Plasmid-mediated azithromycin resistance in non-typhoidal Salmonella recovered from human infections.

OBJECTIVES: Mechanisms of non-typhoidal Salmonella (NTS) resistance to azithromycin have rarely been reported. Here we investigate the epidemiology and genetic features of 10 azithromycin-resistant NTS isolates. METHODS: A total of 457 NTS isolates were collected from a tertiary hospital in Guangzhou. We performed antimicrobial susceptibility tests, conjugation experiments, efflux pump expression tests, whole-genome sequencing and bioinformatics analysis to conduct the study. RESULTS: The results showed that 10 NTS isolates (2.8%) were resistant to azithromycin with minimum inhibitory concentration values ranging from 128 to 512 mg/L and exhibited multidrug resistance. The phylogenetic tree revealed that 5 S. London isolates (AR1-AR5) recognized at different times and departments were closely related [3-74 single-nucleotide polymorphisms (SNPs)] and 2 S. Typhimurium isolates (AR7 and AR8) were clones (<3 SNPs) at 3-month intervals. The azithromycin resistance was conferred by mph(A) gene found on different plasmids, including IncFIB, IncHI2, InFII, IncC and IncI plasmids. Among them, IncFIB, InFII and IncHI2 plasmids carried different IS26-class 1 integron (intI1) arrangement patterns that mediated multidrug resistance transmission. Conjugative IncC plasmid encoded resistance to ciprofloxacin, ceftriaxone and azithromycin. Furthermore, phylogenetic analysis demonstrated that mph(A)-positive plasmids closely related to 10 plasmids in this study were mainly discovered from NTS, Escherichia coli, Klebsiella pneumonia and Enterobacter hormaechei. The genetic environment of mph(A) in 10 NTS isolates was IS26-mph(A)-mrx(A)-mphR(A)-IS6100/IS26 that co-arranged with intI1 harbour multidrug-resistant (MDR) gene cassettes on diverse plasmids. CONCLUSIONS: These findings highlighted that the dissemination of these plasmids carrying mph(A) and various intI1 MDR gene cassettes would seriously restrict the availability of essential antimicrobial agents for treating NTS infections.

FAM134B deletion exacerbates apoptosis and epithelial-to-mesenchymal transition in rat lungs exposed to hyperoxia.

Oxygen therapy is widely used in clinical practice; however, prolonged hyperoxia exposure may result in hyperoxic acute lung injury (HALI). In this study, we investigated the role of FAM134B in hyperoxia-induced apoptosis, cell proliferation, and epithelial-to-mesenchymal transition (EMT) using RLE-6TN cells and rat lungs. We also studied the effect of CeO2-NPs on RLE-6TN cells and lungs following hyperoxia exposure. FAM134B was inhibited in RLE-6TN cells and rat lungs following hyperoxia exposure. Overexpressing FAM134B promoted cell proliferation, and reduced EMT and apoptosis following hyperoxia exposure. FAM134B activation increased ER-phagy, decreased apoptosis, improved lung structure damage, and decreased collagen fiber deposition to limit lung injury. These effects could be reversed by PI3K/AKT pathway inhibitor LY294002. Additionally, CeO2-NPs protected RLE-6TN cells and lung damage following hyperoxia exposure by ameliorating impaired ER-phagy. Therefore, FAM134B restoration is a potential therapeutic target for the HALI. Moreover, CeO2-NPs can be used for the treatment of HALI.

Rare case of simultaneous occurrence of chronic neutrophil leukemia and T lymphoblastic lymphoma: case report and literature review.

Chronic neutrophil leukemia (CNL) is a rare and life-threatening disease. Cases of CNL combined with lymphoma are rare. Here, we report a case of CNL with T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) in a 28-year-old male. After a regimen of ruxolitinib, VICLP (Vincristine, Idarubicin, Cyclophosphamide, Prednisone, Peg-asparaginase) regimen, high-dose cytarabine, and methotrexate regimens, the patient's bone marrow condition partially resolved. However, when the disease relapsed four months later, despite attempts with selinexor, venetoclax, and CAG(aclarubicin hydrochloride, Algocytidine, Granulocyte Stimulating Factor) chemotherapy, the leukocytes and peripheral blood primitive cells reduced, but the bone marrow did not achieve remission. This pathogenesis may be related to microenvironmental immune escape under prolonged inflammatory stimulation and gene disruption affecting protein function due to colony-stimulating factor 3 receptor gene (CSF3R) mutations. For this type of disease, early intervention may delay disease progression.

