Weight loss after initiating anti-obesity medications and gout among overweight and obesity individuals: a population-based cohort study.

OBJECTIVES: Weight loss is conditionally recommended for gout management; however, its impact on incident gout and recurrent gout flares among overweight and obese individuals remains unknown. We aimed to investigate the relationship between weight loss rate following the initiation of anti-obesity medications and the risk of incident gout and recurrent gout flares among overweight/obese individuals. METHODS: Using data from The Health Improvement Network, we selected individuals aged 18 and older who were overweight or obese and started anti-obesity medication. We emulated a target trial to examine the association of different weight loss rates, slow (2-5%), moderate (5-10%), or fast (≥10%), within the first year of treatment with incident gout and recurrent gout flares during a 5-year follow-up period. RESULTS: Among 131,000 participants without gout starting orlistat, the 5-year risk of incident gout was 1.6% for those with weight gain/stable, compared with 1.5%, 1.3%, and 1.2% for those with slow, moderate, and fast weight loss, respectively. Compared with the weight gain/stable arm, the hazard ratios were 0.91 (95% confidence interval [CI]: 0.81 to 1.01), 0.82 (95%CI: 0.72 to 0.92), and 0.73 (95%CI: 0.62 to 0.86) for slow, moderate and fast rate of weight loss arms, respectively. Similar results were observed for the recurrent gout flares among 3,847 overweight or obese individuals with gout starting orlistat. CONCLUSIONS: A higher rate of weight loss after initiating orlistat within 1-year was associated with lower risks of incident gout and lower rates of recurrent gout flares among overweight or obese people.

Bimetallic Au/Ag coated on In2O3 for the effective removal of emerging organic contaminants under natural sunlight irradiation.

Antibiotics-polluted wastewater, likely causing the spread of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs), can be effectively remediated by photocatalytic degradation driven by endless solar energy. Herein, bimetallic Au/Ag is deposited on In2O3 surface via a one-step sintering process followed by a controllable chemical reduction approach. Under natural sunlight irradiation, the optimal Au/Ag/In2O3 (UGI-1.0) photocatalyst possesses a considerable norfloxacin (NOR) degradation rate constant of 0.013 min-1, which is 3.25, 1.63, and 1.86 times higher than that of In2O3, Ag/In2O3, and Au/In2O3 respectively. The effect of many water characteristics (e.g., humic acid, water bodies, pH values, and coexisting anions) on the photodegradation performance of NOR over UGI-1.0 is investigated. Moreover, other persistent organic pollutants (ofloxacin, phenol, 2,4-dichlorophenol, and rhodamine B) can also be degraded over UGI-1.0, suggesting its universal oxidation capacity. To settle the challenge of powder photocatalyst recovery, the UGI-1.0 photocatalyst is coated on a frosted glass sheet, which exhibits outstanding activity and stability for degrading NOR. The bimetallic Au/Ag deposited on In2O3 promote its photo-absorption, and enhance its photoinduced charge separation and transfer efficiency by serving as electron accepter, leading to the boosted activity of Au/Ag/In2O3 catalysts. Particularly, the cultivation of staphylococcus aureus (S. aureus) and cabbage seeds reveals the efficient toxicity reduction of NOR by photocatalytic degradation and the nontoxic characteristic of UGI-1.0 catalyst. This work unveils the feasibility of UGI-1.0 to remediate real wastewater with the assistance of solar energy.

Memantine attenuates the development of osteoarthritis by blocking NMDA receptor mediated calcium overload and chondrocyte senescence.

