Potential mediation effect of insulin resistance on the association between iron metabolism indicators and non-alcoholic fatty liver disease.

OBJECTIVES: Iron metabolism and insulin resistance (IR) are closely related to non-alcoholic fatty liver disease (NAFLD). However, the interplay between them on the occurrence and progression of NAFLD is not fully understood. We aimed to disentangle the crosstalk between iron metabolism and IR and explore its impact on NAFLD. METHODS: We analyzed data from the National Health and Nutritional Examination Survey (NHANES) 2017-2018 to evaluate the association between serum iron metabolism indicators (ferritin, serum iron, unsaturated iron-binding capacity [UIBC], total iron-binding capacity [TIBC], transferrin saturation, and transferrin receptor) and NAFLD/non-alcoholic steatohepatitis (NASH). Mediation analysis was conducted to explore the role of IR played in these relationship. RESULTS: A total of 4812 participants were included, among whom 43.7% were diagnosed with NAFLD and 13.2% were further diagnosed with NASH. After adjusting the covariates, the risk of NAFLD increases with increasing serum ferritin (adjusted odds ratio [aOR] 1.71, 95% confidence interval [CI] 1.37-2.14), UIBC (aOR 1.45, 95% CI 1.17-1.79), and TIBC (aOR 1.36, 95% CI 1.11-1.68). Higher levels of serum ferritin (aOR 3.70, 95% CI 2.25-6.19) and TIBC (aOR 1.69, 95% CI 1.13-2.56) were also positively associated with NASH. Participants with IR were more likely to have NAFLD/NASH. Moreover, IR-mediated efficacy accounted for 85.85% and 64.51% between ferritin and NAFLD and NASH, respectively. CONCLUSION: Higher levels of serum ferritin and TIBC are closely associated with the occurrence of NAFLD and NASH. IR may be considered a possible link between NAFLD or NASH and increased serum ferritin levels.

Visible-Light-Driven Coupling of 1,3,4-Oxadiazoles and Hydroxamic Acid Derivatives.

A visible-light-induced radical-radical cross-coupling reaction between 1,3,4-oxadiazoles and hydroxamic acid derivatives has been realized under base- and metal-free conditions. The protocol was characterized by broad substrate scope, excellent functional group tolerance, and simple operation procedures. By using this protocol, a variety of biologically important 5-aryl-1,3,4-oxadiazole-2-methylamines were obtained in good yields with excellent chemoselectivity.

COVID-19-induced acute loss of consciousness in Marchiafava-Bignami disease: a case report.

Among the various manifestations of COVID-19, the neurological implications of SARS-CoV-2 infection are of significant concern. Marchiafava-Bignami disease (MBD), a neurodegenerative disorder, exhibits a clinical spectrum ranging from mild progressive dementia in its chronic form to states of acute coma and varied mortality rates. Acute MBD primarily occurs in chronic alcoholics and malnourished individuals and is characterized by sudden loss of consciousness, seizures, confusion, and psychosis. We herein report a case of MBD presenting as acute loss of consciousness after the development of COVID-19. The patient presented with a history of fever and upper respiratory infection and was diagnosed with SARS-CoV-2 infection. He developed a neurological syndrome characterized by altered consciousness and convulsions, and brain magnetic resonance imaging revealed abnormal signals in the corpus callosum and frontoparietal lobes. Considering his alcohol intake history and the absence of other differential diagnoses, we diagnosed him with acute MBD triggered by COVID-19. After high-dose vitamin B1 and corticosteroid therapy, his clinical symptoms improved. In this case, we observed a temporal sequence between the development of COVID-19 and acute exacerbation of MBD. This case adds to the mounting evidence suggesting the potential effect of SARS-CoV-2 on the neurological system.

Revolutionizing agriculture with nanotechnology: Innovative approaches in fungal disease management and plant health monitoring.

