DNA-TCP complex structures reveal a unique recognition mechanism for TCP transcription factor families.

Plant-specific TCP transcription factors are key regulators of diverse plant functions. TCP transcription factors have long been annotated as basic helix-loop-helix (bHLH) transcription factors according to remote sequence homology without experimental validation, and their consensus DNA-binding sequences and protein-DNA recognition mechanisms have remained elusive. Here, we report the crystal structures of the class I TCP domain from AtTCP15 and the class II TCP domain from AtTCP10 in complex with different double-stranded DNA (dsDNA). The complex structures reveal that the TCP domain is a distinct DNA-binding motif and the homodimeric TCP domains adopt a unique three-site recognition mode, binding to dsDNA mainly through a central pair of ß-strands formed by the dimer interface and two basic flexible loops from each monomer. The consensus DNA-binding sequence for class I TCPs is a perfectly palindromic 11 bp (GTGGGNCCCAC), whereas that for class II TCPs is a near-palindromic 11 bp (GTGGTCCCCAC). The unique DNA binding mode allows the TCP domains to display broad specificity for a range of DNA sequences even shorter than 11 bp, adding further complexity to the regulatory network of plant TCP transcription factors.

Renoprotective effects of empagliflozin in high-fat diet-induced obesity-related glomerulopathy by regulation of gut-kidney axis.

The increasing prevalence of obesity-related glomerulopathy (ORG) poses a significant threat to public health. Sodium-glucose cotransporter-2 (SGLT2) inhibitors effectively reduce body weight and total fat mass in individuals with obesity and halt the progression of ORG. However, the underlying mechanisms of their reno-protective effects in ORG remain unclear. We established a high-fat diet-induced ORG model using C57BL/6J mice, which were divided into three groups: normal chow diet (NCD group), high-fat diet (HFD) mice treated with placebo (ORG group), and HFD mice treated with empagliflozin (EMPA group). We conducted 16S ribosomal RNA gene sequencing of feces and analyzed metabolites from kidney, feces, liver, and serum samples. ORG mice showed increased urinary albumin creatinine ratio, cholesterol, triglyceride levels, and glomerular diameter compared with NCD mice (all P < 0.05). EMPA treatment significantly alleviated these parameters (all P < 0.05). Multitissue metabolomics analysis revealed lipid metabolic reprogramming in ORG mice, which was significantly altered by EMPA treatment. MetOrigin analysis showed a close association between EMPA-related lipid metabolic pathways and gut microbiota alterations, characterized by reduced abundances of Firmicutes and Desulfovibrio and increased abundance of Akkermansia (all P < 0.05). The metabolic homeostasis of ORG mice, especially in lipid metabolism, was disrupted and closely associated with gut microbiota alterations, contributing to the progression of ORG. EMPA treatment improved kidney function and morphology by regulating lipid metabolism through the gut-kidney axis, highlighting a novel therapeutic approach for ORG. NEW & NOTEWORTHY Our study uncovered that empagliflozin (EMPA) potentially protects renal function and morphology in obesity-related glomerulopathy (ORG) mice by regulating the gut-kidney axis. EMPA's reno-protective effects in ORG mice are associated with the lipid metabolism, especially in glycerophospholipid metabolism and the pantothenate/CoA synthesis pathways. EMPA's modulation of gut microbiota appears to be pivotal in suppressing glycerol 3-phosphate and CoA synthesis. The insights into gut microbiota-host metabolic interactions offer a novel therapeutic approach for ORG.

Percent duration of heart rate acceleration within the respiratory cycle: a novel approach to assess heart rate asymmetry.

