The Protein Fusion Strategy Facilitates the Structure Determination of Small Membrane Proteins by Cryo-EM.

Despite the resolution revolution of cryo-EM, structures of small membrane proteins (<80 kDa) are still understudied. These proteins are notoriously reluctant to structure determination by single-particle cryo-EM. Protein fusion might represent a plausible strategy to overcome such difficulties. This Perspective enumerates recent exemplary progress and discusses the future potential of the protein fusion strategy.

Apocynin exerts cytoprotective effects on dexamethasone-induced osteoblasts by inhibiting oxidative stress through the Nrf2 signalling pathway.

Steroid-induced femoral head necrosis (SIFHN) is a serious clinical complication that is caused by prolonged or excessive use of glucocorticoids (GCs). Osteoblast apoptosis and osteogenic differentiation dysfunction caused by GC-induced oxidative stress and mitochondrial impairment are strongly implicated in SIFHN. Apocynin (APO) is a kind of acetophenone extracted from an herb. In recent years, APO has received much attention for its antiapoptotic and antioxidant properties. This study aimed to investigate whether APO could protect against SIFHN and explore the mechanism. In our study, low-dose APO had no toxic effects on osteoblasts and restored dexamethasone (Dex)-treated osteoblasts by improving survival, inhibiting OS and restoring mitochondrial dysfunction. Mechanistically, APO alleviated Dex-induced osteoblast injury by activating the Nrf2 pathway, and the use of ML385 to block Nrf2 significantly eliminated the protective effect of APO. In addition, APO could reduce the formation of empty lacunae, restore bone mass and promote the expression of Nrf2 in SIFHN rats. In conclusion, APO protects osteoblasts from Dex-induced oxidative stress and mitochondrial dysfunction through activation of the Nrf2 pathway and may be a beneficial drug for the treatment of SIFHN.

Design and Analysis of a Fluid-Filled RF MEMS Switch.

In the present study, a fluid-filled RF MEMS (Radio Frequency Micro-Electro-Mechanical Systems) switch is proposed and designed. In the analysis of the operating principle of the proposed switch, air, water, glycerol and silicone oil were adopted as filling dielectric to simulate and research the influence of the insulating liquid on the drive voltage, impact velocity, response time, and switching capacity of the RF MEMS switch. The results show that by filling the switch with insulating liquid, the driving voltage can be effectively reduced, while the impact velocity of the upper plate to the lower plate is also reduced. The high dielectric constant of the filling medium leads to a lower switching capacitance ratio, which affects the performance of the switch to some extent. By comparing the threshold voltage, impact velocity, capacitance ratio, and insertion loss of the switch filled with different media with the filling media of air, water, glycerol, and silicone oil, silicone oil was finally selected as the liquid filling medium for the switch. The results show that the threshold voltage is 26.55 V after filling with silicone oil, which is 43% lower under the same air-encapsulated switching conditions. When the trigger voltage is 30.02 V, the response time is 10.12 µs and the impact speed is only 0.35 m/s. The frequency 0-20 GHz switch works well, and the insertion loss is 0.84 dB. To a certain extent, it provides a reference value for the fabrication of RF MEMS switches.

Efficacy of High-Pressure Balloon for the Treatment of Arteriovenous Fistula Stenosis: A Meta-Analysis.

OBJECTIVE: The objective of the present study was to compare the effectiveness of high-pressure balloon (HPB) versus conventional balloon (CB) angioplasty in treating arteriovenous fistula (AVF) stenosis. MATERIALS AND METHODS: A meta-analysis was conducted using data acquired from PubMed, EMBASE, the Cochrane Library, SinoMed, CNKI, WanFang, and VIP databases from the time the databases were established to December 2020. All analyses included in the studies comprised the subgroups of HPB and CB. The patency rates of AVF were compared between 2 groups at 3, 6, and 12 months after operation. RESULTS: Seven studies comprising 364 patients were included in the meta-analyses. The pooled results revealed that restenosis rate of AVFs treated with HPB was significantly lower than that of AVFs treated with CB at 3 months (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.16 to 0.61, p<0.001) and 6 months after operation (OR= 0.29, 95% CI = 0.11 to 0.79, p = 0.01). In addition, the technical success rate of HPB groups was higher (OR = 0.13, 95% CI = 0.05 to 0.36, p<0.001). However, no significant difference was observed between HPB and CB groups at 12 months after operation (OR = 0.68, 95% CI = 0.30 to 1.52, p = 0.35). No significant publication bias was observed in the analyses. CONCLUSION: High-pressure balloon is a potential option for the treatment of AVF stenosis, with a lower 3- and 6-month restenosis rate than CB. However, 12-month patency rate of HPB was not superior to CB. Therefore, further studies should be conducted to investigate the mechanisms of restenosis after angioplasty.