Nanotechnology has emerged as a transformative force in modern agriculture, offering innovative solutions to address challenges related to fungal plant diseases and overall agricultural productivity. Specifically, the antifungal activities of metal, metal oxide, bio-nanoparticles, and polymer nanoparticles were examined, highlighting their unique mechanisms of action against fungal pathogens. Nanoparticles can be used as carriers for fungicides, offering advantages in controlled release, targeted delivery, and reduced environmental toxicity. Nano-pesticides and nano-fertilizers can enhance nutrient uptake, plant health, and disease resistance were explored. The development of nanosensors, especially those utilizing quantum dots and plasmonic nanoparticles, promises early and accurate detection of fungal pathogens, a crucial step in timely disease management. However, concerns about their potential toxic effects on non-target organisms, environmental impacts, and regulatory hurdles underscore the importance of rigorous research and impact assessments. The review concludes by emphasizing the significant prospects of nanotechnology in reshaping the future of agriculture but advocates for a balanced approach that prioritizes safety, sustainability, and environmental stewardship.

Assessing genetic diversity in critically endangered Chieniodendron hainanense populations within fragmented habitats in Hainan.

Habitat fragmentation has led to a reduction in the geographic distribution of species, making small populations vulnerable to extinction due to environmental, demographic, and genetic factors. The wild plant Chieniodendron hainanense, a species with extremely small populations, is currently facing endangerment and thus requires urgent conservation efforts. Understanding its genetic diversity is essential for uncovering the underlying mechanisms of its vulnerability and for developing effective conservation strategies. In our study, we analyzed 35 specimens from six different populations of C. hainanense using genotyping-by-sequencing (GBS) and single nucleotide polymorphism (SNP) methodologies. Our findings indicate that C. hainanense has limited genetic diversity. The observed heterozygosity across the populations ranged from 10.79 to 14.55%, with an average of 13.15%. We categorized the six populations of C. hainanense into two distinct groups: (1) Diaoluoshan and Baishaling, and (2) Wuzhishan, Huishan, Bawangling, and Jianfengling. The genetic differentiation among these populations was found to be relatively weak. The observed loss of diversity is likely a result of the effects of natural selection.

Differential Morpho-Physiological, Ionomic, and Phytohormone Profiles, and Genome-Wide Expression Profiling Involving the Tolerance of Allohexaploid Wheat (Triticum aestivum L.) to Nitrogen Limitation.

Common wheat (Triticum aestivum L.) is a global staple food, while nitrogen (N) limitation severely hinders plant growth, seed yield, and grain quality of wheat. Genetic variations in the responses to low N stresses among allohexaploid wheat (AABBDD, 2n = 6x = 42) genotypes emphasize the complicated regulatory mechanisms underlying low N tolerance and N use efficiency (NUE). In this study, hydroponic culture, inductively coupled plasma mass spectrometry, noninvasive microtest, high-performance liquid chromatography, RNA-seq, and bioinformatics were used to determine the differential growth performance, ionome and phytohormone profiles, and genome-wide expression profiling of wheat plants grown under high N and low N conditions. Transcriptional profiling of NPFs, NRT2s, CLCs, SLACs/SLAHs, AAPs, UPSs, NIAs, and GSs characterized the core members, such as TaNPF6.3-6D, TaNRT2.3-3D, TaNIA1-6B, TaGLN1;2-4B, TaAAP14-5A/5D, and TaUPS2-5A, involved in the efficient transport and assimilation of nitrate and organic N nutrients. The low-N-sensitivity wheat cultivar XM26 showed obvious leaf chlorosis and accumulated higher levels of ABA, JA, and SA than the low-N-tolerant ZM578 under N limitation. The TaMYB59-3D-TaNPF7.3/NRT1.5-6D module-mediated shoot-to-root translocation and leaf remobilization of nitrate was proposed as an important pathway regulating the differential responses between ZM578 and XM26 to low N. This study provides some elite candidate genes for the selection and breeding of wheat germplasms with low N tolerance and high NUE.