Accelerations and decelerations of heart rate are nonsymmetrical in the magnitude and number of beat-to-beat changes. The asymmetric features of heart rate variability are related to respiratory durations. To explore the link between respiration and heart rate asymmetry (HRA), we evaluated 14 seated, healthy young adults who breathed with nine combinations of inspiration duration (TI) and expiration duration (TE), chosen respectively from 2, 4, and 6 s. A 5-min R-R interval (RRI) time series was obtained from each study period to construct an averaged pattern waveform relative to the respiratory cycle. We observed that the time interval between inspiration onset and RRI minimum progressively lengthened as TI and TE increased. The time interval between expiration onset and RRI maximum also lengthened when TE increased but shortened when TI increased. Consequently, TI and TE had different effects on the acceleration time (AT; from RRI maximum to RRI minimum) and deceleration time (DT; from RRI minimum to RRI maximum). The percentage of AT within the respiratory cycle showed a strong correlation with traditional Guzik's (r = 0.862, P < 0.001) and Porta's (r = 0.878, P < 0.001) indexes of HRA assessed in a Poincaré plot analysis. These findings suggest that, in addition to considering the magnitude and number of beat-to-beat changes, HRA can also be assessed based on another aspect: the duration of consecutive changes. The stepwise link between the duration of heart rate change and respiratory duration provides insight into the mechanisms connecting respiration to HRA.NEW & NOTEWORTHY In healthy adults who regulated their breathing across nine combinations of inspiration and expiration durations, we used averaged pattern waveform technique to quantify the durations of heart rate acceleration and deceleration within the respiratory cycle. The percent duration of acceleration showed a strong correlation with traditional heart rate asymmetry indexes, which evaluate the magnitude and number of beat-to-beat changes. This new approach opens a window to explore the asymmetric features of heart rate variability.

TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.

BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment. METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models. RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation. CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.

FGF4 ameliorates the liver inflammation by reducing M1 macrophage polarization in experimental autoimmune hepatitis.

BACKGROUND: The global prevalence of autoimmune hepatitis (AIH) is increasing due in part to the lack of effective pharmacotherapies. Growing evidence suggests that fibroblast growth factor 4 (FGF4) is crucial for diverse aspects of liver pathophysiology. However, its role in AIH remains unknown. Therefore, we investigated whether FGF4 can regulate M1 macrophage and thereby help treat liver inflammation in AIH. METHODS: We obtained transcriptome-sequencing and clinical data for patients with AIH. Mice were injected with concanavalin A to induce experimental autoimmune hepatitis (EAH). The mechanism of action of FGF4 was examined using macrophage cell lines and bone marrow-derived macrophages. RESULTS: We observed higher expression of markers associated with M1 and M2 macrophages in patients with AIH than that in individuals without AIH. EAH mice showed greater M1-macrophage polarization than control mice. The expression of M1-macrophage markers correlated positively with FGF4 expression. The loss of hepatic Fgf4 aggravated hepatic inflammation by increasing the abundance of M1 macrophages. In contrast, the pharmacological administration of FGF4 mitigated hepatic inflammation by reducing M1-macrophage levels. The efficacy of FGF4 treatment was compromised following the in vivo clearance of macrophage populations. Mechanistically, FGF4 treatment activated the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-signal pathway in macrophages, which led to reduced M1 macrophages and hepatic inflammation. CONCLUSION: We identified FGF4 as a novel M1/M2 macrophage-phenotype regulator that acts through the PI3K-AKT-signaling pathway, suggesting that FGF4 may represent a novel target for treating inflammation in patients with AIH.

A novel long noncoding RNA-lncRNA-AABR07066529.3 alleviates inflammation, apoptosis, and pyroptosis by inhibiting MyD88 in lipopolysaccharide-induced myocardial depression.

Sepsis-induced myocardial depression (SIMD) is common in pediatric intensive care units and seriously threatens children's health. Recently, long noncoding RNAs (lncRNAs) have been showed to play important roles in various diseases; however, its role in SIMD is unclear. In this study, we used lipopolysaccharide (LPS)-treated rats and H9c2 cardiomyocytes to mimic SIMD in vivo and in vitro. We found that the expression of a novel lncRNA, we named lncRNA-AABR07066529.3, was elevated in LPS-induced rat heart tissue and H9c2 cardiomyocytes. In addition, LPS-induced inflammation, apoptosis, and pyroptosis were significantly exacerbated after lncRNA-AABR07066529.3 knockdown. Moreover, we found that myeloid differentiation factor 88 (MyD88) was upregulated in LPS-treated groups and was inhibited by lncRNA-AABR07066529.3. Besides, MyD88 knockdown abolished lncRNA-AABR07066529.3 silencing effects on inflammation, apoptosis, and pyroptosis induced by LPS in H9c2 cardiomyocytes. In our study, we found lncRNA-AABR07066529.3 exerted protective effects on LPS-induced cardiomyocytes by regulating MyD88 and might serve as a potential treatment target for SIMD.

Kcnma1 is involved in mitochondrial homeostasis in diabetes-related skeletal muscle atrophy.

