The effects of low ambient temperature on steroidogenesis and mitochondrial functions in the testes of wild ground squirrels (Spermophilus dauricus).

Seasonal reproduction is a widely used breeding strategy in wildlife, especially vertebrates inhabiting temperate regions. Generally, ambient temperature is considered a significant factor influencing the reproductive status of animals. In the present study, wild ground squirrels (Spermophilus dauricus), typical seasonal breeders, were used as an animal model to investigate the mechanism behind the impact of low ambient temperature on testicular function. To simulate the winter environment of wild ground squirrels, we lowered the temperature gradient in the rearing environment to 4 °C. At sampling, the body surface temperature of the squirrels reared under normal ambient temperature (22 °C, NAT group) and the low ambient temperature (4 °C, LAT group) were 31.5 °C and 22.8 °C, respectively. Subsequently, we conducted immunohistochemical assays, qPCR, and enzyme-linked immunosorbent assays (ELISA) to examine the variations in testicular functions, as well as the dynamics and functions of mitochondria, in the squirrels of NAT and LAT groups. As a result, the levels of positive immunostaining for PCNA, P21, and P27 were significantly lower in the testes of LAT group, while the levels of immunostaining for Cleaved Caspase-3 and TUNEL were significantly higher. In addition, the low-temperature treatment reduced the expression level of steroidogenesis-related genes, including LHR, FSHR, GATA-4, P450scc, and P450arom, and decreased the testosterone concentration. Moreover, markers of mitochondrial fission and fusion, DRP1 and MFN2, respectively, were increased in the testes of LAT group. Additionally, the mRNA level of SOD1 was notably higher in the testes of LAT group. In conclusion, the low ambient temperature inhibited spermatogenesis, steroidogenesis, as well as mitochondrial dynamics and functions in the testes of wild ground squirrels.

4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification.

BACKGROUND AND AIMS: Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure. METHODS: Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets. RESULTS: 4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure. CONCLUSIONS: 4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure.

Thrombectomy alone vs thrombectomy with over 2/3-dose intravenous thrombolysis pretreatment in the DIRECT-MT trial.

BACKGROUND: The DIRECT-MT trial showed that endovascular thrombectomy (EVT) alone was noninferior to EVT preceded by intravenous alteplase. However, the infusion of intravenous alteplase was uncompleted before the initiation of EVT in most cases of this trial. Therefore, the additional benefit and risk of over 2/3-dose intravenous alteplase pretreatment remain to be assessed. METHODS: We assessed patients with acute anterior circulation ischemic stroke who received EVT alone or with over 2/3-dose intravenous alteplase pretreatment from the DIRECT-MT trial. Patients were assigned to the thrombectomy-alone group and the alteplase pretreatment group. The primary outcome was the distribution of modified Rankin Scale (mRS) at 90 days. The interaction of treatment allocation and collateral capacity was assessed. RESULTS: A total of 393 patients (thrombectomy alone: 315; alteplase pretreatment: 78) were identified. The thrombectomy alone was comparable with alteplase pretreatment prior to the thrombectomy on the distribution of mRS at 90 days without significant effect modification by collateral capacity (adjusted common odds ratio (acOR), 1.12; 95% CI, 0.72-1.74; adjusted P for interaction = 0.83). Successful reperfusion before thrombectomy and the number of passes in the thrombectomy alone group differed significantly from the alteplase pretreatment group (2.6% vs. 11.5%; corrected P = 0.02 and 2 vs. 1; corrected P = 0.003). There was no interaction between treatment allocation and collateral capacity on all outcomes. CONCLUSIONS: EVT alone and EVT preceded by over 2/3-dose intravenous alteplase might have equal efficacy and safety for patients with acute anterior circulation large vessel occlusion, except for successful perfusion before thrombectomy and the number of passes.

Prognostic Value of Thrombus Volume and Interaction With First-Line Endovascular Treatment Device Choice.