Roles and inhibitors of FAK in cancer: current advances and future directions.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that exhibits high expression in various tumors and is associated with a poor prognosis. FAK activation promotes tumor growth, invasion, metastasis, and angiogenesis via both kinase-dependent and kinase-independent pathways. Moreover, FAK is crucial for sustaining the tumor microenvironment. The inhibition of FAK impedes tumorigenesis, metastasis, and drug resistance in cancer. Therefore, developing targeted inhibitors against FAK presents a promising therapeutic strategy. To date, numerous FAK inhibitors, including IN10018, defactinib, GSK2256098, conteltinib, and APG-2449, have been developed, which have demonstrated positive anti-tumor effects in preclinical studies and are undergoing clinical trials for several types of tumors. Moreover, many novel FAK inhibitors are currently in preclinical studies to advance targeted therapy for tumors with aberrantly activated FAK. The benefits of FAK degraders, especially in terms of their scaffold function, are increasingly evident, holding promising potential for future clinical exploration and breakthroughs. This review aims to clarify FAK's role in cancer, offering a comprehensive overview of the current status and future prospects of FAK-targeted therapy and combination approaches. The goal is to provide valuable insights for advancing anti-cancer treatment strategies.

Imaging, pathology, and diagnosis of solitary fibrous tumor of the pancreas: A case report and review of literature.

BACKGROUND: A solitary fibrous tumor (SFT) is often located in the pleura, while SFT of the pancreas is extremely rare. Here, we report a case of SFT of the pancreas and discuss imaging, histopathology, and immunohistochemistry for accurate diagnosis and treatment. CASE SUMMARY: A 54-year-old man presented to our hospital with pancreatic occupancy for over a month. There were no previous complaints of discomfort. His blood pressure was normal. Blood glucose, tumor markers, and enhanced computed tomography (CT) suggested a malignant tumor. Because the CT appearance of pancreatic cancer varies, we could not confirm the diagnosis; therefore, we performed endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB). Pathology and immunohistochemistry were consistent with SFT of the pancreas. The postoperative pathology and immunohistochemistry were consistent with the puncture results. The patient presented for a follow-up examination one month after discharge with no adverse effects. CONCLUSION: Other diseases must be excluded in patients with a pancreatic mass that cannot be diagnosed. CT and pathological histology have diagnostic value for pancreatic tumors. Endoscopic puncture biopsy under ultrasound can help diagnose pancreatic masses that cannot be diagnosed preoperatively. Surgery is an effective treatment for SFT of the pancreas; however, long-term follow-up is strongly recommended because of the possibility of malignant transformation of the tumor.

Natural compound library screening to identify berberine as a treatment for rheumatoid arthritis.

OBJECTIVE: Fibroblast-like synoviocytes (FLS) play a critical role on the exacerbation and deterioration of rheumatoid arthritis (RA). Aberrant activation of FLS pyroptosis signaling is responsible for the hyperplasia of synovium and destruction of cartilage of RA. This study investigated the screened traditional Chinese medicine berberine (BBR), an active alkaloid extracted from the Coptis chinensis plant, that regulates the pyroptosis of FLS and secretion of inflammatory factors in rheumatoid arthritis. METHODS: First, BBR was screened using a high-throughput drug screening strategy, and its inhibitory effect on RA-FLS was verified by in vivo and in vitro experiments. Second, BBR was intraperitoneally administrated into the collagen-induced arthritis rat model, and the clinical scores, arthritis index, and joint HE staining were evaluated. Third, synovial tissues of CIA mice were collected, and the expression of NLRP3, cleaved-caspase-1, GSDMD-N, Mst1, and YAP was detected by Western blot. RESULTS: The administration of BBR dramatically alleviated the severity of collagen-induced arthritis rat model with a decreased clinical score and inflammation reduction. In addition, BBR intervention significantly attenuates several pro-inflammatory cytokines (interleukin-1ß, interleukin-6, interleukin-17, and interleukin-18). Moreover, BBR can reduce the pyroptosis response (caspase-1, NLR family pyrin domain containing 3, and gasdermin D) of the RA-FLS in vitro, activating the Hippo signaling pathway (Mammalian sterile 20-like kinase 1, yes-associated protein, and transcriptional enhanced associate domains) so as to inhibit the pro-inflammatory effect of RA-FLS. CONCLUSION: These results support the role of BBR in RA and may have therapeutic implications by directly repressing the activation, migration of RA-FLS, which contributing to the attenuation of the progress of CIA. Therefore, targeting PU.1 might be a potential therapeutic approach for RA. Besides, BBR inhibited RA-FLS pyroptosis by downregulating of NLRP3 inflammasomes (NLRP3, caspase-1) and eased the pro-inflammatory activities via activating the Hippo signaling pathway, thereby improving the symptom of CIA.