Comparative efficacy and safety of first-line tyrosine kinase inhibitors in chronic myeloid leukemia: a systematic review and network meta-analysis.

Background: Tyrosine kinase inhibitors (TKIs) have become the preferred drugs for the treatment of chronic phase (CP) chronic myeloid leukemia (CML). This study aims to compare the safety and efficacy of different TKIs as first-line treatments for CML using network meta-analysis (NMA), providing a basis for the precise clinical use of TKIs. Methods: A systematic search was conducted on PubMed, Cochrane Library, Embase, China National knowledge Infrastructure (CNKI), Wanfang, Chinese Science and Technology Periodical Databases (VIP), SinoMed and ClinicalTrials.gov to include RCTs that compared the different TKIs as first line treatment for CML. The search timeline was from inception to 21 July 2023. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the frequentist NMA methods, the efficacy and safety of different TKIs were compared, including the rates of major molecular response (MMR), complete cytogenetic response (CCyR), all grade adverse events, grade 3 or higher hematologic adverse events and liver toxicity. Results: A total of 25 RCTs involving 6,823 patients with CML and 6 types of TKIs were included. In terms of efficacy, second-generation TKIs such as dasatinib, nilotinib, and radotinib showed certain advantages in improving patients' MMR and CCyR compared to imatinib. Additionally, imatinib 800 mg provided better MMRs and CCyRs than imatinib 400 mg. As far as safety was concerned, there was no significant difference in the incidence of all grade adverse events among the different TKIs. All TKIs can cause serious grade 3-4 hematologic adverse events, including anemia, thrombocytopenia, and neutropenia. Dasatinib more likely caused anemia, bosutinib thrombocytopenia, and imatinib neutropenia, whereas nilotinib and flumatinib might have better safety profiles in terms of severe hematologic adverse events. For liver toxicity, radotinib 400 mg and imatinib 800 mg, respectively, had the highest likelihood of ranking first in incidence rates of all grade ALT and AST elevation. Conclusions: In CML, second-generation TKIs are more clinically effective than imatinib even if this last drug has a relatively better safety profile. Thus, as each second-generation TKI has a distinct clinical efficacy and safety, and is associated with different economic factors, its choice should be dictated by the specific patient clinical conditions (patient's specific disease characteristics, comorbid conditions, potential drug interactions, as well as their adherence). Nevertheless, due to the limited number of original research, additional high-quality studies are needed to achieve any firm conclusion on which second-generation TKI is the best choice for that peculiar patient.

Effect of disease duration on the use of tofacitinib: a real-world study in elderly patients with rheumatoid arthritis.

This study aims to test the hypothesis that disease duration may affect the response to generic tofacitinib (TOF) and investigate the influence of concomitant medications with TOF on elderly rheumatoid arthritis (RA). This study retrospectively collected 76 elderly patients (age > 60) treated with TOF from 2019 to 2023 and grouped them according to age of disease onset. Data were collected from baseline to the last follow-up visit within 24 months. The demographic characteristics and follow-up results were compared. TOF retention and the effect of concomitant drugs (methotrexate, MTX, prednisone) were analyzed using Kaplan-Meier plots and COX regression analysis. Canonical correlation analysis (CCA) was used to explore the correlation among demographic characteristics, medication regimen, and improved clinical outcomes. There was no significant difference in the proportion of patients achieving low disease activity (LDA) between different disease duration groups. Patients in the group of MTX had a shorter time of using TOF in follow-up (log-rank p = 0.041). Prednisone dosage at baseline had a predictive value for functionally disabled situation. We found significant associations between discontinuation of TOF in the last follow-up and getting LDA. A total result of CCA yielded a significant positive correlation with set 1 (demographic characteristics and medication regimen) and set 2 (improved clinical outcomes) (canonical coefficient = 0.887, p < 0.001). Disease duration may not affect response to generic TOF and medication regimen was the factor related to efficacy of generic TOF in elderly RA in the real world. Demographic characteristics and medication regimen were correlated positively with improved clinical outcomes. Key Points • There is scarce data from the western area of China regarding the use of tofacitinib in elderly rheumatoid arthritis patients, despite widespread use. • In this retrospective analysis of 76 elderly patients at a single center, we found disease duration may not affect response to generic TOF. • Concomitant MTX might contribute to better control of the disease activity. • Concomitant prednisone dosage at baseline was the independent risk factor for functionally disabled situation.

