Phase separation of hnRNPA1 and TERRA regulates telomeric stability.

Telomeres are repetitive DNA sequences and associated protein complexes located at the end of chromatin. As a result of the DNA replication ending issue, telomeric DNA shortens during each cell cycle. The shelterin protein complex caps telomeric ends and forms a high-order protein-DNA structure to protect telomeric DNA. The stability of telomeres is critical for cellular function and is related to the progression of many human diseases. Telomeric repeat-containing RNA (TERRA) is a noncoding RNA transcribed from telomeric DNA regions. TERRA plays an essential role in regulating and maintaining the stability of telomeres. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-binding proteins associated with complex and diverse biological processes. HnRNPA1 can recognize both TERRA and telomeric DNA. Previous research reported that hnRNPA1, TERRA, and POT1, a component of the shelterin complex, worked coordinately and displaced replication protein A from telomeric ssDNA after DNA replication, promoting telomere capping to preserve genomic integrity. However, the detailed molecular mechanism has remained unclear for over twenty years. Our study revealed the molecular structure through which the hnRNPA1 UP1 domain interacts with TERRA. Through structural analysis, we identified critical residues on the interacting surface between UP1 and TERRA. Furthermore, we proved that nucleic acids significantly increase the phase separation ability of hnRNPA1 and disrupting the UP1-TERRA interaction extraordinarily affects hnRNPA1 droplet formation both in vitro and in vivo. Taken together, these data revealed the molecular mechanism of the droplet formation of hnRNPA1 and TERRA and the possible function of the droplets for maintaining genomic stability.

Functional characterization, structural basis, and protein engineering of a rare flavonoid 2'-O-glycosyltransferase from Scutellaria baicalensis.

Glycosylation is an important post-modification reaction in plant secondary metabolism, and contributes to structural diversity of bioactive natural products. In plants, glycosylation is usually catalyzed by UDP-glycosyltransferases. Flavonoid 2'-O-glycosides are rare glycosides. However, no UGTs have been reported, thus far, to specifically catalyze 2'-O-glycosylation of flavonoids. In this work, UGT71AP2 was identified from the medicinal plant Scutellaria baicalensis as the first flavonoid 2'-O-glycosyltransferase. It could preferentially transfer a glycosyl moiety to 2'-hydroxy of at least nine flavonoids to yield six new compounds. Some of the 2'-O-glycosides showed noticeable inhibitory activities against cyclooxygenase 2. The crystal structure of UGT71AP2 (2.15 Å) was solved, and mechanisms of its regio-selectivity was interpreted by pK a calculations, molecular docking, MD simulation, MM/GBSA binding free energy, QM/MM, and hydrogen‒deuterium exchange mass spectrometry analysis. Through structure-guided rational design, we obtained the L138T/V179D/M180T mutant with remarkably enhanced regio-selectivity (the ratio of 7-O-glycosylation byproducts decreased from 48% to 4%) and catalytic efficiency of 2'-O-glycosylation (k cat/K m, 0.23 L/(s·µmol), 12-fold higher than the native). Moreover, UGT71AP2 also possesses moderate UDP-dependent de-glycosylation activity, and is a dual function glycosyltransferase. This work provides an efficient biocatalyst and sets a good example for protein engineering to optimize enzyme catalytic features through rational design.

Single-cell RNA sequencing integrated with bulk RNA sequencing analysis reveals the protective effects of lactate-mediated lactylation of microglia-related proteins on spinal cord injury.