Upconversion Properties and Temperature-Sensing Behaviors of Alkaline-Earth-Metal Scandate Nanocrystals Doped with Er3+/Yb3+ Ions in the Presence of Alkali Ions (Li+, Na+, and K+).

Temperature-sensing media based on the fluorescence intensity ratio (FIR) of upconversion materials that suffer from low sensitivity owing to the small energy gap still have a need for new compounds with strong upconversion luminescence (UCL). In this work, a series of MSc2O4:Er3+/Yb3+ (M = Mg, Ca, Sr, and Ba) nanocrystals were prepared by a hydrothermal method using NaOH alkaline solution. The structure, morphology, and UCL characteristics of materials were investigated, and the red UCL of the CaSc2O4:Er3+/Yb3+ sample was dramatically enhanced by a factor of ∼12, ∼23, and ∼2000 compared with SrSc2O4, MgSc2O4, and BaSc2O4 samples, respectively. By adjusting alkali ions (Li+, Na+, K+), the UCL intensities of CaSc2O4:Er3+/Yb3+ and SrSc2O4:Er3+/Yb3+ samples were further improved, especially in the presence of Li+ ions. Excellent temperature-sensing behaviors are realized for CaSc2O4:Er3+/Yb3+ and SrSc2O4:Er3+/Yb3+ samples in the presence of Li+ ions, in which the maximum absolute sensitivity SA values are about 0.0041 and 0.0036 K-1 at 600 K and the corresponding relative sensitivity SR values are expressed as 1197/T2 and 1129/T2 (the current optimal SR = 1289/T2), respectively. The intense UCL and excellent SA and SR values indicate that CaSc2O4:Er3+/Yb3+ and SrSc2O4:Er3+/Yb3+ materials are promising candidates for application in high-temperature sensors working under 980 nm excitation.

Urinary metals as influencing factors of coronary heart disease among a population in Guangzhou, China.

The cardiovascular system is highly sensitive to toxic metal exposure and trace element dysregulation. However, previous findings relating to metal exposure and coronary heart disease (CHD) have partially been conflicting and difficult to exhibit the combined effect of metal mixtures. This case-control study investigated urinary concentrations of ten metal/metalloids among clinically-diagnosed CHD patients and healthy adults during May to December 2021 in Guangzhou, China. We found that cadmium (Cd) status in urine from CHD patients was remarkably higher than its reference, while chromium (Cr), nickel (Ni), copper (Cu) and selenium (Se) concentrations were lower (p < 0.05). Spearman correlation analysis showed that urinary arsenic (As) and Se were highly correlated (rs=0.830, p < 0.001), indicating their similar sources. Principal component analysis (PCA) exhibited denser distribution of Cd-Sn in cases than in controls. Logistic regression analysis exhibited significant associations between urinary Cd (adjusted OR: 1.965, 95% CI: 1.222-3.162), Se (0.787, 95% CI: 0.695-0.893), Ni (0.493, 95% CI: 0.265-0.916) and CHD risk. Quantile g-computation showed negative joint effect of metal mixtures on CHD (adjusted OR: 0.383, 95% CI: 0.159-0.932) (p < 0.05), suggesting the need for supplementing essential trace elements. The negative partial effect was primarily attributed to Se and Ni, while positive partial effect was mainly due to tin (Sn) and Cd. Nevertheless, we also found a quantile increase of Cd-Sn level was negatively correlated with 8.26% (95% CI: 3.44-13.08%) decrease of high-density lipoprotein cholesterol (p < 0.001), and 71.2% of the joint effect attributed to Cd. Based on random forest, Se, Cd and Ni were found to be the dominant influencing factors of CHD. The role of Ni in CHD is yet to be uncovered, while excessive Cd exposure and low Se status among CHD patients need to be mitigated.

