Aryl Hydrocarbon Receptor Activation in Pulmonary Alveolar Epithelial Cells Limits Inflammation and Preserves Lung Epithelial Cell Integrity.

The aryl hydrocarbon receptor (AHR) is a receptor/transcription factor widely expressed in the lung. The physiological roles of AHR expressed in the alveolar epithelium remain unclear. In this study, we tested the hypothesis that alveolar epithelial AHR activity plays an important role in modulating inflammatory responses and maintaining alveolar integrity during lung injury and repair. AHR is expressed in alveolar epithelial cells (AECs) and is active. AHR activation with the endogenous AHR ligand, FICZ (5,11-dihydroindolo[3,2-b] carbazole-6-carboxaldehyde), significantly suppressed inflammatory cytokine expression in response to inflammatory stimuli in primary murine AECs and in the MLE-15 epithelial cell line. In an LPS model of acute lung injury in mice, coadministration of FICZ with LPS suppressed protein leak, reduced neutrophil accumulation in BAL fluid, and suppressed inflammatory cytokine expression in lung tissue and BAL fluid. Relevant to healing following inflammatory injury, AHR activation suppressed TGF-ß-induced expression of genes associated with epithelial-mesenchymal transition. Knockdown of AHR in primary AECs with shRNA or in CRISPR-Cas-9-induced MLE-15 cells resulted in upregulation of α-smooth muscle actin (αSma), Col1a1, and Fn1 and reduced expression of epithelial genes Col4a1 and Sdc1. MLE-15 clones lacking AHR demonstrated accelerated wound closure in a scratch model. AHR activation with FICZ enhanced barrier function (transepithelial electrical resistance) in primary murine AECs and limited decline of transepithelial electrical resistance following inflammatory injury. AHR activation in AECs preserves alveolar integrity by modulating inflammatory cytokine expression while enhancing barrier function and limiting stress-induced expression of mesenchymal genes.

ASD2023: towards the integrating landscapes of allosteric knowledgebase.

Allosteric regulation, induced by perturbations at an allosteric site topographically distinct from the orthosteric site, is one of the most direct and efficient ways to fine-tune macromolecular function. The Allosteric Database (ASD; accessible online at http://mdl.shsmu.edu.cn/ASD) has been systematically developed since 2009 to provide comprehensive information on allosteric regulation. In recent years, allostery has seen sustained growth and wide-ranging applications in life sciences, from basic research to new therapeutics development, while also elucidating emerging obstacles across allosteric research stages. To overcome these challenges and maintain high-quality data center services, novel features were curated in the ASD2023 update: (i) 66 589 potential allosteric sites, covering > 80% of the human proteome and constituting the human allosteric pocketome; (ii) 748 allosteric protein-protein interaction (PPI) modulators with clear mechanisms, aiding protein machine studies and PPI-targeted drug discovery; (iii) 'Allosteric Hit-to-Lead,' a pioneering dataset providing panoramic views from 87 well-defined allosteric hits to 6565 leads and (iv) 456 dualsteric modulators for exploring the simultaneous regulation of allosteric and orthosteric sites. Meanwhile, ASD2023 maintains a significant growth of foundational allosteric data. Based on these efforts, the allosteric knowledgebase is progressively evolving towards an integrated landscape, facilitating advancements in allosteric target identification, mechanistic exploration and drug discovery.

Identification of RFC4 as a potential biomarker for pan-cancer involving prognosis, tumour immune microenvironment and drugs.

RFC4 is required for DNA polymerase δ and DNA polymerase ε to initiate DNA template expansion. Downregulated RFC4 inhibits tumour proliferation by causing S-phase arrest and inhibiting mitosis, resulting in the reduction of tumour cells. RFC4 has been implicated that it plays an important role in the initiation and progression of cancers, but a comprehensive analysis of the role of RFC4 in cancer has not been performed. We comprehensively analysed the expression, prognosis, methylation level, splicing level, relationship of RFC4 and immune infiltration, and pan-cancer immunotherapy response used various databases (including TCGA, GTEx, UALCAN, Oncosplicing, TIDE, TISCH, HPA and CAMOIP), and experimented its biological function in HCC. Through pan-cancer analysis, we found that RFC4 is significantly upregulated in most tumours. The tumour patients with high expression of RFC4 have poor prognosis. The methylation level and variable splicing level of RFC4 were abnormal in most tumours compared with the adjacent tissues. Furthermore, RFC4 was closely associated with immune cell infiltration in various cancers. RFC4 was significantly co-expressed with immune checkpoints and other immune-related genes. The expression of RFC4 could indicate the immunotherapy efficacy of some tumours. The RFC4 expression was associated with sensitivity to specific small molecule drugs. Cell experiments have shown that downregulated RFC4 can inhibit cell cycle and tumour cell proliferation. We conducted a systematic pan-cancer analysis of RFC4, and the results showed that RFC4 can serve as a biomarker for cancer diagnosis and prognosis. These findings open new perspectives for precision medicine.