BACKGROUND AND OBJECTIVES: Spinal cord injury (SCI) results in significant neurological deficits, and microglia play the critical role in regulating the immune microenvironment and neurological recovery. Protein lactylation has been found to modulate the function of immune cells. Therefore, this study aimed to elucidate the effects of glycolysis-derived lactate on microglial function and its potential neuroprotective mechanisms via lactylation after SCI. METHODS: Single-cell RNA sequencing (scRNA-seq) data were obtained from figshare to analyze cellular and molecular alterations within the spinal cord post-SCI, further focusing on the expression of microglia-related genes for cell sub-clustering, trajectory analysis, and glycolysis function analysis. We also evaluated the expression of lactylation-related genes in microglia between day 7 after SCI and sham group. Additionally, we established the mice SCI model and performed the bulk RNA sequencing in a time-dependent manner. The expression of glycolysis- and lactylation-related genes was evaluated, as well as the immune infiltration analysis based on the lactylation-related genes. Then, we investigated the bio-effects of lactate on the inflammation and polarization phenotype of microglia. Finally, adult male C57BL/6 mice were subjected to exercise first to increase lactate level, before SCI surgery, aiming to evaluate the protective effects of lactate-mediated lactylation of microglia-related proteins on SCI. RESULTS: scRNA-seq identified a subcluster of microglia, recombinant chemokine C-X3-C-motif receptor 1+ (CX3CR1+) microglia, which is featured by M1-like phenotype and increased after SCI. KEGG analysis revealed the dysfunctional glycolysis in microglia after SCI surgery, and AUCell analysis suggested that the decreased glycolysis an increased oxidative phosphorylation in CX3CR1+ microglia. Differential gene analysis suggested that several lactylation-related genes (Fabp5, Lgals1, Vim, and Nefl) were downregulated in CX3CR1+ microglia at day 7 after SCI, further validated by the results from bulk RNA sequencing. Immunofluorescence staining indicated the expression of lactate dehydrogenase A (LDHA) in CX3CR1+ microglia also decreased at day 7 after SCI. Cellular experiments demonstrated that the administration of lactate could increase the lactylation level and inhibit the pro-inflammatory phenotype in microglia. Functionally, exercise-mediated lactate production resulted in improved locomotor recovery and decreased inflammatory markers in SCI mice compared to SCI alone. CONCLUSIONS: In the subacute phase of SCI, metabolic remodeling in microglia may be key therapeutic targets to promote nerve regeneration, and lactate contributed to neuroprotection after SCI by influencing microglial lactylation and inflammatory phenotype, which offered a novel approach for therapeutic intervention.

Structural basis for TNIP1 binding to FIP200 during mitophagy.

TNIP1 has been increasingly recognized as a security check to finely adjust the rate of mitophagy by disrupting the recycling of the Unc-51-like kinase complex during autophagosome formation. Through tank-binding kinase 1-mediated phosphorylation of the TNIP1 FIP200 interacting region (FIR) motif, the binding affinity of TNIP1 for FIP200, a component of the Unc-51-like kinase complex, is enhanced, allowing TNIP1 to outcompete autophagy receptors. Consequently, FIP200 is released from the autophagosome, facilitating further autophagosome expansion. However, the molecular basis by which FIP200 utilizes its claw domain to distinguish the phosphorylation status of residues in the TNIP1 FIR motif for recognition is not well understood. Here, we elucidated multiple crystal structures of the complex formed by the FIP200 claw domain and various phosphorylated TNIP1 FIR peptides. Structural and isothermal titration calorimetry analyses identified the crucial residues in the FIP200 claw domain responsible for the specific recognition of phosphorylated TNIP1 FIR peptides. Additionally, utilizing structural comparison and molecular dynamics simulation data, we demonstrated that the C-terminal tail of TNIP1 peptide affected its binding to the FIP200 claw domain. Moreover, the phosphorylation of TNIP1 Ser123 enabled the peptide to effectively compete with the peptide p-CCPG1 (the FIR motif of the autophagy receptor CCPG1) for binding with the FIP200 claw domain. Overall, our work provides a comprehensive understanding of the specific recognition of phosphorylated TNIP1 by the FIP200 claw domain, marking an initial step toward fully understanding the molecular mechanism underlying the TNIP1-dependent inhibition of mitophagy.

The efficacy and safety of monoclonal antibody therapies for interstitial cystitis/bladder pain syndrome: A meta-analysis of randomized controlled trials.