Stepwise Asymmetric Allylic Substitution-Isomerization Enabled Mimetic Synthesis of Axially Chiral B,N-Heterocycles.

Axially chiral molecules bearing multiple stereogenic axes are of great importance in the field of organic chemistry. However, the efficient construction of atropisomers featuring two different types of stereogenic axes has rarely been explored. Herein, we report the novel atroposelective synthesis of configurationally stable axially chiral B,N-heterocycles. By using stepwise asymmetric allylic substitution-isomerization (AASI) strategy, diaxially chiral B,N-heterocycles bearing B-C and C-N axes that are related to the moieties of axially chiral enamines and arylborons were also obtained. In this case, all four stereoisomers of diaxially chiral B,N-heterocycles were stereodivergently afforded in high enantioselectivities. Density functional theory (DFT) studies demonstrated that the NH⋅⋅⋅π interactions played a unique role in the promotion of stereospecific isomerization, thereby leading to the highly efficient central-to-axial chirality transfer.

Realizing Fast Synthesis of High-Silica Zeolite Y with Remarkable Catalytic Performance.

High-silica zeolite Y (FAU) plays a vital role in (petro)chemical industries. However, the slow nucleation and growth kinetics of the high-silica FAU framework limit its direct synthesis and the improvement of framework SiO2 /Al2 O3 ratio (SAR). Here, a facile strategy is developed to realize the fast crystallization of high-silica zeolite Y, which involves the combination of high crystallization temperature, ultra-stable Y (USY) seeds and efficient organic-structure directing agent (OSDA). The synthesis can be finished in 5-16 h at 160 °C and with tunable SAR up to 18.2, and the key factors affecting crystallization kinetics and phase purity are elucidated. Moreover, the crystallization process was monitored to reveal the fast crystal growth mechanism. The high-silica products possess high (hydro)thermal stability and abundant strong acid sites, which endow them excellent catalytic cracking performance, obviously superior to commercial USY.

Symmetry-Induced Error Filtering in a Photonic Lieb Lattice.

Quantum computation promises intrinsically parallel information processing capacity by harnessing the superposition and entanglement of quantum states. However, it is still challenging to realize universal quantum computation due that the reliability and scalability are limited by unavoidable noises on qubits. Nontrivial topological properties like quantum Hall phases are found capable of offering protection, but require stringent conditions of topological band gaps and broken time-reversal symmetry. Here, we propose and experimentally demonstrate a symmetry-induced error filtering scheme, showing a more general role of geometry in protection mechanism and applications. We encode qubits in a superposition of two spatial modes on a photonic Lieb lattice. The geometric symmetry endows the system with topological properties featuring a flat band touching, leading to distinctive transmission behaviors of π-phase qubits and 0-phase qubits. The geometry exhibits a significant effect on filtering phase errors, which also enables it to monitor phase deviations in real time. The symmetry-induced error filtering can be a key element for encoding and protecting quantum states, suggesting an emerging field of symmetry-protected universal quantum computation and noisy intermediate-scale quantum technologies.

Macranthoidin B Modulates Key Metabolic Pathways to Enhance ROS Generation and Induce Cytotoxicity and Apoptosis in Colorectal Cancer.

BACKGROUND/AIMS: Induction of oxidative stress and reactive oxygen species (ROS) mediated-apoptosis have been utilized as effective strategies in anticancer therapy. Macranthoidin B (MB) is a potent inducer of ROS-mediated apoptosis in cancer, but its mechanism of action is poorly understood. METHOD: Superoxide production with MB exposure in colorectal cancer (CRC) cells was measured using lucigenin chemiluminescence and real-time PCR. MB's inhibitory effect on proliferation and viability of CRC cells was determined by proliferation assays. MB's effect on apoptosis of CRC cells was determined by Western blotting and annexin V-FITC/PI staining. MB's effect on the growth of CRC xenografts in mice was assessed. An established metabolomics profiling platform combining ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS) with gas chromatography-mass spectrometry (GC-MS) was performed to determine MB's effect on total metabolite variation in CRC cells. RESULTS: We found that MB increases ROS generation via modulating key metabolic pathways. Using metabolomics profiling platform combining LC-MS with GC-MS, a total of 236 metabolites were identified in HCT-116 cells in which 31 metabolites were determined to be significantly regulated (p ≤ 0.05) after MB exposure. A number of key metabolites revealed by metabolomics analysis include glucose, fructose, citrate, arginine, phenylalanine, and S-adenosylhomocysteine (SAH), suggesting specific modulation of metabolism on carbohydrates, amino acids and peptides, lipids, nucleotide, cofactors and vitamins in HCT-116 CRC cells with MB treatment highly associated with apoptosis triggered by enhanced ROS and activated caspase-3. CONCLUSION: Our results demonstrate that MB represses CRC cell proliferation by inducing ROS-mediated apoptosis.