Background: Memantine, which is an FDA-proven drug for the treatment of dementia, exerts its function by blocking the function of NMDA (N-methyl-D-aspartate) receptor, a calcium-permeable ion channel that reduces cytotoxic calcium overload. Chondrocyte senescence is a crucial cellular event that contributes to articular cartilage degeneration during osteoarthritis (OA) development. To date, the effects of memantine and its downstream NMDA receptor on chondrocyte senescence and OA have been rarely reported. Methods: The protein levels of NMDA receptor and its agonistic ligand, glutamate, were compared between normal and OA chondrocytes. The quantity of intracellular calcium ions and the level of mitochondrial damage were evaluated using specific fluorescent probes and transmission electron microscopy (TEM), respectively. Chondrocyte senescence was evaluated by senescence-associated ß-galactosidase (SA-ß-Gal) staining and p16INK4a analysis. The function of NMDA receptor in chondrocyte senescence and OA was tested via agonists activation and gene knockdown experiments. The therapeutic effects of memantine on OA were examined both in vitro and in vivo. Additionally, to verify the findings from animal samples, a propensity score-matched cohort study was conducted using data from a United Kingdom primary care database (i.e., IQVIA Medical Research Database [IMRD]) to compare the risk of OA-related joint replacement involved in memantine initiators versus active comparators (i.e., acetylcholinesterase [AchE] initiators) in patients with dementia. Results: The protein expression of NMDA receptor and the secretion of glutamate were both significantly increased in OA chondrocytes. NMDA receptor activation was found to stimulate chondrocyte calcium overload, which further led to mitochondrial fragmentation and chondrocyte senescence. Blocking the NMDA receptor with memantine and N-methyl-D-aspartate receptor subunit 1(NR1, the gene encoding NMDA receptor) knockdown resulted in reduced calcium influx, mitochondrial fragmentation, as well as cellular senescence in OA chondrocytes. Intra-articular injection of memantine in OA mice also exhibited protective effects against cartilage degeneration. Moreover, in the 1:5 propensity score-matched cohort study consisting of 6218 patients (n = 1435 in the memantine cohort; n = 4783 in the AchE cohort), the memantine initiator was associated with a lower risk of OA-related joint replacement than AchE initiators (Hazard ratio = 0.56, 95 % confidence interval: 0.34 to 0.99). Conclusion: NMDA receptor plays an important role in inflammatory-induced cytotoxic calcium overload in chondrocytes, while memantine can effectively block the NMDA receptor to reduce chondrocyte senescence and retard the development of OA. The translational potential of this article: As a clinically licensed drug used for the treatment of dementia, memantine has shown promising therapeutic effects on OA. Mechanistically, it functions by blocking NMDA receptor from mediating chondrocyte senescence. The protective effects of memantine against OA were verified not only by in vivo and in vitro experiments but also via a propensity score-matched human cohort study. These findings presented robust evidence for repurposing memantine for the treatment of OA.

Bidirectional association identified between synovitis and knee and hand osteoarthritis: a general population-based study.

Background: Synovitis has long been considered a common and modifiable inflammatory feature of osteoarthritis (OA), but current disease-modifying anti-inflammatory treatments appear ineffective in OA clinical trials. Elucidating the temporal relationship between synovitis and OA could provide insight into the role of synovitis in OA. Methods: We conducted a prospective cohort study based on the baseline and three-year follow-up data from the Xiangya Osteoarthritis (XO) Study. We assessed bidirectional associations between ultrasound-detected synovitis and radiographic and symptomatic OA at knee and hand sites using generalized estimating equations. Additionally, we performed bidirectional Mendelian randomization (MR) analyses to test these hypotheses utilising whole-genome sequencing data in the XO population. Age, sex, body mass index, smoking, alcohol consumption, educational level, physical activity, and joint injury history were adjusted for these analyses. Findings: A total of 2211, 2420, 2280, and 2600 participants were enrolled for analyses of radiographic knee OA (RKOA), symptomatic knee OA (SKOA), radiographic hand OA (RHOA) and symptomatic hand OA (SHOA), respectively. The baseline synovitis (i.e., with synovitis vs. without synovitis) was associated with the incident RKOA (76/277 vs. 557/3674 knees), SKOA (49/387 vs. 287/4213 knees), RHOA (171/358 vs. 686/3664 hands) and SHOA (35/689 vs. 76/4327 hands), with adjusted odds ratio (aORs) of 2.2 (95% CI 1.7-3.1), 2.0 (1.3-2.9), 3.4 (2.7-4.4), and 2.4 (1.5-3.8), respectively. The baseline RKOA (with OA vs. without OA: 409/1246 vs. 481/3758 knees), SKOA (200/576 vs. 675/4356 knees), RHOA (192/778 vs. 410/3723 hands), and SHOA (41/162 vs. 548/4285 hands) were also associated with the incident synovitis, with aORs of 3.4 (95% CI 2.9-4.1), 2.7 (2.1-3.4), 2.3 (1.8-2.9) and 1.9 (1.2-2.8), respectively. These bidirectional associations were stronger when more active synovitis was compared with the reference group (all P < 0.05). MR analyses further supported bidirectional associations that synovitis significantly increased the odds of incident OA at both sites and vice versa (all ORs ranged from 1.2-1.7). Interpretation: Our population-based cohort study found novel evidence of a bidirectional association between synovitis and OA, which was further validated through MR analysis and suggested that the bidirectional association is likely causal. Our findings indicated that synovitis is both a risk factor and a consequence of the OA rather than solely a risk factor. Funding: The National Key Research and Development Plan, the National Natural Science Foundation of China, the Key Research and Development Program of Hunan Province, the Natural Science Foundation of Hunan Province, the Central South University Innovation-Driven Research Programme, and the Fundamental Research Funds for the Central Universities of Central South University.