OBJECTIVES: This study aimed to assess the efficacy and safety of monoclonal antibody therapies (MATs) for interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: A systematic search was conducted across databases including PubMed, Embase, clinicalTrial.gov, and the Cochrane Library Central Register of Controlled Trials. Randomized controlled trials (RCTs) comparing MATs versus placebo were included. Primary outcomes comprised the Global Response Assessment (GRA) scale and the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI). Additional analyses encompassed mean daily frequency of voids, the O'Leary-Sant Interstitial Cystitis Problem Index, pain scores, and complications. Statistical analyses were performed using Review Manager 5.3. RESULTS: Five high-quality RCTs, comprising 263 patients with IC/BPS, were ultimately selected. MATs were generally effective in treating IC/BPS. Patients receiving MATs exhibited a higher satisfaction rate (odds ratio [OR]: 2.7, confidence interval [CI]: 1.31-5.58, p = 0.007) and lower ICSI scores (mean difference [MD]: -1.44, CI: -2.36 to -0.52, p = 0.002). Moreover, MAT recipients experienced reduced pain (MD: -0.53, CI: -0.79 to -0.26, p < 0.0001) and decreased frequency of urination (MD: -1.91, CI: -2.55 to -1.27, p < 0.00001). Importantly, there were no disparities regarding complication incidence in the MAT and control groups. CONCLUSIONS: The current findings indicate that MATs are effective and safe for treating IC/BPS. Nonetheless, future RCTs with larger sample sizes and long-term follow-up are warranted.

Association between ambient fine particular matter components and subsequent cognitive impairment in community-dwelling older people: a prospective cohort study from eastern China.

BACKGROUND: Fine particular matter (PM2.5) has been associated with dementia, but limited information is available regarding the association between PM2.5 components and dementia. AIMS: We aimed to identify the major components of PM2.5 that affect cognitive function to further investigate its mechanism of action, and develop a prevention strategy for dementia. METHODS: In this study, we included 7804 participants aged ≥ 60 years recruited from seven counties in Zhejiang province, eastern China. The participants completed the baseline survey between 2014 and 2015, and were followed up until the end of 2020. We adopted single-component robust Poisson regression models for analyses, and estimated relative risks and 95% confidence intervals describing associations between the chemical constituents of PM2.5 exposure and incident cognitive impairment in those who were free from cognitive impairment at baseline. RESULTS: Significantly positive associations were observed between sulfate, nitrate, ammonium, and organic matter in PM2.5 and incident cognitive impairment across different exposure periods; the relative risks of 10-year exposure before enrollment ranged from 1.01 to 1.02. However, we did not find a significant association between black carbon and cognitive impairment. The point estimates of the relative risk values did not change substantially after performing the sensitivity analyses. CONCLUSIONS: Our findings strengthen the idea that long-term exposure to PM2.5 mass and its chemical components is associated with an elevated risk of incident cognitive impairment among older adults.

Modified Tracheal Traction Exercise Reduces the Incidence of Dysphagia in Patients with Multilevel Anterior Cervical Discectomy and Fusion.

OBJECTIVES: Dysphagia, an impairment in swallowing, is a frequent and debilitating complication for patients undergoing anterior cervical discectomy and fusion (ACDF), a common surgical treatment for degenerative cervical myelopathy (DCM). This retrospective study aimed to assess the efficacy of modified tracheal traction exercise (MTTE) in alleviating postoperative dysphagia and improving clinical outcomes for these patients. METHODS: A cohort of 143 patients underwent multilevel fusions, equally distributed between MTTE (n = 75) and traditional tracheal traction exercise (TTTE) (n = 68) groups. Demographic parity was observed in gender distribution, age averages (MTTE: 51.43 ± 11.25 years; TTTE: 52.35 ± 10.43 years), body mass index (BMI), comorbidities, fusion segments, and preoperative hospitalization days. Surgical duration differences were assessed. Clinical outcomes, dysphagia incidence, blood loss, postoperative complications, Cervical Japanese Orthopedic Association (c-JOA) scores, and functional outcome swallowing scale evaluations were conducted. Univariate and multivariate logistic regression analyses were used to explore factors influencing dysphagia. RESULTS: Modified tracheal traction exercise demonstrated advantages with a significantly lower dysphagia incidence (25.33% vs. 44.12%, p = 0.018), reduced blood loss (102.03 ± 17.04 vs. 113.46 ± 14.92, p < 0.001), shorter surgical durations (159.04 ± 9.82 vs. 164.41 ± 12.22 min, p = 0.004), and fewer postoperative complications (choking cough, cerebrospinal fluid leakage, and hoarseness). Postoperative c-JOA scores at 2 and 6 weeks favored MTTE, but no significant differences were observed at 12 and 24 weeks. Functional outcome swallowing scale evaluations favored MTTE with significantly higher percentages of "normal" and lower incidences of "mild" and "moderate dysphagia" at various postoperative intervals compared to TTTE. Factors significantly associated with dysphagia included MTTE, age, and BMI according to logistic regression analyses. CONCLUSION: Modified tracheal traction exercise demonstrates superior short-term outcomes in multilevel ACDF, showcasing reduced dysphagia incidence, blood loss, and specific postoperative complications. Notably, factors contributing to dysphagia, including operation technique and patient-related variables, emphasize the significance of MTTE and patient characteristics in optimizing postoperative outcomes in multilevel ACDF procedures.

