A modified glycosylase base editor without predictable DNA off-target effects.

Glycosylase base editor (GBE) can induce C-to-G transversion in mammalian cells, showing great promise for the treatment of human genetic disorders. However, the limited efficiency of transversion and the possibility of off-target effects caused by Cas9 restrict its potential clinical applications. In our recent study, we have successfully developed TaC9-CBE and TaC9-ABE by separating nCas9 and deaminase, which eliminates the Cas9-dependent DNA off-target effects without compromising editing efficiency. We developed a novel GBE called TaC9-GBEYE1, which utilizes the deaminase and UNG-nCas9 guided by TALE and sgRNA, respectively. TaC9-GBEYE1 showed comparable levels of on-target editing efficiency to traditional GBE at 19 target sites, without any off-target effects caused by Cas9 or TALE. The TaC9-GBEYE1 is a safe tool for gene therapy.

Synthesis of a novel magnetic calcium-rich biochar nanocomposite for efficient removal of phosphate from aqueous solution.

Phosphorus (P) scarcity and eutrophication have triggered the development of new materials for P recovery. In this work, a novel magnetic calcium-rich biochar nanocomposite (MCRB) was prepared through co-precipitation of crab shell derived biochar, Fe2+ and Fe3+. Characteristics of the material demonstrated that the MCRB was rich in calcite and that the Fe3O4 NPs with a diameter range of 18-22 nanometers were uniformly adhered on the biochar surface by strong ether linking (C-O-Fe). Batch tests demonstrated that the removal of P was pH dependent with an optimal pH of 3-7. The MCRB exhibited a superior P removal performance, with a maximum removal capacity of 105.6 mg g-1, which was even higher than the majority lanthanum containing compounds. Study of the removal mechanisms revealed that the P removal by MCRB involved the formation of hydroxyapatite (HAP-Ca5(PO4)3OH), electrostatic attraction and ligand exchange. The recyclability test demonstrated that a certain level (approximately 60%) was still maintained even after the six adsorption-desorption process, suggesting that MCRB is a promising material for P removal from wastewater.

Ultrasound-electrochemistry assisted liquid-phase co-exfoliation of phosphorene decorated by Au-Ag bimetallic nanoparticles as nanozyme for smartphone-based portable sensing of 4-nitrophenol.

The stability of black phosphorene (BP) and its preparation and modification for developing and applying devices have become a hot topic in the interdisciplinary field. We propose ultrasound-electrochemistry co-assisted liquid-phase exfoliation as an eco-friendly one-step method to prepare gold-silver bimetallic nanoparticles (Au-AgNPs)-decorated BP nanozyme for smartphone-based portable sensing of 4-nitrophenol (4-NP) in different water sources. The structure, morphology, composition, and properties of Au-AgNPs-BP nanozyme are characterized by multiple instrumental analyses. Bimetallic salts are induced to efficiently occupy oxidative sites of BP to form highly stable Au-AgNPs-BP nanozyme and guarantee the integrity of the lamellar BP. The electrochemistry shortens the exfoliation time of the BP nanosheet and contributes to the loading efficiency of bimetallic nanoparticles on the BP nanosheet. Au-AgNPs-BP-modified screen-printed carbon electrode coupled with palm-sized smartphone-controlled wireless electrochemical analyzer as a portable wireless intelligent sensing platform was applied to the determination of 4-NP in a linear range of 0.6-10 µM with a limit of detection of 63 nM. It enables on-site determination of 4-NP content in lake water, river water, and irrigation ditch water. This work will provide a reference for an eco-friendly one-step preparation of bimetallic nanoparticle-decorated graphene-like materials as nanozymes and their smartphone-based portable sensing application outdoors.

FoxO1-modulated macrophage polarization regulates osteogenesis via PPAR-γ signaling.