Overlooked Role of Fungi in Drinking Water Taste and Odor Issues.

Taste and odor (T&O) are among the most frequently encountered aesthetic issues in drinking water. While fungi have been reported to produce offensive odors, their contribution to T&O in drinking water remains understudied and often overlooked. In this study, the profiles of fungal community and odorants produced by 10 native fungal isolates were investigated in 36 samples collected from two drinking water treatment plants and a premise plumbing system. A total of 17 odorants were identified with Penicillium, Aspergillus, Paecilomyces, and Alternaria genera exhibiting the highest odorant yields. Significant concentrations of musty/earthy compounds were produced by these fungal isolates, such as 2-methylisoborneol (2-MIB) (26-256 ng/L), geosmin (10-13 ng/L), and 2-isobutyl-3-methoxy-pyrazine (IBMP) (3-13 ng/L). The high odor activity value of the odorants primarily occurred within 4 d, while toxicity continued to increase during the 8 d incubation. UV treatment in premise plumbing significantly (p < 0.05) reduced the gene read counts of Ascomycota phylum, Aspergillus spp., Fusarium spp., Rhizopus spp., and Trichoderma spp., by 2.3-4.0 times. These findings underscore the previously underestimated role of fungi in contributing to T&O issues in drinking water and corresponding risks to consumers and indicate UV as a promising strategy for fungal control in drinking water.

Ciprofol in Children Undergoing Adenoidectomy and Adenotonsillectomy: A Retrospective Cohort Study.

Objective: Ciprofol is a novel anesthetic agent, its efficacy and safety had been verified and its clinical implementation has been expanded. However, the knowledge about ciprofol in children is meager. The aim of study is to evaluate the safety and effectiveness of ciprofol in general anesthesia in children undergoing adenoidectomy and adenotonsillectomy, compared with propofol. Materials: We retrospectively analyzed data of children who underwent adenoidectomy or adenotonsillectomy with general anesthesia from June to August 2023 to evaluate the safety and effectiveness of ciprofol. The primary outcomes included hemodynamic changes during induction and postoperative complications in post-anesthesia care unit. The secondary outcomes were extubation time, pediatric anesthesia emergence delirium (PAED) score. Meanwhile, subgroup analysis was performed based on age. Results: 301 children met the inclusion criteria, 157 received ciprofol induction and 144 received propofol. Patient demographics and operation-related information were similar in the two groups. However, the dosage of dexmedetomidine in the propofol group was significantly higher than that of the ciprofol group (p=0.001). The trends of hemodynamic shift during induction and intubation were the same in the two groups. The PAED scores on post-extubation 10min and 20min were significantly reduced in the ciprofol group (p<0.001 and p=0.046). Moreover, in the ≤72 months and the >72 months subgroups, the scores were also significantly lower in the ciprofol group on post-extubation 10min. With the score of >10, the incidence of emergence delirium of the ciprofol group was significantly lower on post-extubation 10min and 20min in the population and the ≤72 months subgroups (p=0.03 and p=0.02). There were no obvious postoperative complications in both groups. Conclusion: Ciprofol exhibited advantageous characteristics in the induction of children, such as stable hemodynamics, a relatively lower incidence of postoperative delirium without apparent post-anesthesia complications. Ciprofol may emerge as a novel option for general anesthesia in pediatric patients.

Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence.

The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan.

Sorption-based atmospheric water harvesting for continuous water production in the built environment: Assessment of water yield and quality.

