First-Principles Studies on Transition Metal Doped Mo2B2 as Anode Material for Li-Ion Batteries.

New two-dimensional (2D) transition-metal borides have attracted considerable interest in research on electrode materials for Li-ion batteries (LIBs) owing to their promising properties. In this study, 2D molybdenum boride (Mo2 B2 ) with and without transition metal (TM, TM=Mn, Fe, Co, Ni, Ru, and Pt) atom doping was investigated. Our results indicated that all TM-doped Mo2 B2 samples exhibited excellent electronic conductivity, similar to the intrinsic 2D Mo2 B2 metal behavior, which is highly beneficial for application in LIBs. Moreover, we found that the diffusion energy barriers of Li along paths 1 and 2 for all TM-doped Mo2 B2 samples are smaller than 0.30 and 0.24 eV of the pristine Mo2 B2 . In particular, for 2D Co-doped Mo2 B2 , the diffusion energy barriers of Li along paths 1 and 2 are reduced to 0.14 and 0.11 eV, respectively, making them the lowest Li diffusion barriers in both paths 1 and 2. This indicates that TM doping can improve the electrochemical performance of 2D Mo2 B2 and that Co-doped Mo2 B2 is a promising electrode material for LIBs. Our work not only identifies electrode materials with promising electrochemical performance but also provides guidance for the design of high-performance electrode materials for LIBs.

ROCK1 deficiency preserves caveolar compartmentalization of signaling molecules and cell membrane integrity.

In this study, we investigated the roles of ROCK1 in regulating structural and functional features of caveolae located at the cell membrane of cardiomyocytes, adipocytes, and mouse embryonic fibroblasts (MEFs) as well as related physiopathological effects. Caveolae are small bulb-shaped cell membrane invaginations, and their roles have been associated with disease conditions. One of the unique features of caveolae is that they are physically linked to the actin cytoskeleton that is well known to be regulated by RhoA/ROCKs pathway. In cardiomyocytes, we observed that ROCK1 deficiency is coincident with an increased caveolar density, clusters, and caveolar proteins including caveolin-1 and -3. In the mouse cardiomyopathy model with transgenic overexpressing Gαq in myocardium, we demonstrated the reduced caveolar density at cell membrane and reduced caveolar protein contents. Interestingly, coexisting ROCK1 deficiency in cardiomyocytes can rescue these defects and preserve caveolar compartmentalization of ß-adrenergic signaling molecules including ß1-adrenergic receptor and type V/VI adenylyl cyclase. In cardiomyocytes and adipocytes, we detected that ROCK1 deficiency increased insulin signaling with increased insulin receptor activation in caveolae. In MEFs, we identified that ROCK1 deficiency increased caveolar and total levels of caveolin-1 and cell membrane repair ability after mechanical or chemical disruptions. Together, these results demonstrate that ROCK1 can regulate caveolae plasticity and multiple functions including compartmentalization of signaling molecules and cell membrane repair following membrane disruption by mechanical force and oxidative damage. These findings provide possible molecular insights into the beneficial effects of ROCK1 deletion/inhibition in cardiomyocytes, adipocytes, and MEFs under certain diseased conditions.

Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis.

Obesity and associated complications increasingly jeopardize global health and contribute to the rapidly rising prevalence of type 2 diabetes mellitus and obesity-related diseases. Developing novel methods for the prevention and treatment of excess body adipose tissue expansion can make a significant contribution to public health. Rho kinase is a Rho-associated coiled-coil-containing protein kinase (Rho kinase or ROCK). The ROCK family including ROCK1 and ROCK2 has recently emerged as a potential therapeutic target for the treatment of metabolic disorders. Up-regulated ROCK activity has been involved in the pathogenesis of all aspects of metabolic syndrome including obesity, insulin resistance, dyslipidemia and hypertension. The RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in both white and beige adipogenesis. Studies using ROCK pan-inhibitors in animal models of obesity, diabetes, and associated complications have demonstrated beneficial outcomes. Studies via genetically modified animal models further established isoform-specific roles of ROCK in the pathogenesis of metabolic disorders including obesity. However, most reported studies have been focused on ROCK1 activity during the past decade. Due to the progress in developing ROCK2-selective inhibitors in recent years, a growing body of evidence indicates more attention should be devoted towards understanding ROCK2 isoform function in metabolism. Hence, studying individual ROCK isoforms to reveal their specific roles and principal mechanisms in white and beige adipogenesis, insulin sensitivity, energy balancing regulation, and obesity development will facilitate significant breakthroughs for systemic treatment with isoform-selective inhibitors. In this review, we give an overview of ROCK functions in the pathogenesis of obesity and insulin resistance with a particular focus on the current understanding of ROCK isoform signaling in white and beige adipogenesis, obesity and thermogenesis in adipose tissue and other major metabolic organs involved in energy homeostasis regulation.