Uncontrolled diabetes causes a catabolic state with multi-organic complications, of which impairment on skeletal muscle contributes to the damaged mobility. Kcnma1 gene encodes the pore-forming α-subunit of Ca2+ - and voltage-gated K+ channels of large conductance (BK channels), and loss-of-function mutations in Kcnma1 are in regards to impaired myogenesis. Herein, we observed a time-course reduction of Kcnma1 expression in the tibialis anterior muscles of leptin receptor-deficient (db/db) diabetic mice. To investigate the role of Kcnma1 in diabetic muscle atrophy, muscle-specific knockdown of Kcnma1 was achieved by mice receiving intravenous injection of adeno-associated virus-9 (AAV9)-encoding shRNA against Kcnma1 under the muscle creatine kinase (MCK) promoter. Impairment on muscle mass and myogenesis were observed in m/m mice with AAV9-shKcnma1 intervention, while this impairment was more obvious in diabetic db/db mice. Simultaneously, damaged mitochondrial dynamics and biogenesis showed much severer in db/db mice with AAV9-shKcnma1 intervention. RNA sequencing revealed the large transcriptomic changes resulted by Kcnma1 knockdown, and changes in mitochondrial homeostasis-related genes were validated. Besides, the artificial alteration of Kcnma1 in mouse C2C12 myoblasts was achieved with an adenovirus vector. Consistent results were demonstrated by Kcnma1 knockdown in palmitate-treated cells, whereas opposite results were exhibited by Kcnma1 overexpression. Collectively, we document Kcnma1 as a potential keeper of mitochondrial homeostasis, and the loss of Kcnma1 is a critical event in priming skeletal muscle loss in diabetes.

Utilizing Single-Branched Stent in Combination With Fenestration or Chimney for Endovascular Repair of Aortic Arch Lesions With Aberrant Subclavian Artery.

OBJECTIVE: The study was to figure out the feasibility, efficacy, and safety of a single-branched stent graft, namely Castor, in combination with fenestration or chimney in the context of aortic arch lesions presenting with aberrant subclavian artery (ASA) and/or Kommerell's diverticulum (KD). METHODS: All consecutive patients with aortic arch lesions and ASA and/or KD receiving Castor from June 2018 to June 2023 were investigated. RESULTS: Incorporating 18 patients, the study encompassed 11 cases with KD, 3 cases with dysphagia; 2 cases of right-sided aortic arch with left-sided aberrant left subclavian artery (ALSA), and 16 cases of left-sided aortic arch with right-sided aberrant right subclavian artery (ARSA). The mean operation time was 132±23 minutes. The mean measured proximal aortic diameter was 30.9±1.6 mm, and proximal diameter of Castor stent was 34 (32, 34.5) mm, with oversize of 9.1±1.6%; the mean measured branch diameter was 8.8±0.97 mm, and branch diameter of Castor stent was 10 (8, 10) mm, with oversize of 0.86±0.57 mm. Technical success rate was 100%, and no in-hospital mortality, no stroke, and no endoleak were identified. One (5.6%) case with spinal cord ischemia and one (5.6%) case with poor healing of operative site were identified. During the follow-up period, no aortic-related death or secondary intervention was recorded. The maximal aortic diameter was significantly reduced at the sixth postoperative month (padj=0.031); KD diameter was significantly reduced at the third (padj=0.001) and sixth (padj<0.001) postoperative month. CONCLUSION: Totally endovascular repair of aortic arch lesions with ASA and KD via Castor stent in combination with fenestration or chimney is feasible, effective, and safe, which can achieve an encouraging medium-term outcome and provide excellent remodeling at the lesions. CLINICAL IMPACT: Single branched stent in combination with fenestration or chimney achieved a sufficient proximal landing zone and provided an encouraging medium-term outcome in this retrospective review of 18 patients receiving endovascular treatment of pathological aortic arch with aberrant subclavian artery and/or Kommerell's diverticulum. The authors suggest this time-saving and efficient technique to establish systematic experience for the treatment in this kind of patients.

Computational Insights into SARS-CoV-2 Main Protease Mutations and Nirmatrelvir Efficacy: The Effects of P132H and P132H-A173V.