Dual inhibition of ATR and DNA-PKcs radiosensitizes ATM-mutant prostate cancer.

In advanced castration resistant prostate cancer (CRPC), mutations in the DNA damage response (DDR) gene ataxia telangiectasia mutated ( ATM ) are common. While poly(ADP-ribose) polymerase inhibitors are approved in this context, their clinical efficacy remains limited. Thus, there is a compelling need to identify alternative therapeutic avenues for ATM mutant prostate cancer patients. Here, we generated matched ATM-proficient and ATM-deficient CRPC lines to elucidate the impact of ATM loss on DDR in response to DNA damage via irradiation. Through unbiased phosphoproteomic screening, we unveiled that ATM-deficient CRPC lines maintain dependence on downstream ATM targets through activation of ATR and DNA-PKcs kinases. Dual inhibition of ATR and DNA-PKcs effectively inhibited downstream γH2AX foci formation in response to irradiation and radiosensitized ATM-deficient lines to a greater extent than either ATM-proficient controls or single drug treatment. Further, dual inhibition abrogated residual downstream ATM pathway signaling and impaired replication fork dynamics. To circumvent potential toxicity, we leveraged the RUVBL1/2 ATPase inhibitor Compound B, which leads to the degradation of both ATR and DNA-PKcs kinases. Compound B effectively radiosensitized ATM-deficient CRPC in vitro and in vivo , and impacted replication fork dynamics. Overall, dual targeting of both ATR and DNA-PKcs is necessary to block DDR in ATM-deficient CRPC, and Compound B could be utilized as a novel therapy in combination with irradiation in these patients.

Melanoma progression and prognostic models drawn from single-cell, spatial maps of benign and malignant tumors.

Melanoma clinical outcomes emerge from incompletely understood genetic mechanisms operating within the tumor and its microenvironment. Here, we used single-cell RNA-based spatial molecular imaging (RNA-SMI) in patient-derived archival tumors to reveal clinically relevant markers of malignancy progression and prognosis. We examined spatial gene expression of 203,472 cells inside benign and malignant melanocytic neoplasms, including melanocytic nevi and primary invasive and metastatic melanomas. Algorithmic cell clustering paired with intratumoral comparative two-dimensional analyses visualized synergistic, spatial gene signatures linking cellular proliferation, metabolism, and malignancy, validated by protein expression. Metastatic niches included up-regulation of CDK2 and FABP5, which independently predicted poor clinical outcome in 473 patients with melanoma via Cox regression analysis. More generally, our work demonstrates a framework for applying single-cell RNA-SMI technology toward identifying gene regulatory landscapes pertinent to cancer progression and patient survival.

Three-year results of central corneal stromal thickness reduction in small-incision lenticule extraction for high myopia correction.

BACKGROUND: To investigate the long-term corneal stromal remodeling and central stromal thickness (CST) reduction accuracy after small-incision lenticule extraction (SMILE) for high myopia correction. METHODS: This prospective study included 30 patients (50 eyes) who had undergone SMILE. Measurements of CST reduction using optical coherence tomography were performed at 1 month, 6 months, 1 year, and 3 years after surgery. Correlations were performed between planned and achieved CST reductions. RESULTS: The study enrolled 50 eyes of 30 patients. The mean spherical equivalent was -9.25±1.52 D(diopters). The postoperative CST increased in the first month after surgery and remained stable for a year. Thereafter, it remained stable during follow-up from 1 to 3 years postoperatively. The predicted CST reduction was 146.4 ± 10.3 µm. The achieved CST reductions at 1 month, 6 months, 1 year, and 3 years after surgery were 135.3 ± 12.1 µm, 130.8 ± 10.6 µm, 125.9 ± 9.4 µm, and 122.2 ± 10.6 µm, respectively. An overestimation of CST reduction was observed three years after surgery. Correlation analysis revealed a strong correlation between planned and achieved CST reductions; however, no correlation was found between CST reductions predicted error and the planned CST reductions. CONCLUSION: During long-term follow-up, our findings revealed a significant stromal remodeling following SMILE in patients with high myopia. Therefore, clinicians should consider it when screening patients with high myopia for SMILE.