The effect of heteroatom doping on the active metal site of CoS2 for hydrogen evolution reaction.

The exploration of cost-effective hydrogen evolution reaction (HER) electrocatalysts through water splitting is important for developing clean energy technology and devices. The application of CoS2 in HER has been drawing more and more attention due to its low cost and relatively satisfactory HER catalytic performance. And CoS2 was found to exhibit excellent HER catalytic performance after appropriate doping according to other experimental investigations. However, the theoretical simulation and the intrinsic catalytic mechanism of CoS2 remains insufficiently investigated. Therefore, in this study, density functional theory is used to investigate the HER catalytic activity of CoS2 doped with a heteroatom. The results show that Pt-, N- and O-doped CoS2 demonstrates smaller Gibbs free energies close to that of Pt, compared with the original CoS2 and CoS2 doped with other atoms. Furthermore, HER catalytic performance of CoS2 can be improved by tuning d-band centers of H adsorption sites. This study provides an effective method to achieve modified CoS2 for high-performance HER and to investigate other transition metal sulfides as HER electrode.

Insight on the effect of Ni and Ni-N co-doping on SnO2 anode materials for lithium-ion batteries.

With the increased demand for high-rate performance Li-ion batteries, it is necessary to find available methods to improve the rate properties of SnO2 electrodes. It is noteworthy that doping was considered to be a feasible means. The electronic structures and diffusion energy barriers of Ni-doped and Ni-N co-doped SnO2 were calculated based on density functional theory. The results estimated that the energy gaps of Ni-doped and Ni-N co-doped SnO2 are 1.07 eV and 0.94 eV, which both are smaller than the value of 2.08 eV of SnO2. These exhibit that the conduction properties of SnO2 can be enhanced by doping with the Ni or Ni-N atoms. Moreover, the diffusion properties of Li can also be improved by doping with Ni-N atoms due to the diffusion energy barrier of Li from the B to C point for Ni-N co-doped SnO2 being 0.12 eV smaller than the value of 0.24 eV for the pristine SnO2. Meanwhile, the diffusion energy barriers of Li along other pathways for Ni-N co-doped SnO2 are almost the same as 0.24 eV for SnO2. These results show that both the electronic and ionic conductivity of SnO2 can be enhanced by Ni-N co-doping, which provides a theoretical explanation to promote the rate properties of SnO2 by Ni-N co-doping as anode materials for Li-ion batteries.

Rho Kinases in Embryonic Development and Stem Cell Research.

The Rho-associated coiled-coil containing kinases (ROCKs or Rho kinases) belong to the AGC (PKA/PKG/PKC) family of serine/threonine kinases and are major downstream effectors of small GTPase RhoA, a key regulator of actin-cytoskeleton reorganization. The ROCK family contains two members, ROCK1 and ROCK2, which share 65% overall identity and 92% identity in kinase domain. ROCK1 and ROCK2 were assumed to be functionally redundant, based largely on their major common activators, their high degree kinase domain homology, and study results from overexpression with kinase constructs or chemical inhibitors. ROCK signaling research has expanded to all areas of biology and medicine since its discovery in 1996. The rapid advance is befitting ROCK's versatile functions in modulating various cell behavior, such as contraction, adhesion, migration, proliferation, polarity, cytokinesis, and differentiation. The rapid advance is noticeably driven by an extensive linking with clinical medicine, including cardiovascular abnormalities, aberrant immune responsive, and cancer development and metastasis. The rapid advance during the past decade is further powered by novel biotechnologies including CRISPR-Cas and single cell omics. Current consensus, derived mainly from gene targeting and RNA interference approaches, is that the two ROCK isoforms have overlapping and distinct cellular, physiological and pathophysiology roles. In this review, we present an overview of the milestone discoveries in ROCK research. We then focus on the current understanding of ROCK signaling in embryonic development, current research status using knockout and knockin mouse models, and stem cell research.

ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice.

The RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in adipogenesis. The two ROCK isoforms, ROCK1 and ROCK2, are highly homologous. The contribution of ROCK2 to adipogenesis in vivo has not been elucidated. The present study aimed at the in vivo and in vitro roles of ROCK2 in the regulation of adipogenesis and the development of obesity. We performed molecular, histological, and metabolic analyses in ROCK2+/- and ROCK2+/KD mouse models, the latter harboring an allele with a kinase-dead (KD) mutation. Both ROCK2+/- and ROCK2+/KD mouse models showed a lean body mass phenotype during aging, associated with increased amounts of beige cells in subcutaneous white adipose tissue (sWAT) and increased thermogenic gene expression in all fat depots. ROCK2+/- mice on a high-fat diet showed increased energy expenditure accompanying by reduced obesity, and improved insulin sensitivity. In vitro differentiated ROCK2+/- stromal-vascular (SV) cells revealed increased beige adipogenesis associated with increased thermogenic gene expressions. Treatment with a selective ROCK2 inhibitor, KD025, to inhibit ROCK2 activity in differentiated SV cells reproduced the pro-beige phenotype of ROCK2+/- SV cells. In conclusion, ROCK2 activity-mediated actin cytoskeleton dynamics contribute to the inhibition of beige adipogenesis in WAT, and also promotes age-related and diet-induced fat mass gain and insulin resistance.

Eliminating Trap-States and Functionalizing Vacancies in 2D Semiconductors by Electrochemistry.

One major challenge that limits the applications of 2D semiconductors is the detrimental electronic trap states caused by vacancies. Here using grand-canonical density functional theory calculations, a novel approach is demonstrated that uses aqueous electrochemistry to eliminate the trap states of the vacancies in 2D transition metal dichalcogenides while leaving the perfect part of the material intact. The success of this electrochemical approach is based on the selectivity control by the electrode potential and the isovalence between oxygen and chalcogen. Motivated by these results, electrochemical conditions are further identified to functionalize the vacancies by incorporating various single metal atoms, which can bring in magnetism, tune carrier concentration/polarity, and/or activate single-atom catalysis, enabling a wide range of potential applications. These approaches may be generalized to other 2D materials. The results open up a new avenue for improving the properties and extending the applications of 2D materials.

High-performance all-solid-state batteries enabled by salt bonding to perovskite in poly(ethylene oxide).

Flexible and low-cost poly(ethylene oxide) (PEO)-based electrolytes are promising for all-solid-state Li-metal batteries because of their compatibility with a metallic lithium anode. However, the low room-temperature Li-ion conductivity of PEO solid electrolytes and severe lithium-dendrite growth limit their application in high-energy Li-metal batteries. Here we prepared a PEO/perovskite Li3/8Sr7/16Ta3/4Zr1/4O3 composite electrolyte with a Li-ion conductivity of 5.4 × 10-5 and 3.5 × 10-4 S cm-1 at 25 and 45 °C, respectively; the strong interaction between the F- of TFSI- (bis-trifluoromethanesulfonimide) and the surface Ta5+ of the perovskite improves the Li-ion transport at the PEO/perovskite interface. A symmetric Li/composite electrolyte/Li cell shows an excellent cyclability at a high current density up to 0.6 mA cm-2 A solid electrolyte interphase layer formed in situ between the metallic lithium anode and the composite electrolyte suppresses lithium-dendrite formation and growth. All-solid-state Li|LiFePO4 and high-voltage Li|LiNi0.8Mn0.1Co0.1O2 batteries with the composite electrolyte have an impressive performance with high Coulombic efficiencies, small overpotentials, and good cycling stability.

Disruption of both ROCK1 and ROCK2 genes in cardiomyocytes promotes autophagy and reduces cardiac fibrosis during aging.

