The role of dietary preferences in osteoarthritis: a Mendelian randomization study using genome-wide association analysis data from the UK Biobank.

Background: To understand the impact of individual preferences for specific dietary items on OA, and to help inform the development of effective and targeted OA prevention and management strategies, we performed a Mendelian randomization analysis between dietary preferences and osteoarthritis. Methods: This study utilized genetic data from the UK Biobank to investigate the association between OA and 21 different common dietary items. Instrumental variables representing European populations were carefully selected based on their genetic significance and linkage disequilibrium. In cases where a dietary item had few relevant genetic markers, a more lenient selection threshold was applied. To prevent bias, the analysis excluded single nucleotide polymorphisms (SNPs) associated with factors such as body mass index (BMI) and cholesterol. Using inverse-variance weighting (IVW) and Mendelian randomization, significant associations were detected between certain dietary items and OA. Results: Using Mendelian randomization to examine the relationship between 21 different dietary items and OA, significant associations were found for coffee, peas, watercress, and cheese, where the first two had a promoting effect and the last two an inhibiting effect on OA. Due to heterogeneity in the test results for cheese, a random IVW representation was used. The results of sensitivity analysis showed no significant heterogeneity or horizontal pleiotropy in the selected SNPS, demonstrating the reliability of Mendelian randomization analysis. Conclusion: This study identified coffee, peas, watercress, and cheese as food items that may have significant dietary effects on osteoarthritis. This information may be useful to consider in the development of OA management strategies.

Artificial intelligence for diagnosis and prognosis prediction of natural killer/T cell lymphoma using magnetic resonance imaging.

Accurate diagnosis and prognosis prediction are conducive to early intervention and improvement of medical care for natural killer/T cell lymphoma (NKTCL). Artificial intelligence (AI)-based systems are developed based on nasopharynx magnetic resonance imaging. The diagnostic systems achieve areas under the curve of 0.905-0.960 in detecting malignant nasopharyngeal lesions and distinguishing NKTCL from nasopharyngeal carcinoma in independent validation datasets. In comparison to human radiologists, the diagnostic systems show higher accuracies than resident radiologists and comparable ones to senior radiologists. The prognostic system shows promising performance in predicting survival outcomes of NKTCL and outperforms several clinical models. For patients with early-stage NKTCL, only the high-risk group benefits from early radiotherapy (hazard ratio = 0.414 vs. late radiotherapy; 95% confidence interval, 0.190-0.900, p = 0.022), while progression-free survival does not differ in the low-risk group. In conclusion, AI-based systems show potential in assisting accurate diagnosis and prognosis prediction and may contribute to therapeutic optimization for NKTCL.

HomeOSD: Appliance Operating-Status Detection Using mmWave Radar.

Within the context of a smart home, detecting the operating status of appliances in the environment plays a pivotal role, estimating power consumption, issuing overuse reminders, and identifying faults. The traditional contact-based approaches require equipment updates such as incorporating smart sockets or high-precision electric meters. Non-constant approaches involve the use of technologies like laser and Ultra-Wideband (UWB) radar. The former can only monitor one appliance at a time, and the latter is unable to detect appliances with extremely tiny vibrations and tends to be susceptible to interference from human activities. To address these challenges, we introduce HomeOSD, an advanced appliance status-detection system that uses mmWave radar. This innovative solution simultaneously tracks multiple appliances without human activity interference by measuring their extremely tiny vibrations. To reduce interference from other moving objects, like people, we introduce a Vibration-Intensity Metric based on periodic signal characteristics. We present the Adaptive Weighted Minimum Distance Classifier (AWMDC) to counteract appliance vibration fluctuations. Finally, we develop a system using a common mmWave radar and carry out real-world experiments to evaluate HomeOSD's performance. The detection accuracy is 95.58%, and the promising results demonstrate the feasibility and reliability of our proposed system.

Association between ascites Gustave Roussy immune score and the intratumoural microbiome in malignant ascites secondary to hepatocellular carcinoma.