BACKGROUND: A larger thrombus in patients with acute ischemic stroke might result in more complex endovascular treatment procedures, resulting in poorer patient outcomes. Current evidence on thrombus volume and length related to procedural and functional outcomes remains contradicting. This study aimed to assess the prognostic value of thrombus volume and thrombus length and whether this relationship differs between first-line stent retrievers and aspiration devices for endovascular treatment. METHODS: In this multicenter retrospective cohort study, 670 of 3279 patients from the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) for endovascularly treated large vessel occlusions were included. Thrombus volume (0.1 mL) and length (0.1 mm) based on manual segmentations and measurements were related to reperfusion grade (expanded Treatment in Cerebral Infarction score) after endovascular treatment, the number of retrieval attempts, symptomatic intracranial hemorrhage, and a shift for functional outcome at 90 days measured with the reverted ordinal modified Rankin Scale (odds ratio >1 implies a favorable outcome). Univariable and multivariable linear and logistic regression were used to report common odds ratios (cORs)/adjusted cOR and regression coefficients (B/aB) with 95% CIs. Furthermore, a multiplicative interaction term was used to analyze the relationship between first-line device choice, stent retrievers versus aspiration device, thrombus volume, and outcomes. RESULTS: Thrombus volume was associated with functional outcome (adjusted cOR, 0.83 [95% CI, 0.71-0.97]) and number of retrieval attempts (aB, 0.16 [95% CI, 0.16-0.28]) but not with the other outcome measures. Thrombus length was only associated with functional independence (adjusted cOR, 0.45 [95% CI, 0.24-0.85]). Patients with more voluminous thrombi had worse functional outcomes if endovascular treatment was based on first-line stent retrievers (interaction cOR, 0.67 [95% CI, 0.50-0.89]; P=0.005; adjusted cOR, 0.74 [95% CI, 0.55-1.0]; P=0.04). CONCLUSIONS: In this study, patients with a more voluminous thrombus required more endovascular thrombus retrieval attempts and had a worse functional outcome. Patients with a lengthier thrombus were less likely to achieve functional independence at 90 days. For more voluminous thrombi, first-line stent retrieval compared with first-line aspiration might be associated with worse functional outcome.

Combination of robot-assisted laparoscopy and ureteroscopy for the management of complex ureteral strictures.

BACKGROUND: To summarize the efficacy of combined robot-assisted laparoscopy and ureteroscopy in treating complex ureteral strictures. METHODS: Eleven patients underwent combined robot-assisted laparoscopy and ureteroscopy for ureteral strictures between January 2020 and August 2022. Preoperative B-ultrasound, glomerular filtration rate measurement, and intravenous pyelography showed different degrees of hydronephrosis in the affected kidney and moderate to severe stenosis in the corresponding part of the ureter. During the operation, stricture segment resection and end-to-end anastomosis were performed using the da Vinci robot to find the stricture point under the guidance of a ureteroscopic light source in the lateral or supine lithotomy position. RESULTS: All the patients underwent robot-assisted laparoscopy and ureteroscopy combined with end-to-end ureterostenosis. There were no conversions to open surgery or intraoperative complications. Significant ureteral stricture segments were found in all patients intraoperatively; however, stricture length was not significantly different from the imaging findings. Patients were followed up for 3-27 months. Two months postoperatively, the double-J stent was removed, a ureteroscopy was performed, the ureteral mucosa at the end-to-end anastomosis grew well, and the lumen was patent in all patients. Furthermore, imaging examination showed that hydronephrosis was significantly improved in all patients, with grade I hydronephrosis in three cases and grade 0 hydronephrosis in eight cases. No recurrence of ureteral stricture was observed in patients followed up for > 1 year. CONCLUSION: Robot-assisted laparoscopy combined with ureteroscopy is an effective method for treating complex ureteral strictures and can achieve accurate localization of the structured segment.

Catalyst-assisted heteroepitaxial strategy for highly orderedß-Ga2O3nanoarrays and their optical property investigation.

In this work, we demonstrate the growth of highly orderedß-Ga2O3nanoarrays with (001) preferred growth plane for the first time through a facile heteroepitaxial strategy using metal Ga and c-sapphire as Ga precursor and monocrystalline substrate. The (001) preferred growth plane means that theß-Ga2O3nanowires grow along the normal direction of the (001) plane. Theß-Ga2O3nanoarrays along (001) preferential plane exhibit inclined six equivalent directions that correspond to the six crystallographic symmetry of (0001)α-Al2O3. High-resolution transmission electron microscopy analyses confirm the good crystallinity and the existence of unusual epitaxial relationship of {310}ß-Ga2O3ǁ (0001)α-Al2O3and <001>ß-Ga2O3or <132>ß-Ga2O3ǁ [11¯00]α-Al2O3. UV-vis and cathodoluminescence measurements reveal the wide band gap of 4.8 eV and the strong UV-blue luminescence (300-500 nm) centered at ∼388 nm. Finally, the luminescence mechanism is further investigated with the assistance of x-ray photoelectron spectroscopy. The heteroepitaxial strategy of highly orderedß-Ga2O3nanoarrays in this work will undoubtedly pave a solid way toward the fundamental research and the applications of Ga2O3nanodevices in optoelectronic, gas sensor, photocatalyst and next-generation power electronics.