A through-space charge transfer pyrene-based fluorophore with anti-quenching behavior for deep-blue organic light-emitting devices.

A through-space charge transfer pyrene-based fluorophore has been developed for organic light-emitting devices (OLEDs). This material exhibits deep-blue fluorescence, bipolar characteristics, and anti-quenching behavior in the solid state. It proves to be an effective emitter for both doped and nondoped deep-blue OLEDs.

A novel red fluorescent and dynamic nanocomposite hydrogel based on chitosan and alginate doped with inclusion complex of carbon dots.

Red fluorescent hydrogels possessing injectable and self-healing properties have widespread potential in biomedical field. It is still a challenge to achieve a biomacromolecules based dynamic hydrogels simultaneously combining with excellent red fluorescence, good mechanical properties, and biocompatibility. Here we first explore hydrophilic inclusion complex of (R-CDs@α-CD) derived from hydrophobic red fluorescent carbon dots (R-CDs) and α-cyclodextrin (α-CD), and then achieved a red fluorescent and dynamic polysaccharide R-CDs@α-CD/CEC-l-OSA hydrogel. The nanocomposite hydrogel can be fabricated through controlled doping of red fluorescent R-CDs@α-CD into dynamic polymer networks, taking reversibly crosslinked N-carboxyethyl chitosan (CEC) and oxidized sodium alginate (OSA) as an example. The versatile red fluorescent hydrogel simultaneously combines the features of injection, biocompatibility, and augmented mechanical properties and self-healing behavior, especially in rapid self-recovery even after integration. The R-CDs@α-CD uniformly dispersed into dynamic hydrogel played the role of killing two birds with one stone, that is, endowing red emission of a hydrophilic fluorescent substance, and improving mechanical and self-healing properties as a dynamic nano-crosslinker, via forming hydrogen bonds as reversible crosslinkings. The novel red fluorescent and dynamic hydrogel based on polysaccharides is promising for using as biomaterials in biomedical field.

Asymmetric catalytic synthesis of chiral covalent organic framework composite (S)-DTP-COF@SiO2 for HPLC enantioseparations by normal-phase and reversed-phase chromatographic modes.

A novel CCOF core-shell composite material (S)-DTP-COF@SiO2 was prepared via asymmetric catalytic and in situ growth strategy. The prepared (S)-DTP-COF@SiO2 was utilized as separation medium for HPLC enantioseparation using normal-phase and reversed-phase chromatographic modes, which displays excellent chiral separation performance for alcohols, esters, ketones, and epoxides, etc. Compared with chiral commercial chromatographic columns (Chiralpak AD-H and Chiralcel OD-H columns) and some previously reported chiral CCOF@SiO2 (CC-MP CCTF@SiO2 and MDI-ß-CD-modified COF@SiO2)-packed columns, there are 4, 3, 13, and 15 tested racemic compounds that could not be resolved on the Chiralpak AD-H column, Chiralcel OD-H column, CC-MP CCTF@SiO2 column, and MDI-ß-CD-modified COF@SiO2 column, respectively, which indicates that the resolution effect of (S)-DTP-COF@SiO2-packed column can be complementary to the other ones. The effects of the analyte mass, column temperature, and mobile phase composition on the enantiomeric separation were investigated. The chiral column exhibits good reproducibility after multiple consecutive injections. The RSDs (n = 5) of the peak area and retention time were less than 1.5% for repetitive separation of 2-methoxy-2-phenylethanol and 1-phenyl-1-pentanol. The chiral core-shell composite (S)-DTP-COF@SiO2 exhibited good enantiomeric separation performance, which not only demonstrates its potential as a novel CSP material in HPLC but also expands the range of applications for chiral COFs.