Depressive symptoms and associated factors among older patients with arthritis: evidence from a community-based study in eastern China.

Introduction: Depressive symptoms are often experienced by patients with arthritis and are correlated with poor health outcomes. However, the association between depressive symptoms and multidimensional factors (sociodemographic characteristics, health conditions, health behaviors, and social support) among older patients with arthritis in China remains poorly understood. This study aimed to explore the prevalence of depressive symptoms in older patients with arthritis in eastern China and identify the associated factors. Methods: We analyzed data of 1,081 older patients with arthritis using secondary data from 2014 to 2020 from a community-based ongoing study initiated in 2014 in eastern China. The prevalence of depressive symptoms was calculated, and univariate and multilevel logistic regression analyses were used to identify the associated factors. Results: The mean age of older patients with arthritis was 69.16 ± 7.13 years; 42.92% were men and 57.08% were women. The prevalence of depressive symptoms in older patients with arthritis was 14.99% (95% confidence interval: 12.91-17.26%), about 1.8 times higher than that in older adults without arthritis (8.49%, p < 0.001). Multilevel logistic regression identified perception of poor economic status (odds ratio [OR] = 5.52, p < 0.001), multimorbidity (OR = 1.96, p = 0.001), limitations in activities of daily living (OR = 2.36, p = 0.004), and living alone (OR = 3.13, p = 0.026) as factors positively associated with depressive symptoms. Patients diagnosed with arthritis at an older age had lower odds of experiencing depressive symptoms (OR = 0.67, p = 0.046). Conclusion: Screening for depressive symptoms is essential among older patients with arthritis, especially those who perceive themselves as having a poor economic status, are diagnosed at an earlier age, have multimorbidity, have limitations in activities of daily living, and live alone. The associations of age at arthritis diagnosis and dietary behaviors with depressive symptoms require further research.

Effects of cigarette smoking associated with sarcopenia in persons 60 years and older: a cross-sectional study in Zhejiang province.

PURPOSE: Smoking is a risk factor for sarcopenia. Nevertheless, few studies analyzed the independent effects of various smoking dimensions (duration, intensity, cumulative dose) on sarcopenia risk. This is a cross-sectional study based on an older population in Zhejiang Province to determine which smoking dimensions are mainly important for sarcopenia risk and to explore the dose-response relationship between them. METHODS: Our study included 783 patients with sarcopenia and 4918 non-sarcopenic individuals. Logistic regression and restricted cubic with logistic regression (for nonlinear dose effects) were used to obtain odds ratios (ORs) and 95% confidence intervals as well as restricted cubic splines (RCS) curves. RESULTS: Compared with never-smokers, current smokers had an increased risk of sarcopenia (OR = 1.786; 95% CI 1.387-2.301) after adjusting for confounders such as age, sex, education, alcohol consumption, disease history, etc. There was no significant association between smoking intensity and sarcopenia after more than 20 cigarettes per day (OR = 1.484; 95% CI 0.886-2.487), whereas the risk of sarcopenia increased significantly with increasing duration of smoking after more than 40 years (OR = 1.733; 95% CI 1.214-2.473). Meanwhile, there was a significant non-linear dose-response relationship between smoking duration or intensity and the risk of sarcopenia. However, the risk of sarcopenia increased linearly with the number of pack-years of smoking, which is not a significant nonlinear dose-response relationship. CONCLUSIONS: This study indicated the association between smoking and sarcopenia. Both smoking duration and cumulative dose were significantly and positively associated with sarcopenia. These findings reflect the important role of the number of years of smoking in increasing the risk of sarcopenia and provide scientific evidence that different smoking dimensions may influence the risk of the sarcopenia.