Deficiency of NOX1/nicotinamide adenine dinucleotide phosphate, reduced form oxidase leads to pulmonary vascular remodeling.

OBJECTIVE: Involvement of reactive oxygen species derived from nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase has been documented in the development of hypoxia-induced model of pulmonary arterial hypertension (PAH). Because the PAH-like phenotype was demonstrated in mice deficient in Nox1 gene (Nox1(-/Y)) raised under normoxia, the aim of this study was to clarify how the lack of NOX1/NADPH oxidase could lead to pulmonary pathology. APPROACH AND RESULTS: Spontaneous enlargement and hypertrophy of the right ventricle, accompanied by hypertrophy of pulmonary vessels, were demonstrated in Nox1(-/Y) 9 to 18 weeks old. Because an increased number of α-smooth muscle actin-positive vessels were observed in Nox1(-/Y), pulmonary arterial smooth muscle cells (PASMCs) were isolated and characterized by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. In Nox1(-/Y) PASMCs, the number of apoptotic cells was significantly reduced without any change in the expression of endothelin-1, and hypoxia-inducible factors HIF-1α and HIF-2α, factors implicated in the pathogenesis of PAH. A significant decrease in a voltage-dependent K(+) channel, Kv1.5 protein, and an increase in intracellular potassium levels were demonstrated in Nox1(-/Y) PASMCs. When a rescue study was performed in Nox1(-/Y) crossed with transgenic mice overexpressing rat Nox1 gene, impaired apoptosis and the level of Kv1.5 protein in PASMCs were almost completely recovered in Nox1(-/Y) harboring the Nox1 transgene. CONCLUSIONS: These findings suggest a critical role for NOX1 in cellular apoptosis by regulating Kv1.5 and intracellular potassium levels. Because dysfunction of Kv1.5 is among the features demonstrated in PAH, inactivation of NOX1/NADPH oxidase may be a causative factor for pulmonary vascular remodeling associated with PAH.

Structures reveal how SGLT inhibitors work.

Sodium glucose cotransporters (SGLTs) transport glucose against its concentration gradient by harnessing the electrochemical potential gradient of sodium ions. SGLT inhibitors are widely prescribed to treat diabetes and other conditions. Recent structural studies have uncovered how chemically diverse SGLT inhibitors bind and inhibit the transporter at the atomic level.

H2-Promoted Benign Coke Strategy for Dimethyl Ether Carbonylation with Long-Term Stability and High Activity.

Zeolite-catalyzed dimethyl ether (DME) carbonylation provides a novel route to producing methyl acetate (MeOAc). Mordenite (MOR) has drawn significant interest because of its remarkable MeOAc selectivity in DME carbonylation, albeit with limited catalytic stability. Herein, novel MOR-based DME carbonylation catalysts, distinguished by long-term stability and high activity were successfully developed, based on an H2-promoted benign coke strategy. Both the H2 cofeeds and the presence of metal species with hydrogenation capability are demonstrated to be crucial for the regulation of coke depositions. The coke deposits can potentially cover the acid sites in the 12-MR main channels, thereby mitigating the occurrence of undesirable methanol-to-hydrocarbon side reactions. Meanwhile, the elimination of ultralarge coke species under the assistance of H2 and Cu species could ensure smooth mass transfer within the catalyst, contributing to its remarkable catalytic performance. The most highlighted DME carbonylation performance was achieved on coke-mediated CuZn-HMOR with a high MeOAc yield of 0.4-0.5 g·gcat-1·h-1 for over 520 h (over 50× enhancement versus HMOR), exhibiting promising industrial application potential. The current strategy is expected to inspire further research into zeolite-catalyzed reactions, which could be potentially improved by the presence of benign coke.