Sorption-based atmospheric water harvesting (SAWH) is a promising solution for localized high-quality water production. Application of SAWH indoors offers dual benefits of on-site water generation and humidity control. This study evaluated the use of SAWH for water production in residential or office buildings, employing a portable zeolite-based SAWH device. Over the twelve-month testing period in the arid southwestern USA, the device achieved a median water yield of 3.6 L/day at a cost 30 % less than bottled water sold in the U.S. A mathematical model was developed for predicting water yield under different temperature and relative humidity (RH) conditions. Daily water yields were well fitted with the modified Langmuir model, with absolute humidity serving as the only prediction variable. Water extracted from a well-ventilated office building generally met the drinking water standards set by USEPA. However, elevated levels of dissolved organic carbon (DOC) were detected in the samples collected from the residential house (median = 32.6 mg/L), emphasizing the influence of human activities (e.g., cooking) on the emission of volatile and semi-volatile organic compounds in the air, which consequently reside in harvested water. Aldehydes and volatile fatty acids (formate, acetate) comprised roughly 50 % of the DOC found in the AWE water. A carbon fiber filter was not effective at removing these substances, highlighting the need for further research into effective treatment methods for DOC management before the safe use of AWE water. Overall, this study provides critical insights for the practical application of indoor SAWH as a decentralized source of high-quality water and emphasizes the need to identify and manage DOC for its safe use.

Inflammation primes the murine kidney for recovery by activating AZIN1 adenosine-to-inosine editing.

The progression of kidney disease varies among individuals, but a general methodology to quantify disease timelines is lacking. Particularly challenging is the task of determining the potential for recovery from acute kidney injury following various insults. Here, we report that quantitation of post-transcriptional adenosine-to-inosine (A-to-I) RNA editing offers a distinct genome-wide signature, enabling the delineation of disease trajectories in the kidney. A well-defined murine model of endotoxemia permitted the identification of the origin and extent of A-to-I editing, along with temporally discrete signatures of double-stranded RNA stress and adenosine deaminase isoform switching. We found that A-to-I editing of antizyme inhibitor 1 (AZIN1), a positive regulator of polyamine biosynthesis, serves as a particularly useful temporal landmark during endotoxemia. Our data indicate that AZIN1 A-to-I editing, triggered by preceding inflammation, primes the kidney and activates endogenous recovery mechanisms. By comparing genetically modified human cell lines and mice locked in either A-to-I-edited or uneditable states, we uncovered that AZIN1 A-to-I editing not only enhances polyamine biosynthesis but also engages glycolysis and nicotinamide biosynthesis to drive the recovery phenotype. Our findings implicate that quantifying AZIN1 A-to-I editing could potentially identify individuals who have transitioned to an endogenous recovery phase. This phase would reflect their past inflammation and indicate their potential for future recovery.

Numerical simulation of premixed n-heptane/air combustion in micro tube with internal channel optimization.

In military and aerospace fields, petrol and aviation kerosene are the preferred fuels for micro power systems due to their reduced carrying load and convenient fuel source. Therefore, n-heptane, an alternative to petrol and aviation paraffin, was chosen as the fuel. A micro quartz glass tube was used as the combustor, and the premixed combustion characteristics of n-heptane/air were investigated using numerical simulations. The method used to improve the internal flow channel includes a built-in cross baffle and scaled backward-facing step. The resulting optimized combustion characteristics, such as internal flow line, wall temperature, CO emission, and wall radiation, have been analyzed. The results indicate that, with a fixed equivalence ratio of 1.0 and a n-heptane mass flow rate of 2.70 mg/s, the built-in cross baffle concentrates and stabilizes the high temperature zone of the flame, resulting in a significant increase in wall temperature. Conversely, the use of the micro tube with scaled backward-facing step creates a reflux zone due to the sudden expansion of the inlet cross-section, which promotes better fuel mixing and flame anchoring. Furthermore, after comparing the output efficiencies of micro tube with different internal structures, it was discovered that enhancing the internal channel of the micro tube is crucial for increasing the wall radiation efficiency.

SDC-DeepLabv3+: Lightweight and Precise Localization Algorithm for Safflower-Harvesting Robots.