Utilizing structure based drug design and metabolic soft spot identification to optimize the in vitro potency and in vivo pharmacokinetic properties leading to the discovery of novel reversible Bruton's tyrosine kinase inhibitors.

Bruton's tyrosine kinase (BTK) is an essential node on the BCR signaling in B cells, which are clinically validated to play a critical role in B-cell lymphomas and various auto-immune diseases such as Multiple Sclerosis (MS), Pemphigus, and rheumatoid arthritis (RA). Although non-selective irreversible BTK inhibitors have been approved for oncology, due to the emergence of drug resistance in B-cell lymphoma associated with covalent inhibitor, there an unmet medical need to identify reversible, selective, potent BTK inhibitor as viable therapeutics for patients. Herein, we describe the identification of Hits and subsequence optimization to improve the physicochemical properties, potency and kinome selectivity leading to the discovery of a novel class of BTK inhibitors. Utilizing Met ID and structure base design inhibitors were synthesized with increased in vivo metabolic stability and oral exposure in rodents suitable for advancing to lead optimization.

Microwave-assisted method to degrade phenol using persulfate or hydrogen peroxide catalyzed by Cu-bearing silicon carbide.

The radical generation properties of hydrogen peroxide and persulfate for phenol degradation were investigated under microwave irradiation using copper-doped silicon carbide (Cu/SiC) composites as catalyst. The results showed that 90% and 70% of phenol and total organic carbon (TOC), respectively, were removed within 7 min. Microwave activation of hydrogen peroxide and sodium persulfate in terms of thermal effects and accelerated electron transfer was analyzed by degradation kinetics and X-ray photoelectron spectroscopy (XPS). The microwave activation of Na2S2O8 demonstrated that the hot spots promote decomposition of persulfate more rapidly and the rate of persulfate decomposition was more than three times the activation rate of a normal heating method. There is a synergistic effect between Cu and microwave radiation, which is highlighted by the H2O2 activation; ·OH was generated due to the redox cycle between Cu(I)/Cu(II) and was responsible for phenol degradation using H2O2. High performance liquid chromatography (HPLC) analysis indicated that hydroxylation and sulfate radicals addition of phenol were the initial oxidation reaction steps of hydrogen peroxide and persulfate, respectively, followed by further oxidation to form short-chain carboxylic acids.

Hydrothermal Approach to Spinel-Type 2D Metal Oxide Nanosheets.

The peculiar physical and chemical properties of 2D nanostructures have aroused global research interest in developing new members, synthetic technology, and exploring their potential applications in functional nanodevices. However, it is extremely challenging to directly obtain the 2D nanosheets for these extrinsic layered structures using conventional routines. In this work, we demonstrate the facile and general synthesis of 2D spinel-type metal oxides nanosheets through a simple hydrothermal reaction. Using this method, cubic γ-Ga2O3, ZnGa2O4 and MnGa2O4 nanosheets with triangular/hexagonal configuration and ultrathin thickness have been synthesized, and all these nanosheets show preferential growth along (111) plane with the minimum formation energy. Microstructural and composition analyses using HRTEM, EDS, XPS, and so on reveal that the as-synthesized 2D nanosheets are well-crystallized in cubic fcc-phase and show high purity in composition, and the formation process of MGa2O4 nanosheets can be regarded as the competition of M2+ and Ga3+ in tetrahedral site. Spatially resolved cathodoluminescence measurement of individual 2D nanosheet shows that the γ-Ga2O3, ZnGa2O4, and MnGa2O4 nanosheets exhibit distinct luminescence behavior, and ZnGa2O4 nanosheets show the strongest emission in visible region. It is expected that the facile synthesis of spinel-type metal oxides of γ-Ga2O3, ZnGa2O4, and MnGa2O4 nanosheets will further promote the exploration of a variety of semiconductor nanostructures that could not be achieved using conventional technology suitable for layered structures and will also open up some opportunities for the integration of advanced functional nanodevices such as photodetectors, phosphors on the basis of them.

