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HighlightsRecent advances in biomedical applications of metal–organic framework (MOF) nanocarriers for drug delivery are summarized.State-of-the-art strategies to functionalize MOFs with therapeutic agents, as well as their merits and drawbacks, are comprehensively discussed.Investigation of metal–organic frameworks (MOFs) for biomedical applications has attracted much attention in recent years. MOFs are regarded as a promising class of nanocarriers for drug delivery owing to well-defined structure, ultrahigh surface area and porosity, tunable pore size, and easy chemical functionalization. In this review, the unique properties of MOFs and their advantages as nanocarriers for drug delivery in biomedical applications were discussed in the first section. Then, state-of-the-art strategies to functionalize MOFs with therapeutic agents were summarized, including surface adsorption, pore encapsulation, covalent binding, and functional molecules as building blocks. In the third section, the most recent biological applications of MOFs for intracellular delivery of drugs, proteins, and nucleic acids, especially aptamers, were presented. Finally, challenges and prospects were comprehensively discussed to provide context for future development of MOFs as efficient drug delivery systems.

Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.Postmortem studies indicate reduced synaptic density in schizophrenia. Sellgren et al. show increased synaptic pruning in patient-derived cell models and provide evidence that C4 risk variants increase engulfment, while minocycline decreases it.

With the rapid development of e-commerce, the logistics industry faces multiple challenges, including high delivery costs, long delivery times, and a shortage of delivery personnel. Truck–drone collaborative delivery combines the high load capacity of trucks with the flexibility and speed of drones, offering an innovative and practical solution. This paper proposes the Truck–Drone Collaborative Delivery Routing Problem (TDCRPTW) and develops a multi-objective optimization model that minimizes delivery costs and maximizes time reliability under capacity and time window constraints in multi-truck, multi-drone scenarios. To solve the model, an innovative two-stage solution strategy that combines the adaptive k-means++ clustering algorithm with temperature-controlled memory simulated annealing (TCMSA) is proposed. The experimental results demonstrate that the proposed model reduces delivery costs by 10% to 50% and reduces delivery time by 15% to 40%, showcasing the superiority of the truck–drone collaborative delivery model. Moreover, the proposed algorithm demonstrates outstanding performance and reliability across multiple dimensions. Therefore, the proposed approach provides an efficient solution to the truck–drone collaborative delivery problem and offers valuable insights for enhancing the efficiency and reliability of e-commerce logistics systems.

Although many cases of genetic adaptations to high elevations have been reported, the processes driving these modifications and the pace of their evolution remain unclear. Many high-elevation adaptations (HEAs) are thought to have arisen in situ as populations rose with growing mountains. In contrast, most high-elevation lineages of the Qinghai-Tibetan Plateau appear to have colonized from low-elevation areas. These lineages provide an opportunity for studying recent HEAs and comparing them with ancestral low-elevation alternatives. Herein, we compare four frogs (three species of Nanorana and a close lowland relative) and four lizards (Phrynocephalus) that inhabit a range of elevations on or along the slopes of the Qinghai-Tibetan Plateau. The sequential cladogenesis of these species across an elevational gradient allows us to examine the gradual accumulation of HEA at increasing elevations. Many adaptations to high elevations appear to arise gradually and evolve continuously with increasing elevational distributions. Numerous related functions, especially DNA repair and energy metabolism pathways, exhibit rapid change and continuous positive selection with increasing elevations. Although the two studied genera are distantly related, they exhibit numerous convergent evolutionary changes, especially at the functional level. This functional convergence appears to be more extensive than convergence at the individual gene level, although we found 32 homologous genes undergoing positive selection for change in both high-elevation groups. We argue that species groups distributed along a broad elevational gradient provide a more powerful system for testing adaptations to high-elevation environments compared with studies that compare only pairs of high-elevation versus low-elevation species.