Integrative analysis of bulk and single-cell RNA sequencing reveals the gene expression profile and the critical signaling pathways of type II CPAM.

BACKGROUD: Type II congenital pulmonary airway malformation (CPAM) is a rare pulmonary microcystic developmental malformation. Surgical excision is the primary treatment for CPAM, although maternal steroids and betamethasone have proven effective in reducing microcystic CPAM. Disturbed intercellular communication may contribute to the development of CPAM. This study aims to investigate the expression profile and analyze intercellular communication networks to identify genes potentially associated with type II CPAM pathogenesis and therapeutic targets. METHODS: RNA sequencing (RNA-seq) was performed on samples extracted from both the cystic area and the adjacent normal tissue post-surgery in CPAM patients. Iterative weighted gene correlation network analysis (iWGCNA) was used to identify genes specifically expressed in type II CPAM. Single-cell RNA-seq (scRNA-seq) was integrated to unveil the heterogeneity in cell populations and analyze the communication and interaction within epithelial cell sub-populations. RESULTS: A total of 2,618 differentially expressed genes were identified, primarily enriched in cilium-related biological process and inflammatory response process. Key genes such as EDN1, GPR17, FPR2, and CHRM1, involved in the G protein-coupled receptor (GPCR) signaling pathway and playing roles in cell differentiation, apoptosis, calcium homeostasis, and the immune response, were highlighted based on the protein-protein interaction network. Type II CPAM-associated modules, including ciliary function-related genes, were identified using iWGCNA. By integrating scRNA-seq data, AGR3 (related to calcium homeostasis) and SLC11A1 (immune related) were identified as the only two differently expressed genes in epithelial cells of CPAM. Cell communication analysis revealed that alveolar type 1 (AT1) and alveolar type 2 (AT2) cells were the predominant communication cells for outgoing and incoming signals in epithelial cells. The ligands and receptors between epithelial cell subtypes included COLLAGEN genes enriched in PI3K-AKT singaling and involved in epithelial to mesenchymal transition. CONCLUSIONS: In summary, by integrating bulk RNA-seq data of type II CPAM with scRNA-seq data, the gene expression profile and critical signaling pathways such as GPCR signaling and PI3K-AKT signaling pathways were revealed. Abnormally expressed genes in these pathways may disrupt epithelial-mesenchymal transition and contribute to the development of CPAM. Given the effectiveness of prenatal treatments of microcystic CPAM using maternal steroids and maternal betamethasone administration, targeting the genes and signaling pathways involved in the development of CPAM presents a promising therapeutic strategy.

Visual analysis of abdominal aortitis treatment using the CiteSpace bibliometric method.

BACKGROUND: Abdominal aortitis can induce aneurysms, and tumor rupture can lead to organ ischemia or even sudden death. At present, there is a lack of extensive understanding and identification of key problems in the treatment of abdominal aortitis, which needs to be further analyzed using bibliometric analysis. AIM: To discuss the research hotspot and development trend of abdominal aortitis treatment. METHODS: We searched the English literature (published from January 1, 2000 to March 12, 2024) on the treatment of abdominal aortitis in the Web of Science database. Then, we identified and screened duplicate literature using CiteSpace 6.1R2 software. We conducted an analysis of the number of papers, a co-occurrence analysis of the authors and institutions, and co-occurrence and cluster analyses of the keywords. Then, we drew the author, institution, and keywords of the studies into graphs for visualization. Finally, we expounded on the author, institutional network interactions, and hot keywords of the studies on the treatment of abdominal aortitis. RESULTS: We included 210 English literature articles involving 190 authors; the author cooperation team was mainly represented by Caradu Caroline, Berard Xavier, Lu Guanyi, Harada Kenichi, and Sharma Ashish K. In the keyword analysis, high-frequency keywords include abdominal aortic aneurysm (38), abdominal aorta (24), Takayasu arteritis (22), etc. The three most central keywords were disease (0.69), classification (0.68), and abdominal aortic aneurysm (0.55). The first nine clusters of keywords are case report, abdominal aortic aneurysm, Takayasu arteritis, dyspnea hematuria, aortic elastic, IgG4-related disease, report, mid aortic dysplastic syndrome, and statin. In the keyword emergent analysis, 14 emergent words were obtained. Among them, seven keywords with strong abruptness were Takayasu arteritis, abdominal aortic aneurysm, disease, retroperitoneal fibrosis, expression, management, and large vessel vasculitis. In the past 3 years, the incidences of abdominal aortic aneurysm (intensity: 4.62) and inflammation (intensity: 1.99) were higher. CONCLUSION: The number of published papers is on the increase, but the cooperation among authors is scattered. The research focus is mainly on the pathogenesis and treatment of abdominal aortitis-related diseases.