Periodontitis, a common chronic inflammatory disease, epitomizes a significant impairment in the host immune system and an imbalance of bone metabolism. Macrophage polarization, a dynamic process dictated by the microenvironment, intricately contributes to the interplay between the immune system and bone remodeling, namely the osteoimmune system. Forkhead box protein O1 (FoxO1) has been shown to play a dramatic role in mediating oxidative stress, bone mass, as well as cellular metabolism. Nevertheless, the function and underlying mechanisms of FoxO1 in regulating macrophage polarization-mediated osteogenesis in periodontitis remain to be further elucidated. Here, we found that FoxO1 expression was closely linked to periodontitis, accompanied by aggravated inflammation. Notably, FoxO1 knockdown skewed macrophage polarization from M1 to the antiinflammatory M2 phenotype under inflammatory conditions, which rescued the impaired osteogenic potential. Mechanistically, we revealed that the enhancement of the transcription of peroxisome proliferator-activated receptor (PPAR) signaling in FoxO1-knockdown macrophages. In agreement with this contention, GW9662, a specific inhibitor of PPAR-γ signaling, greatly aggravated macrophage polarization from M2 to the M1 phenotype and attenuated osteogenic potential under inflammatory conditions. Additionally, PPAR-γ signaling agonist rosiglitazone (RSG) was applied to address ligature-induced periodontitis with attenuated inflammation. Our data lend conceptual credence to the function of FoxO1 in mediating macrophage polarization-regulated osteogenesis which serves as a novel therapeutic target for periodontitis.

TRIM65 deficiency alleviates renal fibrosis through NUDT21-mediated alternative polyadenylation.

Chronic kidney disease (CKD) is a major global health concern and the third leading cause of premature death. Renal fibrosis is the primary process driving the progression of CKD, but the mechanisms behind it are not fully understood, making treatment options limited. Here, we find that the E3 ligase TRIM65 is a positive regulator of renal fibrosis. Deletion of TRIM65 results in a reduction of pathological lesions and renal fibrosis in mouse models of kidney fibrosis induced by unilateral ureteral obstruction (UUO)- and folic acid. Through screening with a yeast-hybrid system, we identify a new interactor of TRIM65, the mammalian cleavage factor I subunit CFIm25 (NUDT21), which plays a crucial role in fibrosis through alternative polyadenylation (APA). TRIM65 interacts with NUDT21 to induce K48-linked polyubiquitination of lysine 56 and proteasomal degradation, leading to the inhibition of TGF-ß1-mediated SMAD and ERK1/2 signaling pathways. The degradation of NUDT21 subsequently altered the length and sequence content of the 3'UTR (3'UTR-APA) of several pro-fibrotic genes including Col1a1, Fn-1, Tgfbr1, Wnt5a, and Fzd2. Furthermore, reducing NUDT21 expression via hydrodynamic renal pelvis injection of adeno-associated virus 9 (AAV9) exacerbated UUO-induced renal fibrosis in the normal mouse kidneys and blocked the protective effect of TRIM65 deletion. These findings suggest that TRIM65 promotes renal fibrosis by regulating NUDT21-mediated APA and highlight TRIM65 as a potential target for reducing renal fibrosis in CKD patients.

Does Patellar Denervation with Electrocautery Benefits for Total Knee Arthroplasty without Patellar Resurfacing: A Meta-analysis of Randomized Controlled Trails.

To investigate the effects of patellar denervation (PD) and non-patellar denervation (NPD) after primary total knee arthroplasty (TKA) without patellar resurfacing, this study conducted systematic electronic searches in November 2023 using PubMed, Embase, Web of Science, Cochrane, and Scopus, adhering to Cochrane Collaboration recommendations. Only randomized controlled trials (RCTs) were included. Additionally, a manual search was performed to identify potentially eligible studies from the reference lists of review articles. Two researchers independently conducted literature reviews, data extraction, and risk of bias assessments. The outcome analysis encompassed the incidence of anterior knee pain (AKP), visual analogue scale (VAS), range of motion (ROM), American Knee Society Score (KSS), Oxford Knee Score (OKS), patellar score (PS), complications, and reoperations. Meta-analysis was executed using RevMan 5.3 software. To enhance the credibility of the study, TSA v0.9 software was utilized to perform power analysis on the overall efficacy of primary and secondary outcomes. Twelve studies involving 1745 patients (1587 knees) were included, with 852 undergoing PD and 893 undergoing NPD. Results indicated a superior reduction in AKP incidence in the PD group compared to the NPD group. Statistically significant differences were observed between PD and NPD in KSS, OKS, and PS. However, the upper limit of the 95% confidence interval for each outcome fell below the minimal clinically important difference (MCID). No significant differences were found in VAS and ROM between PD and NPD. Additionally, PD was not associated with an increased incidence of complications or reoperations. Within 12 months and beyond, PD was proven to be a beneficial intervention in reducing AKP following TKA without patellar resurfacing, achieved without an increase in complications or reoperations. Regarding KSS, OKS, and PS, the minimal advantage achievable through PD may not be clinically significant.