BACKGROUNDS: The Gustave Roussy Immune (GRIm) score predicts survival outcomes in several cancers. However, the prognostic significance of the GRIm score in patients with malignant ascites has not yet been investigated. METHODS: Clinical samples were collected from a cohort of patients with malignant ascites secondary to hepatocellular carcinoma (HCC). We calculated serum GRIm (sGRIm) and ascites GRIm (aGRIm) scores and divided the samples into low and high GRIm score groups. Survival analysis was used to compare the prognostic significance of the sGRIm and aGRIm scores. 16S rRNA sequencing was performed to determine the profiles of the intratumoral microbiota in the groups. A fluorescent multiplex immunohistochemistry (mIHC) assay was used to detect the expression of different immune cells by labeling seven markers of malignant ascites. RESULTS: 155 patients with HCC and malignant ascites were enrolled in this study. Survival analysis revealed that the aGRIm score showed a superior prognostic significance compared to the sGRIm score. Microbial analysis demonstrated that the bacterial richness and diversity were higher in the low aGRIm score group than in the high aGRIm score group. LefSe analysis revealed that certain bacteria were correlated with high aGRIm scores. Fluorescent mIHC displayed the tumor microenvironment of malignant ascites and found that the density of CD8 + T cells was significantly higher in the low aGRIm score group than in the high aGRIm score group. CONCLUSIONS: Our present study identified a novel scoring system (aGRIm score) that can predict the survival outcome of patients with malignant ascites secondary to HCC.

Ascitic microbiota alteration is associated with portal vein tumor thrombosis occurrence and prognosis in hepatocellular carcinoma.

Portal vein tumor thrombosis (PVTT) frequently leads to malignant ascites (MA) in individuals with hepatocellular carcinoma (HCC), remaining a bottleneck in the treatment. This study aimed to explore the differences in microbes in paired groups and provide novel insights into PVTT and MA-related treatments. Formalin-fixed paraffin embedding ascite samples were collected from MA secondary to HCC and benign ascites (BA) secondary to liver cirrhosis (LC). Ascitic microbiota profiles were determined in the HCC and LC groups by 16S rRNA sequencing. Prognostic risk factors were screened using survival analysis. The correlation between the significantly different microbial signatures in the groups with PVTT (WVT) and non-PVTT (NVT) and clinical characteristics was explored. The expression of different immune cells was determined by labeling four markers in the MA tissue chips using multiplex immunohistochemistry. A total of 240 patients (196 with HCC with MA and 44 with LC with BA) were included in this study. Microbial profiles differed between the HCC and LC groups. PVTT and Barcelona Clinic Liver Cancer stage were shown to be prognostic risk factors. Significant differences in the alpha and beta diversities were observed between the WVT and NVT groups. Gammaproteobacteria and Acinetobacter were the most abundant in the HCC MA. Differences in microbial signatures between the WVT and NVT groups were correlated with the level of C-reactive protein and apolipoprotein A1. This study revealed the microbial differences in the tumor microenvironment of MA secondary to HCC and BA secondary to LC.IMPORTANCEFirst, we explored the alteration of the ascites ecosystem through the microbiota in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Second, this is the first clinical study to investigate the differences between patients with HCC with and without portal vein tumor thrombosis via 16S rRNA sequencing. These results revealed a decreased microbial diversity and metabolic dysregulation in individuals with HCC and portal vein tumor thrombosis. Gammaproteobacteria and Acinetobacter were the most abundant in the HCC malignant ascitic fluid. Our study provides a new perspective on treating malignant ascites secondary to HCC.

Texture analysis of apparent diffusion coefficient maps: can it identify nonresponse to neoadjuvant chemotherapy for additional radiation therapy in rectal cancer patients?