Optimization of novel reversible Bruton's tyrosine kinase inhibitors identified using Tethering-fragment-based screens.

Since the approval of ibrutinib for the treatment of B-cell malignancies in 2012, numerous clinical trials have been reported using covalent inhibitors to target Bruton's tyrosine kinase (BTK) for oncology indications. However, a formidable challenge for the pharmaceutical industry has been the identification of reversible, selective, potent molecules for inhibition of BTK. Herein, we report application of Tethering-fragment-based screens to identify low molecular weight fragments which were further optimized to improve on-target potency and ADME properties leading to the discovery of reversible, selective, potent BTK inhibitors suitable for pre-clinical proof-of-concept studies.

Studies on the reaction mechanism of Cu/SiC catalytic oxidation for degradation of methyl orange in presence of microwave.

The removal of methyl orange (MO) in a copper-loaded silicon carbide (Cu/SiC) system under microwave (MW) irradiation was studied. Cu/SiC was synthesized by employing an impregnation method and the effects of parameters such as reaction time, catalyst dosage, hydrogen peroxide (H2O2) dosage, microwave power and pH on the rate of degradation of MO were also studied. The obtained results showed that almost complete degradation was obtained in the presence of Cu/SiC catalyst within 8 min of irradiation when 100 mL of MO solution (20 mg/L), 3 ml/L of H2O2, 2 g/L of catalyst dose, 600 W of MW power, and pH 7 were applied. The Cu-bearing catalyst with H2O2 formed a Fenton-like system and the rate of generation of hydroxyl radicals (·OH) was also accelerated by subjecting to MW. From the kinetic analysis, it is revealed that the degradation of MO using the MW-Cu/SiC-H2O2 system follows the pseudo-first-order.

Phosphorylation of connexin 43 induced by traumatic brain injury promotes exosome release.

Traumatic brain injury (TBI) caused by the external force leads to the neuronal dysfunction and even death. TBI has been reported to significantly increase the phosphorylation of glial gap junction protein connexin 43 (Cx43), which in turn propagates damages into surrounding brain tissues. However, the neuroprotective and anti-apoptosis effects of glia-derived exosomes have also been implicated in recent studies. Therefore, we detected whether TBI-induced phosphorylation of Cx43 would promote exosome release in rat brain. To generate TBI model, adult male Sprague-Dawley rats were subjected to lateral fluid percussion injury. Phosphorylated Cx43 protein levels and exosome activities were quantified using Western blot analysis following TBI. Long-term potentiation (LTP) was also tested in rat hippocampal slices. TBI significantly increased the phosphorylated Cx43 and exosome markers expression in rat ipsilateral hippocampus, but not cortex. Blocking the activity of Cx43 or ERK, but not JNK, significantly suppressed TBI-induced exosome release in hippocampus. Furthermore, TBI significantly inhibited the induction of LTP in hippocampal slices, which could be partially but significantly restored by pretreatment with exosomes. The results imply that TBI-activated Cx43 could mediate a nociceptive effect by propagating the brain damages, as well as a neuroprotective effect by promoting exosome release. NEW & NOTEWORTHY We have demonstrated in rat traumatic brain injury (TBI) models that both phosphorylated connexin 43 (p-Cx43) expression and exosome release were elevated in the hippocampus following TBI. The promoted exosome release depends on the phosphorylation of Cx43 and requires ERK signaling activation. Exosome treatment could partially restore the attenuated long-term potentiation. Our results provide new insight for future therapeutic direction on the functional recovery of TBI by promoting p-Cx43-dependent exosome release but limiting the gap junction-mediated bystander effect.

Composition and Band Gap Tailoring of Crystalline (GaN)1- x(ZnO) x Solid Solution Nanowires for Enhanced Photoelectrochemical Performance.

Photoelectrochemical water splitting has emerged as an effective artificial photosynthesis technology to generate clean energy of H2 from sunlight. The core issue in this reaction system is to develop a highly efficient photoanode with a large fraction of solar light absorption and greater active surface area. In this work, we take advantage of energy band engineering to synthesize (GaN)1- x(ZnO) x solid solution nanowires with ZnO contents ranging from 10.3% to 47.6% and corresponding band gap tailoring from 3.08 to 2.77 eV on the basis of the Au-assisted VLS mechanism. The morphology of nanowires directly grown on the conductive substrate facilitates the charge transfer and simultaneously improves the surface reaction sites. As a result, a photocurrent approximately 10 times larger than that for a conventional powder-based photoanode is obtained, which indicates the potential of (GaN)1- x(ZnO) x nanowires in the preparation of superior photoanodes for enhanced water splitting. It is anticipated that the water-splitting capability of (GaN)1- x(ZnO) x nanowire can be further increased through alignment control for enhanced visible light absorption and reduction of charge transfer resistance.