Fusion Genes Landscape of Lung Cancer Patients From Inner Mongolia, China.

Lung cancer is the leading cause of cancer-related deaths globally. Gene fusion, a key driver of tumorigenesis, has led to the identification of numerous driver gene fusions for lung cancer diagnosis and treatment. However, previous studies focused on Western populations, leaving the possibility of unrecognized lung cancer-associated gene fusions specific to Inner Mongolia due to its unique genetic background and dietary habits. To address this, we conducted DNA sequencing analysis on tumor and adjacent nontumor tissues from 1200 individuals with lung cancer in Inner Mongolia. Our analysis established a comprehensive fusion gene landscape specific to lung cancer in Inner Mongolia, shedding light on potential region-specific molecular mechanisms underlying the disease. Compared to Western cohorts, we observed a higher occurrence of ALK and RET fusions in Inner Mongolian patients. Additionally, we discovered eight novel fusion genes in three patients: SLC34A2-EPHB1, CCT6P3-GSTP1, BARHL2-APC, HRAS-MELK, FAM134B-ERBB2, ABCB1-GIPC1, GPR98-ALK, and FAM134B-SALL1. These previously unreported fusion genes suggest potential regional specificity. Furthermore, we characterized the fusion genes' structures based on breakpoints and described their impact on major functional gene domains. Importantly, the identified novel fusion genes exhibited significant clinical and pathological relevance. Notably, patients with SLC34A2-EPHB1, CCT6P3-GSTP1, and BARHL2-APC fusions showed sensitivity to the combination of chemotherapy and immunotherapy. Patients with HRAS-MELK, FAM134B-ERBB2, and ABCB1-GIPC1 fusions showed sensitivity to chemotherapy. In summary, our study provides novel insights into the frequency, distribution, and characteristics of specific fusion genes, offering valuable guidance for the development of effective clinical treatments, particularly in Inner Mongolia.

Effects of Exclusive Breastfeeding Duration on Pneumonia Occurrence and Course in Infants Up to 6 Months of Age: A Case-Control Study.

We aimed to analyze the effects of exclusive breastfeeding duration on the occurrence and course of pneumonia in infants aged up to 6 months. Prospective case-control study. This study was conducted from August 2020 to August 2022 at a maternity and child health hospital in China. A total of 218 infants up to 6 months of age with pneumonia were included in the analyses. Health data were obtained using a hospitalization information system or an interview-based questionnaire. Univariate and multivariate logistic regression analyses were performed to analyze the data. The incidence of pneumonia, hospitalization duration, and costs to participants were significantly affected by the duration of exclusive breastfeeding (p < 0.01). The incidence of pneumonia among participants with different exclusive breastfeeding durations also differed significantly (p < 0.01). The shorter the duration of exclusive breastfeeding, the higher the incidence of pneumonia among infants. We found that the longer the exclusive breastfeeding duration in infants up to 6 months of age, the lower the recurrence of pneumonia, the shorter the hospital stay, and the lower the hospital costs. The rate of exclusive breastfeeding for infants up to 6 months of age should be increased as much as possible to reduce the occurrence of pneumonia and hospital costs.

Three cassava A20/AN1 family genes, Metip3 (5, and 7), can bestow on tolerance of plants to multiple abiotic stresses but show functional convergence and divergence.