Structural basis of pri-let-7 recognition by human pseudouridine synthase TruB1.

Let-7 was one of the first microRNAs (miRNAs) to be discovered and its expression promotes differentiation during development and function as tumor suppressors in various cancers. The maturation process of let-7 miRNA is tightly regulated by multiple RNA-binding proteins. For example, LIN28 binds to the terminal loops of the precursors of let-7 family and block their processing into mature miRNAs. Trim25 promotes the uridylation-mediated degradation of pre-let-7 modified by LIN28/TUT4. Recently, human pseudouridine synthase TruB1 has been reported to facilitate let-7 maturation by directly binding to pri-let-7 and recruiting Drosha-DGCR8 microprocessor. Through biochemical assay and structural investigation, we show that human TruB1 binds specifically the terminal loop of pri-let-7a1 at nucleotides 31-41, which folds as a small stem-loop architecture. Although TruB1 recognizes the terminal loop of pri-let-7a1 in a way similar to how E. coli TruB interacts with tRNA, a conserved KRKK motif in human and other higher eukaryotes adds an extra binding interface and strengthens the recognition of TruB1 for pri-let-7a1 through electrostatic interactions. These findings reveal the structural basis of TruB1-pri-let-7 interaction which may assists the elucidation of precise role of TruB1 in biogenesis of let-7.

Structural insights into curdlan degradation via a glycoside hydrolase containing a disruptive carbohydrate-binding module.

BACKGROUND: Degradation via enzymatic processes for the production of valuable ß-1,3-glucooligosaccharides (GOS) from curdlan has attracted considerable interest. CBM6E functions as a curdlan-specific ß-1,3-endoglucanase, composed of a glycoside hydrolase family 128 (GH128) module and a carbohydrate-binding module (CBM) derived from family CBM6. RESULTS: Crystallographic analyses were conducted to comprehend the substrate specificity mechanism of CBM6E. This unveiled structures of both apo CBM6E and its GOS-complexed form. The GH128 and CBM6 modules constitute a cohesive unit, binding nine glucoside moieties within the catalytic groove in a singular helical conformation. By extending the substrate-binding groove, we engineered CBM6E variants with heightened hydrolytic activities, generating diverse GOS profiles from curdlan. Molecular docking, followed by mutation validation, unveiled the cooperative recognition of triple-helical ß-1,3-glucan by the GH128 and CBM6 modules, along with the identification of a novel sugar-binding residue situated within the CBM6 module. Interestingly, supplementing the CBM6 module into curdlan gel disrupted the gel's network structure, enhancing the hydrolysis of curdlan by specific ß-1,3-glucanases. CONCLUSIONS: This study offers new insights into the recognition mechanism of glycoside hydrolases toward triple-helical ß-1,3-glucans, presenting an effective method to enhance endoglucanase activity and manipulate its product profile. Furthermore, it discovered a CBM module capable of disrupting the quaternary structures of curdlan, thereby boosting the hydrolytic activity of curdlan gel when co-incubated with ß-1,3-glucanases. These findings hold relevance for developing future enzyme and CBM cocktails useful in GOS production from curdlan degradation.

Identification of an SCF Ubiquitin Ligase Complex that Contributes to Resistance Against Valsa Canker in Apple.

