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Temperature and pressure conditions of deep shale are beyond experiment range, and the amount of adsorbed gas is difficult to determine. To predict the adsorbed gas content of deep shales under formation conditions, isothermal adsorption experiments and model building were conducted on shale samples from Longmaxi Formation in China. A temperature-dependent adsorption model based on the Langmuir equation is proposed, which can be well-fitted by observed isotherms with a high correlation coefficient. Based on the fitted parameters at 303.15 K, the isothermal adsorption curves at 333.15 K, 363.15 K, and 393.15 K are predicted, showing a good agreement with experimental curves available. Compared with previous prediction methods, the biggest advantage of the proposed method is that it can be carried out only based on one-time isothermal adsorption experiment. Based on the predictions, the downward trend of the excess adsorption curves will slow down under high temperature and pressure conditions, and when the pressure reaches a certain level (> 80 MPa), the temperature has little effect on the excess adsorption capacity. While for absolute adsorption, the gas adsorption reaches saturation much slowly at high temperature, it can also reach saturation under formation pressure. Under the burial depth of marine shale, temperature plays a major role in controlling the adsorbed gas, resulting in the decrease of adsorbed gas content in deep shale, and its ratio will further decrease as the depth increases. [ABSTRACT FROM AUTHOR]

Continuous fibre-reinforced thermoplastics (FRTPs) are replacing metals in certain applications in the aerospace industry due to their superior properties e.g., high strength-to-weight ratio and good fatigue resistance. Adopting these lightweight materials in vehicles is a solution for improving vehicle efficiency across the transport industry. Among various manufacturing techniques for FRTP parts, stamp forming is one of the most advantageous when small structures and mass production are targeted. However, a significant barrier for this technique is the quality control of manufacturing. The current paper reviews the development of stamp forming technology, benefits of using such technology and the typical quality issues in stamp forming of FRTP parts. First, advantages of stamp forming, compared to other thermoforming techniques, are discussed, followed by a review of the historical development of the process. Second, deformation mechanisms of FRTPs during stamp forming are examined, with particular focuses on the frictional behaviour and testing thereof. Third, the main defects associated with stamp forming are considered, alongside suggestions towards reducing their presence. Finally, an extensive survey of the effect of process parameters on the mechanical properties of formed parts is included, with generally expected trends highlighted and methodologies for finding optimum conditions presented. Based on the thorough review of state-of-the-art stamp forming, future trends and research gaps to be tackled for widening the applicability of FRTP stamp forming are suggested. [ABSTRACT FROM AUTHOR]

Introduction: To explore the prevalence of depressive symptoms and the associated risk factors in frontline nurses under COVID-19 pandemic. Methods: This cross-sectional study was conducted from February 20, 2020 to March 20, 2020 and involved 562 frontline nurses. The effective response rate was 87.68%. After propensity score matched, there were 498 participants left. Extensive characteristics, including demographics, dietary habits, life-related factors, work-related factors, and psychological factors were collected based on a self-reported questionnaire. Specific scales measured the levels of sleep quality, physical activity, depressive symptoms, perceived organization support and psychological capital. Adjusted odds ratios and 95% confidence intervals were determined by binary paired logistic regression. Results: Of the nurses enrolled in the study, 50.90% had depressive symptoms. Three independent risk factors were identified: poor sleep quality (OR = 1.608, 95% CI: 1.384–1.896), lower optimism of psychological capital (OR = 0.879, 95% CI: 0.805–0.960) and no visiting friend constantly (OR = 0.513, 95% CI: 0.286–0.920). Conclusions: This study revealed a considerable high prevalence of depressive symptoms in frontline nurses during the COVID-19 outbreak, and identified three risk factors, which were poor sleep quality, lower optimism of psychological capital, and no visiting friend constantly. Protecting mental health of nurses is important for COVID-19 pandemic control and their wellbeing. These findings enrich the existing theoretical model of depression and demonstrated a critical need for additional strategies that could address the mental health in frontline nurses for policymakers. [ABSTRACT FROM AUTHOR]

