Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells.

OBJECTIVE: Research has shown that celastrol can effectively treat a variety of diseases, yet when passing a certain dosage threshold, celastrol becomes toxic, causing complications such as liver and kidney damage and erythrocytopenia, among others. With this dichotomy in mind, it is extremely important to find ways to preserve celastrol's efficacy while reducing or preventing its toxicity. METHODS: In this study, insulin-resistant HepG2 (IR-HepG2) cells were prepared using palmitic acid and used for in vitro experiments. IR-HepG2 cells were treated with celastrol alone or in combination with N-acetylcysteine (NAC) or ferrostatin-1 (Fer-1) for 12, 24 or 48 h, at a range of doses. Cell counting kit-8 assay, Western blotting, quantitative reverse transcription-polymerase chain reaction, glucose consumption assessment, and flow cytometry were performed to measure celastrol's cytotoxicity and whether the cell death was linked to ferroptosis. RESULTS: Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-HepG2 cells. Celastrol downregulated glutathione peroxidase 4 (GPX4) mRNA. Molecular docking models predicted that solute carrier family 7 member 11 (SLC7A11) and GPX4 were covalently bound by celastrol. Importantly, we found for the first time that the application of ferroptosis inhibitors (especially NAC) was able to reduce celastrol's toxicity while preserving its ability to improve insulin sensitivity in IR-HepG2 cells. CONCLUSION: One potential mechanism of celastrol's cytotoxicity is the induction of ferroptosis, which can be alleviated by treatment with ferroptosis inhibitors. These findings provide a new strategy to block celastrol's toxicity while preserving its therapeutic effects. Please cite this article as: Liu JJ, Zhang X, Qi MM, Chi YB, Cai BL, Peng B, Zhang DH. Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells. J Integr Med. 2024; Epub ahead of print.

PARP1 UFMylation ensures the stability of stalled replication forks.

The S-phase checkpoint involving CHK1 is essential for fork stability in response to fork stalling. PARP1 acts as a sensor of replication stress and is required for CHK1 activation. However, it is unclear how the activity of PARP1 is regulated. Here, we found that UFMylation is required for the efficient activation of CHK1 by UFMylating PARP1 at K548 during replication stress. Inactivation of UFL1, the E3 enzyme essential for UFMylation, delayed CHK1 activation and inhibits nascent DNA degradation during replication blockage as seen in PARP1-deficient cells. An in vitro study indicated that PARP1 is UFMylated at K548, which enhances its catalytic activity. Correspondingly, a PARP1 UFMylation-deficient mutant (K548R) and pathogenic mutant (F553L) compromised CHK1 activation, the restart of stalled replication forks following replication blockage, and chromosome stability. Defective PARP1 UFMylation also resulted in excessive nascent DNA degradation at stalled replication forks. Finally, we observed that PARP1 UFMylation-deficient knock-in mice exhibited increased sensitivity to replication stress caused by anticancer treatments. Thus, we demonstrate that PARP1 UFMylation promotes CHK1 activation and replication fork stability during replication stress, thus safeguarding genome integrity.

Long Non-Coding RNA Nuclear-Enriched Abundant Transcript 1 (NEAT1) Facilitates Foam Cell Formation and Atherosclerosis Progression Through the miR-17-5p/Itchy E3 Ubiquitin Protein Ligase (ITCH)/Liver Kinase B1 (LKB1) Axis.

BACKGROUND: Foam cell formation is an important step for atherosclerosis (AS) progression. We investigated the mechanism by which the long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) regulates foam cell formation during AS progression.Methods and Results: An in vivo AS model was created by feeding ApoE-/-mice a high-fat diet. Oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages were used as a cellular AS model. Interactions between NEAT1, miR-17-5p, itchy E3 ubiquitin protein ligase (ITCH) and liver kinase B1 (LKB1) were analyzed. NEAT1 and ITCH were highly expressed in clinical samples collected from 10 AS patients and in ox-LDL-treated macrophages, whereas expression of both miR-17-5p and LKB1 was low. ITCH knockdown inhibited ox-LDL-induced lipid accumulation and LDL uptake in macrophages. Mechanistically speakingly, ITCH promoted LDL uptake and lipid accumulation in macrophages by mediating LKB1 ubiquitination degradation. NEAT1 knockdown reduced LDL uptake and lipid accumulation in macrophages and AS progression in vivo. NEAT1 promoted ITCH expression in macrophages by acting as a sponge for miR-17-5p. Inhibition of miR-17-5p facilitated ox-LDL-induced increase in LDL uptake and lipid accumulation in macrophages, which was reversed by NEAT1/ITCH knockdown. CONCLUSIONS: NEAT1 accelerated foam cell formation during AS progression through the miR-17-5p/ITCH/LKB1 axis.