In this study, we investigated the pathophysiological impact of Rho-associated coiled-coil-containing protein kinase (ROCK)1 and ROCK2 double deletion vs. single deletion on cardiac remodeling. Utilizing a cardiomyocyte-specific and tamoxifen-inducible MerCreMer recombinase (MCM), 3 mouse lines (MCM/ROCK1fl/fl/ROCK2fl/fl, MCM/ROCK1fl/fl, and MCM/ROCK2fl/fl) were generated. As early as 5 d after inducible deletion, the double ROCK knockout hearts exhibited reduced phosphorylation of myosin light chain (MLC) and focal adhesion kinase (FAK), supporting a role for ROCK activity in regulating the nonsarcomeric cytoskeleton. Moreover, the autophagy marker microtubule-associated proteins 1A-1B light chain 3B was increased in the double ROCK knockout, and these early molecular features persisted throughout aging. Mechanistically, the double ROCK knockout promoted age-associated or starvation-induced autophagy concomitant with reduced protein kinase B (AKT), mammalian target of rapamycin (mTOR), Unc-51-like kinase signaling, and cardiac fibrosis. In contrast, ROCK2 knockout hearts showed increased phosphorylated (p)-MLC and p-FAK levels, which were mostly attributable to a compensatory ROCK1 overactivation. Autophagy was inhibited at the baseline accompanying increased mTOR activity, leading to increased cardiac fibrosis in the ROCK2 knockout hearts. Finally, the loss of ROCK1 had no significant effect on p-MLC and p-FAK levels, mTOR signaling, or autophagy at baseline. In summary, deletions of ROCK isoforms in cardiomyocytes have different, even opposite, effects on endogenous ROCK activity and the MLC/FAK/AKT/mTOR signaling pathway, which is involved in autophagy and fibrosis of the heart.-Shi, J., Surma, M., Yang, Y., Wei, L. Disruption of both ROCK1 and ROCK2 genes in cardiomyocytes promotes autophagy and reduces cardiac fibrosis during aging.

Stable Metal Anode enabled by Porous Lithium Foam with Superior Ion Accessibility.

Lithium (Li) metal anodes have attracted much interest recently for high-energy battery applications. However, low coulombic efficiency, infinite volume change, and severe dendrite formation limit their reliable implementation over a wide range. Here, an outstanding stability for a Li metal anode is revealed by designing a highly porous and hollow Li foam. This unique structure is capable of tackling many Li metal problems simultaneously: first, it assures uniform electrolyte distribution over the inner and outer electrode's surface; second, it reduces the local current density by providing a larger electroactive surface area; third, it can accommodate volume expansion and dissipate heat efficiently. Moreover, the structure shows superior stability compared to fully Li covered foam with low porosity, and bulky Li foil electrode counterparts. This Li foam exhibits small overpotential (≈25 mV at 4 mA cm-2 ) and high cycling stability for 160 cycles at 4 mA cm-2 . Furthermore, when assembled, the porous Li metal as the anode with LiFePO4 as the cathode for a full cell, the battery has a high-rate performance of 138 mAh g-1 at 0.2 C. The beneficial structure of the Li hollow foam is further studied through density functional theory simulations, which confirms that the porous structure has better charge mobility and more uniform Li deposition.

Substantial Impact of Charge on Electrochemical Reactions of Two-Dimensional Materials.

Two-dimensional (2D) materials have attracted great interest in catalyzing electrochemical reactions such as water splitting, oxygen reduction, and carbon dioxide reduction. Quantum mechanical simulations have been extensively employed to study the catalytic mechanisms. These calculations typically assume that the catalyst is charge neutral for computational simplicity; however, in reality, the catalyst is usually charged to match its Fermi level with the applied electrode potential. These contradictions urge an evaluation of the charge effects. Here, using the example of hydrogen adsorption on the common 2D electrocatalysts (N-doped graphene and MoS2) and 3D metal catalysts, and employing the grand canonical density functional theory, we show that the charge on 2D materials can have a much stronger impact on the electrochemical reaction than the charge on 3D metals (the reaction energy can differ by >1 eV after including the charge effects). This arises from the charge-induced change in the occupation of electronic states, which is more significant for 2D materials due to their limited density of states. Our work provides a fundamental understanding of the charge effects in 2D materials, calls for re-evaluation of the previously suggested mechanisms by including the overlooked charge effects, and offers practical guidelines for designing 2D catalysts.

Defect-enriched iron fluoride-oxide nanoporous thin films bifunctional catalyst for water splitting.