The strengthened impact of water availability at interannual and decadal time scales on vegetation GPP.

Water availability (WA) is a key factor influencing the carbon cycle of terrestrial ecosystems under climate warming, but its effects on gross primary production (EWA-GPP ) at multiple time scales are poorly understood. We used ensemble empirical mode decomposition (EEMD) and partial correlation analysis to assess the WA-GPP relationship (RWA-GPP ) at different time scales, and geographically weighted regression (GWR) to analyze their temporal dynamics from 1982 to 2018 with multiple GPP datasets, including near-infrared radiance of vegetation GPP, FLUXCOM GPP, and eddy covariance-light-use efficiency GPP. We found that the 3- and 7-year time scales dominated global WA variability (61.18% and 11.95%), followed by the 17- and 40-year time scales (7.28% and 8.23%). The long-term trend also influenced 10.83% of the regions, mainly in humid areas. We found consistent spatiotemporal patterns of the EWA-GPP and RWA-GPP with different source products: In high-latitude regions, RWA-GPP changed from negative to positive as the time scale increased, while the opposite occurred in mid-low latitudes. Forests had weak RWA-GPP at all time scales, shrublands showed negative RWA-GPP at long time scales, and grassland (GL) showed a positive RWA-GPP at short time scales. Globally, the EWA-GPP , whether positive or negative, enhanced significantly at 3-, 7-, and 17-year time scales. For arid and humid zones, the semi-arid and sub-humid zones experienced a faster increase in the positive EWA-GPP , whereas the humid zones experienced a faster increase in the negative EWA-GPP . At the ecosystem types, the positive EWA-GPP at a 3-year time scale increased faster in GL, deciduous broadleaf forest, and savanna (SA), whereas the negative EWA-GPP at other time scales increased faster in evergreen needleleaf forest, woody savannas, and SA. Our study reveals the complex and dynamic EWA-GPP at multiple time scales, which provides a new perspective for understanding the responses of terrestrial ecosystems to climate change.

The role of HLA-DR on plasmacytoid dendritic cells in mediating the effects of Butyrivibrio gut microbiota on Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is viewed as a progressively deteriorating neurodegenerative disorder, the exact etiology of which remains not fully deciphered to this date. The gut microbiota could play a crucial role in PD development by modulating the human immune system. OBJECTIVE: This study aims to explore the relationship between gut microbiota and PD, focusing on how immune characteristics may both directly and indirectly influence their interaction. METHODS: Utilizing cumulative data from genome-wide association studies (GWAS), our research conducted a two-sample Mendelian randomization (MR) analysis to clarify the association between the gut microbiome and PD. Additionally, by employing a two-step MR approach, we assessed the impact of gut microbiota on PD development via immune characteristics and quantified HLA-DR mediation effect on plasmacytoid dendritic cells (pDCs). RESULTS: We discovered significant associations between PD and microbiota, comprising one class, one order, two families, and two genera. Furthermore, we explored the extent to which HLA-DR on pDCs mediates the effect of Butyrivibrio gut microbiota on PD. CONCLUSION: Our study emphasizes the complex interactions between the gut microbiota, immune characteristics, and PD. The relationships and intermediary roles identified in our research provide important insights for developing potential therapies that target the gut microbiome to alleviate symptoms in PD patients.

Designing drugs and chemical probes with the dualsteric approach.