Nirmatrelvir, a pivotal component of the oral antiviral Paxlovid for COVID-19, targets the SARS-CoV-2 main protease (Mpro) as a covalent inhibitor. Here, we employed combined computational methods to explore how the prevalent Omicron variant mutation P132H, alone and in combination with A173V (P132H-A173V), affects nirmatrelvir's efficacy. Our findings suggest that P132H enhances the noncovalent binding affinity of Mpro for nirmatrelvir, whereas P132H-A173V diminishes it. Although both mutants catalyze the rate-limiting step more efficiently than the wild-type (WT) Mpro, P132H slows the overall rate of covalent bond formation, whereas P132H-A173V accelerates it. Comprehensive analysis of noncovalent and covalent contributions to the overall binding free energy of the covalent complex suggests that P132H likely enhances Mpro sensitivity to nirmatrelvir, while P132H-A173V may confer resistance. Per-residue decompositions of the binding and activation free energies pinpoint key residues that significantly affect the binding affinity and reaction rates, revealing how the mutations modulate these effects. The mutation-induced conformational perturbations alter drug-protein local contact intensities and the electrostatic preorganization of the protein, affecting noncovalent binding affinity and the stability of key reaction states, respectively. Our findings inform the mechanisms of nirmatrelvir resistance and sensitivity, facilitating improved drug design and the detection of resistant strains.

Electroantennographic and Behavioral Responses of the Melon fly, Zeugodacus cucurbitae (Coquillett), to Volatile Compounds of Ridge Gourd, Luffa acutangular L.

The melon fly, Zeugodacus cucurbitae (Coquillett), is a major invasive pest, widely distributed in the Asia-Pacific region and some parts of Africa. Melon fly attractants could improve the effectiveness of current pest management measures. Previous studies have shown that some host fruits are attractive to melon flies but few have investigated the chemical compounds responsible for their attraction. In this study, we aimed to identify the volatile compounds from Luffa acutangula L that attract Z. cucurbitae. In headspace trapping, chemical profiling identified 19 compounds from ridge gourds, with 1-pentadecene being the major component. EAG results revealed that seven compounds elicited antennal responses in Z. cucurbitae, and significant differences in antennal responses between male and female Z. cucurbitae adults were recorded to p-xylene, alpha-pinene, and 1-octadecene. Behavioral experiments demonstrated that the EAG-active compounds methyl isovalerate and methyl myristate had either attractive or repellent effects on Z. cucurbitae at different concentrations, and 1-octadecene attracted Z. cucurbitae. Our findings provide a theoretical basis producing repellents or attractants for effective Integrated Pest Management of Z. cucurbitae.

Design, synthesis, molecular modeling and evaluation of 2,4-diaminopyrimidine analogues as promising colorectal cancer drugs.

The potential of cyclin-dependent kinases (CDKs) as therapeutic targets in cancer treatment is well established. In this study, we present our investigation into a group of 2,4-diaminopyrimidine derivatives that potently inhibit CDK9 and are cytotoxic when tested in colorectal cancer cell lines. We designed and synthesized forty analogues by altering substitutions at C-2 and C-4 position of the pyrimidine system. Among them, compounds 16 h and 16j exhibited strong inhibitory potency against both CDK9 enzymes (IC50 = 11.4 ± 1.4 nM, IC50 = 10.2 ± 1.3 nM respectively) with a significant preference for one over the other, and cytotoxic potency (IC50 = 61 ± 2 nM, IC50 = 20 ± 1 nM respectively) against HCT-116 was discovered through substantial modifications to its structure. Further investigations revealed that compounds 16 h and 16j were directly bound to CDK9, resulting in the suppression of its downstream signaling pathway. This inhibition of cell proliferation occurred by impeding the progression of the cell cycle and inducing apoptosis in cells by suppressing the phosphoryl RNA pol II Ser2. Significantly, compound 16 h and 16j effectively suppressed tumor growth in a xenograft mouse model and exhibited no apparent toxicity. This indicates that CDK9 inhibitors hold great potential as a therapeutic approach for colorectal cancer treatment. Therefore, the aforementioned discoveries are vital for the development of CDK9 inhibitors for the treatment of cancer.

Hypertension and iron deficiency anemia: Exploring genetic associations and causal inference.