Template Approach to Crystalline GaN Nanosheets.

Crystalline GaN nanosheets hold great challenge in growth and promising application in optoelectronic nanodevices. In this work, we reported an accessible template approach toward the rational synthesis of GaN nanosheets through the nitridation of metastable γ-Ga2O3 nanosheets synthesized from a hydrothermal reaction. The cubic γ-Ga2O3 nanosheets with smooth surface and decent crystallinity can be directly converted into hexagonal GaN nanosheets with similar morphology framework and comparable crystal quality in NH3 at 850 °C. UV-vis spectrum measurement reveals that the GaN nanosheets show a band gap of 3.30 eV with strong visible absorption in the range of 370-500 nm. The template synthetic strategy proposed in this work will open up more opportunities for the achievement of a variety of sheetlike nanostructures that can not be obtained through conventional routines and will undoubtedly further promote the fundamental research of newly emerging sheetlike nanostructures and nanotechnology.

Semiconductor Solid-Solution Nanostructures: Synthesis, Property Tailoring, and Applications.

The innovation of band-gap engineering in advanced materials caused by the alloying of different semiconductors into solid-solution nanostructures provides numerous opportunities and advantages in optoelectronic property tailoring. The semiconductor solid-solution nanostructures have multifarious emission wavelength, adjustability of absorption edge, tunable electrical resistivity, and cutting-edge photoredox capability, and these advantages can be rationalized by the assorted synthesis strategies such as, binary, ternary, and quaternary solid-solutions. In addition, the abundance of elements in groups IIB, IIIA, VA, VIA, and VIIA provides sufficient room to tailor-make the semiconductor solid-solution nanostructures with the desired properties. Recent progress of semiconductor solid-solution nanostructures including synthesis strategies, structure and composition design, band-gap engineering related to the optical and electrical properties, and their applications in different fields is comprehensively reviewed. The classification, formation principle, synthesis routes, and the advantage of semiconductor solid-solution nanostructures are systematically reviewed. Moreover, the challenges faced in this area and the future prospects are discussed. By combining the information together, it is strongly anticipated that this Review may shed new light on understanding semiconductor solid-solution nanostructures while expected to have continuous breakthroughs in band-gap engineering and advanced optoelectronic nanodevices.

Effect of ultrasonic processing on the changes in activity, aggregation and the secondary and tertiary structure of polyphenol oxidase in oriental sweet melon (Cucumis melo var. makuwa Makino).

BACKGROUND: Polyphenol oxidase (PPO) mainly contributes to the browning reaction of fruits and vegetables and causes serious damage to the quality of sweet melon products. However, traditional methods to inactivate browning may induce more unexpected risks than ultrasonic processing. Meanwhile, there are no reports on the effect of ultrasound on PPO directly purified from sweet melon. RESULTS: The PPO in the original juice was less inactivated than the purified form when treated with ultrasound. As for purified PPO, superior to thermal treatment, less heat was needed to inactivate the PPO with ultrasonic treatment. At intensity lower than 200 W, ultrasound did not significantly affect the structure and activity of PPO (P > 0.05), and latent PPO was activated. At intensity higher than 200 W, ultrasound inactivated PPO, induced aggregation and dissociation of PPO particles and significantly decreased the α-helix structure content. CONCLUSION: Low-frequency high-intensity ultrasound caused an inactivation effect and conformational changes of purified PPO from oriental sweet melons. Changes in the PPO structure induced by ultrasound eventually inactivated the enzyme. Ultrasound may be a potential method to inactivate PPO in oriental sweet melons. © 2016 Society of Chemical Industry.

Involvement of Connexin40 in the Protective Effects of Ginsenoside Rb1 Against Traumatic Brain Injury.