Three-dimensional choroidal vascularity index and choroidal thickness in fellow eyes of acute and chronic primary angle-closure using swept-source optical coherence tomography.

AIM: To compare the three-dimensional choroidal vascularity index (CVI) and choroidal thickness between fellow eyes of acute primary angle-closure (F-APAC) and chronic primary angle-closure glaucoma (F-CPACG) and the eyes of normal controls. METHODS: This study included 37 patients with unilateral APAC, 37 with asymmetric CPACG without prior treatment, and 36 healthy participants. Using swept-source optical coherence tomography (SS-OCT), the macular and peripapillary choroidal thickness and three-dimensional CVI were measured and compared globally and sectorally. Pearson's correlation analysis and multivariate regression models were used to evaluate choroidal thickness or CVI with related factors. RESULTS: The mean subfoveal CVIs were 0.35±0.10, 0.33±0.09, and 0.29±0.04, and the mean subfoveal choroidal thickness were 315.62±52.92, 306.22±59.29, and 262.69±45.55 µm in the F-APAC, F-CPACG, and normal groups, respectively. All macular sectors showed significantly higher CVIs and choroidal thickness in the F-APAC and F-CPACG eyes than in the normal eyes (P<0.05), while there were no significant differences between the F-APAC and F-CPACG eyes. In the peripapillary region, the mean overall CVIs were 0.21±0.08, 0.20±0.08, and 0.19±0.05, and the mean overall choroidal thickness were 180.45±54.18, 174.82±50.67, and 176.18±37.94 µm in the F-APAC, F-CPACG, and normal groups, respectively. There were no significant differences between any of the two groups in all peripapillary sectors. Younger age, shorter axial length, and the F-APAC or F-CPACG diagnosis were significantly associated with higher subfoveal CVI and thicker subfoveal choroidal thickness (P<0.05). CONCLUSION: The fellow eyes of unilateral APAC or asymmetric CPACG have higher macular CVI and choroidal thickness than those of the normal controls. Neither CVI nor choroidal thickness can distinguish between eyes predisposed to APAC or CPACG. A thicker choroid with a higher vascular volume may play a role in the pathogenesis of primary angle-closure glaucoma.

Morpho-physiological, Genomic, and Transcriptional Diversities in Response to Potassium Deficiency in Rapeseed (Brassica napus L.) Genotypes.

Variations in the resistance to potassium (K) deficiency among rapeseed genotypes emphasize complicated regulatory mechanisms. In this study, a low-K-sensitivity accession (L49) responded to K deficiency with smaller biomasses, severe leaf chlorosis, weaker photosynthesis ability, and deformed stomata morphology compared to a low-K resistant accession (H280). H280 accumulated more K+ than L49 under low K. Whole-genome resequencing (WGS) revealed a total of 5,538,622 single nucleotide polymorphisms (SNPs) and 859,184 insertions/deletions (InDels) between H280 and L49. RNA-seq identified more differentially expressed K+ transporter genes with higher expression in H280 than in L49 under K deficiency. Based on the K+ profiles, differential expression profiling, weighted gene coexpression network analysis, and WGS data between H280 and L49, BnaC4.AKT1 was proposed to be mainly responsible for root K absorption-mediated low K resistance. BnaC4.AKT1 was expressed preferentially in the roots and localized on the plasma membrane. An SNP and an InDel found in the promoter region of BnaC4.AKT1 were proposed to be responsible for its differential expression between rapeseed genotypes. This study identified a gene resource for improving low-K resistance. It also facilitates an integrated knowledge of the differential physiological and transcriptional responses to K deficiency in rapeseed genotypes.

Novel berberine derivatives as p300 histone acetyltransferase inhibitors in combination treatment for breast cancer.