As part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Phelps et al., 2016) that described how we intended to replicate selected experiments from the paper 'Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs' (Tay et al., 2011). Here, we report the results. We found depletion of putative PTEN competing endogenous mRNAs (ceRNAs) in DU145 cells did not impact PTEN 3'UTR regulation using a reporter, while the original study reported decreased activity when SERINC1, VAPA, and CNOT6L were depleted (Figure 3C; Tay et al., 2011). Using the same reporter, we found decreased activity when ceRNA 3'UTRs were overexpressed, while the original study reported increased activity (Figure 3D; Tay et al., 2011). In HCT116 cells, ceRNA depletion resulted in decreased PTEN protein levels, a result similar to the findings reported in the original study (Figure 3G,H; Tay et al., 2011); however, while the original study reported an attenuated ceRNA effect in microRNA deficient (DicerEx5) HCT116 cells, we observed increased PTEN protein levels. Further, we found depletion of the ceRNAs VAPA or CNOT6L did not statistically impact DU145, wild-type HCT116, or DicerEx5 HCT116 cell proliferation. The original study reported increased DU145 and wild-type HCT116 cell proliferation when these ceRNAs were depleted, which was attenuated in the DicerEx5 HCT116 cells (Figure 5B; Tay et al., 2011). Differences between the original study and this replication attempt, such as variance between biological repeats, are factors that might have influenced the results. Finally, we report meta-analyses for each result. [ABSTRACT FROM AUTHOR]

A wide range of highly correlated ab initio methods has been used to predict the geometrical parameters of the linear (X 2Π) and H-bridged (X 2A1 and à 2B1) Ga2H isomers and two isomerization transition states (X 2A′ and à 2A″) connecting the three minima. Dipole moments and vibrational frequencies are also obtained. The global minimum X 2A1 ground state of the H-bridged GaHGa isomer is predicted to lie only 1.6 [1.9 with the zero-point vibrational energy (ZPVE) corrections] kcal mol-1 below the à 2B1 state. The X 2A1 state lies 5.4 kcal mol-1 below the X 2Π ground state of the linear GaGaH isomer at the coupled-cluster with single, double, and perturbative triple excitations [CCSD(T)] level of theory with the augmented correlation-consistent polarized valence quadruple-zeta (aug-cc-pVQZ) basis set. The full triples coupled-cluster method is found to alter these CCSD(T) predictions by as much as 0.3 kcal mol-1. The forward isomerization barriers from the linear ground state to the X 2A′ and à 2A″ transition states are determined to be 3.3 and 5.3 kcal mol-1, respectively. The reverse isomerization barrier between the X 2A1 GaHGa structure and the X 2Π GaGaH structure is predicted to be 8.6 (8.2 with the ZPVE corrections) kcal mol-1 at the aug-cc-pVQZ CCSD(T) level of theory. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence has suggested that miR-29b plays an antitumor effect in multiple malignancies via the regulation of cell proliferation, apoptosis, invasion and migration. In the present study, we aimed to explore the underlying function and mechanism of miR-29b in multiple myeloma (MM). Methods: The expression of miR-29b in MM cell lines and tissues was detected by quantitative real-time PCR (qRT-PCR). CCK-8 and flow cytometry analyses were performed to assess cell proliferation, cycles and apoptosis. Bioinformatics, Dual-Luciferase reporter and qRT-PCR assays were employed to explore the possible correlation between miR-29b and FOXP1. Xenograft model was established to confirm the role of miR-29b on tumor growth in vivo. Results: miR-29b expression was markedly decreased in MM cell lines and tissues and downregulated miR-29b was closely related to International Staging System (ISS) stages. Exogenous overexpression of miR-29b inhibited the proliferation but induced MM cell cycle arrest and apoptosis. FOXP1 was identified as a direct target gene for miR-29b, and restoration of FOXP1 weakened miR-29b-induced anti-proliferation and pro-apoptosis in MM cell lines. Finally, the inhibitory effects of miR-29b on the growth of MM tumors were validated in mice. Conclusions: miR-29b recedes the progression of MM via downregulating FOXP1, which may provide a potential biological target for MM treatment. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the possible therapeutic mechanism of Shuyu capsules in liver-qi depression. Liver-qi depression rats were prepared based on chronic unpredictable mild stress (CUMS) and delayed constraint. Rats were gavaged with Shuyu capsule, fluoxetine, Radix Bupleuri and Radix Paeoniae Alba to constrct rat models. Body weight test, sucrose preference test and open-field test were applied to test rat models. Western blot analysis and quantitative real-time PCR was applied to determine the relative expression of extracellular signal-regulated protein kinase (ERK), cyclic AMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in hippocampus and frontal lobe tissues. ELISA was used to detect the content of BDNF in serum. Body weight, sugar intake and total distance were significantly decreased in depression group compared with control. The four drugs significantly increased levels of these factors. Compared with control group, ERK, CREB and BDNF expression were significantly decreased in depression group in both hippocampus and frontal lobe tissues at both mRNA and protein level. Shuyu capsule and fluoxetine group showed a significant increase in the expression of ERK, CREB and BDNF at mRNA, p-ERK and p-BDNF at protein level. Compared with Radix Paeoniae Alba, Radix Bupleuri were better in the rescue of ERK, CREB and BDNF expression. In conclusion, the pathogenesis of liver-qi depression associated with lower expression of ERK, CREB and BDNF in hippocampus and frontal. Shuyu capsule and main constitution alleviated the depressive-like behaviors and reversed the disruptions of the p-ERK, p-CREB and BDNF in stressed rats. [ABSTRACT FROM AUTHOR]