ULK1-dependent phosphorylation of PKM2 antagonizes O-GlcNAcylation and regulates the Warburg effect in breast cancer.

Pyruvate kinase M2 (PKM2) is a central metabolic enzyme driving the Warburg effect in tumor growth. Previous investigations have demonstrated that PKM2 is subject to O-linked ß-N-acetylglucosamine (O-GlcNAc) modification, which is a nutrient-sensitive post-translational modification. Here we found that unc-51 like autophagy activating kinase 1 (ULK1), a glucose-sensitive kinase, interacts with PKM2 and phosphorylates PKM2 at Ser333. Ser333 phosphorylation antagonizes PKM2 O-GlcNAcylation, promotes its tetramer formation and enzymatic activity, and decreases its nuclear localization. As PKM2 is known to have a nuclear role in regulating c-Myc, we also show that PKM2-S333 phosphorylation inhibits c-Myc expression. By downregulating glucose consumption and lactate production, PKM2 pS333 attenuates the Warburg effect. Through mouse xenograft assays, we demonstrate that the phospho-deficient PKM2-S333A mutant promotes tumor growth in vivo. In conclusion, we identified a ULK1-PKM2-c-Myc axis in inhibiting breast cancer, and a glucose-sensitive phosphorylation of PKM2 in modulating the Warburg effect.

Analysis of sugar components and identification of SPS genes in citrus fruit development.

Sugar is a primary determinant of citrus fruit flavour, but undergoes varied accumulation processes across different citrus varieties owing to high genetic variability. Sucrose phosphate synthase (SPS), a key enzyme in glucose metabolism, plays a crucial role in this context. Despite its significance, there is limited research on sugar component quality and the expression and regulatory prediction of SPS genes during citrus fruit development. Therefore, we analysed the sugar quality formation process in 'Kiyomi' and 'Succosa', two citrus varieties, and performed a comprehensive genome-wide analysis of citrus CsSPSs. We observed that the accumulation of sugar components significantly differs between the two varieties, with the identification of four CsSPSs in citrus. CsSPS sequences were highly conserved, featuring typical SPS protein domains. Expression analysis revealed a positive correlation between CsSPS expression and sugar accumulation in citrus fruits. However, CsSPS expression displays specificity to different citrus tissues and varieties. Transcriptome co-expression network analysis suggests the involvement of multiple transcription factors in shaping citrus fruit sugar quality through the regulation of CsSPSs. Notably, the expression levels of four CsWRKYs (CsWRKY2, CsWRKY20, CsWRKY28, CsWRKY32), were significantly positively correlated with CsSPSs and CsWRKY20 might can activate sugar accumulation in citrus fruit through CsSPS2. Collectively, we further emphasize the potential importance of CsWRKYs in citrus sugar metabolism, our findings serve as a reference for understanding sugar component formation and predicting CsSPS expression and regulation during citrus fruit development.

GATA3 functions downstream of BRCA1 to promote DNA damage repair and suppress dedifferentiation in breast cancer.

BACKGROUND: Inadequate DNA damage repair promotes aberrant differentiation of mammary epithelial cells. Mammary luminal cell fate is mainly determined by a few transcription factors including GATA3. We previously reported that GATA3 functions downstream of BRCA1 to suppress aberrant differentiation in breast cancer. How GATA3 impacts DNA damage repair preventing aberrant cell differentiation in breast cancer remains elusive. We previously demonstrated that loss of p18, a cell cycle inhibitor, in mice induces luminal-type mammary tumors, whereas depletion of either Brca1 or Gata3 in p18 null mice leads to basal-like breast cancers (BLBCs) with activation of epithelial-mesenchymal transition (EMT). We took advantage of these mutant mice to examine the role of Gata3 as well as the interaction of Gata3 and Brca1 in DNA damage repair in mammary tumorigenesis. RESULTS: Depletion of Gata3, like that of Brca1, promoted DNA damage accumulation in breast cancer cells in vitro and in basal-like breast cancers in vivo. Reconstitution of Gata3 improved DNA damage repair in Brca1-deficient mammary tumorigenesis. Overexpression of GATA3 promoted homologous recombination (HR)-mediated DNA damage repair and restored HR efficiency of BRCA1-deficient cells. Depletion of Gata3 sensitized tumor cells to PARP inhibitor (PARPi), and reconstitution of Gata3 enhanced resistance of Brca1-deficient tumor cells to PARP inhibitor. CONCLUSIONS: These results demonstrate that Gata3 functions downstream of BRCA1 to promote DNA damage repair and suppress dedifferentiation in mammary tumorigenesis and progression. Our findings suggest that PARP inhibitors are effective for the treatment of GATA3-deficient BLBCs.