Adenoviral E1A binding protein p300 (EP300 or p300) and its similar paralog, cyclic-AMP response element binding protein (CBP), are important histone acetyltransferases (HAT) and transcriptional co-activators in epigenetics, participating in numerous cellular pathways including proliferation, differentiation and apoptosis. The overexpression or dysregulation of p300/CBP is closely related to oncology-relevant disease. The inhibition of p300 HAT has been found to be a potential drug target. Berberine has been reported to show anticancer activity and synergistic effect in combination with some of the clinical anticancer drugs via modulation of various pathways. Here, the present study sought to discover more chemotypes of berberine derivatives as p300 HAT inhibitors and to examine the combination of these novel analogues with doxorubicin for the treatment of breast cancer. A series of novel berberine derivatives with modifications of A/B/D rings of berberine have been designed, synthesized and screened. Compound 7b was found to exhibit inhibitory potency against p300 HAT with IC50 values of 1.51 µM. Western blotting proved that 7b decreased H3K27Ac and interfered with the expression of oncology-relevant protein in MCF-7 cells. Further bioactive evaluation showed that combination of compound 7b with doxorubicin could significantly inhibit tumor growth and invasion in vitro and in vivo.

Relationship Between Serum ET-1, HDL-C, and sVCAM-1 and Hearing Loss in Patients with Sudden Deafness.

Vascular causes are most commonly associated with sudden sensorineural hearing loss (SSHL). This study was performed to determine the relationship between serum endothelin-1 (ET-1), high-density lipoprotein cholesterol (HDL-C), soluble vascular cell adhesion molecule-1 (sVCAM-1) levels, and the degree of hearing loss in patients with SSHL. Firstly, 60 SSHL patients were admitted to The First Hospital of Shanxi Medical University. In the same period, 60 healthy subjects matching the age and gender of SSHL patients were selected as the control group. Then, serum levels of ET-1, HDL-C, and sVCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA). Next, the relationship between serum levels of ET-1, HDL-C, and sVCAM-1 with clinicopathological factors and their diagnostic and prognostic values were analyzed and evaluated. Serum ET-1 and sVCAM-1 were increased, and HDL-C was decreased in patients with SSHL. Serum ET-1 and sVCAM-1 were higher and HDL-C was lower in patients aged ≥ 45 years, or severe hearing loss patients (P < 0.05). ROC analysis determined that ET-1 (AUC = 0.839), HDL-C (AUC = 0.830), and sVCAM-1 (AUC = 0.865) had excellent diagnostic values. In addition, patients with low levels of ET-1 and sVCAM-1 and high levels of HDL-C had better hearing prognosis (P < 0.05). Abnormal serum ET-1, HDL-C, and sVCAM-1 in patients with SSHL are closely related to age, and degree of hearing loss, and perform diagnostic and prognostic values.

Relationship between initial red cell distribution width and ΔRDW and mortality in cardiac arrest patients.

AIMS: There has been a lack of research examining the relationship between red cell distribution width (RDW) and the prognosis of cardiac arrest (CA) patients. The prognostic value of the changes in RDW during intensive care unit (ICU) hospitalization for CA patients has not been investigated. This study aims to investigate the correlation between RDW measures at ICU admission and RDW changes during ICU hospitalization and the prognosis of CA patients and then develop a nomogram that predicts the risk of mortality of these patients. METHODS AND RESULTS: A retrospective cohort study is used to collect clinical characteristics of CA patients (>18 years) that are on their first admission to ICU with RDW data measured from the Medical Information Mart for Intensive Care IV Version 2.0 database. Patients are randomly divided into a development cohort (75%) and a validation cohort (25%). The primary outcome is 30 and 360 day all-cause mortality. ΔRDW is defined as the RDW on ICU discharge minus RDW on ICU admission. A multivariate Cox regression model is applied to test whether the RDW represents an independent risk factor that affects the all-cause mortality of these patients. Meanwhile, the dose-response relationship between the RDW and the mortality is described by restricted cubic spine (RCS). A prediction model is constructed using a nomogram, which is then assessed using receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA). A total of 1278 adult CA patients are included in this study. We found that non-survivors have a higher level of RDW and ΔRDW compared with survivors, and the mortality rate is higher in the high RDW group than in the normal RDW group. The Kaplan-Meier survival curve indicates that patients in the normal RDW group had a higher cumulative survival rate at 30 and 360 days than those in the high RDW group (log-rank test, χ2  = 36.710, χ2  = 54.960, both P values <0.05). The multivariate Cox regression analysis shows that elevated RDW at ICU admission (>15.50%) is an independent predictor of 30 [hazard ratio = 1.451, 95% confidence interval (CI) = 1.181-1.782, P < 0.001] and 360 day (hazard ratio = 1.393, 95% CI = 1.160-1.671, P < 0.001) all-cause mortality among CA patients, and an increase in RDW during ICU hospitalization (ΔRDW ≥ 0.4%) can serve as an independent predictor of mortality among these patients. A non-linear relationship between the RDW measured at ICU admission and the increased risk of mortality rate of these patients is shown by the RCS. This study established and validated a nomogram based on six variables, anion gap, first-day Sequential Organ Failure Assessment score, cerebrovascular disease, malignant tumour, norepinephrine use, and RDW, to predict mortality risk in CA patients. The consistency indices of 30 and 360 day mortality of CA patients in the validation cohort are 0.721 and 0.725, respectively. The nomogram proved to be well calibrated in the validation cohort. DCA curves indicated that the nomogram provided a higher net benefit over a wide, reasonable range of threshold probabilities for predicting mortality in CA patients and could be adapted for clinical decision-making. CONCLUSIONS: Elevated RDW levels on ICU admission and rising RDW during ICU hospitalization are powerful predictors of all-cause mortality for CA patients at 30 and 360 days, and they can be used as potential clinical biomarkers to predict the bad prognosis of these patients. The newly developed nomogram, which includes RDW, demonstrates high efficacy in predicting the mortality of CA patients.