Nowadays, heterogeneous CPU-GPU systems have become ubiquitous, but current parallel spatial interpolation (SI) algorithms exploit only one type of processing unit, and thus result in a waste of parallel resources. To address this problem, a hybrid parallel SI algorithm based on a thin plate spline is proposed to integrate both the CPU and GPU to further accelerate the processing of massive LiDAR point clouds. A simple yet powerful parallel framework is designed to enable simultaneous CPU-GPU interpolation, and a fast online training method is then presented to estimate the optimal decomposition granularity so that both types of processing units can run at maximum speed. Based on the optimal granularity, massive point clouds are continuously partitioned into a collection of discrete blocks in a data processing flow. A heterogeneous dynamic scheduler based on the greedy policy is also proposed to achieve better workload balancing. Experimental results demonstrate that the computing power of the CPU and GPU is fully utilized under conditions of optimal granularity, and the hybrid parallel SI algorithm achieves a significant performance boost when compared with the CPU-only and GPU-only algorithms. For example, the hybrid algorithm achieved a speedup of 20.2 on one of the experimental point clouds, while the corresponding speedups of using a CPU or a GPU alone were 8.7 and 12.6, respectively. The interpolation time was reduced by about 12% when using the proposed scheduler, in comparison with other common scheduling strategies. [ABSTRACT FROM AUTHOR]

This study examined the relationship between the expression of p16, a tumor suppressor gene, and lymph node metastasis, as well as patient prognosis, in cases with ovarian cancer. SKOV-3, an ovarian cancer cell line, and IOSE80, a normal human ovarian cell line, were selected for testing. Western blot analysis was used to detect the p16 expression in ovarian cell culture samples. In the study, 20 cases with normal ovarian tissue and 64 cases with ovarian cancer tissue, including 38 cases with lymph node metastasis and 26 cases without lymph node metastasis, were also selected for testing. Immunohistochemical techniques were used to detect the expression of p16 protein in ovarian tissue samples. The influence of p16 protein on SKOV-3 cell invasion ability was studied using p16 gene high-expression vector transfection. Clinical and prognosis data were summarized and the influence of p16 on patient prognosis was analyzed through Kaplan-Meier single-factor survival analysis. The results showed that p16 expression in SKOV-3 was decreased significantly compared with that in IOSE80. The positive rate of p16 protein expression in ovarian cancer tissue was notably decreased compared with that in normal ovarian tissue. The positive rate of p16 protein expression in ovarian cancer tissue of patients with lymph node metastasis was significantly decreased compared with that of patients without lymph node metastasis. Therefore, transfection of the p16 gene significantly inhibited the protein expression and invasion ability of p16 in SKOV-3. Correlation analyses between p16 and survival prognosis demonstrated that lower expression of p16 was negatively correlated with the prognosis of patients with ovarian cancer. Overall, the abnormal expression of p16 in ovarian cancer is associated with an increased invasion ability of ovarian cancer and the lower expression of p16 in tissue samples indicates a poor prognosis in patients with ovarian cancer. [ABSTRACT FROM AUTHOR]

An efficient approach for the direct sulfanylation of 4-hydroxyquinolinones and 4-hydroxypyridones with aryl thiols in the presence of CuI/DMSO has been developed. The substrate scope is broad, allowing facile synthesis of a range of structurally diverse 3-sulfanyl-4-hydroxyquinolinones and 3-sulfanyl-4-hydroxypyridones in good efficiency. [ABSTRACT FROM AUTHOR]

In this study, Dregea sinensis Hemsl. protease called chymosin was extracted and purified from D. sinensis Hemsl. stalk and was used for mozzarella cheese production. Calf rennet and microbial chymosin were used as the control group SDS-PAGE revealed that D. sinensis Hemsl. protease can be used to produce mozzarella cheese as it degrades α-casein of buffalo milk. Volatile acids and carbonyl compounds are the main sources of the flavor in mozzarella cheese. Thus, fifty-two flavor substances were detected through GC-MS. Fresh and sweet glutamic acid and histidine were the dominant free amino acids in examined cheese (P<0.05). Texture profile analysis indicated that the produced cheese was more restorative and flexible compared to the control group. Scanning electron microscopy demonstrated that the produced cheese was smooth, as indicated by the small pore cross-section diameter of mozzarella cheese and its close net structure. Therefore, D. sinensis Hemsl. can be applied to process cheese [ABSTRACT FROM AUTHOR]