Ginsenosides are the major active components of ginseng, which have been proven to be effective in therapies for neurodegenerative diseases. Ginsenoside Rb1 (GS-Rb1) is the most abundant among all the identified ginsenosides and has been shown to exert neuroprotective effects, although the underlying molecular mechanisms remain unclear. Connexins are a family of transmembrane proteins that form gap junctions, which are important for diffusion of cytosolic factors such as ions and second messenger signaling molecules. Previous studies have shown that a subset of connexin proteins is involved in neuroprotection. We investigated the protective effects of GS-Rb1 against traumatic brain injury (TBI) and the potential mechanism using TBI mouse model. We discovered that TBI-induced brain injury and up-regulation of connexin40 (Cx40) protein expression as early as 6 h post-TBI, which was reversed by administration of GS-Rb1. In addition, we found that the protective effects of GS-Rb1 are dose and time dependent and are partially mediated through phosphorylation of ERK1/2 signaling pathway, as evidenced by the abolishment of GS-Rb1-mediated elevation of p-ERK1/2 expression and inhibition of Cx40 expressions when ERK inhibitor U0126 was used. Our study provides evidence that Cx40 is implicated in TBI-induced brain injuries, and GS-Rb1 exerts neuroprotective activity against TBI involving down-regulation of Cx40 expression.

Morphology-controlled syntheses of α-MnO2 for electrochemical energy storage.

Manganese dioxide (MnO2) nanoarchitectures including microspheres assembled by nanosheets and hollow urchins assembled by nanorods have been successfully synthesized using a facile and efficient hydrothermal method at 150 °C. The effects of concentrations of the reactants and reaction time on the structures and morphologies of MnO2 were systematically investigated. The experimental results showed that the morphologies of MnO2 transformed into nanosheet-assembled microspheres (10 min) from nanorod-assembled hollow urchins (5 min) by tuning the suitable reaction time. The nanorod-assembled hollow urchins experienced the morphology transformation cycle from urchin to a disordered structure to urchin with the extension of the reaction time. Furthermore, the nanorods with different diameters and lengths were formed with different concentrations of reactants at the same reaction time (8 h). The MnO2 nanorods fabricated with 0.59 g KMnO4 showed a maximum specific capacitance (198 F g(-1)) with a good rate capability and excellent cycling stability (maintained 94% after 2000 cycles). Furthermore, the nanosheet-assembled microspheres exhibited the higher specific capacitance of 131 F g(-1) at 1 A g(-1) with a long-term cycling stability for the samples at different reaction times. These results indicated their promising applications as high-performance supercapacitor electrodes and provided a generic guideline in developing different nanostructured electrode materials for electrochemical energy storage.

Methyl-substitution of an iminohydantoin spiropiperidine ß-secretase (BACE-1) inhibitor has a profound effect on its potency.

The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 µM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.

Protective effect of ginsenoside Rb1 on integrity of blood-brain barrier following cerebral ischemia.

Ginsenosides, the major bioactive compounds in ginseng root, have been found to have antioxidant, immunomodulatory, and anti-inflammatory activities. In the present study, we sought to investigate whether and how ginsenoside Rb1 (GS-Rb1), the most abundant ginsenoside, can protect blood-brain barrier (BBB) integrity following cerebral ischemia in middle cerebral artery occlusion (MCAO) animal model. ICR mice underwent MCAO and received GS-Rb1 by intraperitoneal injection at 3 h after reperfusion. We evaluated infarction, neurological scores, brain edema, Evans blue (EB) extravasation, and tight junction protein expression at 48 h after MCAO. We further examined whether GS-Rb1 protected BBB integrity by suppressing post-ischemic inflammation-induced activity of matrix metalloproteinase-9 (MMP-9) and nicotinamide adenine dinucleotide phosphate oxidase (NOX). First, GS-Rb1 decreased infarction and improved neurological deficits in MCAO animals. In addition, GS-Rb1 reduced EB extravasation and brain edema and preserved expression of tight junction proteins in the ischemic brain. Moreover, GS-Rb1 inhibited expression of pro-inflammatory factors including nitric oxide synthase and IL-1ß, but increased expression of anti-inflammatory markers arginase 1 and IL-10 in the ischemic brain. Consistently, GS-Rb1 attenuated ischemia-induced expression and activity of MMP9. Finally, GS-Rb1 reduced NOX-4 mRNA expression and NOX activity in ischemic brain. These results suggest that GS-Rb1 protects loss of BBB integrity in ischemic stroke by suppressing neuroinflammation induction of MMP-9 and NOX4-derived free radicals, and indicate its potential for treating brain injuries, such as ischemia and stroke.