Background: Neoadjuvant chemotherapy (NCT) alone can achieve comparable treatment outcomes to chemoradiotherapy in locally advanced rectal cancer (LARC) patients. This study aimed to investigate the value of texture analysis (TA) in apparent diffusion coefficient (ADC) maps for identifying non-responders to NCT. Methods: This retrospective study included patients with LARC after NCT, and they were categorized into nonresponse group (pTRG 3) and response group (pTRG 0-2) based on pathological tumor regression grade (pTRG). Predictive texture features were extracted from pre- and post-treatment ADC maps to construct a TA model using RandomForest. The ADC model was developed by manually measuring pre- and post-treatment ADC values and calculating their changes. Simultaneously, subjective evaluations based on magnetic resonance imaging assessment of TRG were performed by two experienced radiologists. Model performance was compared using the area under the curve (AUC) and DeLong test. Results: A total of 299 patients from two centers were divided into three cohorts: the primary cohort (center A; n = 194, with 36 non-responders and 158 responders), the internal validation cohort (center A; n = 49, with 9 non-responders) and external validation cohort (center B; n = 56, with 33 non-responders). The TA model was constructed by post_mean, mean_change, post_skewness, post_entropy, and entropy_change, which outperformed both the ADC model and subjective evaluations with an impressive AUC of 0.997 (95% confidence interval [CI], 0.975-1.000) in the primary cohort. Robust performances were observed in internal and external validation cohorts, with AUCs of 0.919 (95% CI, 0.805-0.978) and 0.938 (95% CI, 0.840-0.985), respectively. Conclusions: The TA model has the potential to serve as an imaging biomarker for identifying nonresponse to NCT in LARC patients, providing a valuable reference for these patients considering additional radiation therapy.

Effectiveness of personalized meal recommendation in improving dietary behaviors of Chinese community-dwelling elders: study protocol for a cluster randomized controlled trial.

BACKGROUND: Inappropriate eating behaviors, particularly a lack of food diversity and poor diet quality, have a significant impact on the prognosis of certain chronic conditions and exacerbate these conditions in the community-dwelling elderly population. Current dietary interventions for the elderly have not adequately considered the nutritional needs associated with multiple chronic conditions and personal dietary preferences of elderly individuals. A personalized recommendation system has been recognized as a promising approach to address this gap. However, its effectiveness as a component of an elderly-targeted dietary intervention in real-world settings remains unknown. Additionally, it is unclear whether this intervention approach will be user-friendly for the elderly. Therefore, this study aims to examine the effectiveness of a personalized meal recommendation system designed to improve dietary behavior in community-dwelling elders. The implementation process in terms of System usability and satisfaction will also be assessed. METHODS: The trial has been designed as a 6-month, non-blinded, parallel two-arm trial. One hundred fifty community-dwelling elders who meet the eligibility criteria will be enrolled. Subjects will be allocated to either the intervention group, receiving personalized meal recommendations and access to corresponding food provided as one component of the intervention, as well as health education on elder nutrition topics, or the control group, which will receive nutritional health education lectures. Outcomes will be measured at three time points: baseline at 0 months, 3 months, and 6 months. The primary outcomes will include dietary diversity (DDS) and diet quality (CDGI-E) of enrolled community-dwelling elders, representing their dietary behavior improvement, along with dietary behavior adherence to recommended meals. Secondary outcomes will measure the perceived acceptability and usability of the personalized meal recommendation system for the intervention group. Exploratory outcomes will include changes in the nutritional status and anthropometric measurements of the community-dwelling elders. DISCUSSION: This study aims to examine the effectiveness, acceptability, and usability of a personalized meal recommendation system as a data-driven dietary intervention to benefit community-dwelling elders. The successful implementation will inform the future development and integration of digital health strategies in daily nutrition support for the elderly. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300074912. Registered on August 20, 2023, https://www.chictr.org.cn/showproj.html?proj=127583.

Real-world evidence of combined treatment of biologics and exclusive enteral nutrition in patients with ileum-dominant Crohn's disease: A multicenter study.