Non-small cell lung cancer (NSCLC) is a worldwide disease with a high morbidity and mortality rate, which is most derived from its metastasis. Some studies show that the epithelial–mesenchymal transition (EMT) process promotes lung cancer cell migration and invasion, leading to NSCLC metastasis. Total flavonoid aglycones extract (TFAE) isolated from Scutellaria baicalensis was reported to inhibit tumor growth and induce apoptosis. In this study, we found that baicalein, wogonin, and oroxylin-A were the active compounds of TFAE. After reconstructing with these three compounds [baicalein (65.8%), wogonin (21.2%), and oroxylin-A (13.0%)], the reconstructed TFAE (reTFAE) inhibited the EMT process of A549 cells. Then, bioinformatic technology was employed to elucidate the potential pharmacodynamic mechanism network of reTFAE. We identified the relationship between reTFAE and PI3K/Akt signaling pathways, with TWIST1 as the key protein. LY294002, the inhibitor of the PI3K/Akt signaling pathway, and knock-down TWIST1 could significantly enhance the efficacy of reTFAE, with increasing expression of epithelial markers and decreasing expression of mesenchymal markers in A549 cells at the same time. Furthermore, stable isotope dimethyl-labeled proteomics technology was conducted to complement the follow-up mechanism that the EMT-inhibition process may be realized through the glycolysis pathway. In conclusion, we claim that TWIST1-targeted flavonoids could provide a new strategy to inhibit EMT progress for the treatment of NSCLC.

Group I metabotropic glutamate receptors (mGlu 1 and mGlu 5 ) are promising targets for multiple psychiatric and neurodegenerative disorders. Understanding the subtype selectivity of mGlu 1 and mGlu 5 allosteric sites is essential for the rational design of novel modulators with single- or dual-target mechanism of action. In this study, starting from the deposited mGlu 1 and mGlu 5 crystal structures, we utilized computational modeling approaches integrating docking, molecular dynamics simulation, and efficient post-trajectory analysis to reveal the subtype-selective mechanism of mGlu 1 and mGlu 5 to 10 diverse drug scaffolds representing known negative allosteric modulators (NAMs) in the literature. The results of modeling identified six pairs of non-conserved residues and four pairs of conserved ones as critical features to distinguish the selective NAMs binding to the corresponding receptors. In addition, nine pairs of residues are beneficial to the development of novel dual-target NAMs of group I metabotropic glutamate receptors. Furthermore, the binding modes of a reported dual-target NAM (VU0467558) in mGlu 1 and mGlu 5 were predicted to verify the identified residues that play key roles in the receptor selectivity and the dual-target binding. The results of this study can guide rational structure-based design of novel NAMs, and the approach can be generally applicable to characterize the features of selectivity for other G-protein-coupled receptors.

The relationship between Systemic Inflammation Response Index (SIRI) and abdominal aortic calcification (AAC) remains unexplored. Data from the 2013–2014 National Health and Nutrition Examination Survey (NHANES) cohort were analyzed. AAC and severe AAC (SAAC) were quantified using the Kauppila scoring system. Multivariate linear and logistic regression were applied to examine the correlation between SIRI and AAC scores, as well as SIRI and SAAC. The predictive value of SIRI and the Systemic Immune Inflammatory Index (SII) for SAAC was compared using ROC curves and Delong test. A nomogram model for SAAC prediction was also constructed. A total of 3,047 participants were included. Results showed a significant positive association between SIRI and higher AAC scores, with scores increasing progressively across higher SIRI quartiles. A similar positive trend was observed between SIRI and SAAC prevalence. Subgroup analysis revealed that the relationship between SIRI and AAC scores was stronger in the elderly. The SAAC predictive model, incorporating SIRI and other factors, achieved an area under the curve (AUC) of 0.86 in the training set and 0.81 in the validation set. This study suggests that higher SIRI is positively associated with both AAC and SAAC, with superior predictive value for SAAC compared to SII.

Nonalcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population worldwide, and persistent overnutrition is one of the major causes. However, the underlying molecular basis has not been fully elucidated, and no specific drug has been approved for this disease. Here, we identify a regulatory mechanism that reveals a novel function of Rab2A in the progression of NAFLD based on energy status and PPARγ. The mechanistic analysis shows that nutrition repletion suppresses the phosphorylation of AMPK-TBC1D1 signaling, augments the level of GTP-bound Rab2A, and then increases the protein stability of PPARγ, which ultimately promotes the hepatic accumulation of lipids in vitro and in vivo. Furthermore, we found that blocking the AMPK-TBC1D1 pathway in TBC1D1 S231A -knock-in (KI) mice led to a markedly increased GTP-bound Rab2A and subsequent fatty liver in aged mice. Our studies also showed that inhibition of Rab2A expression alleviated hepatic lipid deposition in western diet-induced obesity (DIO) mice by reducing the protein level of PPARγ and the expression of PPARγ target genes. Our findings not only reveal a new molecular mechanism regulating the progression of NAFLD during persistent overnutrition but also have potential implications for drug discovery to combat this disease.