Design and Synthesis of Bistetrazole-Based Energetic Salts Bearing the Nitrogen-Rich Fused Ring.

A series of bistetrazole-based energetic salts bearing a nitrogen-rich fused ring were designed and synthesized. Among them, compounds 4-10 showed good detonation properties and excellent thermostability. By treating nitrogen-rich fused ring 3 with concentrated hydrochloric acid, a new type of Dimroth rearrangement was observed that afforded compound 12 efficiently. This new transformation herein constitutes a valuable addition to the Dimroth rearrangement.

A numerical study of the hemodynamic behavior and gas transport in cardiovascular systems with severe cardiac or cardiopulmonary failure supported by venoarterial extracorporeal membrane oxygenation.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been extensively demonstrated as an effective means of bridge-to-destination in the treatment of patients with severe ventricular failure or cardiopulmonary failure. However, appropriate selection of candidates and management of patients during Extracorporeal membrane oxygenation (ECMO) support remain challenging in clinical practice, due partly to insufficient understanding of the complex influences of extracorporeal membrane oxygenation support on the native cardiovascular system. In addition, questions remain as to how central and peripheral venoarterial extracorporeal membrane oxygenation modalities differ with respect to their hemodynamic impact and effectiveness of compensatory oxygen supply to end-organs. In this work, we developed a computational model to quantitatively address the hemodynamic interaction between the extracorporeal membrane oxygenation and cardiovascular systems and associated gas transport. Model-based numerical simulations were performed for cardiovascular systems with severe cardiac or cardiopulmonary failure and supported by central or peripheral venoarterial extracorporeal membrane oxygenation. Obtained results revealed that: 1) central and peripheral venoarterial extracorporeal membrane oxygenation modalities had a comparable capacity for elevating arterial blood pressure and delivering oxygenated blood to important organs/tissues, but induced differential changes of blood flow waveforms in some arteries; 2) increasing the rotation speed of extracorporeal membrane oxygenation pump (ω) could effectively improve arterial blood oxygenation, with the efficiency being especially high when ω was low and cardiopulmonary failure was severe; 3) blood oxygen indices (i.e., oxygen saturation and partial pressure) monitored at the right radial artery could be taken as surrogates for diagnosing potential hypoxemia in other arteries irrespective of the modality of extracorporeal membrane oxygenation; and 4) Left ventricular (LV) overloading could occur when ω was high, but the threshold of ω for inducing clinically significant left ventricular overloading depended strongly on the residual cardiac function. In summary, the study demonstrated the differential hemodynamic influences while comparable oxygen delivery performance of the central and peripheral venoarterial extracorporeal membrane oxygenation modalities in the management of patients with severe cardiac or cardiopulmonary failure and elucidated how the status of arterial blood oxygenation and severity of left ventricular overloading change in response to variations in ω. These model-based findings may serve as theoretical references for guiding the application of venoarterial extracorporeal membrane oxygenation or interpreting in vivo measurements in clinical practice.

Structures of human SGLT in the occluded state reveal conformational changes during sugar transport.

Sodium-Glucose Cotransporters (SGLT) mediate the uphill uptake of extracellular sugars and play fundamental roles in sugar metabolism. Although their structures in inward-open and outward-open conformations are emerging from structural studies, the trajectory of how SGLTs transit from the outward-facing to the inward-facing conformation remains unknown. Here, we present the cryo-EM structures of human SGLT1 and SGLT2 in the substrate-bound state. Both structures show an occluded conformation, with not only the extracellular gate but also the intracellular gate tightly sealed. The sugar substrate are caged inside a cavity surrounded by TM1, TM2, TM3, TM6, TM7, and TM10. Further structural analysis reveals the conformational changes associated with the binding and release of substrates. These structures fill a gap in our understanding of the structural mechanisms of SGLT transporters.

Study on creep characteristics and component model of saline soil in hexi corridor.