A State-Dependent Elasto-Plastic Model for Hydrate-Bearing Cemented Sand Considering Damage and Cementation Effects.

In order to optimize the efficiency and safety of gas hydrate extraction, it is essential to develop a credible constitutive model for sands containing hydrates. A model incorporating both cementation and damage was constructed to describe the behavior of hydrate-bearing cemented sand. This model is based on the critical state theory and builds upon previous studies. The damage factor Ds is incorporated to consider soil degradation and the reduction in hydrate cementation, as described by plastic shear strain. A computer program was developed to simulate the mechanisms of cementation and damage evolution, as well as the stress-strain curves of hydrate-bearing cemented sand. The results indicate that the model replicates the mechanical behavior of soil cementation and soil deterioration caused by impairment well. By comparing the theoretical curves with the experimental data, the compliance of the model was calculated to be more than 90 percent. The new state-dependent elasto-plastic constitutive model based on cementation and damage of hydrate-bearing cemented sand could provide vital guidance for the construction of deep-buried tunnels, extraction of hydrocarbon compounds, and development of resources.

Continuous planting of euhalophyte Suaeda salsa enhances microbial diversity and multifunctionality of saline soil.

Halophyte-based remediation emerges as a novel strategy for ameliorating saline soils, offering a sustainable alternative to conventional leaching methods. While bioremediation is recognized for its ability to energize soil fertility and structure, the complex interplays among plant traits, soil functions, and soil microbial diversity remain greatly unknown. Here, we conducted a 5-year field experiment involving the continuous cultivation of the annual halophyte Suaeda salsa in saline soils to explore soil microbial diversity and their relationships with plant traits and soil functions. Our findings demonstrate that a decline in soil salinity corresponded with increases in the biomass and seed yield of S. salsa, which sustained a consistent seed oil content of approximately 22% across various salinity levels. Significantly, prolonged cultivation of halophytes substantially augmented soil microbial diversity, particularly from the third year of cultivation. Moreover, we identified positive associations between soil multifunctionality, seed yield, and taxonomic richness within a pivotal microbial network module. Soils enriched with taxa from this module showed enhanced multifunctionality and greater seed yields, correlating with the presence of functional genes implicated in nitrogen fixation and nitrification. Genomic analysis suggests that these taxa have elevated gene copy numbers of crucial functional genes related to nutrient cycling. Overall, our study emphasizes that the continuous cultivation of S. salsa enhances soil microbial diversity and recovers soil multifunctionality, expanding the understanding of plant-soil-microbe feedback in bioremediation.IMPORTANCEThe restoration of saline soils utilizing euhalophytes offers a viable alternative to conventional irrigation techniques for salt abatement and soil quality enhancement. The ongoing cultivation of the annual Suaeda salsa and its associated plant traits, soil microbial diversity, and functionalities are, however, largely underexplored. Our investigation sheds light on these dynamics, revealing that cultivation of S. salsa sustains robust plant productivity while fostering soil microbial diversity and multifunctionality. Notably, the links between enhanced soil multifunctionality, increased seed yield, and network-dependent taxa were found, emphasizing the importance of key microbial taxa linked with functional genes vital to nitrogen fixation and nitrification. These findings introduce a novel understanding of the role of soil microbes in bioremediation and advance our knowledge of the ecological processes that are vital for the rehabilitation of saline environments.

The ARID1A-METTL3-m6A axis ensures effective RNase H1-mediated resolution of R-loops and genome stability.