Background Systemic lupus erythematosus (SLE) patients are at high risk for depression and anxiety. However, the estimated prevalence of these disorders varies substantially between studies. This systematic review aimed to establish pooled prevalence levels of depression and anxiety among adult SLE patients. Methods We systematically reviewed databases including PubMed, Embase, PsycINFO, and the Cochrane database library from their inception to August 2016. Studies presenting data on depression and/or anxiety in adult SLE patients and having a sample size of at least 60 patients were included. A random-effect meta-analysis was conducted on all eligible data. Results A total of 59 identified studies matched the inclusion criteria, reporting on a total of 10828 adult SLE patients. Thirty five and thirteen methods of defining depression and anxiety were reported, respectively. Meta-analyses revealed that the prevalence of major depression and anxiety were 24% (95% CI, 16%-31%, I 2  = 95.2%) and 37% (95% CI, 12%–63%, I 2  = 98.3%) according to clinical interviews. Prevalence estimates of depression were 30% (95% CI, 22%–38%, I 2  = 91.6%) for the Hospital Anxiety and Depression Scale with thresholds of 8 and 39% (95% CI, 29%–49%, I 2  = 88.2%) for the 21-Item Beck Depression Inventory with thresholds of 14, respectively. The main influence on depression prevalence was the publication years of the studies. In addition, the corresponding pooled prevalence was 40% (95% CI, 30%–49%, I 2  = 93.0%) for anxiety according to the Hospital Anxiety and Depression Scale with a cutoff of 8 or more. Conclusions The prevalence of depression and anxiety was high in adult SLE patients. It indicated that rheumatologists should screen for depression and anxiety in their patients, and referred them to mental health providers in order to identify effective strategies for preventing and treating depression and anxiety among adult SLE patients. Trial registration Current Meta-analysis PROSPERO Registration Number: CRD 42016044125 . Registered 4 August 2016.

The positive association between the total duration of physical activity and performances of physical function may vary at different times of the day as circadian rhythm regulates individuals in response to external stimulations. We aimed to examine the association of timing-specific and overall moderate-to-vigorous physical activity (MVPA) with performances of physical function in older adults. A cross-sectional analysis was conducted among 118 older adults (mean age = 70.0 ± 5.0 years). We assessed and identified timing-specific (morning: 06:01–12:00; afternoon: 12:01–18:00; evening: 18:01–24:00) and overall MVPA using a triaxial accelerometer. Different measures of physical function were evaluated including handgrip strength (by grip dynamometer), gait speed (5-m walk test), basic functional mobility (timed up and go test), and lower limb strength (five times sit-to-stand test). Multivariate linear regression models adjusting for covariates were used to investigate the associations. Participants spent 25.0 (± 26.2) minutes in MVPA per day on average, half the time spent during the morning (47.7%), followed by during the afternoon (29.9%) and evening (21.6%). The time spent on overall MVPA was generally associated with better physical function performances. There was statistical evidence for the percentages of MVPA engagement during the morning [ B  = 0.214, 95% confidence interval (CI) 0.001 to 0.428] and afternoon ( B  = − 0.273, 95% CI − 0.518 to − 0.027) associated with basic functional mobility but with contrary directions; the percentage of MVPA engagement during the evening was associated with less time spent in gait speed performance ( B  = − 0.237, 95% CI − 0.468 to − 0.006). Our findings inform implications that the overall MVPA engagement was more important than timing-specific MVPA to older adults’ physical function performances. Strategies for accumulating time of MVPA is more practical and effective than encouraging to engage MVPA in specific timing for the enhancement of functional ability and therefore prevent disability among older adults.