BACKGROUND & AIMS: Although biologics were prescribed to achieve and maintain clinical remission of active Crohn's disease (CD), almost half of patients experienced a loss of response or intolerance. Here, we investigated the efficacy of combined treatment of biologics and 16-weeks exclusive enteral nutrition (EEN) in moderate-to-severe CD patients with small intestine lesions. METHODS: This was a real-world, multicenter retrospective study, from October 2016 to March 2023, medical records of patients registered at three IBD centers were reviewed for patients with ileal or ileocolonic CD in moderate-to-severe activity. All patients received treatment of biologics with concomitant 16-week EEN (BioEEN) or biologics alone (Bio). The clinical outcomes and endoscopic outcomes were assessed at week 16 and 52. RESULTS: There was no statistically significant difference between Bio (97 patients) and BioEEN group (100 patients) at baseline for demographic and clinical characteristics. Compared to treatment with biologics alone, patients with BioEEN treatment achieved higher rates of clinical response (95.0% vs. 66.0%), clinical remission (87.0% vs. 52.6%), endoscopic response (91.4% vs. 47.4%) including mucosal healing (85.7% vs. 23.7%) at week 16. The superiority of BioEEN sustained in maintenance, with 84.7% (vs. 49.1%) clinical response, 77.8% (vs. 38.6%) clinical remission, 69.2% (vs. 32.6%) endoscopic response and 51.9% (vs. 18.6%) mucosal healing at week 52. CONCLUSIONS: Combined treatment of biologics and 16-week EEN was an efficient therapeutic strategy with affirmative effectiveness for small intestine diseases of active CD.

Olanzapine for the prevention of postoperative nausea and vomiting after gynecologic laparoscopic surgery: a randomized controlled trial.

Purpose: This study was designed to investigate the prophylactic effect of oral olanzapine in postoperative nausea and vomiting after gynecologic laparoscopic surgery. Methods: ASA I-II, aged 18-75 years, planned to undergo gynecologic laparoscopic surgery with general anesthesia in adult female patients. Using the randomized numbers table, the patients were placed in two groups. Oral olanzapine 5 mg or placebo was given 1 h before anesthesia. All patients received standard antiemetic prophylaxis with dexamethasone and granisetron. The primary outcome was nausea and/or vomiting in the 24 h after the postoperative. Results: A total of 250 patients were randomized, and 241 were analyzed. The primary outcome occurred in 10 of 120 patients (8.3%) in the olanzapine group and 23 of 121 patients (19.2%) in the placebo group (p = 0.014). According to Kaplan-Meier analysis, the probabilities of nausea and/or vomiting in the 24 h after the postoperative in the olanzapine group were lower than in the placebo group (log-rank p = 0.014). In a multivariate Cox analysis, the variables of use of olanzapine [hazard ratio (HR): 0.35, 95% confidence interval (CI): 0.16-0.79; p = 0.012] and use of vasoactive drugs (HR: 2.48, 95% CI: 1.07-5.75; p = 0.034) were independently associated with nausea and/or vomiting in the 24 h after the postoperative. Conclusion: Our data suggest that olanzapine relative to placebo decreased the risk of nausea and/or vomiting in the 24 h after gynecologic laparoscopic surgery. Trial registration: The trial was registered prior to patient enrollment at The Chinese Clinical Trial Registry (https://www.chictr.org.cn/showproj.html?proj=166900, link to registry page, Principal investigator: Nanjin Chen, Date of registration: 25 April 2022).

Preventing nausea and vomiting after laparoscopic gynecological surgery: the benefits of using olanzapine Why was this study done? Despite the use of antiemetics, postoperative nausea and vomiting remain prevalent. Furthermore, patients who undergo gynecological laparoscopic surgery are at an increased risk. Therefore, this study investigated whether oral Olanzapine could reduce the incidence of nausea and vomiting after gynaecological Laparoscopy? What did the researchers do? The research team examined patients who underwent gynecological laparoscopic surgery under general anesthesia. They observed the occurrence of nausea and vomiting within 24 hours after surgery in patients who either received or did not receive Olanzapine treatment. The goal was to assess the effectiveness of Olanzapine in reducing postoperative nausea and vomiting. What did the researchers find? The addition of Olanzapine, when combined with granisetron and dexamethasone, resulted in a decreased risk of nausea and/or vomiting within the 24 hours following gynecologic laparoscopic surgery, as compared to the placebo. Administering oral Olanzapine at a dosage of 5 mg reduced the incidence of nausea and vomiting after gynecological laparoscopy from 19.2% to 8.3%. What do the findings mean? This study has identified a safe and effective medication for preventing postoperative nausea and vomiting. Implementing Olanzapine as a preventive measure can significantly reduce the incidence of nausea and vomiting following surgery, thereby enhancing the overall medical experience for patients.

