Metformin exerts renoprotective effect by reducing proteinuria in spontaneously-hypertensive rats

Purpose: To study the mechanism involved in metformin (DMBG)-induced reduction of albuminuria in spontaneously-hypertensive rats (SHRs). Methods: The SHRs were divided into DMBG SHR group (n = 30) given DMBG (300 mg/kg) and NC SHR group (n = 10) given distilled water (2 ml/day), while Wistar-Kyoto rats (WKY) rats were divided into DMBG WKY group (n = 30) given DMBG (300 mg/kg ) and NC WKY group (n = 10) administered distilled water (2 ml/day). Urinary protein levels were measured and compared. Inflammatory infiltration in renal tissue, and expression of vascular endothelial growth factor (VEGF) were assessed. Abdominal aortic blood was used to measure serum levels of creatinine and blood urea nitrogen (BUN). Results: Urinary protein was markedly elevated in SHRs, while BUN in SHRs was lowered, relative to WKY rats (p < 0.05). Moreover, inflammatory cell population was lower in DMBG SHRs group than in WKY rats (p < 0.05). Kidney expressions of VEGF in SHR and WKY rats treated with metformin  were significantly reduced, relative to those in untreated rats, but VEGF-A in DMBG SHR rats was markedly elevated, relative to NC SHR group, and was also raised in DMBG WKY, when compared with NC WKY rats (p < 0.05). Conclusion: Metformin reduces albuminemia in spontaneously hypertensive rats by up-regulating VEGF expression, thereby exerting renoprotective effect. This finding provides ideas for research and development of other therapeutic approaches. Keywords: Metformin, Spontaneous hypertension, Renoprotective, Albuminuria, Kidney, Vascular endothelial growth factor (VEGF

Prophet: Conflict-Free Sharding Blockchain via Byzantine-Tolerant Deterministic Ordering

Sharding scales throughput by splitting blockchain nodes into parallel groups. However, different shards' independent and random scheduling for cross-shard transactions results in numerous conflicts and aborts, since cross-shard transactions from different shards may access the same account. A deterministic ordering can eliminate conflicts by determining a global order for transactions before processing, as proved in the database field. Unfortunately, due to the intertwining of the Byzantine environment and information isolation among shards, there is no trusted party able to predetermine such an order for cross-shard transactions. To tackle this challenge, this paper proposes Prophet, a conflict-free sharding blockchain based on Byzantine-tolerant deterministic ordering. It first depends on untrusted self-organizing coalitions of nodes from different shards to pre-execute cross-shard transactions for prerequisite information about ordering. It then determines a trusted global order based on stateless ordering and post-verification for pre-executed results, through shard cooperation. Following the order, the shards thus orderly execute and commit transactions without conflicts. Prophet orchestrates the pre-execution, ordering, and execution processes in the sharding consensus for minimal overhead. We rigorously prove the determinism and serializability of transactions under the Byzantine and sharded environment. An evaluation of our prototype shows that Prophet improves the throughput by $3.11\times$ and achieves nearly no aborts on 1 million Ethereum transactions compared with state-of-the-art sharding

Fluorine speciation and origin of Early-Middle Triassic bentonite deposits in Sichuan Basin, South China

Fluorine (F) is one of the most important environmentally harmful elements released by volcanic activity, and the bentonite deposits that formed from volcanic ashes are potentially harmful to the environment. However, the mechanisms governing F-rich bentonite formation and its F speciation composition remain enigmatic. The F-rich bentonite deposits are widely distributed in the Early-Middle Strata of the Sichuan Basin, South China. Detailed mineralogical and geochemical studies were conducted on the bentonite deposits from five sections of the Sichuan Basin. X-ray diffraction (XRD) analyses indicate that the F-rich bentonites mainly contain quartz, carbonates (calcite and dolomite) or gypsum, and clay minerals, while the clay minerals are dominated by illite and illite/smectite (I/S). Clay mineralogical studies suggest that bentonites were transformed from volcanic ashes during diagenesis by smectite illitization. The major and trace element distribution in F-rich bentonite deposits altered from volcanic ashes is most likely derived from felsic magmas, and alteration of the parent rocks (e.g., rhyolites) to bentonite is associated with leaching and subsequent removal of F. The total fluorine content (FTOT) of the bentonite samples ranged from 1,162 mg/kg to 2,604 mg/kg (average = 1773 mg/kg), well above the average FTOT contents of soils in the world. The results of the sequential extraction experiments show that the highest content is residual-fluorine (Fres), followed by carbonate-fluorine (Fcar) with a mean value of 1,556 mg/kg and 186 mg/kg, indicating carbonate is an important F sink in bentonite deposits. The average fluorine value of organic fluorine (For), Fe/Mn oxide-fluorine (Ffm) and exchangeable fluorine (Fex) are relatively low with an average value of 17.5 mg/kg, 6.8 mg/kg and 4.1 mg/kg, respectively. However, water-soluble fluorine (Fws) has a mean value of 4.0 mg/kg, which is higher than the corresponding average value in soils in an area susceptible to endemic fluorosis in China. Based on the characteristic of fluorine speciation, the fluorine in bentonite deposits may pose a risk to the environment. This study makes an important contribution to a better understanding of the characteristic of fluorine speciation in bentonites and the formation mechanism that governs fluorine enrichment in bentonites