Harvesting robots had difficulty extracting filament phenotypes for small, numerous filaments, heavy cross-obscuration, and similar phenotypic characteristics with organs. Robots experience difficulty in localizing under near-colored backgrounds and fuzzy contour features. It cannot accurately harvest filaments for robots. Therefore, a method for detecting and locating filament picking points based on an improved DeepLabv3+ algorithm is proposed in this study. A lightweight network structure, ShuffletNetV2, was used to replace the backbone network Xception of the traditional DeepLabv3+. Convolutional branches for 3 different sampling rates were added to extract information on the safflower features under the receptive field. Convolutional block attention was incorporated into feature extraction at the coding and decoding layers to solve the interference problem of the near-color background in the feature-fusion process. Then, using the region of interest of the safflower branch obtained by the improved DeepLabv3+, an algorithm for filament picking-point localization was designed based on barycenter projection. The tests demonstrated that this method was capable of accurately localizing the filament. The mean pixel accuracy and mean intersection over union of the improved DeepLabv3+ were 95.84% and 96.87%, respectively. The detection rate and weights file size required were superior to those of other algorithms. In the localization test, the depth-measurement distance between the depth camera and target safflower filament was 450 to 510 mm, which minimized the visual-localization error. The average localization and picking success rates were 92.50% and 90.83%, respectively. The results show that the proposed localization method offers a viable approach for accurate harvesting localization.

Summary of evidence on prevention and management of bladder dysfunction in patients after radical hysterectomy.

AIM: To retrieve, analyse and summarize the relevant evidence on the prevention and management of bladder dysfunction in patients with cervical ancer after radical hysterectomy. DESIGN: Overview of systematic reviews. METHODS: 11 databases were searched for relevant studies from top to bottom according to the '6S' model of evidence-based resources. Two independent reviewers selected the articles, extracted the data and appraised the quality of the included reviews based on different types of evaluation tools. RESULTS: A total of 13 studies were identified, including four clinical consultants, four guidelines, four systematic reviews and one randomized controlled trial. 29 best evidence were summarized from five aspects, including definition, risk factors, assessment, prevention and management.

YTH domain family protein 3 accelerates non-small cell lung cancer immune evasion through targeting CD8+ T lymphocytes.

Immune evasion is one of the critical hallmarks of malignant tumors, especially non-small cell lung cancer (NSCLC). Emerging findings have illustrated the roles of N6-methyladenosine (m6A) on NSCLC immune evasion. Here, this study investigated the function and underlying mechanism of m6A reader YTH domain family protein 3 (YTHDF3) on NSCLC immune evasion. YTHDF3 was found to be highly expressed in NSCLC tissue and act as an independent prognostic factor for overall survival. Functionally, up-regulation of YTHDF3 impaired the CD8+ T antitumor activity to deteriorate NSCLC immune evasion, while YTHDF3 silencing recovered the CD8+ T antitumor activity to inhibit immune evasion. Besides, YTHDF3 up-regulation reduced the apoptosis of NSCLC cells. Mechanistically, PD-L1 acted as the downstream target for YTHDF3, and YTHDF3 could upregulate the transcription stability of PD-L1 mRNA. Overall, YTHDF3 targeted PD-L1 to promote NSCLC immune evasion partially through escaping effector cell cytotoxicity CD8+ T mediated killing and antitumor immunity. In summary, this study provides an essential insight for m6A modification on CD8+ T cell-mediated antitumor immunity in NSCLC, which might inspire an innovation for lung cancer tumor immunotherapy.

Chromomycins from soil-derived Streptomyces sp. inhibit the growth of human non-small cell lung cancer cells by targeting c-FLIP.

Three chromomycin derivatives, chromomycins A3 (1, CA3), A5 (2, CA5), and monodeacetylchromomycin A3 (3, MDA-CA3), were identified from the soil-derived Streptomyces sp. CGMCC 26516. A reinvestigation of the structure of CA5 is reported, of which the absolute configuration was unambiguously determined for the first time to be identical with that of CA3 based on nuclear magnetic resonance (NMR) data analysis as well as NMR and electronic circular dichroism calculations. Compounds 1-3 showed potent cytotoxicity against the non-small-cell lung cancer (NSCLC) cells (A549, H460, H157-c-FLIP, and H157-LacZ) and down-regulated the protein expression of c-FLIP in A549 cells. The IC50 values of chromomycins in H157-c-FLIP were higher than that in H157-LacZ. Furthermore, si-c-FLIP promoted anti-proliferation effect of chromomycins in NSCLC cells. In nude mice xenograft model, 1 and 2 both showed more potent inhibition on the growth of H157-lacZ xenografts than that of H157-c-FLIP xenografts. These results verify that c-FLIP mediates the anticancer effects of chromomycins in NSCLC.

Driver Fatigue Detection Using Heart Rate Variability Features from 2-Minute Electrocardiogram Signals While Accounting for Sex Differences.