Developing cost-effective electrocatalysts operated in the same electrolyte for water splitting, including oxygen and hydrogen evolution reactions, is important for clean energy technology and devices. Defects in electrocatalysts strongly influence their chemical properties and electronic structures, and can dramatically improve electrocatalytic performance. However, the development of defect-activated electrocatalyst with an efficient and stable water electrolysis activity in alkaline medium remains a challenge, and the understanding of catalytic origin is still limited. Here, we highlight defect-enriched bifunctional eletrocatalyst, namely, three-dimensional iron fluoride-oxide nanoporous films, fabricated by anodization/fluorination process. The heterogeneous films with high electrical conductivity possess embedded disorder phases in crystalline lattices, and contain numerous scattered defects, including interphase boundaries, stacking faults, oxygen vacancies, and dislocations on the surfaces/interface. The heterocatalysts efficiently catalyze water splitting in basic electrolyte with remarkable stability. Experimental studies and first-principle calculations suggest that the surface/edge defects contribute significantly to their high performance.

Disruption of ROCK1 gene restores autophagic flux and mitigates doxorubicin-induced cardiotoxicity.

Doxorubicin is among the essential medicines with a wide antitumor spectrum, but its clinical application is limited by its cardiotoxicity. We recently discovered that ROCK1 is a key molecule in mediating cardiac remodeling in response to various stresses. To determine the roles of ROCK1 in doxorubicin cardiotoxicity, we gave three doses of doxorubicin injections to wild type (WT) and ROCK1-/- mice with one week intervals between treatments, the cumulative dose being 24 mg/kg. ROCK1-/- mice exhibited preserved cardiac function, reduced apoptosis, autophagy and fibrosis compared to the WT mice. To further determine the cellular mechanisms, we have examined the role of ROCK1 in cardiomyocytes using cardiomyocyte-specific knockout mice, MHC-Cre/ROCK1fl/fl, which partially reproduced the cardioprotective characteristics of ROCK1-/- mice, indicating that ROCK1 in both cardiomyocytes and non-cardiomyocytes mediates doxorubicin cardiotoxicity. To elucidate the molecular mechanisms, a detailed time course study after a single doxorubicin injection at 10 mg/kg was performed in ROCK1-/- and MHC-Cre/ROCK1fl/fl mice. The molecular analysis revealed that both ROCK1-/- and MHC-Cre/ROCK1fl/fl hearts exhibited significant reduction of doxorubicin-induced early responses including increased apoptotic (Bax) and autophagic (p62/SQSTM1 and LC3-II) markers, associated with reduced Beclin 1 phosphorylation on Thr119, supporting reduced Beclin 1-mediated autophagy initiation due to increased association of Beclin 1 with Bcl 2 or Bcl-XL in these hearts compared to the WT or ROCK1fl/fl mice. These results support that ROCK1 deficiency is cardioprotective against doxorubicin-induced cardiotoxicity at least in part through reducing Beclin 1-mediated autophagy initiation in cardiomyocytes and restoring autophagic flux to ameliorate doxorubicin cardiotoxicity.

ROCK1 via LIM kinase regulates growth, maturation and actin based functions in mast cells.

Understanding mast cell development is essential due to their critical role in regulating immunity and autoimmune diseases. Here, we show how Rho kinases (ROCK) regulate mast cell development and can function as therapeutic targets for treating allergic diseases. Rock1 deficiency results in delayed maturation of bone marrow derived mast cells (BMMCs) in response to IL-3 stimulation and reduced growth in response to stem cell factor (SCF) stimulation. Further, integrin-mediated adhesion and migration, and IgE-mediated degranulation are all impaired in Rock1-deficient BMMCs. To understand the mechanism behind altered mast cell development in Rock1-/- BMMCs, we analyzed the activation of ROCK and its downstream targets including LIM kinase (LIMK). We observed reduced activation of ROCK, LIMK, AKT and ERK1/2 in Rock1-deficient BMMCs in response to SCF stimulation. Further, loss of either Limk1 or Limk2 also demonstrated altered BMMC maturation and growth; combined deletion of both Limk1 and Limk2 resulted in further reduction in BMMC maturation and growth. In passive cutaneous anaphylaxis model, deficiency of Rock1 or treatment with ROCK inhibitor Fasudil protected mice against IgE-mediated challenge. Our results identify ROCK/LIMK pathway as a novel therapeutic target for treating allergic diseases involving mast cells.