R-loops are three-stranded structures that can pose threats to genome stability. RNase H1 precisely recognizes R-loops to drive their resolution within the genome, but the underlying mechanism is unclear. Here, we report that ARID1A recognizes R-loops with high affinity in an ATM-dependent manner. ARID1A recruits METTL3 and METTL14 to the R-loop, leading to the m6A methylation of R-loop RNA. This m6A modification facilitates the recruitment of RNase H1 to the R-loop, driving its resolution and promoting DNA end resection at DSBs, thereby ensuring genome stability. Depletion of ARID1A, METTL3, or METTL14 leads to R-loop accumulation and reduced cell survival upon exposure to cytotoxic agents. Therefore, ARID1A, METTL3, and METTL14 function in a coordinated, temporal order at DSB sites to recruit RNase H1 and to ensure efficient R-loop resolution. Given the association of high ARID1A levels with resistance to genotoxic therapies in patients, these findings open avenues for exploring potential therapeutic strategies for cancers with ARID1A abnormalities.

Decreased TET2/5-hmC reduces the integrity of the epidermal barrier via epigenetic dysregulation of filaggrin in psoriatic lesions.

BACKGROUND: TET2 participates in tumor progression and intrinsic immune homeostasis via epigenetic regulation. TET2 has been reported to be involved in maintaining epithelial barrier homeostasis and inflammation. Abnormal epidermal barrier function and TET2 expression have been detected in psoriatic lesions. However, the mechanisms underlying the role of TET2 in psoriasis have not yet been elucidated. OBJECTIVE: To define the role of TET2 in maintaining epithelial barrier homeostasis and the exact epigenetic mechanism in the dysfunction of the epidermal barrier in psoriasis. METHODS: We analyzed human psoriatic skin lesions and datasets from the GEO database, and detected the expression of TET2/5-hmC together with barrier molecules by immunohistochemistry. We constructed epidermal-specific TET2 knockout mice to observe the effect of TET2 deficiency on epidermal barrier function via toluidine blue penetration assay. Further, we analyzed changes in the expression of epidermal barrier molecules by immunofluorescence in TET2-specific knockout mice and psoriatic model mice. RESULTS: We found that decreased expression of TET2/5-hmC correlated with dysregulated barrier molecules in human psoriatic lesions. Epidermal-specific TET2 knockout mice showed elevated transdermal water loss associated with abnormal epidermal barrier molecules. Furthermore, we observed that TET2 knockdown in keratinocytes reduced filaggrin expression via filaggrin promoter methylation. CONCLUSION: Aberrant epidermal TET2 affects the integrity of the epidermal barrier through the epigenetic dysregulation of epidermal barrier molecules, particularly filaggrin. Reduced TET2 expression is a critical factor contributing to an abnormal epidermal barrier in psoriasis.

Salinity inhibits seed germination and embryo growth by reducing starch mobilization efficiency in barley.

Barley is one of the world's earliest domesticated crops, which is widely used for beer production, animal feeding, and health care. Barley seed germination, particularly in increasingly saline soils, is key to ensure the safety of crop production. However, the mechanism of salt-affected seed germination in barley remains elusive. Here, two different colored barley varieties were used to independently study the regulation mechanism of salt tolerance during barley seed germination. High salinity delays barley seed germination by slowing down starch mobilization efficiency in seeds. The starch plate test revealed that salinity had a significant inhibitory effect on α-amylase activity in barley seeds. Further, NaCl treatment down-regulated the expression of Amy1, Amy2 and Amy3 genes in germinated seeds, thereby inhibiting α-amylase activity. In addition, the result of embryogenic culture system in vitro showed that the shoot elongation of barley was significantly inhibited by salt stress. These findings indicate that it is a feasible idea to study the regulation mechanism of salinity on barley seed germination and embryo growth from the aspect of starch-related source-sink communication.

The effect of intelligent management interventions in intensive care units to reduce false alarms: An integrative review.