Acremosides A-G, Sugar Alcohol-Conjugated Acyclic Sesquiterpenes from a Sponge-Derived Acremonium Species.

Seven new sugar alcohol-conjugated acyclic sesquiterpenes, acremosides A-G (1-7), were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 cultivated with heat-killed Pseudomonas aeruginosa. The structures were determined by comprehensive analyses of 1D and 2D NMR spectroscopic data. The relative configurations were established by J-based configuration analysis and acetonide derivatization. The absolute configurations were elucidated by the Mosher ester method and ECD calculations. The structures of acremosides E-G (5-7) featured the linear sesquiterpene skeleton with a tetrahydrofuran moiety attached to a sugar alcohol. Acremosides A (1) and C-E (3-5) showed significant inhibitory activities against hepatitis C virus (EC50 values of 4.8-8.8 µM) with no cytotoxicity (CC50 of >200 µM).

The NeuroProtect Formula: A Preventive Approach to AD Targeting the HIF-1/PI3K-AKT Signaling Pathway Evaluated through In Vivo, In Vitro, and Network Pharmacology Approaches.

OBJECTIVE: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with limited options for reversing its middle-to-late stages. Early intervention is crucial to slow down disease progression. This study aimed to investigate the potential of the NeuroProtect (NP) formula, a combination of geniposide and Panax notoginseng saponins, in preventing AD. We evaluated the effects of the NP formula on amyloid plaque accumulation, neuronal degeneration, and molecular signaling pathways using in vivo and in vitro models. METHODS: To predict functional pathways and potential downstream targets of NP intervention, we employed network pharmacology. The preventative impact of the NP formula was assessed using APP/PS1 mice. We conducted HE staining, ELISA assay, Golgi staining, and immunohistochemistry to detect the protective effect of NP. Additionally, cell experiments were performed to assess cell activity and target protein expression. RESULTS: Network pharmacology analysis revealed 145 drug-disease interactions and identified 5 core active targets associated with AD. Molecular docking results demonstrated strong binding affinity between the components of the NP formula (GP, GN-Rb1, GN-Rg1, NS-R1) and target proteins (STAT3, HIF1A, TLR4, mTOR, VEGFA). Notably, the binding energy between NS-R1 and mTOR was -11.4kcal/mol. Among the top 10 enriched KEGG pathways, the HIF-1 and PI3K-AKT signaling pathways were highlighted. In vivo experiments demonstrated that the NP formula significantly ameliorated pathological changes, decreased the Aß42/Aß40 ratio in the hippocampus and cortex, and increased dendritic spine density in the CA1 region during the early stage of AD. In vitro experiments further illustrated the NP formula's ability to reverse the inhibitory effects of Aß25-35 on cell viability and regulate the expression of Tlr4, Mtor, Hif1a, Stat3, and Vegfa. CONCLUSION: Our findings suggest that NP exhibits neuroprotective effects during the early stages of AD, positioning it as a potential candidate for AD prevention. The NP formula may exert its preventive effects through the HIF-1/PI3K-AKT signaling pathway, with mTOR identified as a key target.

Combinational strategy using albumin-based nanoparticles to enable synergetic anti-rheumatic efficacy and reduced hepatotoxicity.

