale cancer specimens identified potential therapeutic targets and our experimental studies revealed a novel CHD7-AK4-AMPK-p53 axis that plays an oncogenic role in colorectal cancer.

Effects of Different Pesticides on the Brewing of Wine Investigated by GC-MS-Based Metabolomics.

The application of pesticides is critical during the growth of high-quality grape for wine making. However, pesticide residues have significant influence on the wine flavor. In this study, gas chromatography-mass spectrometry (GC-MS) was performed and the obtained datasets were analyzed with multivariate statistical methods to investigate changes in flavor substances in wine during fermentation. The principal component analysis (PCA) score plot showed significant differences in the metabolites of wine treated with various pesticides. In trials using five pesticides (hexaconazole, difenoconazole, flutriafol, tebuconazole, and propiconazole), more than 86 metabolites were changed. Most of these metabolites were natural flavor compounds, like carbohydrates, amino acids, and short-chain fatty acids and their derivatives, which essentially define the appearance, aroma, flavor, and taste of the wine. Moreover, the five pesticides added to grape pulp exhibited different effects on the metabolic pathways, involving mainly alanine, aspartate and glutamate metabolism, butanoate metabolism, arginine, and proline metabolism. The results of this study will provide new insight into the potential impact of pesticide residues on the metabolites and sensory profile of wine during fermentation.

Enhancing regioselectivity of sucrose phosphorylase by loop engineering for glycosylation of L-ascorbic acid.

Sucrose phosphorylase (SPase) has a remarkable capacity to synthesize numerous glucosides from abundantly available sucrose under mild conditions but suffers from specificity and regioselectivity issues. In this study, a loop engineering strategy was introduced to enhance the regioselectivity and substrate specificity of SPase for the efficient synthesis of 2-O-α-D-glucopyranosyl-L-ascorbic acid (AA-2G) via L-ascorbic acid (L-AA). P134, L341, and L343 were identified as "hotspots" for modulating the flexibility of loops, which significantly influenced the H-bonding network of L-AA in the active site, as well as the entrance of the substrate channel, thereby altering the regioselectivity and substrate specificity. Finally, the mutant L341V/L343F, with near-perfect control of the selectivity synthesis of the 2-OH group of L-AA (> 99%), was obtained. The AA-2G production by the mutant reached 244 g L-1 in a whole-cell biotransformation system, and the conversion rate of L-AA reached 64%, which is the highest level reported to date. Our work also provides a successful loop engineering case for modulating the regioselectivity and specificity of sucrose phosphorylase. KEY POINTS: • "Hotspots" were identified in the flexible loops of sucrose phosphorylase. • Mutants exhibited improved regioselectivity and specificity against L-ascorbic acid. • Synthesized AA-2G with high yield and regioselectivity by whole-cell of mutant.

The optimized biocatalytic synthesis of (S)-methyl 2-chlorobutanoate by Acinetobacter sp. lipase.

Epilepsy is a chronic disease caused by sudden abnormal discharge of brain neurons, leading to transient brain dysfunction. Levetiracetam, developed by the UCB company in Belgium, is an effective drug for the treatment of epilepsy. (S)-Methyl 2-chlorobutanoate is an important chiral building block of levetiracetam, which has attracted a great deal of attention. In this study, a strain of lipase-produced Acinetobacter sp. zjutfet-1 was screened from soil samples. At optimized conditions for fermentation and biocatalysis, the bacterial lipase exhibited high catalytic activity for hydrolysis and stereoselectivity toward racemic methyl 2-chlorobutanoate. When the enzymatic reaction was carried out in 6% of racemic substrate, the enantiomeric excess (e.e.s ) reached more than 95%, with a yield of over 86%. Therefore, this lipase can efficiently resolve racemic methyl 2-chlorobutanoate and obtain (S)-methyl 2-chlorobutanoate, which presents great potential in the industrial production of levetiracetam.