Traditionally, drugs are monovalent, targeting only one site on the protein surface. This includes orthosteric and allosteric drugs, which bind the protein at orthosteric and allosteric sites, respectively. Orthosteric drugs are good in potency, whereas allosteric drugs have better selectivity and are solutions to classically undruggable targets. However, it would be difficult to simultaneously reach high potency and selectivity when targeting only one site. Also, both kinds of monovalent drugs suffer from mutation-caused drug resistance. To overcome these obstacles, dualsteric modulators have been proposed in the past twenty years. Compared to orthosteric or allosteric drugs, dualsteric modulators are bivalent (or bitopic) with two pharmacophores. Each of the two pharmacophores bind the protein at the orthosteric and an allosteric site, which could bring the modulator with special properties beyond monovalent drugs. In this study, we comprehensively review the current development of dualsteric modulators. Our main effort reason and illustrate the aims to apply the dualsteric approach, including a "double win" of potency and selectivity, overcoming mutation-caused drug resistance, developments of function-biased modulators, and design of partial agonists. Moreover, the strengths of the dualsteric technique also led to its application outside pharmacy, including the design of highly sensitive fluorescent tracers and usage as molecular rulers. Besides, we also introduced drug targets, designing strategies, and validation methods of dualsteric modulators. Finally, we detail the conclusions and perspectives.

Application of a New Monitoring Variable: Effects of Power Loss During Squat Training on Strength Gains and Sports Performance.

ABSTRACT: Zhang, M, Chen, L, Dai, J, Yang, Q, Huang, Z, He, J, Ji, H, Sun, J, and Li, D. Application of a new monitoring variable: Effects of power loss during squat training on strength gains and sports performance. J Strength Cond Res 38(4): 656-670, 2024-This study aimed to compare the effects of power loss (PL) autoregulated volume (PL10 and PL20) with standardized fixed-load (FL) prescription on strength, sports performance, and lean body mass (LBM). Thirty-five female basketball players from a sports college were randomly assigned to 3 experimental groups (PL10, n = 12; PL20, n = 12; and FL, n = 11, respectively) that performed a resistance training (RT) program with wave-like periodization for 10 weeks using the back squat exercise. Assessments performed before (Pre) and after (Post) intervention included assessed 1 repetition maximum (1RM), body composition, 20-m sprint (T20M), change of direction (COD), and jump performance, including countermovement jump with arm swing, maximum vertical jump, and reactive strength index. Three groups showed significant improvements in strength (effect size [ES]: PL10 = 2.98, PL20 = 3.14, and FL = 1.90; p < 0.001) and jump performance (ES: PL10 = 0.74, PL20 = 1.50, and FL = 0.50; p <0.05-0.001). However, PL10 and PL20 demonstrated different advantages in sports performance compared with FL (group × time interaction, p <0.05). Specifically, PL10 significantly improved COD performance (ES = -0.79 ∼ -0.53, p <0.01), whereas PL20 showed greater improvements in sprint (ES = -0.57, p <0.05) and jump performance (ES = 0.67-1.64, p <0.01-0.001). Moreover, PL10 resulted in similar gains to PL20 and beneficial improvements compared with FL in LBM, despite performing the least repetitions. Overall, the study indicates that power loss-based autoregulation induces greater gains in LBM and sports performance, as well as eliciting a higher efficiency dose response than standardized FL prescriptions, particularly for PL10. Therefore, incorporating PL monitoring in training programs is recommended, and further studies on power-based RT would be worthwhile.

The enhancement of explosive power contributes to the development of anaerobic capacity: A comparison of autoregulatory progressive resistance exercise and velocity-based resistance training.