E3 ubiquitin ligases play a critical role in plant disease resistance. Among them, the Skp1-Cullin-F-box protein (SCF) ubiquitin ligase complex is the largest family and regulates the ubiquitination of a wide range of proteins. Apple Valsa canker (AVC) is a fungal disease of apple trees caused by the fungus Valsa mali, which can lead to significant economic losses. However, the function of the SCF complex in apple resistance to this disease is still largely unknown. In this study, we identified an SCF ubiquitin ligase complex that can enhance resistance to Valsa canker in apple. Disease evaluation experiments demonstrated that MdSkp1 increased apple resistance to AVC. Furthermore, MdSkp1 interacted with an F-box protein, MdSKIP14, and interacted with a cullin-1 protein, MdCUL1, to form an SCF ubiquitin ligase complex. Additionally, we revealed both MdSKIP14 and MdCUL1 as positive regulators of AVC resistance. In conclusion, our results identified an SCF complex capable of contributing to apple resistance against AVC, providing a theoretical basis for apple disease resistance and the sustainable development of the industry. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Structural insights into the recognition of the A/T-rich motif in target gene promoters by the LMX1a homeobox domain.

LIM homeodomain transcription factor 1-alpha (LMX1a) is a neuronal lineage-specific transcription activator that plays an essential role during the development of midbrain dopaminergic (mDA) neurons. LMX1a induces the expression of multiple key genes, which ultimately determine the morphology, physiology, and functional identity of mDA neurons. This function of LMX1a is dependent on its homeobox domain. Here, we determined the structures of the LMX1a homeobox domain in complex with the promoter sequences of the Wnt family member 1 (WNT1) or paired like homeodomain 3 (Pitx3) gene, respectively. The complex structures revealed that the LMX1a homeobox domain employed its α3 helix and an N-terminal loop to achieve specific target recognition. The N-terminal loop (loop1) interacted with the minor groove of the double-stranded DNA (dsDNA), whereas the third α-helix (α3) was tightly packed into the major groove of the dsDNA. Structure-based mutations in the α3 helix of the homeobox domain significantly reduced the binding affinity of LMX1a to dsDNA. Moreover, we identified a nonsyndromic hearing loss (NSHL)-related mutation, R199, which yielded a more flexible loop and disturbed the recognition in the minor groove of dsDNA, consistent with the molecular dynamics (MD) simulations. Furthermore, overexpression of Lmx1a promoted the differentiation of SH-SY5Y cells and upregulated the transcription of WNT1 and PITX3 genes. Hence, our work provides a detailed elucidation of the specific recognition between the LMX1a homeobox domain and its specific dsDNA targets, which represents valuable information for future investigations of the functional pathways that are controlled by LMX1a during mDA neuron development.

Synergistically enhancing electrocatalysis and non-enzymatic sensing for glucose by iridium single-atom/nickel oxide/N-doped graphene.

The development of novel catalyst with high catalytic activity is important for electrochemical non-enzymatic glucose sensing. Here, iridium single-atom/nickel oxide nanoparticle/N-doped graphene nanosheet (Ir1/NiO/NG) with the loading of 1.13 wt% Ir was successfully synthesized for constructing electrochemical non-enzymatic glucose sensor for the first time. The morphology and structure of Ir1/NiO/NG were characterized by XRD, SEM, TEM, HRTEM, and XPS, and the presence of Ir SAs was confirmed by AC-HAADF-STEM. The Ir1/NiO/NG shows 65 mV lower oxidation potential and 3.3 times higher response current than Ni(OH)2/NG. In addition, Ir1/NiO/NG exhibits high sensitivity (70.09 µA mM-1 cm-2), excellent selectivity, low detection limit (2.00 µM), and great stability (91.53% current remaining after 21 days) for electrochemical non-enzymatic glucose sensing. The outstanding catalytic and sensing performance of Ir1/NiO/NG is mainly attributed to synergistic effect of Ir SAs, NiO nanoparticles, and highly conductive NG, which modulate the electronic and geometric structure of Ir1/NiO/NG. This work shows the promising potential of SACs in electrochemical sensing.

Major depressive disorder and the risk of irritable bowel syndrome: A Mendelian randomization study.