Active-matrix GaN micro light-emitting diode display with unprecedented brightness

Displays based on microsized gallium nitride light-emitting diodes possess extraordinary brightness. It is demonstrated here both theoretically and experimentally that the layout of the n-contact in these devices is important for the best device performance. We highlight, in particular, the significance of a nonthermal increase of differential resistance upon multipixel operation. These findings underpin the realization of a blue microdisplay with a luminance of 10⁶ cd/m²

Stick-slip meta-instability of coal under uniaxial loading and AE and EMR response characteristics

Meta-instability stage is the most abundant precursory information and the most intense change stage in the process of fault stick-slip instability. In order to deeply explore the characteristics of coal meta-instability and the response law of acoustic and electrical signals in this process, the uniaxial graded loading experiments of coal samples with different prefabricated crack angles were carried out. The internal fracture source location, surface displacement field, acoustic emission and electromagnetic radiation signals of the samples were synchronously collected, and the mechanical behavior and acoustic and electrical characteristics of coal meta-instability were analyzed. The results show that: ① The inclination angle of the prefabricated crack significantly affects the internal stress distribution of the loaded coal sample, and even the expansion distribution of the new cracks in the meta-instability stage. The acoustic emission count and energy have obvious responses to stress and failure. When the meta-instability is near, the acoustic emission count and energy increase sharply at the same time, and the signal proportion is close to 20%. The response characteristics can be used as the basis for judging the crack coal sample entering the meta-instability stage. ② After entering the meta-instability state, the electromagnetic radiation activity is the most intense, which is almost consistent with the occurrence time of stress drop. Before the main fracture occurs, the energy and amplitude of electromagnetic radiation increase sharply, and the peak energy increases first and then decreases with the increase of crack dip angle. When the crack dip angle is 45°, the electromagnetic radiation count accounts for the largest proportion of the total instability process. ③ The fracture profile of the coal sample in the meta-instability stage has been basically formed. The inclination angle of the prefabricated crack has a significant impact on the duration of the meta-instability stage of the coal sample. When the inclination angle is 45°, the duration of the meta-instability stage is the longest, and when the inclination angle is 60°, the duration proportion is the shortest. The research results can be used to formulate the monitoring scheme of fault meta-instability, and the evolution and disaster of large-scale rock burst in fault structural are

Hole transport assisted by the piezoelectric field in In0.4Ga0.6N/GaN quantum wells under electrical injection

The authors observe the significant penetration of electrically injected holes through InGaN/GaN quantum wells (QWs) with an indium mole fraction of 40%. This effect and its current density dependence were analysed by studies on micro-pixel light-emitting diodes, which allowed current densities to be varied over a wide range up to 5 kA/cm2. The systematic changes in electroluminescence spectra are discussed in the light of the piezoelectric field in the high-indium-content QWs and its screening by the carriers. Simulations were also carried out to clarify the unusual hole transport mechanism and the underlying physics in these high-indium QWs

Hole transport assisted by the piezoelectric field in In0.4Ga0.6N/GaN quantum wells under electrical injection

The authors observe the significant penetration of electrically injected holes through InGaN/GaN quantum wells (QWs) with an indium mole fraction of 40%. This effect and its current density dependence were analysed by studies on micro-pixel light-emitting diodes, which allowed current densities to be varied over a wide range up to 5 kA/cm2. The systematic changes in electroluminescence spectra are discussed in the light of the piezoelectric field in the high-indium-content QWs and its screening by the carriers. Simulations were also carried out to clarify the unusual hole transport mechanism and the underlying physics in these high-indium QWs