Solvent Effects on the Phenolic Compounds and Antioxidant Activity Associated with Camellia polyodonta Flower Extracts.

Camellia polyodonta flowers contain limited information available regarding the composition of their bioactive compounds and activity. The objective of this study was to identify phenolic compounds and investigate the effect of different solvents (ethanol and methanol) on the phenolic content and antioxidant activity in C. polyodonta flowers. The analysis using UPLC-Q-TOF-MS/MS revealed the presence of 105 phytochemicals and the most common compounds were flavonols, procyanidins, and ellagitannins. Interestingly, flavonol triglycosides were identified for the first time in these flowers. The study demonstrated that the concentration of the solvent had a significant impact on the total phenolic compound (TPC), total flavonoid compound (TFC), and total proanthocyanidin content (TPAC). The TPC, TFC, and TPAC showed a remarkable increase with the increasing concentration of the solvent, reaching their maximum levels (138.23 mg GAE/g DW, 421.62 mg RE/g DW, 60.77 mg PB2E/g DW) at 70% ethanol. However, the total anthocyanin content reached its maximum at low concentrations (0.49 mg CGE/g DW). Similar trends were observed in the antioxidant activity, as measured by the DPPH· assay (DPPH radical scavenging activity), ABTS·+ assay (ABTS radical cation scavenging activity), and FRAP assay (Ferric reducing antioxidant power). The maximum antioxidant activity was observed at 100% solvents and 70% methanol. Among the 14 individual phenolic compounds, 70% methanol yielded the highest content for 8 (cyanidin-3-O-glucoside, procyanidin B2, procyanidin B4, epicatechin, rutin, kaempferol-3-O-rutinoside, astragaline and quercitrin) out of the 14 compounds. Additionally, it was found that epicatechin was the most abundant phenolic compound, accounting for approximately 20339.37 µg/g DW. Based on these findings, it can be concluded that 70% methanol is the most effective solvent for extracting polyphenols from C. polyodonta flowers. These results provided chemical information and potential antioxidant value for further research in C. polyodonta flowers.

Unveiling Mechanistic Insight into Accelerating Oxygen Molecule Activation by Oxygen Defects in Co3O4-x/g-C3N4 p-n Heterojunction for Efficient Photo-Assisted Uranium Extraction from Seawater.

Photo-assisted uranium extraction from seawater (UES) is regarded as an efficient technique for uranium resource recovery, yet it currently faces many challenges, such as issues like biofouling resistance, low charge separation efficiency, slow carrier transfer, and a lack of active sites. Based on addressing the above challenges, a novel oxygen-deficient Co3O4-x/g-C3N4 p-n heterojunction is developed for efficient photo-assisted uranium extraction from seawater. Relying on the defect-coupling heterojunction synergistic effect, the redistribution of molecular charge density formed the built-in electric field as revealed by DFT calculations, significantly enhancing the separation efficiency of carriers and accelerating their migration rate. Notably, oxygen vacancies served as capture sites for oxygen, effectively promoting the generation of reactive oxygen species (ROS), thereby significantly improving the photo-assisted uranium extraction performance and antibacterial activity. Thus, under simulated sunlight irradiation with no sacrificial reagent added, Co3O4-x/g-C3N4 extracted a high uranium extraction amount of 1.08 mg g-1 from 25 L of natural seawater after 7 days, which is superior to most reported carbon nitride-based photocatalysts. This study elaborates on the important role of surface defects and inerface engineering strategies in enhancing photocatalytic performance, providing a new approach to the development and design of uranium extraction material from seawater.