Objectives: Due to the character of the taekwondo, the adenosine triphosphate-phosphocreatine system provides the energy for each kick, the glycolytic system supports the repeated execution of kicks, and the aerobic system promotes recovery between these movements and the bout. Therefore, taekwondo athletes require high explosive power and anaerobic capacity in order to carry out sustained and powerful attacks. So, the purpose of this study is to compare the effects of APRE and VBRT on lower-limb explosive power and anaerobic capacity in college taekwondo players. Methods: A total of 30 taekwondo players completed an 8-week training intervention with autoregulatory progressive resistance exercise (APRE; n = 15) and velocity-based resistance training (VBRT; n = 15). Testing included the one-repetition maximum squat, countermovement jump (CMJ), taekwondo anaerobic intermittent kick test (TAIKT), and 30-s Wingate anaerobic test (WAnT). Results: (1) Intragroup comparisons revealed significant effects for one-repetition maximum squat, peak power of CMJ (CMJPP), relative peak power of CMJ (CMJRPP), and total number of TAIKT (TAIKTTN) in both the APRE and VBRT groups. The VBRT group exhibited small effect sizes for time at peak power of WAnT (WAnTPPT) and moderate effect sizes for peak power of WAnT (WAnTPP), relative peak power of WAnT (WAnTRPP), and fatigue index of TAIKT (TAIKTFI), whereas the APRE group exhibited small effect sizes for TAIKTFI. (2) Intergroup comparisons revealed no significant effects in any of the results. However, VBRT demonstrated a moderate advantage in WAnTPP and WAnTRPP, whereas APRE had a small advantage in CMJPP and CMJRPP. Conclusions: These findings suggest that APRE improved explosive power (CMJPP and CMJRPP) more, whereas VBRT improved anaerobic power output (WAnTPP and WAnTRPP) more. Both methods were found to have similar effects in improving the anaerobic endurance (WAnTPPT and TAIKTTN) and fatigue index (power drop of WAnT and TAIKTFI).

A Heterogeneous Single Atom Cobalt Catalyst for Highly Efficient Acceptorless Dehydrogenative Coupling Reactions.

A fundamental understanding of metal active sites in single-atom catalysts (SACs) is important and challenging in the development of high-performance catalyst systems. Here, a highly efficient and straightforward molten-salt-assisted approach is reported to create atomically dispersed cobalt atoms supported over vanadium pentoxide layered material, with each cobalt atom coordinated with four neighboring oxygen atoms. The liquid environment and the strong polarizing force of the molten salt at high temperatures potentially favor the weakening of VO bonding and the formation of CoO bonding on the vanadium oxide surface. This cobalt SAC achieves extraordinary catalytic efficiency in acceptorless dehydrogenative coupling of alcohols with amines to give imines, with more than 99% selectivity under almost 100% conversion within 3 h, along with a high turnover frequency (TOF) of 5882 h-1 , exceeding those of previously reported benchmarking catalysts. Moreover, it delivers excellent recyclability, reaction scalability, and substrate tolerance. Density functional theory (DFT) calculations further confirm that the optimized coordination environment and strong electronic metal-support interaction contribute significantly to the activation of reactants. The findings provide a feasible route to construct SACs at the atomic level for use in organic transformations.

Histone methyltransferase SETD1A interacts with notch and promotes notch transactivation to augment ovarian cancer development.

BACKGROUND: High expression of SETD1A, a histone methyltransferase that specifically methylates H3K4, acted as a key oncogene in several human cancers. However, the function and underlying molecular mechanism of SETD1A in ovarian cancer (OV) remain markedly unknown. METHODS: The expression of SETD1A in OV were detected by Western blot and analyzed online, and the prognosis of STED1A in OV were analyzed online. The protein and mRNA levels were determined by Western blot and RT-qPCR. The cell proliferatin, migration and invasion were measured by CCK-8 and transwell assays. The protein interaction was detected by co-IP assay. The interaction between protein and DNA was performed by ChIP assay. The tumor growth in vivo was performed by xenograft tumor model. RESULTS: SETD1A was overexpressed in OV and a predictor of poor prognosis. Overexpression of SETD1A augmented the abilities of cell proliferation, migration, and invasion in MRG1 and OVCAR5 cells. In comparison, SETD1A knockdown suppressed cell growth, migration, and invasion in SKOV3 and Caov3 cells. Specifically, SETD1A enhanced Notch signaling by promoting the expression of Notch target genes, such as Hes1, Hey1, Hey2, and Heyl. Mechanistically, SETD1A interacted with Notch1 and methylated H3K4me3 at Notch1 targets to enhance Notch signaling. In addition, restoration of Notch1 in SETD1A-knockdown OV cells recovered cell proliferation, migration and invasion, which was inhibited by SETD1A knockdown. Furthermore, reduction of SETD1A suppressed tumorigenesis in vivo. CONCLUSION: In conclusion, our results highlighted the key role of SETD1A in OV development and proved that SETD1A promotes OV development by enhancing Notch1 signaling, indicating that SETD1A may be a novel target for OV treatment.

Incorporating a Lipophilic Disulfide-Bridged Linoleic Prodrug into a Self-Microemulsifying Drug Delivery System to Facilitate Oral Absorption of Paclitaxel.