Localized High-Concentration Electrolytes Get More Localized Through Micelle-Like Structures

Liquid electrolytes in batteries are typically treated as macroscopically homogeneous ionic transport media despite having complex chemical composition and atomistic solvation structures, leaving a knowledge gap of microstructural characteristics. Here, we reveal a unique micelle-like structure in a localized high-concentration electrolyte (LHCE), in which the solvent acts as a surfactant between an insoluble salt in diluent. The miscibility of the solvent with the diluent and simultaneous solubility of the salt results in a micelle-like structure with a smeared interface and an increased salt concentration at the centre of the salt-solvent clusters that extends the salt solubility. These intermingling miscibility effects have temperature dependencies, wherein an exemplified LHCE peaks in localized cluster salt concentration near room temperature and is utilized to form a stable solid-electrolyte interphase (SEI) on Li-metal anode. These findings serve as a guide to predicting a stable ternary phase diagram and connecting the electrolyte microstructure with electrolyte formulation and formation protocols to form stable SEI for enhanced battery cyclability

Dual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systems

XPO1 has recently emerged as a viable treatment target for solid malignancies, including glioblastoma (GBM), the most common primary malignant brain tumor in adults. However, given that tumors become commonly resistant to single treatments, the identification of combination therapies is critical. Therefore, we tested the hypothesis that inhibition of anti-apoptotic Bcl-2 family members and XPO1 are synthetically lethal. To this purpose, two clinically validated drug compounds, the BH3-mimetic, ABT263, and the XPO1 inhibitor, Selinexor, were used in preclinical GBM model systems. Our results show that inhibition of XPO1 reduces cellular viability in glioblastoma cell cultures. Moreover, addition of ABT263 significantly enhances the efficacy of XPO1 inhibition on the reduction of cellular viability, which occurs in a synergistic manner. While selinexor inhibits the proliferation of glioblastoma cells, the combination treatment of ABT263 and selinexor results in substantial induction of cell death, which is accompanied by activation of effector- initiator caspases and cleavage of PARP. Mechanistically we find that XPO1 inhibition results in down-regulation of anti-apoptotic Mcl-1 and attenuates ABT263 driven Mcl-1 up-regulation. Consistently, siRNA mediated silencing of Mcl-1 sensitizes for ABT263 mediated cell death and partially for the combination treatment. By using a human patient-derived xenograft model of glioblastoma in mice, we demonstrate that the combination treatment of ABT263 and Selinexor reduces tumor growth significantly more than each compound alone. Collectively, these results suggest that inhibition of XPO1 and Bcl-2/Bcl-xL might be a potential strategy for the treatment of malignant glial tumors

Inhibition of HDAC1/2 Along with TRAP1 Causes Synthetic Lethality in Glioblastoma Model Systems

The heterogeneity of glioblastomas, the most common primary malignant brain tumor, remains a significant challenge for the treatment of these devastating tumors. Therefore, novel combination treatments are warranted. Here, we showed that the combined inhibition of TRAP1 by gamitrinib and histone deacetylases (HDAC1/HDAC2) through romidepsin or panobinostat caused synergistic growth reduction of established and patient-derived xenograft (PDX) glioblastoma cells. This was accompanied by enhanced cell death with features of apoptosis and activation of caspases. The combination treatment modulated the levels of pro- and anti-apoptotic Bcl-2 family members, including BIM and Noxa, Mcl-1, Bcl-2 and Bcl-xL. Silencing of Noxa, BAK and BAX attenuated the effects of the combination treatment. At the metabolic level, the combination treatment led to an enhanced reduction of oxygen consumption rate and elicited an unfolded stress response. Finally, we tested whether the combination treatment of gamitrinib and panobinostat exerted therapeutic efficacy in PDX models of glioblastoma (GBM) in mice. While single treatments led to mild to moderate reduction in tumor growth, the combination treatment suppressed tumor growth significantly stronger than single treatments without induction of toxicity. Taken together, we have provided evidence that simultaneous targeting of TRAP1 and HDAC1/2 is efficacious to reduce tumor growth in model systems of glioblastoma