Atorvastatin exerts a preventive effect against steroid-induced necrosis of the femoral head by modulating Wnt5a release.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent form of osteonecrosis in young individuals. More efficacious clinical strategies must be used to prevent and treat this condition. One of the mechanisms through which SONFH operates is the disruption of normal differentiation in bone marrow adipocytes and osteoblasts due to prolonged and extensive use of glucocorticoids (GCs). In vitro, it was observed that atorvastatin (ATO) effectively suppressed the impact of dexamethasone (DEX) on bone marrow mesenchymal stem cells (BMSCs), specifically by augmenting their lipogenic differentiation while impeding their osteogenic differentiation. To investigate the underlying mechanisms further, we conducted transcriptome sequencing of BMSCs subjected to different treatments, leading to the identification of Wnt5a as a crucial gene regulated by ATO. The analyses showed that ATO exhibited the ability to enhance the expression of Wnt5a and modulate the MAPK pathway while regulating the Wnt canonical signaling pathway via the WNT5A/LRP5 pathway. Our experimental findings provide further evidence that the combined treatment of ATO and DEX effectively mitigates the effects of DEX, resulting in the upregulation of osteogenic genes (Runx2, Alpl, Tnfrsf11b, Ctnnb1, Col1a) and the downregulation of adipogenic genes (Pparg, Cebpb, Lpl), meanwhile leading to the upregulation of Wnt5a expression. So, this study offers valuable insights into the potential mechanism by which ATO can be utilized in the prevention of SONFH, thereby holding significant implications for the prevention and treatment of SONFH in clinical settings.

Predicting complication risks after sleeve lobectomy for non-small cell lung cancer.

Background: Sleeve lobectomy is a challenging procedure with a high risk of postoperative complications. To facilitate surgical decision-making and optimize perioperative treatment, we developed risk stratification models to quantify the probability of postoperative complications after sleeve lobectomy. Methods: We retrospectively analyzed the clinical features of 691 non-small cell lung cancer (NSCLC) patients who underwent sleeve lobectomy between July 2016 and December 2019. Logistic regression models were trained and validated in the cohort to predict overall complications, major complications, and specific minor complications. The impact of specific complications in prognostic stratification was explored via the Kaplan-Meier method. Results: Of 691 included patients, 232 (33.5%) developed complications, including 35 (5.1%) and 197 (28.5%) patients with major and minor complications, respectively. The models showed robust discrimination, yielding an area under the receiver operating characteristic (ROC) curve (AUC) of 0.853 [95% confidence interval (CI): 0.705-0.885] for predicting overall postoperative complication risk and 0.751 (95% CI: 0.727-0.762) specifically for major complication risks. Models predicting minor complications also achieved good performance, with AUCs ranging from 0.78 to 0.89. Survival analyses revealed a significant association between postoperative complications and poor prognosis. Conclusions: Risk stratification models could accurately predict the probability and severity of complications in NSCLC patients following sleeve lobectomy, which may inform clinical decision-making for future patients.

HiDiff: Hybrid Diffusion Framework for Medical Image Segmentation.

Medical image segmentation has been significantly advanced with the rapid development of deep learning (DL) techniques. Existing DL-based segmentation models are typically discriminative; i.e., they aim to learn a mapping from the input image to segmentation masks. However, these discriminative methods neglect the underlying data distribution and intrinsic class characteristics, suffering from unstable feature space. In this work, we propose to complement discriminative segmentation methods with the knowledge of underlying data distribution from generative models. To that end, we propose a novel hybrid diffusion framework for medical image segmentation, termed HiDiff, which can synergize the strengths of existing discriminative segmentation models and new generative diffusion models. HiDiff comprises two key components: discriminative segmentor and diffusion refiner. First, we utilize any conventional trained segmentation models as discriminative segmentor, which can provide a segmentation mask prior for diffusion refiner. Second, we propose a novel binary Bernoulli diffusion model (BBDM) as the diffusion refiner, which can effectively, efficiently, and interactively refine the segmentation mask by modeling the underlying data distribution. Third, we train the segmentor and BBDM in an alternate-collaborative manner to mutually boost each other. Extensive experimental results on abdomen organ, brain tumor, polyps, and retinal vessels segmentation datasets, covering four widely-used modalities, demonstrate the superior performance of HiDiff over existing medical segmentation algorithms, including the state-of-the-art transformer- and diffusion-based ones. In addition, HiDiff excels at segmenting small objects and generalizing to new datasets. Source codes are made available at https://github.com/takimailto/HiDiff.