Rnd3/RhoE Modulates Hypoxia-Inducible Factor 1α/Vascular Endothelial Growth Factor Signaling by Stabilizing Hypoxia-Inducible Factor 1α and Regulates Responsive Cardiac Angiogenesis.

The insufficiency of compensatory angiogenesis in the heart of patients with hypertension contributes to heart failure transition. The hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling cascade controls responsive angiogenesis. One of the challenges in reprograming the insufficient angiogenesis is to achieve a sustainable tissue exposure to the proangiogenic factors, such as HIF1α stabilization. In this study, we identified Rnd3, a small Rho GTPase, as a proangiogenic factor participating in the regulation of the HIF1α-VEGF signaling cascade. Rnd3 physically interacted with and stabilized HIF1α, and consequently promoted VEGFA expression and endothelial cell tube formation. To demonstrate this proangiogenic role of Rnd3 in vivo, we generated Rnd3 knockout mice. Rnd3 haploinsufficient (Rnd3(+/-)) mice were viable, yet developed dilated cardiomyopathy with heart failure after transverse aortic constriction stress. The poststress Rnd3(+/-) hearts showed significantly impaired angiogenesis and decreased HIF1α and VEGFA expression. The angiogenesis defect and heart failure phenotype were partially rescued by cobalt chloride treatment, a HIF1α stabilizer, confirming a critical role of Rnd3 in stress-responsive angiogenesis. Furthermore, we generated Rnd3 transgenic mice and demonstrated that Rnd3 overexpression in heart had a cardioprotective effect through reserved cardiac function and preserved responsive angiogenesis after pressure overload. Finally, we assessed the expression levels of Rnd3 in the human heart and detected significant downregulation of Rnd3 in patients with end-stage heart failure. We concluded that Rnd3 acted as a novel proangiogenic factor involved in cardiac responsive angiogenesis through HIF1α-VEGFA signaling promotion. Rnd3 downregulation observed in patients with heart failure may explain the insufficient compensatory angiogenesis involved in the transition to heart failure.

Novel Insights into the Roles of Rho Kinase in Cancer.

Rho-associated coiled-coil kinase (ROCK) is a major downstream effector of the small GTPase RhoA. The ROCK family, consisting of ROCK1 and ROCK2, plays a central role in the organization of the actin cytoskeleton, and is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, proliferation, and apoptosis. Since the discovery of effective inhibitors such as fasudil and Y27632, the biological roles of ROCK have been extensively explored in numerous diseases, including cancer. Accumulating evidence supports the concept that ROCK plays important roles in tumor development and progression through regulating many key cellular functions associated with malignancy, including tumorigenicity, tumor growth, metastasis, angiogenesis, tumor cell apoptosis/survival and chemoresistance as well. This review focuses on the new advances of the most recent 5 years from the studies on the roles of ROCK in cancer development and progression; the discussion is mainly focused on the potential value of ROCK inhibitors in cancer therapy.

Association of THADA, FOXP4, GPRC6A/RFX6 genes and 8q24 risk alleles with prostate cancer in Northern Chinese men.