Integrative analysis from multi-center studies identifies a weighted gene co-expression network analysis-based Tregs signature in ovarian cancer.

Ovarian cancer (OC) is a malignancy associated with poor prognosis and has been linked to regulatory T cells (Tregs) in the immune microenvironment. Nevertheless, the association between Tregs-related genes (TRGs) and OC prognosis remains incompletely understood. The xCell algorithm was used to analyze Tregs scores across multiple cohorts. Weighted gene co-expression network analysis (WGCNA) was utilized to identify potential TRGs and molecular subtypes. Furthermore, we used nine machine learning algorithms to create risk models with prognostic indicators for patients. Reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining were used to demonstrate the immunosuppressive ability of Tregs and the expression of key TRGs in clinical samples. Our study found that higher Tregs scores were significantly correlated with poorer overall survival. Recurrent patients exhibited increased Tregs infiltration and reduced CD8+ T cell. Moreover, molecular subtyping using seven key TRGs revealed that subtype B exhibited higher enrichment of multiple oncogenic pathways and had a worse prognosis. Notably, subtype B exhibited high Tregs levels, suggesting immune suppression. In addition, we validated machine learning-derived prognostic models across multiple platform cohorts to better distinguish patient survival and predict immunotherapy efficacy. Finally, the differential expression of key TRGs was validated using clinical samples. Our study provides novel insights into the role of Tregs in the immune microenvironment of OC. We identified potential therapeutic targets derived from Tregs (CD24, FHL2, GPM6A, HOXD8, NAP1L5, REN, and TOX3) for personalized treatment and created a machining learning-based prognostic model for OC patients, which could be useful in clinical practice.

Emodin inhibits HDAC6 mediated NLRP3 signaling and relieves chronic inflammatory pain in mice.

Chronic pain reduces the quality of life and ability to function of individuals suffering from it, making it a common public health problem. Neuroinflammation which is mediated by the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in the spinal cord participates and modulates chronic pain. A chronic inflammatory pain mouse model was created in the current study by intraplantar injection of complete Freund's adjuvant (CFA) into C57BL/6J left foot of mice. Following CFA injection, the mice had enhanced pain sensitivities, decreased motor function, increased spinal inflammation and activated spinal astrocytes. Emodin (10 mg/kg) was administered intraperitoneally into the mice for 3 days. As a result, there were fewer spontaneous flinches, higher mechanical threshold values and greater latency to fall. Additionally, in the spinal cord, emodin administration reduced leukocyte infiltration level, downregulated protein level of IL-1ß, lowered histone deacetylase (HDAC)6 and NLRP3 inflammasome activity and suppressed astrocytic activation. Emodin also binds to HDAC6 via four electrovalent bonds. In summary, emodin treatment blocked the HDAC6/NLRP3 inflammasome signaling, suppresses spinal inflammation and alleviates chronic inflammatory pain.