BACKGROUND AND AIM: Observational studies have suggested a potential association between hypertension and Iron deficiency anemia (IDA). However, it is unclear whether there is a genetic and causal link between hypertension and IDA. METHODS AND RESULTS: Genome-Wide Association Studies (GWAS) data for hypertension were sourced from the UK Biobank and FinnGen. Genetic variants data for IDA were extracted from FinnGen and the IEU Open GWAS project, all derived from European populations. The genetic association between hypertension and IDA was assessed using Linkage Disequilibrium Score Regression (LDSC), with MR employed to determine causality. Inverse variance weighted (IVW) as a major analytical method for MR. Sensitivity and heterogeneity analyses were conducted to ensure result reliability. Furthermore, validation analysis was performed to further strengthen the robustness of the findings. A genetic association between hypertension and IDA was observed (rg = 0.121, P = 0.002). Our findings suggest that hypertension increases the risk of developing IDA (OR = 2.493,P = 0.038), and IDA maybe serve as a risk factor for hypertension (OR = 1.006,P < 0.001). Validation analysis yielded consistent results. Importantly, our findings demonstrated no heterogeneity or horizontal pleiotropy. CONCLUSION: Additional insights into the connection between hypertension and IDA were gained. Regular testing of iron ions and anemia-related markers in hypertensive patients is crucial for early identification of IDA. Furthermore, it is imperative to closely monitor the blood pressure of patients with IDA to promptly identify and diagnose hypertension. The implementation of these integrated health strategies is vital for global efforts to tackle the dual challenges of hypertension and IDA.

Recent trends in preparation and biomedical applications of iron oxide nanoparticles.

The iron oxide nanoparticles (IONPs), possessing both magnetic behavior and semiconductor property, have been extensively used in multifunctional biomedical fields due to their biocompatible, biodegradable and low toxicity, such as anticancer, antibacterial, cell labelling activities. Nevertheless, there are few IONPs in clinical use at present. Some IONPs approved for clinical use have been withdrawn due to insufficient understanding of its biomedical applications. Therefore, a systematic summary of IONPs' preparation and biomedical applications is crucial for the next step of entering clinical practice from experimental stage. This review summarized the existing research in the past decade on the biological interaction of IONPs with animal/cells models, and their clinical applications in human. This review aims to provide cutting-edge knowledge involved with IONPs' biological effects in vivo and in vitro, and improve their smarter design and application in biomedical research and clinic trials.

Different effects of inspiratory duration and expiratory duration on heart rate deceleration capacity and heart rate asymmetry.

PURPOSE: Low values of heart rate deceleration capacity (DC) and heart rate asymmetry (HRA) are associated with cardiovascular risks. Slow respiration has been proven to enhance the magnitudes of these indexes, but individual inspiratory (TI) and expiratory (TE) durations were not controlled in most studies. This study aims to examine whether the effects of TI and TE on these indexes would be the same and, if not, how to adjust TI and TE to maximize the effect of slow respiration. METHODS: We evaluated 14 seated healthy young adults who randomly controlled their breathing to nine combinations of TI and TE, each chosen respectively from 2, 4, and 6 s. A 5-min R-R interval time series was obtained from each study period for further analysis. RESULTS: The magnitude of DC increased when TI or TE increased, while that of acceleration capacity (AC) remained almost unchanged by TI. We further defined a new index as 100 × DC2/(DC2 + AC2) and found it to be correlated with conventional Guzik's (r = 0.94) and Porta's (r = 0.99) indexes of HRA during different combinations of TI and TE. Increasing TI and increasing TE both enhanced the magnitudes of HRA indexes, with TI taking effect when ≤ 4 s, and TE taking effect when > 4 s. DC and HRA indexes were maximized with a TI of 4 s and a TE of 6 s. CONCLUSION: We suggest that a TI of 3-4 s with a TE of 7-6 s is an appropriate standard for slow respiration.

Identification of a Novel Subset of Human Airway Epithelial Basal Stem Cells.

The basal cell maintains the airway's respiratory epithelium as the putative resident stem cell. Basal cells are known to self-renew and differentiate into airway ciliated and secretory cells. However, it is not clear if every basal cell functions as a stem cell. To address functional heterogeneity amongst the basal cell population, we developed a novel monoclonal antibody, HLO1-6H5, that identifies a subset of KRT5+ (cytokeratin 5) basal cells. We used HLO1-6H5 and other known basal cell-reactive reagents to isolate viable airway subsets from primary human airway epithelium by Fluorescence Activated Cell Sorting. Isolated primary cell subsets were assessed for the stem cell capabilities of self-renewal and differentiation in the bronchosphere assay, which revealed that bipotent stem cells were, at minimum 3-fold enriched in the HLO1-6H5+ cell subset. Crosslinking-mass spectrometry identified the HLO1-6H5 target as a glycosylated TFRC/CD71 (transferrin receptor) proteoform. The HLO1-6H5 antibody provides a valuable new tool for identifying and isolating a subset of primary human airway basal cells that are substantially enriched for bipotent stem/progenitor cells and reveals TFRC as a defining surface marker for this novel cell subset.