PURPOSE: Prostate cancer (PCa) is one of the most common malignancies in males, and multiple genetic studies have confirmed association with susceptibility to PCa. However, the risk conferred in men living in China is unkown. We selected 6 previously identified variants as candidates to define their association with PCa in Chinese men. METHODS: We genotyped 6 single nucleotide polymorphisms (SNPs) (rs1465618, rs1983891, rs339331, rs16901966, rs1447295 and rs10090154) using high resolution melting (HRM) analysis and assessed their association with PCa risk in a case-control study of 481 patients and 480 controls in a Chinese population. In addition, the individual and cumulative contribution for the risk of PCa and clinical covariates were analysed. RESULTS: We found that 5 of the 6 genetic variants were associated with PCa risk. The T allele of rs339331 and the G allele of rs16901966 showed a significant association with PCa susceptibility: OR (95%CI)= 0.78 (0.64-0.94), p<0.009 and OR (95%CI)= 0.66 (0.54-0.81), p<0.0001, as well as A allele of rs1447295 (OR [95%CI]=1.46 (1.17-1.84), p<0.001) and T allele of rs10090154 (OR [95%CI]= 0.58 (0.46-0.74), p<0.0001). rs339331(T) was associated with a 0.71-fold and 1.42-fold increase of PCa risk by dominant model (p=0.007) and recessive model (p=0.007). rs16901966 (G) was associated with a 0.51-fold and 1.98-fold increase of PCa risk by dominant model (p=0.006) and recessive model (p=0.0058). rs10090154 (T) was associated with a 1.89-fold and 0.53-fold increase of PCa risk by dominant model (p=0.000006) and recessive model (p=0.000006). And, rs1983891(C) was associated with a 0.77-fold increase of PCa risk by recessive model (p=0.045). rs1447295 was associated with a 1.57-fold increase of PCa risk by dominant model (p=0.008). rs1465618 showed no significant association with PCa. The cumulative effects test of risk alleles (rs rs1983891, rs339331, rs16901966, rs1447295 and rs10090154) showed an increasing risk to PCa in a frequency-dependent manner (ptrend=0.001), and men with more than 3 risk alleles had the most significant susceptibility to PCa (OR=1.99, p=0.001), compared with those who had one risk allele (OR=1.17, p=0.486). CONCLUSION: Our results provide further support for association of the THADA, FOXP4, GPRC6A/RFX6 and 8q24 genes with Pca in Asian populations. Further work is still required to determine the functional variations and finally clarify the underlying biological mechanisms.

Dissecting the Mechanisms of Doxorubicin and Oxidative Stress-Induced Cytotoxicity: The Involvement of Actin Cytoskeleton and ROCK1.

We have recently reported that ROCK1 deficiency in mouse embryonic fibroblasts (MEF) has superior anti-apoptotic and pro-survival effects than antioxidants against doxorubicin, a chemotherapeutic drug. Although oxidative stress is the most widely accepted mechanism, our studies suggest that ROCK1-dependent actin cytoskeleton remodeling plays a more important role in mediating doxorubicin cytotoxicity on MEFs. To further explore the contributions of ROCK1-dependent actin cytoskeleton remodeling in response to stress, this study investigates the mechanistic differences between the cytotoxic effects of doxorubicin versus hydrogen peroxide (H2O2), with a focus on cytoskeleton alterations, apoptosis and necrosis induction. We found that both types of stress induce caspase activation but with different temporal patterns and magnitudes in MEFs: H2O2 induces the maximal levels (2 to 4-fold) of activation of caspases 3, 8, and 9 within 4 h, while doxorubicin induces much higher maximal levels (15 to 25-fold) of caspases activation at later time points (16-24 h). In addition, necrosis induced by H2O2 reaches maximal levels within 4 h while doxorubicin-induced necrosis largely occurs at 16-24 h secondary to apoptosis. Moreover, both types of stress induce actin cytoskeleton remodeling but with different characteristics: H2O2 induces disruption of stress fibers associated with cytosolic translocation of phosphorylated myosin light chain (p-MLC) from stress fibers, while doxorubicin induces cortical F-actin formation associated with cortical translocation of p-MLC from central stress fibers. Furthermore, N-acetylcysteine (an antioxidant) is a potent suppressor for H2O2-induced cytotoxic effects including caspase activation, necrosis, and cell detachment, but shows a much reduced inhibition on doxorubicin-induced changes. On the other hand, ROCK1 deficiency is a more potent suppressor for the cytotoxic effects induced by doxorubicin than by H2O2. These results support the notion that doxorubicin induces caspase activation, necrosis, and actin cytoskeleton alterations largely through ROCK1-dependent and oxidative stress-independent pathways.

Comparison of tetragonal and cubic tin as anode for Mg ion batteries.

Using first-principles calculation based on density functional theory, diffusion of Mg atom into α- and ß-Sn was investigated. The diffusion barriers are 0.395 and 0.435 eV for an isolated Mg atom in the α- and ß-Sn, respectively. However, the diffusion barriers of the Mg atom decrease in the α-Sn, whereas they increase in the ß-Sn, when an additional Mg atom was inserted near the original diffusing Mg atom, which is mainly due to strong binding of Mg-Mg atoms in the ß-Sn. Therefore, it is better to use the α-Sn, rather than the ß-Sn, as an anode material for Mg ion batteries.