Objective: In intensive care units (ICU), frequent false alarms from medical equipment can cause alarm fatigue among nurses, which might lead to delayed or missed responses and increased risk of adverse patient events. This review was conducted to evaluate the effectiveness of intelligent management interventions to reduce false alarms in ICU. Method: Following the framework of Whitmore and Knafl, the reviewers systematically searched six databases: PubMed, EMBASE, CINAHL, OVID, Cochrane Library, and Scopus, and studies included intelligent management of clinical alarms published in the English or Chinese language from the inception of each database to December 2022 were retrieved. The researchers used the PICOS framework to formulate the search strategy, developed keywords, screened literature, and assessed the studies' quality using the Joanna Briggs Institute-Meta-Analysis of Statistics, Assessment, and Review Instrument (JBI-MAStARI). The review was preregistered on PROSPERO (CRD42023411552). Results: Seven studies met the inclusion criteria. The results showed that different interventions for intelligent management of alarms were beneficial in reducing the number of false alarms, the duration of alarms, the response time to important alarms for nurses, and the alarm fatigue levels among nurses. Positive results were found in practice after the application of the novel alarm management approaches. Conclusion: Intelligent management intervention may be an effective way to reduce false alarms. The application of systems or tools for the intelligent management of clinical alarms is urgent in hospitals. To ensure more effective patient monitoring and less distress for nurses, more alarm management approaches combined with artificial intelligence will be needed in the future to enable accurate identification of critical alarms, ensure nurses are responding accurately to alarms, and make a real difference to alarm-ridden healthcare environments.

Pesticide residue detection technology for herbal medicine: current status, challenges, and prospects.

The domains of cancer therapy, disease prevention, and health care greatly benefit from the use of herbal medicine. Herbal medicine has become the mainstay of developing characteristic agriculture in the planting area increasing year by year. One of the most significant factors in affecting the quality of herbal medicines is the pesticide residue problem caused by pesticide abuse during the cultivation of herbal medicines. It is urgent to solve the problem of detecting pesticide residues in herbal medicines efficiently and rapidly. In this review, we provide a comprehensive description of the various methods used for pesticide residue testing, including optical detection, the enzyme inhibition rate method, molecular detection methods, enzyme immunoassays, lateral immunochromatographic, nanoparticle-based detection methods, colorimetric immunosensor, chemiluminescence immunosensor, smartphone-based immunosensor, etc. On this basis, we systematically analyze the mechanisms and some of the findings of the above detection strategies and discuss the challenges and prospects associated with the development of pesticide residue detection tools.

Status and related factors of professional growth among young nursing talents: a cross-sectional study in China.

BACKGROUND: The shortage of nurses has been a global human resources problem. A good professional growth environment is essential to developing potential nursing students and attracting nurses to join, and it has great significance in reducing nurse turnover. However, nurses' comprehensive perceptions of professional growth have not yet been examined. METHODS: A cluster sampling method was used to conduct a professional growth questionnaire survey on young nursing talents from a large Chinese public tertiary A hospital in March 2022. RESULTS: The score of professional growth among 243 young nursing talents was 57.92 ± 9.607, with a scoring rate of 77.23%. The scores for dimensions of professional growth, from lowest to highest, were rehabilitation growth, promotion speed, professional goal progress, and professional ability development. Attitudes towards participating in training, service as the quality manager or clinical teacher, self-efficacy, professional title, work-family support, education, and organizational commitment of young nursing talents were significantly associated with professional growth. CONCLUSION: The professional growth of young nursing talents was at a moderate level and needed to be strengthened. Nursing leaders and managers are expected to develop management practices to enhance young nursing talents' professional growth in combination with the related factors.

Greatly Improved the Tunable Amplitude of Ferromagnetism Based on Interface Effect of Flexible Pt/YIG Heterojunctions.

Flexible quantum spin electronic devices based on ferromagnetic insulators have attracted wide attention due to their outstanding advantages of low-power dissipation and noncontact sensing. However, ferromagnetic insulators, such as monocrystalline yttrium iron garnet (Y3Fe5O12, YIG), hve weak stress effects with a small magnetostrictive coefficient (λ110, 10 ppm), making it difficult to achieve a large magnetic tunable amplitude. In this paper, large-scale (with a diameter of 40 mm), flexible Pt/YIG heterojunctions were obtained by double-cavity magnetron sputtering technology, indicating typical soft magnetism and good bending fatigue characteristics. Here, the 3 nm thickness of the Pt layer triggers an obvious magnetic proximity effect, in which the in-plane ferromagnetic resonance field is decreased by 70 Oe compared to flexible Cu/YIG heterojunctions. Meanwhile, it shows a wide tunable amplitude of 110 Oe under the flexible bending stresses, which is induced by the sensitive interface effect of Pt (3 nm)/YIG heterojunctions. The saturation magnetization of Pt/YIG heterojunctions is negatively correlated with Pt thickness rather than the relative stability of Cu/YIG heterojunctions, depending on the magnetic proximity effect. It brings greater application possibilities for flexible stress-sensitive magnetic oxides in spin logic electronic devices.