Development of multifunctional chitosan-based composite film loaded with tea polyphenol nanoparticles for strawberry preservation.

Incorporating polysaccharide-based composite films with nanobiotechnology offers a new strategy for food preservation. This study initially focuses on the preparation of tea polyphenol nanoparticles (TPNP), novel and derived from natural antibacterial agents, which serve to improve stability. Afterwards chitosan-based composite films loaded with TPNP (CTN film) were developed using solution casting method. The incorporation of TPNP significantly improved the UV/water/oxygen barrier properties, mechanical properties and thermal stability, alongside notable physical properties including water contact angle (93.65 ± 0.04°), low water vapor permeability (33.72 ± 3.32 g/m2h) and oxygen permeability (0.11 ± 0.02 g/m2h), tensile strength (61.83 ± 0.70 %), and elongation at break (31.60 ± 6.12 %). The CTN film not only exhibited exceptional biodegradability and nontoxicity, but also demonstrated remarkable antimicrobial efficacy against Escherichia coli and Bacillus subtilis. Additionally, it showcased potent antioxidant activity, boasting DPPH and ABTS radical scavenging rates up to 89.25 ± 0.18 % and 93.84 ± 0.42 %. The CTN film was successfully formed on the surface of strawberries through dip-coating process and their shelf life was extended from 4 to 6 days at 20 °C without side-effect on the weight loss, harness, pH and total soluble solids, illustrating its potential for enhancing food preservation.

SlMDH3 Interacts with Autophagy Receptor Protein SlATI1 and Positively Regulates Tomato Heat Tolerance.

Autophagy, a highly conserved protein degradation system, plays an important role in protecting cells from adverse environmental conditions. ATG8-INTERACTING PROTEIN1 (ATI1) acts as an autophagy receptor, but its functional mechanisms in plants' heat stress tolerance remain unclear. In this study, using LC-MS/MS, we identified malate dehydrogenase (SlMDH3) as a SlATI1-interacting protein. Further studies showed that heat stress induced the expression of SlMDH3 and SlMDH3 co-localized with SlATI1 under both 22 °C and 42 °C heat treatment conditions. Moreover, silencing of SlMDH3 increased the sensitivity of tomato to heat stress, as evidenced by exacerbated degradation of chlorophyll; accumulation of MDA, H2O2, and dead cells; increased relative conductivity; and inhibition of stress-related gene expression. Conversely, overexpression of SlMDH3 improved tomato's heat tolerance, leading to opposite effects on physiological indicators and gene expression compared to SlMDH3 silencing. Taken together, our study suggests that SlMDH3 interacts with SlATI1 and positively regulates tomato heat tolerance.

Impact of Diabetes, Drug-Induced Liver Injury, and Sepsis on Outcomes in MAFLD-Related Acute-on-Chronic Liver Failure.