Traffic accidents due to fatigue account for a large proportion of road fatalities. Based on simulated driving experiments with drivers recruited from college students, this paper investigates the use of heart rate variability (HRV) features to detect driver fatigue while considering sex differences. Sex-independent and sex-specific differences in HRV features between alert and fatigued states derived from 2 min electrocardiogram (ECG) signals were determined. Then, decision trees were used for driver fatigue detection using the HRV features of either all subjects or those of only males or females. Nineteen, eighteen, and thirteen HRV features were significantly different (Mann-Whitney U test, p < 0.01) between the two mental states for all subjects, males, and females, respectively. The fatigue detection models for all subjects, males, and females achieved classification accuracies of 86.3%, 94.8%, and 92.0%, respectively. In conclusion, sex differences in HRV features between drivers' mental states were found according to both the statistical analysis and classification results. By considering sex differences, precise HRV feature-based driver fatigue detection systems can be developed. Moreover, in contrast to conventional methods using HRV features from 5 min ECG signals, our method uses HRV features from 2 min ECG signals, thus enabling more rapid driver fatigue detection.

Hypoxia-Specific Metal-Organic Frameworks Augment Cancer Immunotherapy of High-Intensity Focused Ultrasound.

As a noninvasive treatment modality, high-intensity focused ultrasound (HIFU)-induced antitumor immune responses play a vital role in surgery prognosis. However, limited response intensity largely hinders postoperative immunotherapy. Herein, a hypoxia-specific metal-organic framework (MOF) nanosystem, coordinated by Fe3+, hypoxic-activated prodrug AQ4N, and IDO-1 signaling pathway inhibitor NLG919, is developed for the potentiating immunotherapy of HIFU surgery. The loaded AQ4N enhances the photoacoustic imaging effects to achieve accurate intraoperative navigation. Within the HIFU-established severe hypoxic environment, AQ4N is activated sequentially, following which it cooperates with Fe3+ to effectively provoke immunogenic cell death. In addition, potent NLG919 suppresses IDO-1 activity and degrades the immunosuppressive tumor microenvironment aggravated by postoperative hypoxia. In vivo studies demonstrate that the MOF-mediated immunotherapy greatly inhibits the growth of primary/distant tumors and eliminates lung metastasis. This work establishes a robust delivery platform to improve immunotherapy and the overall prognosis of HIFU surgery with high specificity and potency.

Macrophage-derived extracellular vesicles regulate skeletal stem/progenitor Cell lineage fate and bone deterioration in obesity.

Obesity-induced chronic inflammation exacerbates multiple types of tissue/organ deterioration and stem cell dysfunction; however, the effects on skeletal tissue and the underlying mechanisms are still unclear. Here, we show that obesity triggers changes in the microRNA profile of macrophage-secreted extracellular vesicles, leading to a switch in skeletal stem/progenitor cell (SSPC) differentiation between osteoblasts and adipocytes and bone deterioration. Bone marrow macrophage (BMM)-secreted extracellular vesicles (BMM-EVs) from obese mice induced bone deterioration (decreased bone volume, bone microstructural deterioration, and increased adipocyte numbers) when administered to lean mice. Conversely, BMM-EVs from lean mice rejuvenated bone deterioration in obese recipients. We further screened the differentially expressed microRNAs in obese BMM-EVs and found that among the candidates, miR-140 (with the function of promoting adipogenesis) and miR-378a (with the function of enhancing osteogenesis) coordinately determine SSPC fate of osteogenic and adipogenic differentiation by targeting the Pparα-Abca1 axis. BMM miR-140 conditional knockout mice showed resistance to obesity-induced bone deterioration, while miR-140 overexpression in SSPCs led to low bone mass and marrow adiposity in lean mice. BMM miR-378a conditional depletion in mice led to obesity-like bone deterioration. More importantly, we used an SSPC-specific targeting aptamer to precisely deliver miR-378a-3p-overloaded BMM-EVs to SSPCs via an aptamer-engineered extracellular vesicle delivery system, and this approach rescued bone deterioration in obese mice. Thus, our study reveals the critical role of BMMs in mediating obesity-induced bone deterioration by transporting selective extracellular-vesicle microRNAs into SSPCs and controlling SSPC fate.

Anatomical characteristics of superior and subsuperior segment in right lower lobe based on three-dimensional reconstruction.