The work presented here addresses the problem of robust waveform design for collocated multiple-input multipleoutput (MIMO) radar in the presence of clutter. Robust design is needed due to the fact that MIMO radar waveform design is often sensitive to estimation errors in the initial parameter estimates, which tries to systematically ease this sensitivity by including a parameter estimation error model into the optimisation issue. Following the min-max approach, the robust MIMO radar waveform design is considered in this study to improve the worst-case estimation accuracy in the presence of clutter on the basis of the Cramér-Rao bound. To tackle the resultant NP-hard problem, a new diagonal loading based iterative method is developed to design the waveform covariance matrix for improving the worst-case accuracy, each step in which can be formulated into a convex optimisation issue, and hence can be solved efficiently. An optimal solution to the initial issue can be obtained via the least squares fitting of the solution acquired by the iterative algorithm. Numerical simulations show the efficiency of the proposed method. [ABSTRACT FROM AUTHOR]

Phenolic compounds could be separated through their formation of deep eutectic solvent (DES). This process was different from normal liquid-liquid extraction and was more efficient and environmental. In this work, the thermodynamic process of this kind of separation was studied. Ternary liquid-liquid equilibrium data were systematically measured at atmospheric pressure and temperatures from 303.15 to 313.15 K. The experimental data were regressed by NRTL and UNIQUAC models, and the validated results revealed that NRTL model were more consistent with experimental data. The above-mentioned parameters could be used to predict ternary mixture interactions and then applied in subsequent design and optimization of the separation process of corresponding systems. This extraction process was further optimized using Aspen Plus with NRTL as thermodynamic model. The simulation results were in good agreement with the experimental outcomes. [ABSTRACT FROM AUTHOR]

A novel type of π-extended 1,10-phenanthroline, specifically with fused thiophene groups at the less exploited 3-, 4-, 7-, and 8-positions of the phenanthroline ring, and its conjugated polymers were designed and synthesized. The current developed route is based on the Bischler-Napieralski cyclization of the (1,2-phenylene)diamide precursor, which offers a facile and versatile strategy for preparing soluble and well-defined 1,10-phenanthroline derivatives and their analogues. High molecular weight poly(phenanthroline-co-fluorene)s with good solubility in common organic solvents or water were prepared by palladium-catalyzed Suzuki-Miyaura-Schlüter polycondensation. The optical responsive properties of these thiophene-fused 1,10-phenanthroline-containing polymers have demonstrated these polymers could be a good candidate for potential applications as luminescent chemosensor materials thanks to the specific repeating unit along the backbone. [ABSTRACT FROM AUTHOR]

The OH radical reaction with Br2 and the subsequent reaction HOBr + Br are of exceptional importance to atmospheric chemistry and environmental chemistry. The entrance complex, transition state, and exit complex for both reactions have been determined using the coupled-cluster method with single, double, and perturbative triple excitations CCSD(T) with correlation consistent basis sets up to size cc-pV5Z and cc-pV5Z-PP. Coupled cluster effects with full triples (CCSDT) and full quadruples (CCSDTQ) are explicitly investigated. Scalar relativistic effects, spin-orbit coupling, and zero-point vibrational energy corrections are evaluated. The results from the all-electron basis sets are compared with those from the effective core potential (ECP) pseudopotential (PP) basis sets. The results are consistent. The OH + Br2 reaction is predicted to be exothermic 4.1 ± 0.5 kcal/mol, compared to experiment, 3.9 ± 0.2 kcal/mol. The entrance complex HO···BrBr is bound by 2.2 ± 0.2 kcal/mol. The transition state lies similarly well below the reactants OH + Br2. The exit complex HOBr···Br is bound by 2.7 ± 0.6 kcal/mol relative to separated HOBr + Br. The endothermicity of the reaction HOBr + Br ? HBr + BrO is 9.6 ± 0.7 kcal/mol, compared with experiment 8.7 ± 0.3 kcal/mol. For the more important reverse (exothermic) HBr + BrO reaction, the entrance complex BrO···HBr is bound by 1.8 ± 0.6 kcal/mol. The barrier for the HBr + BrO reaction is 6.8 ± 0.9 kcal/mol. The exit complex (Br···HOBr) for the HBr + BrO reaction is bound by 1.9 ± 0.2 kcal/mol with respect to the products HOBr + Br. [ABSTRACT FROM AUTHOR]