BACKGROUND: The prevalence of Metabolic dysfunction associated fatty liver disease (MAFLD) and its complication, MAFLD-related acute on chronic liver failure (MAFLD-ACLF), is rising. Yet, factors determining patient outcomes in MAFLD-ACLF remain understudied. METHODS: Patients with MAFLD-ACLF were recruited from the AARC registry. The diagnosis of MAFLD-ACLF was made when the treating unit had identified the etiology of chronic liver disease (CLD) as MAFLD (or previous nomenclature such as NAFLD, NASH, or NASH-cirrhosis). Patients with coexisting other etiologies of CLD (such as alcohol, HBV, HCV, etc.) were excluded. Data was randomly split into derivation (n=258) and validation (n=111) cohorts at a 70:30 ratio. The primary outcome was 90-day mortality. Only the baseline clinical, laboratory features and severity scores were considered. RESULTS: The derivation group had 258 patients; 60% were male, with a mean age of 53. Diabetes was noted in 27%, and hypertension in 29%. The dominant precipitants included viral hepatitis (HAV and HEV, 32%), drug-induced injury (DILI, 29%) and sepsis (23%). MELD-Na and AARC scores upon admission averaged 32±6 and 10.4±1.9. At 90 days, 51% survived. Non-viral precipitant, diabetes, bilirubin, INR, and encephalopathy were independent factors influencing mortality. Adding diabetes and precipitant to MELD-Na and AARC scores, the novel MAFLD-MELD-Na score (+12 for diabetes, +12 for non-viral precipitant) and MAFLD-AARC score (+5 for each) were formed. These outperformed the standard scores in both cohorts. CONCLUSION: Almost half of MAFLD-ACLF patients die within 90 days. Diabetes and non-viral precipitants such as DILI and sepsis lead to adverse outcomes. The new MAFLD-MELD-Na and MAFLD-AARC scores provide reliable 90-day mortality predictions for MAFLD-ACLF patients.

Integrating Network Pharmacology, Transcriptomics to Reveal Neuroprotective of Curcumin Activate PI3K / AKT Pathway in Parkinson's Disease.

Background: Parkinson's disease (PD) is the most prevalent movement disorder. Curcumin, a polyphenol with hydrophobic properties, has been proved against Parkinson. Our previous study suggested that curcumin's effectiveness in treating Parkinson's disease may be linked to the gut-brain axis, although the specific mechanism by which curcumin exerts neuroprotective effects in the brain remains unknown. Methods: The therapeutic efficacy of curcumin was evaluated using behavioral tests, immunofluorescence of tyrosine hydroxylase (TH). Network pharmacology and transcriptomics predicted the mechanisms of curcumin in PD. Activation of the phosphatidylinositol 3-kinase PI3K/AKT pathway was confirmed by quantitative polymerase chain reaction (qPCR) and immunofluorescence. Results: Curcumin restored the dyskinesia and dopaminergic neurons damage of MPTP-induced mice. Curcumin against Parkinson's disease by regulating inflammation, oxidative stress, and aging. The mechanisms of these were associated with activation of PI3K / AKT pathway. Conclusion: In conclusion, the neuroprotective mechanisms of curcumin activate PI3K / AKT pathway in Parkinson's disease was revealed by our study.

Engineering Corynebacterium glutamicum for the efficient production of 3-hydroxypropionic acid from glucose via the ß-alanine pathway.

3-Hydroxypropionic Acid (3-HP) is recognized as a high value-added chemical with a broad range of applications. Among the various biosynthetic pathways for 3-HP production, the ß-alanine pathway is particularly noteworthy due to its capacity to generate 3-HP from glucose at a high theoretical titer. In this study, the ß-alanine biosynthesis pathway was introduced and optimized in Corynebacterium glutamicum. By strategically regulating the supply of precursors, we successfully engineered a strain capable of efficiently synthesizing 3-HP through the ß-alanine pathway, utilizing glucose as the substrate. The engineered strain CgP36 produced 47.54 g/L 3-HP at a yield of 0.295 g/g glucose during the fed-batch fermentation in a 5 L fermenter, thereby attaining the highest 3-HP titer obtained from glucose via the ß-alanine pathway.

Astrocytic Neuroligin-3 influences gene expression and social behavior, but is dispensable for synapse number.