Methotrexate (MTX) is recognized as the golden standard for rheumatoid arthritis (RA) treatment. However, it can cause liver damage in long-term application. Although nanomedicines can target to inflamed sites, most of them tend to accumulate in liver. Glycyrrhizinic acid (GA) holds potential to reverse MTX-associated hepatotoxicity. The combination of GA and MTX might achieve a synergistic anti-inflammatory efficacy and reduced hepatotoxicity. As MTX and GA have totally different in vivo performance, it is necessary to co-encapsulate them in one carrier to coordinate their in vivo fates. Here, we co-delivered MTX and GA to arthritic joints using a human serum albumin-based nanoparticle (HSN). We found the dual drug-loaded albumin nanoparticles (HSN/MTX/GA) could preferentially distribute in inflamed joints, where GA can extend MTX retention by inhibiting the expression of efflux pumps for MTX, thereby exerting synergistic therapeutic effect. In liver tissues, GA was able to reverse the MTX-induced liver damage by activating anti-oxidant defense Nrf2/HO-1 and anti-apoptosis Bcl-2/Bax signaling. We offer a combinational strategy to effectively overcome the MTX-induced hepatotoxicity and enhance the anti-rheumatic efficacy simultaneously. Furthermore, we verified the underlying mechanism about how GA cooperated with MTX in vivo for the first time. Our findings can provide valuable insights for long-term treatment of RA.

3D bioprinting approaches for spinal cord injury repair.

Regenerative healing of spinal cord injury (SCI) poses an ongoing medical challenge by causing persistent neurological impairment and a significant socioeconomic burden. The complexity of spinal cord tissue presents hurdles to successful regeneration following injury, due to the difficulty of forming a biomimetic structure that faithfully replicates native tissue using conventional tissue engineering scaffolds. 3D bioprinting is a rapidly evolving technology with unmatched potential to create 3D biological tissues with complicated and hierarchical structure and composition. With the addition of biological additives such as cells and biomolecules, 3D bioprinting can fabricate preclinical implants, tissue or organ-like constructs, andin vitromodels through precise control over the deposition of biomaterials and other building blocks. This review highlights the characteristics and advantages of 3D bioprinting for scaffold fabrication to enable SCI repair, including bottom-up manufacturing, mechanical customization, and spatial heterogeneity. This review also critically discusses the impact of various fabrication parameters on the efficacy of spinal cord repair using 3D bioprinted scaffolds, including the choice of printing method, scaffold shape, biomaterials, and biological supplements such as cells and growth factors. High-quality preclinical studies are required to accelerate the translation of 3D bioprinting into clinical practice for spinal cord repair. Meanwhile, other technological advances will continue to improve the regenerative capability of bioprinted scaffolds, such as the incorporation of nanoscale biological particles and the development of 4D printing.

Generating robust aptamers for food analysis by sequence-based configuration optimization.

Advanced analytical techniques are emerging in the food industry. Aptamer-based biosensors achieve rapid and highly selective analysis, thus drawing particular attention. Aptamers are oligonucleotide probes screened via in vitro Systematic Evolution of Ligands by EXponential Enrichment (SELEX), which can bind with their specific targets by folding into three-dimensional configurations and accept various modifications to be incorporated into biosensors, showing great potential in food analysis. Unfortunately, aptamers obtained by SELEX may not possess satisfactory affinity. Post-SELEX strategies were proposed to optimize aptamers' configuration and enhance the binding affinity, with specificity confirmed. Sequence-based optimization strategies exhibit great advantages in simple operation, good generalization, low cost, etc. This review summarizes the latest study (2015-2023) on generating robust aptamers for food targets by sequence-based configuration optimization, as well as the generated aptamers and aptasensors, with an expectation to provide inspirations for developing aptamer and aptasensors with high performance for food analysis and to safeguard food quality and safety.

A case report of Vancomycin in the treatment of Q fever endocarditis.