A20/AN1 zinc-finger domain-containing genes are very promising candidates in improving plant tolerance to abiotic stresses, but considerably less is known about functions and mechanisms for many of them. In this study, Metip3 (5, and 7), cassava (Manihot esculenta) A20/AN1 genes carrying one A20 domain and one AN1 domain, were functionally characterized at different layers. Metip3 (5, and 7) proteins were all located in the nucleus. No interactions were found between these three proteins. Metip3 (5, and 7)-expressing Arabidopsis was more tolerant to multiple abiotic stresses by Na, Cd, Mn, Al, drought, high temperature, and low temperature. Metip3- and Metip5-expressing Arabidopsis was sensitive to Cu stress, while Metip7-expressing Arabidopsis was insensitive. The H2O2 production significantly decreased in all transgenic Arabidopsis, however, O2·- production significantly decreased in Metip3- and Metip5-expressing Arabidopsis but did not significantly changed in Metip7-expressing Arabidopsis under drought. Metip3 (5, and 7) expression-silenced cassava showed the decreased tolerance to drought and NaCl, presented significant decreases in superoxide dismutase and catalase activities and proline content, and displayed a significant increase in malondialdehyde content under drought. Taken together with transcriptome sequencing analysis, it is suggested that Metip5 gene can not only affect signal transduction related to plant hormone, mitogen activated protein kinases, and starch and sucrose metabolism, DRE-binding transcription factors, and antioxidants, conferring the drought tolerance, but also might deliver the signals from DREB2A INTERACTING PROTEIN1, E3 ubiquitin-protein ligases to proteasome, leading to the drought intolerance. The results are informative not only for further study on evolution of A20/AN1 genes but also for development of climate resilient crops.

Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis.

Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.

Hepatocyte-specific Selenoi deficiency predisposes mice to hepatic steatosis and obesity.

Selenoprotein I (Selenoi) is highly expressed in liver and plays a key role in lipid metabolism as a phosphatidylethanolamine (PE) synthase. However, the precise function of Selenoi in the liver remains elusive. In the study, we generated hepatocyte-specific Selenoi conditional knockout (cKO) mice on a high-fat diet to identify the physiological function of Selenoi. The cKO group exhibited a significant increase in body weight, with a 15.6% and 13.7% increase in fat accumulation in white adipose tissue (WAT) and the liver, respectively. Downregulation of the lipolysis-related protein (p-Hsl) and upregulation of the adipogenesis-related protein (Fasn) were observed in the liver of cKO mice. The cKO group also showed decreased oxygen consumption (VO2), carbon dioxide production (VCO2), and energy expenditure (p < .05). Moreover, various metabolites of the steroid hormone synthesis pathway were affected in the liver of cKO mice. A potential cascade of Selenoi-phosphatidylethanolamine-steroid hormone synthesis might serve as a core mechanism that links hepatocyte-specific Selenoi cKO to biochemical and molecular reactions. In conclusion, we revealed that Selenoi inhibits body fat accumulation and hepatic steatosis and elevates energy consumption; this protein could also be considered a therapeutic target for such related diseases.

Microdeletion on Xq27.1 in a Chinese VACTERL-Like Family with Kidney and Anal Anomalies.

Objective: VATER/VACTERL-like association is associated with adverse pregnancy outcomes. Genetic evidence of this disorder is sporadic. In this study, we aimed to provide genetic insights to improve the diagnosis of VACTERL. Methods: We have described a Chinese family in which four members were affected by renal defects or agenesis, anal atresia, and anovaginal fistula, which is consistent with the diagnosis of a VACTERL-like association. Pedigree and genetic analyses were conducted using genome and exome sequencing. Results: Segregation analysis revealed the presence of a recessive X-linked microdeletion in two living affected individuals, harboring a 196-380 kb microdeletion on Xq27.1, which was identified by familial exome sequencing. Genome sequencing was performed on the affected male, confirming a -196 kb microdeletion in Xq27.1, which included a 28% loss of the CDR-1 gene. Four family members were included in the co-segregation analysis, and only VACTERL-like cases with microdeletions were reported in X27.1. Conclusion: These results suggest that the 196-380 kb microdeletion in Xq27.1 could be a possible cause of the VATER/VACTERL-like association. However, further genetic and functional analyses are required to confirm or rule out genetic background as the definitive cause of the VACTERL association.