Antifeedant, Antifungal Cryptic Polyketides with Six Structural Frameworks from Tea Endophyte Daldinia eschscholtzii Propelled by the Antagonistic Coculture with Phytopathogen Colletotrichum pseudomajus and Different Culture Methods.

The antagonistic coculture with tea phytopathogen Colletotrichum pseudomajus induces antifungal cryptic metabolites from isogenesis endophyte Daldinia eschscholtzii against tea phytopathogens. Sixteen new polyketides with six structural frameworks including ten cryptic ones, named coldaldols A-C (1-3), collediol (5), and daldinrins A-L (10-20 and 23), were found from the coculture of C. pseudomajus and D. eschscholtzii by different culture methods. The unique framework of compounds 11 and 12 featured a benzopyran-C7 polyketone hybrid, and compounds 13-16 were characterized by the novel benzopyran dimer. The structures were determined mainly by spectroscopic methods, including extensive one-dimensional (1D), two-dimensional (2D) NMR, high resolution electrospray ionisation mass spectroscopy (HRESIMS), ECD calculation, and single-crystal X-ray diffraction. The configuration of acyclic compounds 5 and 18 were determined by application of the universal NMR database. Most compounds showed significant antifungal activities against the tea pathogens C. pseudomajus and Alternaria sp. with MICs of 1-8 µg/mL. Compound 12 had stronger antifungal activity than that of positive drug nystatin. The ether bond at C-4 of the benzopyran derivative increased the antifungal activity. Compounds 4-9 and 11-23 showed antifeedant activities against silkworms with feeding deterrence indices of 15-100% at the concentration of 50 µg/cm2.

SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer.

A common mRNA modification is 5-methylcytosine (m5C), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of m5C and impaired SRSF2 m5C binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in m5C recognition and the impact of the prevalent leukemia-associated mutation SRSF2P95H. We show that SRSF2 binding and m5C colocalize within transcripts. Furthermore, knocking down the m5C writer NSUN2 decreases mRNA m5C, reduces SRSF2 binding, and alters RNA splicing. We also show that the SRSF2P95H mutation impairs the ability of the protein to read m5C-marked mRNA, notably reducing its binding to key leukemia-related transcripts in leukemic cells. In leukemia patients, low NSUN2 expression leads to mRNA m5C hypomethylation and, combined with SRSF2P95H, predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver.

Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort.

BACKGROUND: The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene (MMACHC) c.482G > A mutation in 195 Chinese cases with CblC disease. METHODS: We carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months. RESULTS: Among 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower (P < 0.05) than those in the non-c.482G > A group, while the concentration of urinary methylmalonic acid was slightly lower (P > 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels (P < 0.05). In patients carrying the c.482G > A variant compared with the non-c.428G > A group, there were markedly lower rates of mortality (0.5% vs. 2.0%) and developmental delay (20.5% vs. 65.5%). When compared with individuals diagnosed due to disease onset, those identified through NBS in either group exhibited a reduced proportion of disease onset (6.7% vs. 100% in the c.482G > A group, 54.4% vs. 100% in the non-c.482G > A group), lower mortality (0.0% vs. 1.7% in the c.482G > A group, 0.0% vs. 3.6% in the non-c.482G > A group), and had a higher percentage of patients exhibiting normal psychomotor and language development (99.3% vs. 33.3% in the c.482G > A group, 58.9% vs. 10.9% in the non-c.482G > A group). CONCLUSIONS: The c.482G > A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease. Patients with this mutation tend to have a relatively better response to hydroxocobalamin, better metabolic control, and more favorable neurological outcomes. NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis, resulting in favorable clinical outcomes. Video Abstract (MP4 136794 kb).

Access to Amides and Lactams via Pyridotriazole as a Transformable Directing Group.

Amide and lactam frameworks were synthesized via an efficient two-step strategy. In this protocol, pyridotriazoles were first treated with isocyanates to form the corresponding amides, which were found to be sufficiently reactive to undergo subsequent intramolecular N-H insertion in the absence of any additional reagents or catalysts.