The patient, a 43-year-old male, was admitted to the hospital with gradually aggravated exertional palpitations and chest tightness over a 2-day period. Upon hospital admission, a cardiac ultrasound revealed aortic valve redundancy, however multiple blood culture investigations came back negative. Blood mNGS was perfected, revealing Coxiella burnetii, and the diagnosis of Q fever (query fever) was established. The temperature and inflammatory indices of the patient were all normal with the treatment of vancomycin before cardiac surgery. But for the potential liver damage of and the Coxiella burnetii was still positive in the anti-phase II IgG titer, the doxycycline and hydroxychloroquine instead of vancomycin were applied for the patient. Despite receiving standardized anti-infective therapy of doxycycline combined with hydroxychloroquine, this patient had fever and increased leukocytes following surgery. After the addition of vancomycin as an anti-infective treatment, the temperature and leukocytes improved quickly. During the treatment of vancomycin, a discovery of liver injury may have resulted. These findings provide new therapy options for future professionals.

Ångstrom-scale gold particles loaded with alendronate via alpha-lipoic acid alleviate bone loss in osteoporotic mice.

Osteoporosis is a highly prevalent metabolic disease characterized by low systemic bone mass and deterioration of bone microarchitecture, resulting in reduced bone strength and increased fracture risk. Current treatment options for osteoporosis are limited by factors such as efficacy, cost, availability, side effects, and acceptability to patients. Gold nanoparticles show promise as an emerging osteoporosis therapy due to their osteogenic effects and ability to allow therapeutic delivery but have inherent constraints, such as low specificity and the potential for heavy metal accumulation in the body. This study reports the synthesis of ultrasmall gold particles almost reaching the Ångstrom (Ång) dimension. The antioxidant alpha-lipoic acid (LA) is used as a dispersant and stabilizer to coat Ångstrom-scale gold particles (AuÅPs). Alendronate (AL), an amino-bisphosphonate commonly used in drug therapy for osteoporosis, is conjugated through LA to the surface of AuÅPs, allowing targeted delivery to bone and enhancing antiresorptive therapeutic effects. In this study, alendronate-loaded Ångstrom-scale gold particles (AuÅPs-AL) were used for the first time to promote osteogenesis and alleviate bone loss through regulation of the WNT signaling pathway, as shown through in vitro tests. The in vivo therapeutic effects of AuÅPs-AL were demonstrated in an established osteoporosis mouse model. The results of Micro-computed Tomography, histology, and tartrate-resistant acid phosphatase staining indicated that AuÅPs-AL significantly improved bone density and prevented bone loss, with no evidence of nanoparticle-associated toxicity. These findings suggest the possible future application of AuÅPs-AL in osteoporosis therapy and point to the potential of developing new approaches for treating metabolic bone diseases using Ångstrom-scale gold particles.

SUMOylation of GMFB regulates its stability and function in retinal pigment epithelial cells under hyperglycemia.

BACKGROUND: Glia maturation factor beta (GMFB) is a growth and differentiation factor that acts as an intracellular regulator of signal transduction pathways. The small ubiquitin-related modifier (SUMO) modification, SUMOylation, is a posttranslational modification (PTM) that plays a key role in protein subcellular localization, stability, transcription, and enzymatic activity. Recent studies have highlighted the importance of SUMOylation in the inflammation and progression of numerous diseases. However, the relationship between GMFB and SUMOylation is unclear. RESULTS: Here, we report for the first time that GMFB and SUMO1 are markedly increased in retinal pigment epithelial (RPE) cells at the early stage of diabetes mellitus (DM) under hyperglycemia. The GMFΒ protein could be mono-SUMOylated by SUMO1 at the K20, K35, K58 or K97 sites. SUMOylation of GMFB led to its increased protein stability and subcellular translocation. Furthermore, deSUMOylation of GMFΒ downregulates multiple signaling pathways, including the Jak-STAT signaling pathway, p38 pathway and NF-kappa B signaling pathway. CONCLUSIONS: This work provides novel insight into the role of SUMOylated GMFB in RPE cells and provides a novel therapeutic target for diabetic retinopathy (DR).

Decomposing cortical activity through neuronal tracing connectome-eigenmodes in marmosets.