Prevalence and risk factors of cognitive frailty among pre-frail and frail older adults in nursing homes.

BACKGROUND: The purpose of this research was to stratify the level of frailty to examine the risk factors associated with reversible cognitive frailty (RCF) and potentially reversible cognitive frailty (PRCF) in nursing homes to provide a basis for hierarchical management in different stages of frailty. METHODS: The study was a cross-sectional study conducted from September to November 2022; 504 people were selected by stratified random sampling after convenience selection from the Home for the Aged Guangzhou. The structured questionnaire survey was conducted through face-to-face interviews using the general data questionnaire, Fried Frailty Phenotype, Montreal Cognitive Assessment Scale. RESULTS: In total, 452 individuals were included for analysis. A total of 229 cases (50.7%) were PRCF, 70 (15.5%) were RCF. Multivariate logistic regression analysis showed that in pre-frailty, the Geriatric Depression Scale (GDS-15) score (odds ratio (OR) 1.802; 95% CI 1.308-2.483), Instrumental Activities of Daily Living Scale (IADL) score (0.352; 0.135-0.918) and energy (0.288; 0.110-0.755) were influencing factors of RCF. GDS-15 score (1.805; 1.320-2.468), IADL score (0.268; 0.105-0.682), energy (0.377; 0.150-0.947), lack of intellectual activity (6.118; 1.067-35.070), admission time(>3 years) (9.969; 1.893-52.495) and low education (3.465; 1.211-9.912) were influencing factors of PRCF. However, RCF with frailty was associated with the Short-Form Mini-Nutritional Assessment (MNA-SF) score (0.301; 0.123-0.739) and low education time (0 ~ 12 years) (0.021; 0.001-0.826). PRCF with frailty was associated with age (1.327; 1.081-1.629) and weekly exercise time (0.987; 0.979-0.995). CONCLUSIONS: The prevalence of RCF and PRCF was high among pre-frail and frail older adults in nursing homes. Different levels of frailty had different influencing factors for RCF and PRCF. Depression, daily living ability, energy, intellectual activity, admission time, education level, nutrition status, age and exercise time were associated with RCF and PRCF. Hierarchical management and intervention should be implemented for different stages of frailty to prevent or delay the progression of cognitive frailty.

O-GlcNAcylation stabilizes the autophagy-initiating kinase ULK1 by inhibiting chaperone-mediated autophagy upon HPV infection.

Human papillomaviruses (HPVs) cause a subset of head and neck squamous cell carcinomas (HNSCCs). Previously, we demonstrated that HPV16 oncogene E6 or E6/E7 transduction increases the abundance of O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT), but OGT substrates affected by this increase are unclear. Here, we focus on the effects of O-GlcNAcylation on HPV-positive HNSCCs. We found that upon HPV infection, Unc-51-like kinase 1 (ULK1), an autophagy-initiating kinase, is hyper-O-GlcNAcylated, stabilized, and linked with autophagy elevation. Through mass spectrometry, we identified that ULK1 is O-GlcNAcylated at Ser409, which is distinct from the previously reported Thr635/Thr754 sites. It has been demonstrated that PKCα mediates phosphorylation of ULK1 at Ser423, which attenuates its stability by shunting ULK1 to the chaperone-mediated autophagy (CMA) pathway. Using biochemical assays, we demonstrate that ULK1 Ser409Ser410 O-GlcNAcylation antagonizes its phosphorylation at Ser423. Moreover, mutations of Ser409A and its neighboring site Ser410A (2A) render ULK1 less stable by promoting interaction with the CMA chaperone HSC70 (heat shock cognate 70 kDa protein). Furthermore, ULK1-2A mutants attenuate the association of ULK1 with STX17, which is vital for the fusion between autophagosomes and lysosomes. Analysis of The Cancer Genome Atlas (TCGA) database reveals that ULK1 is upregulated in HPV-positive HNSCCs, and its level positively correlates with HNSCC patient survival. Overall, our work demonstrates that O-GlcNAcylation of ULK1 is altered in response to environmental changes. O-GlcNAcylation of ULK1 at Ser409 and perhaps Ser410 stabilizes ULK1, which might underlie the molecular mechanism of HPV-positive HNSCC patient survival.