Nanoparticulate bioceramic putty suppresses osteoclastogenesis and inflammatory bone loss in mice via inhibition of TRAF6-mediated signalling pathways: A laboratory investigation.

AIM: This study aimed to determine the effects of iRoot BP Plus on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in vitro and inflammation-mediated bone resorption in vivo and investigated the underlying molecular mechanisms. METHODOLOGY: CCK-8 was performed to test cell viability in RANKL-induced RAW 264.7 cells and BMDMs in response to iRoot BP Plus. The effect of iRoot BP Plus on osteoclastogenesis was determined using TRAP staining and phalloidin staining, respectively. Pit formation assay was conducted to measure osteoclast resorptive capacity. Western blot and qPCR were performed to examine osteoclast-related proteins and gene expression, respectively. Western blot was also used to investigate the signalling pathways involved. For in vivo experiments, an LPS-induced mouse calvarial bone resorption model was established to analyse the effect of iRoot BP Plus on bone resorption (n = 6 per group). At 7 days, mouse calvaria were collected and prepared for histological analysis. RESULTS: We identified that iRoot BP Plus extracts significantly attenuated RANKL-induced osteoclastogenesis, reduced sealing zone formation, restrained osteolytic capacity and decreased osteoclast-specific gene expression (p < .01). Mechanistically, iRoot BP Plus extracts reduced TRAF6 via proteasomal degradation, then suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), blocked the nuclear translocation of c-Fos and diminished nuclear factor-κB (NF-κB) p65 and NFATc1 accumulation. Consistent with the in vitro results, iRoot BP Plus extracts attenuated osteoclast activity thus protecting against inflammatory bone resorption in vivo (p < .05), which was accompanied by a suppression of TRAF6, c-Fos, NFATc1 and cathepsin K expression. CONCLUSION: These findings provide valuable insights into the signalling mechanisms underlying nanoparticulate bioceramic putty-mediated bone homeostasis.

Site-Directed Mutagenesis of VvCYP76F14 (Cytochrome P450) Unveils Its Potential for Selection in Wine Grape Varieties Linked to the Development of Wine Bouquet.

Bouquet is a fascinating wine characteristic that serves as an indicator of wine quality, developing during the aging process. The multifunctional monoterpenol oxidase VvCYP76F14 in wine grapes sequentially catalyzes three reactions to produce (E)-8-carboxylinalool, a crucial precursor for wine bouquet. Previous studies indicated that the activity of VvCYP76F14 derived from different wine grape varieties did not correlate with the amino acid sequence differences. In this study, 54 wine grape varieties were categorized into neutral, aromatic, and full-bodied types based on the sequence differences of VvCYP76F14, closely correlated with the content of wine lactone precursors. Computer modeling and molecular docking analysis of the full-bodied CYP76F14 revealed 17, 19, and 18 amino acid residues in the VvCYP76F14-linalool, VvCYP76F14-(E)-8-hydroxylinalool, and VvCYP76F14-(E)-8-oxolinalool complexes, respectively. Site-directed mutagenesis and in vitro enzyme activity analysis confirmed the substitutions of the key amino acid residues in neutral and aromatic varieties. Notably, the D299 mutation of VvCYP76F14 resulted in the complete loss of (E)-8-oxolinalool and (E)-8-carboxylinalool activities, aligning with the undetectable levels of (E)-8-oxolinalool and (E)-8-carboxylinalool in "Yantai 2-3-37", which harbors the D299T substitution. Favorably, VvCYP76F14 could serve as a cost-effective fingerprint marker for screening superior hybrid offspring with the desired levels of wine lactone precursors.

Risk Factors and Prediction Models for Postoperative Pathologically Malignant TI-RADS 3 Thyroid Nodules.