Accurate mastery of the creep characteristics of unsaturated saline soil is extremely important for the long-term stability and safe operation of all types of buildings. In this paper, the research object focused on the saline soil of the Zhangye area, Hexi corridor. The indoor triaxial CU creep test was carried out by means of graded loading to study the creep characteristics of saline soil under different salt content and loading stress. The Merchant and Burgers models were used to predict the creep behavior of the saline soils, and the predicted results were compared with the experimental values. The results showed that the triaxial creep curve of saline soil developed in stage III. Namely, transient creep stage, deceleration creep stage and steady-state creep stage. The creep deformation increases with the increase of salt content and loading stress. The stress-strain isochronous curve has non-linear growth, and the cluster of curves develops from dense to sparse after increasing to long-term strength (100∼150 kPa). The parameters of the Merchant and Burgers model vary with salt content and loading stress, and the creep curve predicted by the Burgers model is closer to the test value.

Identification and Validation of Hub Genes in the Stenosis of Arteriovenous Fistula.

Arteriovenous fistula (AVF) is the most widely used hemodialysis vascular access in China. However, stenosis of the AVF limits its use. The mechanism of AVF stenosis is currently unknown. Therefore, the purpose of our study was to explore the mechanisms of AVF stenosis. In this study, we identified the differentially expressed genes (DEGs) based on the Gene Expression Omnibus (GEO) dataset (GSE39488) between venous segments of AVF and normal veins. A protein-protein interaction (PPI) network was constructed to identify hub genes of AVF stenosis. Finally, six hub genes (FOS, NR4A2, EGR2, CXCR4, ATF3, and SERPINE1) were found. Combined with the results of the PPI network analysis and literature search, FOS and NR4A2 were selected as the target genes for further investigation. We validated the bioinformatic results via reverse transcription PCR (RT-PCR) and Western blot analyses on human and rat samples. The expression levels of the mRNA and protein of FOS and NR4A2 were upregulated in both human and rat samples. In summary, we found that FOS may play an important role in AVF stenosis, which could be a potential therapeutic target of AVF stenosis.

Efficient hydrodeoxygenation of methyl levulinate into pentanoic biofuels over Ru/USY catalysts.

Catalytic hydrodeoxygenation of neat methyl levulinate into pentanoic biofuels is one of the pivotal reactions in biomass valorization. A combined pentanoic acid/methyl pentanoate yield of 92% can be achieved for Ru/USY with a Si/Al ratio of 15 at 220 °C and 40 bar H2. The superior performance of Ru/USY-15 for the efficient production of pentanoic biofuels is attributed to the optimal site balance between the Ru species and strong acid sites (ca. 1 : 5).

Causal association of epigenetic aging and osteoporosis: a bidirectional Mendelian randomization study.

BACKGROUND: The relationship between aging and osteoporosis is well established. However, the relationship between the body's physiological age, i.e. epigenetic age, and osteoporosis is not known. Our goal is to analyze the bidirectional causal relationship between epigenetic clocks and osteoporosis using a bidirectional Mendelian randomization study. METHODS: We used SNPs closely associated with GrimAge, Hannum, PhenoAge, and HorvathAge in epigenetic age and SNPs closely associated with femoral neck bone mineral density, lumbar spine bone mineral density, and forearm bone mineral density as instrumental variables, respectively, using the inverse variance weighting method and several other MR methods to assess the bidirectional causal relationship between epigenetic age and osteoporosis. RESULT: There was no evidence of a clear causal relationship of epigenetic age (GrimAge, Hannum, PhenoAge, and HorvathAge) on femoral neck bone mineral density, lumbar spine bone mineral density, and forearm bone mineral density. In reverse Mendelian randomization analysis showed a significant causal effect of lumbar spine bone mineral density on GrimAge: odds ratio (OR) = 0.692, 95% confidence interval (CI) = (0.538-0.890), p = 0.004. The results suggest that a decrease in lumbar spine bone mineral density promotes an acceleration of GrimAge. CONCLUSION: There was no significant bidirectional causal relationship between epigenetic age and osteoporosis A decrease in lumbar spine bone density may lead to an acceleration of the epigenetic clock "GrimAge". Our study provides partial evidence for a bidirectional causal effect between epigenetic age and Osteoporosis.