The oral absorption of paclitaxel (PTX) is restricted by poor solubility in the gastrointestinal tract (GIT), low permeability, and high first-pass metabolism. Lipid carriers, such as a self-microemulsifying drug delivery system (SMEDDS), have been deemed as promising vehicles for promoting oral delivery of PTX. Herein, a lipophilic disulfide-bridged linoleic prodrug (PTX-S-S-LA) was synthesized and efficiently incorporated into SMEDDS to facilitate the oral absorption of PTX. This study mainly aims to evaluate the usefulness of the disulfide-bridged linoleic prodrug incorporated with SMEDDS and provides a new strategy for efficient oral delivery of PTX. The prodrug SMEDDS showed a markedly higher drug loading efficiency (3-fold) compared to that of parent PTX. PTX-S-S-LA SMEDDS significantly increased the drug partition (about 1.9-fold) in the intestinal micellar aqueous phase compared to PTX in the in vitro lipolysis study. Additionally, the gastrointestinal (GI) biodistribution study demonstrated that SMEDDS could enhance the GI biological adhesion and go through the lymphatic system to transport. Moreover, it was found that the reduction-sensitive prodrug (PTX-S-S-LA) has good stability in the GIT, leading to an improved antitumor efficiency without significant GI toxicity. Overall, the PTX-linoleic prodrug (PTX-S-S-LA) in combination with SMEDDS provides a promising way to enable effective oral delivery of PTX.

Broad activation of the Parkin pathway induces synaptic mitochondrial deficits in early tauopathy.

Mitochondrial defects are a hallmark of early pathophysiology in Alzheimer's disease, with pathologically phosphorylated tau reported to induce mitochondrial toxicity. Mitophagy constitutes a key pathway in mitochondrial quality control by which damaged mitochondria are targeted for autophagy. However, few details are known regarding the intersection of mitophagy and pathologies in tauopathy. Here, by applying biochemical and cell biological approaches including time-lapse confocal imaging in live tauopathy neurons, combined with gene rescue experiments via stereotactic injections of adeno-associated virus particles into tauopathy mouse brains, electrophysiological recordings and behavioural tests, we demonstrate for the first time that mitochondrial distribution deficits at presynaptic terminals are an early pathological feature in tauopathy brains. Furthermore, Parkin-mediated mitophagy is extensively activated in tauopathy neurons, which accelerates mitochondrial Rho GTPase 1 (Miro1) turnover and consequently halts Miro1-mediated mitochondrial anterograde movement towards synaptic terminals. As a result, mitochondrial supply at tauopathy synapses is disrupted, impairing synaptic function. Strikingly, increasing Miro1 levels restores the synaptic mitochondrial population by enhancing mitochondrial anterograde movement and thus reverses tauopathy-associated synaptic failure. In tauopathy mouse brains, overexpression of Miro1 markedly elevates synaptic distribution of mitochondria and protects against synaptic damage and neurodegeneration, thereby counteracting impairments in learning and memory as well as synaptic plasticity. Taken together, our study reveals that activation of the Parkin pathway triggers an unexpected effect-depletion of mitochondria from synaptic terminals, a characteristic feature of early tauopathy. We further provide new mechanistic insights into how parkin activation-enhanced Miro1 degradation and impaired mitochondrial anterograde transport drive tauopathy-linked synaptic pathogenesis and establish a foundation for future investigations into new therapeutic strategies to prevent synaptic deterioration in Alzheimer's disease and other tauopathies.

Assessing Regional Ecosystem Conditions Using Geospatial Techniques-A Review.

Ecosystem conditions at the regional level are critical factors for environmental management, public awareness, and land use decision making. Regional ecosystem conditions may be examined from the perspectives of ecosystem health, vulnerability, and security, as well as other conceptual frameworks. Vigor, organization, and resilience (VOR) and pressure-stress-response (PSR) are two commonly adopted conceptual models for indicator selection and organization. The analytical hierarchy process (AHP) is primarily used to determine model weights and indicator combinations. Although there have been many successful efforts in assessing regional ecosystems, they remain affected by a lack of spatially explicit data, weak integration of natural and human dimensions, and uncertain data quality and analyses. In the future, regional ecosystem condition assessments may be advanced by incorporating recent improvements in spatial big data and machine learning to create more operative indicators based on Earth observations and social metrics. The collaboration between ecologists, remote sensing scientists, data analysts, and scientists in other relevant disciplines is critical for the success of future assessments.