The mechanistic basis of sodium exclusion in Puccinellia tenuiflora under conditions of salinity and potassium deprivation.

Soil salinity is a significant threat to global agriculture. Understanding salt exclusion mechanisms in halophyte species may be instrumental in improving salt tolerance in crops. Puccinellia tenuiflora is a typical salt-excluding halophytic grass often found in potassium-deprived saline soils. Our previous work showed that P. tenuiflora possesses stronger selectivity for K+ than for Na+ ; however, the mechanistic basis of this phenomenon remained elusive. Here, P. tenuiflora PutHKT1;5 was cloned and the functions of PutHKT1;5 and PutSOS1 were characterized using heterologous expression systems. Yeast assays showed that PutHKT1;5 possessed Na+ transporting capacity and was highly selective for Na+ over K+ . PutSOS1 was located at the plasma membrane and operated as a Na+ /K+ exchanger, with much stronger Na+ extrusion capacity than its homolog from Arabidopsis. PutHKT2;1 mediated high-affinity K+ and Na+ uptake and its expression levels were upregulated by mild salinity and K+ deprivation. Salinity-induced changes of root PutHKT1;5 and PutHKT1;4 transcript levels matched the expression pattern of root PutSOS1, which was consistent with root Na+ efflux. The transcript levels of root PutHKT2;1 and PutAKT1 were downregulated by salinity. Taken together, these findings demonstrate that the functional activity of PutHKT1;5 and PutSOS1 in P. tenuiflora roots is fine-tuned under saline conditions as well as by operation of other ion transporters/channel (PutHKT1;4, PutHKT2;1, and PutAKT1). This leads to the coordination of radial Na+ and K+ transport processes, their loading to the xylem, or Na+ retrieval and extrusion under conditions of mild salinity and/or K+ deprivation.

Flower color polymorphism of a wild Iris on the Qinghai-Tibet plateau.

BACKGROUND: Flower color plays a crucial role in attracting pollinators and facilitating environmental adaptation. Investigating the causes of flower color polymorphism and understanding their potential effects on both ecology and genetics can enhance our understanding of flower color polymorphism in wild plant. RESULTS: In this study, we examined the differences of potential male and female fitness between purple- and yellow- flower individuals in Iris potaninii on the Qinghai-Tibet Plateau, and screened key genes and positively selective genes involved in flower color change. Our results showed that yellow flower exhibited a higher pollen-to-ovule ratio. Yellow flowers were derived from purple flowers due to the loss of anthocyanins, and F3H could be an essential gene affecting flower color variation though expression regulation and sequence polymorphism in this species. Furthermore, our findings suggest that genes positively selected in yellow-flowered I. potaninii might be involved in nucleotide excision repair and plant-pathogen interactions. CONCLUSIONS: These results suggest that F3H induces the flower color variation of Iris potaninii, and the subsequent ecological and additive positive selection on yellow flowers may further enhance plant adaptations to alpine environments.

Underwater image restoration based on adaptive parameter optimization of the physical model.

Underwater images have the advantage of carrying high information density and are widely used for marine information acquisition. Due to the complex underwater environment, the captured images are often unsatisfactory and often suffer from color distortion, low contrast, and blurred details. Physical model-based methods are often used in relevant studies to obtain clear underwater images; however, water selectively absorbs light, making the use of a priori knowledge-based methods no longer applicable and thus rendering the restoration of underwater images ineffective. Therefore, this paper proposes an underwater image restoration method based on adaptive parameter optimization of the physical model. Firstly, an adaptive color constancy algorithm is designed to estimate the background light value of underwater image, which effectively guarantees the color and brightness of underwater image. Secondly, aiming at the problem of halo and edge blur in underwater images, a smoothness and uniformity transmittance estimation algorithm is proposed to make the estimated transmittance smooth and uniform, and eliminate the halo and blur of the image. Then, in order to further smooth the edge and texture details of the underwater image, a transmittance optimization algorithm for smoothing edge and texture details is proposed to make the obtained scene transmittance more natural. Finally, combined with the underwater image imaging model and histogram equalization algorithm, the image blurring is eliminated and more image details are retained. The qualitative and quantitative evaluation on the underwater image dataset (UIEBD) shows that the proposed method has obvious advantages in color restoration, contrast and comprehensive effect, and has achieved remarkable results in application testing. It shows that the proposed method can effectively restore underwater degraded images and provide a theoretical basis for the construction of underwater imaging models.