Deciphering the complex relationship between neuroanatomical connections and functional activity in primate brains remains a daunting task, especially regarding the influence of monosynaptic connectivity on cortical activity. Here, we investigate the anatomical-functional relationship and decompose the neuronal-tracing connectome of marmoset brains into a series of eigenmodes using graph signal processing. These cellular connectome eigenmodes effectively constrain the cortical activity derived from resting-state functional MRI, and uncover a patterned cellular-functional decoupling. This pattern reveals a spatial gradient from coupled dorsal-posterior to decoupled ventral-anterior cortices, and recapitulates micro-structural profiles and macro-scale hierarchical cortical organization. Notably, these marmoset-derived eigenmodes may facilitate the inference of spontaneous cortical activity and functional connectivity of homologous areas in humans, highlighting the potential generalizing of the connectomic constraints across species. Collectively, our findings illuminate how neuronal-tracing connectome eigenmodes constrain cortical activity and improve our understanding of the brain's anatomical-functional relationship.

Integrative multi-omics analysis identifies genetically supported druggable targets and immune cell specificity for myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by fluctuating muscle weakness. Despite the availability of established therapies, the management of MG symptoms remains suboptimal, partially attributed to lack of efficacy or intolerable side-effects. Therefore, new effective drugs are warranted for treatment of MG. METHODS: By employing an analytical framework that combines Mendelian randomization (MR) and colocalization analysis, we estimate the causal effects of blood druggable expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) on the susceptibility of MG. We subsequently investigated whether potential genetic effects exhibit cell-type specificity by utilizing genetic colocalization analysis to assess the interplay between immune-cell-specific eQTLs and MG risk. RESULTS: We identified significant MR results for four genes (CDC42BPB, CD226, PRSS36, and TNFSF12) using cis-eQTL genetic instruments and three proteins (CTSH, PRSS8, and CPN2) using cis-pQTL genetic instruments. Six of these loci demonstrated evidence of colocalization with MG susceptibility (posterior probability > 0.80). We next undertook genetic colocalization to investigate cell-type-specific effects at these loci. Notably, we identified robust evidence of colocalization, with a posterior probability of 0.854, linking CTSH expression in TH2 cells and MG risk. CONCLUSIONS: This study provides crucial insights into the genetic and molecular factors associated with MG susceptibility, singling out CTSH as a potential candidate for in-depth investigation and clinical consideration. It additionally sheds light on the immune-cell regulatory mechanisms related to the disease. However, further research is imperative to validate these targets and evaluate their feasibility for drug development.

Mechanical Unloading Promotes Osteoclastic Differentiation and Bone Resorption by Modulating the MSC Secretome to Favor Inflammation.

Aging, space flight, and prolonged bed rest have all been linked to bone loss, and no effective treatments are clinically available at present. Here, with the rodent hindlimb unloading (HU) model, we report that the bone marrow (BM) microenvironment was significantly altered, with an increased number of myeloid cells and elevated inflammatory cytokines. In such inflammatory BM, the osteoclast-mediated bone resorption was greatly enhanced, leading to a shifted bone remodeling balance that ultimately ends up with disuse-induced osteoporosis. Using Piezo1 conditional knockout (KO) mice (Piezo1fl/fl;LepRCre), we proved that lack of mechanical stimuli on LepR+ mesenchymal stem cells (MSCs) is the main reason for the pathological BM inflammation. Mechanically, the secretome of MSCs was regulated by mechanical stimuli. Inadequate mechanical load leads to increased production of inflammatory cytokines, such as interleukin (IL)-1α, IL-6, macrophage colony-stimulating factor 1 (M-CSF-1), and so on, which promotes monocyte proliferation and osteoclastic differentiation. Interestingly, transplantation of 10% cyclic mechanical stretch (CMS)-treated MSCs into HU animals significantly alleviated the BM microenvironment and rebalanced bone remodeling. In summary, our research revealed a new mechanism underlying mechanical unloading-induced bone loss and suggested a novel stem cell-based therapy to potentially prevent disuse-induced osteoporosis.