Decoding the Conformational Selective Mechanism of FGFR Isoforms: A Comparative Molecular Dynamics Simulation.

Fibroblast growth factor receptors (FGFRs) play critical roles in the regulation of cell growth, differentiation, and proliferation. Specifically, FGFR2 gene amplification has been implicated in gastric and breast cancer. Pan-FGFR inhibitors often cause large toxic side effects, and the highly conserved ATP-binding pocket in the FGFR1/2/3 isoforms poses an immense challenge in designing selective FGFR2 inhibitors. Recently, an indazole-based inhibitor has been discovered that can selectively target FGFR2. However, the detailed mechanism involved in selective inhibition remains to be clarified. To this end, we performed extensive molecular dynamics simulations of the apo and inhibitor-bound systems along with multiple analyses, including Markov state models, principal component analysis, a cross-correlation matrix, binding free energy calculation, and community network analysis. Our results indicated that inhibitor binding induced the phosphate-binding loop (P-loop) of FGFR2 to switch from the open to the closed conformation. This effect enhanced extensive hydrophobic FGFR2-inhibitor contacts, contributing to inhibitor selectivity. Moreover, the key conformational intermediate states, dynamics, and driving forces of this transformation were uncovered. Overall, these findings not only provided a structural basis for understanding the closed P-loop conformation for therapeutic potential but also shed light on the design of selective inhibitors for treating specific types of cancer.

Facile Synthesis of Single Iron Atoms over MoS2 Nanosheets via Spontaneous Reduction for Highly Efficient Selective Oxidation of Alcohols.

The facile creation of high-performance single-atom catalysts (SACs) is intriguing in heterogeneous catalysis, especially on 2D transition-metal dichalcogenides. An efficient spontaneous reduction approach to access atomically dispersed iron atoms supported over defect-containing MoS2 nanosheets is herein reported. Advanced characterization methods demonstrate that the isolated iron atoms situate atop of molybdenum atoms and coordinate with three neighboring sulfur atoms. This Fe SAC delivers exceptional catalytic efficiency (1 atm O2 @ 120 °C) in the selective oxidation of benzyl alcohol to benzaldehyde, with 99% selectivity under almost 100% conversion. The turnover frequency is calculated to be as high as 2105 h-1 . Moreover, it shows admirable recyclability, storage stability, and substrate tolerance. Density functional theory calculations reveal that the high catalytic activity stems from the optimized electronic structure of single iron atoms over the MoS2 support.

Hybrid membrane-external-cavity surface-emitting laser.

We develop, analyze, and demonstrate an optically-pumped semiconductor disk laser using an active mirror architecture formed by sandwiching the semiconductor gain membrane between two heatspreaders, one of which is coated with a high-reflectivity multilayer. Thermal modeling indicates that this structure outperforms traditional VECSELs. Employing an InGaAs/GaAs MQW gain structure, we demonstrate output powers of approximately 30 W at a center wavelength of λ ≈ 1178 nm in a TEM00 mode using an in-well pumped geometry.

Autophagy inhibition facilitates wound closure partially dependent on the YAP/IL-33 signaling in a mouse model of skin wound healing.