Neuroligin-3 (Nlgn3) is an autism-associated cell-adhesion molecule that interacts with neurexins and is robustly expressed in both neurons and astrocytes. Neuronal Nlgn3 is an essential regulator of synaptic transmission but the function of astrocytic Nlgn3 is largely unknown. Given the high penetrance of Nlgn3 mutations in autism and the emerging role of astrocytes in neuropsychiatric disorders, we here asked whether astrocytic Nlgn3 might shape neural circuit properties in the cerebellum similar to neuronal Nlgn3. Imaging of tagged Nlgn3 protein produced by CRISPR/Cas9-mediated genome editing showed that Nlgn3 is enriched in the cell body but not the fine processes of cerebellar astrocytes (Bergmann glia). Astrocyte-specific knockout of Nlgn3 did not detectably alter the number of synapses, synaptic transmission, or astrocyte morphology in mouse cerebellum. However, spatial transcriptomic analyses revealed a significant shift in gene expression among multiple cerebellar cell types after the deletion of astrocytic Nlgn3. Hence, in contrast to neuronal Nlgn3, astrocytic Nlgn3 in the cerebellum is not involved in shaping synapses but may modulate gene expression in specific brain areas.

Genetic evidence supports a causal relationship between air pollution and brain imaging-derived phenotypes.

BACKGROUND: Observational studies have reported associations between air pollutants and brain imaging-derived phenotypes (IDPs); however, whether this relationship is causal remains uncertain. METHODS: We conducted bidirectional two-sample Mendelian randomization (MR) analyses to explore the causal relationships between 5 types of air pollutants (N=423,796 to 456,380 individuals) and 587 reliable IDPs (N=33,224 individuals). Two-step MR was also conducted to assess whether the identified effects are mediated through the modulation of circulating cytokines (N=8293). RESULTS: We found genetic evidence supporting the association of nitrogen oxides (NOx) with mean intra-cellular volume fraction (ICVF) in the left uncinate fasciculus (IVW ß=-0.42, 95 % CI -0.62 to -0.23, P=1.51×10-5) and mean fractional anisotropy (FA) in the left uncinate fasciculus (IVW ß=-0.42, 95 % CI -0.62 to -0.21, P=4.89×10-5). In further two-step MR analyses, we did not find evidence that genetic predictions of any circulating cytokines mediated the association between NOx and IDPs. CONCLUSION: This study provides evidence for the association between air pollutants and brain IDPs, emphasizing the importance of controlling air pollution to improve brain health.

Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms.

The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, effectors of the SidE family interfere with host protein ubiquitination in a process that involves production of phosphoribosyl ubiquitin (PR-Ub). Here, we show that effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (SHxxxE) present in a large family of toxins from diverse bacterial pathogens. Thus, our study sheds light on the mechanisms by which a pathogen maintains ubiquitin homeostasis and identifies a family of enzymes capable of protein AMPylation.

Prevalence and trends in overactive bladder among men in the United States, 2005-2020.

The purpose of present study was to examine the current prevalence and recent trends of overactive bladder (OAB) among US adult men and examine the correlations between OAB and several potential risk factors. The study used the nationally representative data between 2005 and 2020 from the National Health and Nutrition Examination Survey in the US. A total of 18,386 participants aged ≥ 20 years were included in the study. We divided the data into three groups: 2005-2008, 2009-2014 and 2015-2020 to investigate the trends in OAB prevalence. The weighted prevalence and corresponding 95% confidence intervals (CI) of OAB were calculated. The differences (95% CI) in prevalence between the surveys were calculated and multivariate-adjusted weighted logistic regression analysis was performed to determine the correlates of OAB. Among all US adult men, the overall prevalence of OAB increased slightly from 11.3% in 2005-2008 to 11.7% in 2009-2014 and significantly increased to 14.5% in 2015-2020 (difference, 3.2% [95% CI (1.9-4.4%)]; P < 0.05). Increases in OAB prevalence especially concentrated on those who were 40-59 years, non-Hispanic White, non-Hispanic Black and those who were overweight and obese. Older age, non-Hispanic Black, lower educational level and family poverty ratio, diabetes, depression, sleep disorder, other chronic comorbidities, less intense recreational activity, poorer health condition and unsafe food were independent risk factors of OAB. The contemporary prevalence of OAB was high, affecting 14.5% US men and the estimated overall prevalence significantly increased from 2005 to 2020. Therefore, future research should be focused to prevent and remedy this growing socioeconomic and individually troublesome malady.