OBJECTIVE: Segmentectomy has been widely performed in clinical practice, which required a comprehensive understanding of anatomical structure. In right lower lobe, studies of superior segment (S6) were relatively small-sized. And only one study focusing on subsuperior segment (S∗) was published, which showed different results with previous ones. As the close relationship between S6 and S∗, variation types and their prevalence rate were reported, aiming to providing larger-size study of S6 and showing new evidence on anatomical structure of S∗. METHODS: 800 CT imaging data were collected from patients in our hospital. Three-dimensional reconstruction was performed after quality check. All images were screened according to the definition of corresponding segment and anatomical variations were analyzed. RESULTS: The proportion of S6 variation types in the largest scale (718 patients) was reported with no significant difference compared to previous studies and newly classified subtypes of two-stem V6. The prevalence rate for S∗ in right lower lobe reached 28.3 % (203/718) with similar proportion of three types. Variation types and origins of pulmonary artery were analyzed in detail, finding two-stem A∗ only be observed in type III B∗. CONCLUSIONS: Through this study, the variation types and incidence rate of S6 were confirmed, and a different result of S∗ has been provided as well. The feasibility of the current classification standards and proposed new subclassifications were verified. The results would be a supplement to lung segmental anatomy and could advance researches in the future.

Antidepressant effect of carvedilol on streptozotocin-induced diabetic peripheral neuropathy mice by altering gut microbiota.

RATIONALE: Although diabetic peripheral neuropathic pain (DPNP) and depression have been recognized for many years, their co-morbidity relationship and effective treatment choices remain uncertain. OBJECTIVES: To evaluate the antidepressant effect of carvedilol on streptozotocin-induced DPNP mice, and the relationship with gut microbiota. METHODS: The hyperalgesia and depressive behaviors of mice with comorbidity of DPNP and depression were confirmed by pain threshold of the mechanical sensitivity test (MST), immobility time of the tail suspension test (TST) and the forced swimming test (FST). The anti-depressive effect and fecal gut microbiota composition were studied in DPNP mice treated with carvedilol (10 mg/kg/day), and the relationships between them were analyzed by Spearman's correlation. RESULTS: Depression was successfully induced in DPNP mice. Carvedilol can reverse the decreased mechanical pain threshold and relieve the depressive behaviors of DPNP mice, while increasing the abundance of Prevotella, Ruminococcus, Helicobacter and Desulfovibrio, and decreasing the abundance of Akkermansia and Allobaculum. CONCLUSIONS: Carvedilol can alleviate the mechanical hyperalgesia and alter gut microbiota to ameliorate the depression-like behaviors which induced by DPNP.

The mediation effects of malalignment on the relation of sex to the risk of incidence tibiofemoral osteoarthritis.

OBJECTIVE: To investigate to what extent the higher risk of tibiofemoral radiographic osteoarthritis (TFROA) in females vs. males can be explained by knee malalignment. DESIGN: Using data from Multicenter Osteoarthritis Study (MOST) and Osteoarthritis Initiative (OAI), we examined the relation of sex to the incident medial and lateral TFROA and performed mediation analyses to assess to what extent varus and valgus malalignments account for sex differences in the incident medial or lateral TFROA. RESULTS: Of the 3462 knees without medial and lateral TFROA in MOST, the 7-year risks of medial and lateral TFROA were 16.9% and 10.0% in females, and 15.8% and 4.2% in males, respectively. Females had 2.31-fold (95% confidence interval [95% CI]: 1.73 to 3.08) higher incident lateral TFROA than males, and the relative risk (RR) of the indirect effect of sex on lateral TFROA through valgus malalignment was 1.15 (95% CI: 1.09 to 1.20), accounting for 23% of its total effect on lateral TFROA. In OAI (n = 3095 knees), females had 1.54-fold (95% CI: 1.15 to 2.04) higher incident lateral TFROA than males, and RR of the indirect effect of sex on lateral TFROA through valgus malalignment was 1.10 (95% CI: 1.04 to 1.21), accounting for 26% of its total effect on lateral TFROA. No apparent sex difference in the incident medial TFROA was found in MOST (RR = 1.05, 95% CI: 0.89 to 1.25) or OAI (RR = 1.02, 95% CI: 0.84 to 1.19). CONCLUSION: Females had a higher risk of developing lateral TFROA than males; however, valgus malalignment only modestly explained such a difference.