BACKGROUND: The association between major depressive disorder (MDD) and irritable bowel syndrome (IBS) has been found in observational research; however, the causative relationship between MDD and IBS remains uncertain. Using the two-sample Mendelian randomization (MR) approach, we attempted to examine the causal effect of MDD on IBS. METHODS: Independent genetic variants for MDD identified by Howard et al. based on a genome-wide meta-analysis were selected for this study. Gene-Outcome associations for IBS were gathered from UK Biobank and FinnGen databases. The MR analysis included inverse variance weighted (IVW), MR-Egger regression, weighted median, weighted mode, and MR-PRESSO sensitivity analyses. RESULTS: FinnGen database subjected to inverse variance weighted (IVW) analysis revealed that MDD may be a risk factor for the development of IBS (OR = 1.356, 95% CI: 1.125-1.632, p = 0.0013). The same finding was reached in UK Biobank for IVW (OR = 1.011, 95% CI: 1.006-1.015, p = 3.18 × 10-7 ), MR-Egger progression (OR = 1.030, 95% CI: 1.008-1.051, p = 0.007), and weighted median (OR = 1.011, 95% CI: 1.005-1.016, p = 0.0001). CONCLUSION: Our findings supported a causal relationship between MDD and IBS, which may have implications for the clinical management of IBS in individuals with MDD.

Catalytic Nanodots-Driven Pyroptosis Suppression in Nucleus Pulposus for Antioxidant Intervention of Intervertebral Disc Degeneration.

Low back pain resulting from intervertebral disc degeneration (IVDD) is a prevalent global concern; however, its underlying mechanism remains elusive. Single-cell sequencing analyses revealed the critical involvement of pyroptosis in IVDD. Considering the involvement of reactive oxygen species (ROS) as the primary instigator of pyroptosis and the lack of an efficient intervention approach, this study developed carbonized Mn-containing nanodots (MCDs) as ROS-scavenging catalytic biomaterials to suppress pyroptosis of nucleus pulposus (NP) cells to efficiently alleviate IVDD. Catalytic MCDs have superior efficacy in scavenging intracellular ROS and rescuing homeostasis in the NP microenvironment compared with N-acetylcysteine, a classical antioxidant. The data validates that pyroptosis plays a vital role in mediating the protective effects of catalytic MCDs against oxidative stress. Systematic in vivo assessments substantiate the effectiveness of MCDs in rescuing a puncture-induced IVDD rat model, further demonstrating their ability to suppress pyroptosis. This study highlights the potential of antioxidant catalytic nanomedicine as a pyroptosis inhibitor and mechanistically unveils an efficient strategy for the treatment of IVDD.

Biomechanical Comparison of Anterior Cervical Corpectomy Decompression and Fusion, Anterior Cervical Discectomy and Fusion, and Anterior Controllable Antedisplacement and Fusion in the Surgical Treatment of Multilevel Cervical Spondylotic Myelopathy: A Finite Element Analysis.

PURPOSE: Multilevel cervical spondylotic myelopathy poses significant challenges in selecting optimal surgical approaches, warranting a comprehensive understanding of their biomechanical impacts. Given the lack of consensus regarding the most effective technique, this study aims to fill this critical knowledge gap by rigorously assessing and comparing the biomechanical properties of three distinct surgical interventions, including anterior controllable antedisplacement and fusion (ACAF), anterior cervical corpectomy decompression and fusion (ACCF), and anterior cervical discectomy and fusion (ACDF). The study offers pivotal insights to enhance treatment precision and patient outcomes. METHODS: The construction of the cervical spine model involved a detailed process using CT data, specialized software (Mimics, Geomagic Studio, and Hypermesh) and material properties obtained from prior studies. Surgical instruments were modeled (titanium mesh, anterior cervical plate, interbody cage, and self-tapping screws) to simulate three surgical approaches: ACAF, ACCF, and ACDF, each with specific procedures replicating clinical protocols. A 75-N follower load with 2 Nm was applied to simulate biomechanical effects. RESULTS: The range of motion decreased more after surgery for ACAF and ACDF than for ACCF, especially in flexion and lateral bending. ACCF have higher stress peaks in the fixation system than those of ACAF and ACDF, especially in flexion. The maximum von Mises stresses of the bone-screw interfaces at C3 of ACCF were higher than those of ACAF and ACDF. The maximum von Mises stresses of the bone-screw interfaces at C6 of ACDF were much higher than those of ACAF and ACCF. The maximum von Mises stresses of the grafts of ACCF and ACAF were much higher than those of ACDF. The maximum von Mises stresses of the endplate of ACCF were much higher than those of ACAF and ACDF. CONCLUSION: The ACAF and ACDF models demonstrated superior cervical reconstruction stability over the ACCF model. ACAF exhibited lower risks of internal fixation failure and cage subsidence compared to ACCF, making it a promising approach. However, while ACAF revealed improved stability over ACCF, higher rates of subsidence and internal fixation failure persisted compared to ACDF, suggesting the need for further exploration of ACAF's long-term efficacy and potential improvements in clinical outcomes.