Autophagy is a self-phagocytic and highly evolutionarily conserved intracellular lysosomal catabolic system, which plays a vital role in a variety of trauma models, including skin wound healing (SWH). However, the roles and potential mechanisms of autophagy in SWH are still controversial. We firstly investigated the role of autophagy in SWH-induced wound closure rate, inflammatory response, and histopathology, utilizing an inhibitor of autophagy 3-methyladenine (3-MA) and its agonist rapamycin (RAP). As expected, we found 3-MA treatment remarkably increased the wound closure rate, combated inflammation response, and mitigated histopathological changes, while RAP delivery aggravated SWH-induced pathological damage. To further exploit the underlying mechanism of autophagy regulating inflammation, the specific inhibitors of yes-associated protein (YAP), Verteporfin, and Anti-IL-33 were applied. Herein, treating with 3-MA markedly suppressed the expression of tumor necrosis factor-α (TNF-α), IL-1ß, and IL-6, promoted that of IL-10, IL-33, and ST2, while RAP administration reverted SWH-induced the up-regulation of these inflammatory cytokines mentioned above. Importantly, Verteporfin administration not only down-regulated the expression levels of YAP, TNF-α, and IL-6 but also up-regulated that of IL-33 and IL-10. Unexpectedly, 3-MA or RAP retreatment did not have any impact on the changes in IL-33 among these inflammatory indicators. Furthermore, elevated expression of IL-33 promoted wound closure and alleviated the pathological damage, whereas, its antagonist Anti-IL-33 treatment overtly reversed the above-mentioned effects of IL-33. Moreover, 3-MA in combination with anti-IL-33 treatment reversed the role of 3-MA alone in mitigated pathological changes, but they failed to revert the effect of anti-IL-33 alone on worsening pathological damage. In sum, emerging data support the novel contribution of the YAP/IL-33 pathway in autophagy inhibition against SWH-induced pathological damage, and highlight that the autophagy/YAP/IL-33 signal axis is expected to become a new therapeutic target for SWH.

Synthesis of trans-stilbenes via phosphine-catalyzed coupling reactions of benzylic halides.

An efficient and practical phosphine-catalyzed homo-coupling reaction of benzyl chlorides is described. The reactions proceed smoothly in the presence of CsF/B(OMe)3 and NaH as the base, respectively, to provide trans-stilbenes in good yields with a broad scope. Unsymmetrical stilbenes are also generated from the reactions of benzyl chlorides with phosphonium salts. Several P-based key intermediates have been detected by NMR and HRMS analyses, which shed light on the postulated catalytic cycle. In the presence of different bases, the transformations involve two different pathways, in which phenylcarbene and phosphonium alkoxide are considered as key intermediates, respectively. The two pathways are complementary in synthesis but different in mechanisms. The synthetic utility, including gram-scale reactions and straightforward access to π-conjugated molecules, has been demonstrated as well.

Platelet membrane-camouflaged nanoparticles carry microRNA inhibitor against myocardial ischaemia‒reperfusion injury.

The incidence of myocardial ischaemia‒reperfusion injury (MIRI) is increasing every year, and there is an urgent need to develop new therapeutic approaches. Nrf2 is thought to play a protective role during MIRI and it is regulated by microRNAs (miRNAs). This study focused on PLGA nanoparticles camouflaged by platelet membrane vesicles (PMVs) (i.e., PMVs@PLGA complexes) carrying microRNA inhibitors, which regulate Nrf2 and can play a therapeutic role in the MIRI process. In vitro and in vivo characterization showed that PMVs@PLGA has excellent transfection efficiency, low toxicity and good targeting. MicroRNAs that effectively regulate Nrf2 were identified, and then PMVs@PLGA-miRNA complexes were prepared and used for in vitro and in vivo treatment. PMVs@PLGA-miRNA complexes can effectively target the delivery of inhibitors to cardiomyocytes. Our results suggest that PMVs@PLGA complexes are a novel delivery system and a novel biological approach to the treatment of MIRI.

Comparison of Velocity and Percentage-based Training on Maximal Strength: Meta-analysis.

The purpose was to analyze the comparison of velocity-based resistance training and one-repetition maximum (%1RM) percentage-based training in maximal strength improvement by meta-analyzing and to find the reasons for the controversial findings of different studies. Ten studies were included in the systematic review and seven were subjected to meta-analysis. A total of 139 subjects were selected from the included articles after exclusion, including athletes of different specialties (N=93) and non-athletes mainly from fitness groups (N=46). The overall effect size was SMD=0.26 (95%CL 0.03 to 0.49, P=0.03, I²=0). As for the comparison of the analysis of different intervention objects as subgroups, the effect size of athletes as the subgroup was 0.35 (95%CI 0.06 to 0.64, p=0.02, I²=0), indicating that in the RCT with athletes as the intervention target, the effect of VBRT in improving the maximal strength was significantly different from that of PBT. Velocity-based resistance training might be more effective than percentage-based training in maximal strength improvement, in which velocity-based resistance training is more suitable for athletes in season, while percentage-based training is more suitable for the general sports population. More high-quality researches should deal with the effect of other athletic performance with velocity-based resistance training in the future.