Objective: Our goal was to detect the risk factors for malignant TI-RADS 3 nodule and to construct a predictive model. Patients and Methods: All 199 patients with TI-RADS 3 nodule underwent first-time thyroid surgery from January 2018 to September 2021. Univariate analysis identified potential risk covariates and then incorporated these covariates into multivariate logistic regression to determine the risk factors for malignant TI-RADS 3 nodule and construct a predictive model. Results: Binary logistic regression analysis showed that age [odds ratio (OR): 0.926, 95% CI: 0.865-0.992; P = .029), low level of parathyroid hormone (OR: 0.940, 95% CI: 0.890-0.993; P = .027), and preoperative ultrasound features of TI-RADS 3 nodule, such as echogenicity (OR: 8.496, 95% CI: 1.377-52.406; P = .021), echogenic foci (OR: 8.611, 95% CI: 1.484-49.957; P = .016), and maximum tumor diameter (OR: 0.188, 95% CI: 0.040-0.888; P = .035) were independent risk factors for malignant TI-RADS 3 nodule. Based on these independent risk factors, a logistic regression model was established. The area under curve of the prediction model for TI-RADS 3 thyroid cancer was 0.921 (95% CI: 0.856-0.986, P < 0.001). The maximum Youden index was 0.698. The cut-off value, sensitivity, and specificity were 0.074, 84.6%, and 85.2%, respectively. Conclusion: Young age, iso/hypo/very hypo echo, echogenic foci, nodule diameter <30 mm, and low level of PTH are independent risk factors for TI-RADS 3 thyroid carcinomas. This prediction model has a high sensitivity and specificity. A prediction model value of more than 0.074 implies that the TI-RADS 3 nodule has undergone a malignant transformation, and fine needle aspiration is recommended in these cases.

Knockdown of CCM3 promotes angiogenesis through activation and nuclear translocation of YAP/TAZ.

Angiogenesis, a finely regulated process, plays a crucial role in the progression of various diseases. Cerebral cavernous malformation 3 (CCM3), alternatively referred to as programmed cell death 10 (PDCD10), stands as a pivotal functional gene with a broad distribution across the human body. However, the precise role of CCM3 in angiogenesis regulation has remained elusive. YAP/TAZ, as core components of the evolutionarily conserved Hippo pathway, have garnered increasing attention as a novel mechanism in angiogenesis regulation. Nonetheless, whether CCM3 regulates angiogenesis through YAP/TAZ mediation has not been comprehensively explored. In this study, our primary focus centers on investigating the regulation of angiogenesis through CCM3 knockdown mediated by YAP/TAZ. Silencing CCM3 significantly enhances the proliferation, migration, and tubular formation of human umbilical vein endothelial cells (HUVECs), thereby promoting angiogenesis. Furthermore, we observe an upregulation in the expression levels of VEGF and VEGFR2 within HUVECs upon silencing CCM3. Mechanistically, the evidence we provide suggests for the first time that endothelial cell CCM3 knockdown induces the activation and nuclear translocation of YAP/TAZ. Finally, we further demonstrate that the YAP/TAZ inhibitor verteporfin can reverse the pro-angiogenic effects of siCCM3, thereby confirming the role of CCM3 in angiogenesis regulation dependent on YAP/TAZ. In summary, our findings pave the way for potential therapeutic targeting of the CCM3-YAP/TAZ signaling axis as a novel approach to promote angiogenesis.

The influence of social participation and depressive symptoms on cognition among middle-aged and older adults.

Background: The global aging phenomenon has raised concerns about the cognitive abilities of older individuals. This study aimed to explore the relationship between social participation, depressive symptoms, and cognitive function among middle-aged and older adults. Methods: This study utilized data from the China Longitudinal Study of Health and Retirement (CHARLS) from wave 1 to wave 4. We used linear regression and generalized estimation equations to investigate the correlation between social participation, depressive symptoms, and cognitive function. Moreover, three models were constructed by adjusting covariates, and we used the sobel test and bootstrap method to analyze the mediating effects of depressive symptoms on social activities and cognitive function. Results: The results of both linear regression and generalized estimation equation showed that social participation had a positive correlation with cognitive function (P < 0.05), and the impact of social participation on cognition increased with the number of social activity types. Meanwhile, depressive symptoms had a negative association with cognitive function (P < 0.05). Furthermore, there was no interaction between social participation and depressive symptoms on cognitive function. Finally, after adjusting the model, social participation could affect cognitive function by affecting depressive symptoms (P < 0.05). Conclusion: The study emphasizes the mediating role of depressive symptoms in the relationship between social participation and cognitive function. Notably, no interaction was observed between social participation and depressive symptoms. These findings highlight the potential of active social participation in reducing depressive symptoms and enhancing cognitive function in middle-aged and older adults.