Structural insights into the specific recognition of mitochondrial ribosome-binding factor hsRBFA and 12 S rRNA by methyltransferase METTL15.

Mitochondrial rRNA modifications are essential for mitoribosome assembly and its proper function. The m4C methyltransferase METTL15 maintains mitochondrial homeostasis by catalyzing m4C839 located in 12 S rRNA helix 44 (h44). This modification is essential to fine-tuning the ribosomal decoding center and increasing decoding fidelity according to studies of a conserved site in Escherichia coli. Here, we reported a series of crystal structures of human METTL15-hsRBFA-h44-SAM analog, METTL15-hsRBFA-SAM, METTL15-SAM and apo METTL15. The structures presented specific interactions of METTL15 with different substrates and revealed that hsRBFA recruits METTL15 to mitochondrial small subunit for further modification instead of 12 S rRNA. Finally, we found that METTL15 deficiency caused increased reactive oxygen species, decreased membrane potential and altered cellular metabolic state. Knocking down METTL15 caused an elevated lactate secretion and increased levels of histone H4K12-lactylation and H3K9-lactylation. METTL15 might be a suitable model to study the regulation between mitochondrial metabolism and histone lactylation.

Valsa mali PR1-like protein modulates an apple valine-glutamine protein to suppress JA signaling-mediated immunity.

Apple Valsa canker (AVC) is a devastating disease of apple (Malus × domestica), caused by Valsa mali (Vm). The Cysteine-rich secretory protein, Antigen 5, and Pathogenesis-related protein 1 (CAP) superfamily protein PATHOGENESIS-RELATED PROTEIN 1-LIKE PROTEIN c (VmPR1c) plays an important role in the pathogenicity of Vm. However, the mechanisms through which it exerts its virulence function in Vm-apple interactions remain unclear. In this study, we identified an apple valine-glutamine (VQ)-motif-containing protein, MdVQ29, as a VmPR1c target protein. MdVQ29-overexpressing transgenic apple plants showed substantially enhanced AVC resistance as compared with the wild type. MdVQ29 interacted with the transcription factor MdWRKY23, which was further shown to bind to the promoter of the jasmonic acid (JA) signaling-related gene CORONATINE INSENSITIVE 1 (MdCOI1) and activate its expression to activate the JA signaling pathway. Disease evaluation in lesion areas on infected leaves showed that MdVQ29 positively modulated apple resistance in a MdWRKY23-dependent manner. Furthermore, MdVQ29 promoted the transcriptional activity of MdWRKY23 toward MdCOI1. In addition, VmPR1c suppressed the MdVQ29-enhanced transcriptional activation activity of MdWRKY23 by promoting the degradation of MdVQ29 and inhibiting MdVQ29 expression and the MdVQ29-MdWRKY23 interaction, thereby interfering with the JA signaling pathway and facilitating Vm infection. Overall, our results demonstrate that VmPR1c targets MdVQ29 to manipulate the JA signaling pathway to regulate immunity. Thus, this study provides an important theoretical basis and guidance for mining and utilizing disease-resistance genetic resources for genetically improving apples.