Two hypotheses have been advanced in the recent literature with respect to the so-called Interlanguage Speech Intelligibility Benefit (ISIB): a nonnative speaker will be better understood by a another nonnative listener than a native speaker of the target language will be (a) only when the nonnatives share the same native language (matched interlanguage) or (b) even when the nonnatives have different mother tongues (non-matched interlanguage). Based on a survey of published experimental materials, the present article will demonstrate that both the restricted (a) and the generalized (b) hypotheses are false when the ISIB effect is evaluated in terms of absolute intelligibility scores. We will then propose a simple way to compute a relative measure for the ISIB (R-ISIB), which we claim is a more insightful way of evaluating the interlanguage benefit, and test the hypotheses in relative (R-ISIB) terms on the same literature data. We then find that our R-ISIB measure only supports the more restricted hypothesis (a) while rejecting the more general hypothesis (b). This finding shows that the native language shared by the interactants biases the listener toward interpreting sounds in terms of the phonology of the shared mother tongue. [ABSTRACT FROM AUTHOR]

Dregea sinensis Hemsl. is used as a milk coagulant to produce goat milk cakes in Yunnan, China. However, the composition of milk-clotting compounds and the related mechanism have not been reported. Crude protease was extracted from the stem, purified, and then separated with a Millipore ultrafiltration centrifuge tube. Cysteine protease (procerain B) was identified as the main milk-clotting protein through electrospray ionization mass spectrometry, and its molecular weight was 23.8 kDa. The protease can partially degrade α-casein (CN) and completely degrade β- and κ-CN, and κ-CN degradation resulted in milk clotting. The molecular weight and AA sequence of the peptide fractions were determined through matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and a peptide sequencer, respectively. The enzyme cleaved κ-CN at Ala90-Gln91 and produced deputy κ-CN and caseinomacropeptide with molecular weights of 12 and 6.9 kDa, respectively. This cleavage site differed from the majority of chymosins cleaved at Phe105-Met106. [ABSTRACT FROM AUTHOR]

Background: Our pilot study using miRNA PCR array found that miRNA-29b (miR-29b) is differentially expressed in primary cultured CD133-positive A549 cells compared with CD133-negative A549 cells. Methods: Ten human non-small cell lung cancer (NSCLC) cell lines and samples from thirty patients with NSCLC were analyzed for the expression of miR-29b by quantitative RT-PCR. Bioinformatics analysis combined with tumor metastasis PCR array showed the potential target genes for miR-29b. miR-29b lentivirus and inhibitors were transfected into NSCLC cells to investigate its role on regulating cell proliferation which was measured by CCK-8 assay in vitro and nude mice xenograft tumor assay in vivo. Cell motility ability was evaluated by transwell assay. The target genes of miR-29b were determined by luciferase assay, quantitative RT-PCR and western blot. Results: Bioinformatics analysis combined with tumor metastasis PCR array showed that matrix metalloproteinase 2 (MMP2) and PTEN could be important target genes of miR-29b. The expression of miR-29b was down regulated in NSCLC tissues compared to the normal tissues. Clinicopathological analysis demonstrated that miR-29b had significant negative correlation with lymphatic metastasis. The gain-of-function studies revealed that ectopic expression of miR-29b decreased cell proliferation, migration and invasion abilities of NSCLC cells. In contrasts, loss-of-function studies showed that inhibition of miR-29b promoted cell proliferation, migration and invasion of NSCLC cells in vitro. Nude mice xenograft tumor assay confirmed that miR-29b inhibited lung cancer growth in vivo. High-invasion (A549-H) and low-invasion (A549-L) NSCLC cell sublines from A549 cells were created by using the repeated transwell assay aimed to confirm the effect of miR-29b on migration and invasion of NSCLC. Furthermore, the dual-luciferase reporter assay demonstrated that miR-29b inhibited the expression of the luciferase gene containing the 3'-UTRs of MMP2 and PTEN mRNA. Western blotting and quantitative RT-PCR indicated that miR-29b down-regulated the expression of MMP2 at the protein and mRNA levels. Conclusion: Taken together, our results demonstrate that miR-29b serves as a tumor metastasis suppressor, which suppresses NSCLC cell metastasis by directly inhibiting MMP2 expression. The results show that miR-29b may be a novel therapeutic candidate target to slow NSCLC metastasis. [ABSTRACT FROM AUTHOR]

Intestinal barrier dysfunction caused by chronic alcohol consumption is closely associated with disruption of the intestinal epithelial apical junction complex. The present study was undertaken to directly display by transmission electron microscopy the abnormal ultrastructure of the intestinal epithelial barrier in mice with alcoholic steatohepatitis. The results showed that chronic alcohol con-sumption could induce obvious liver injury, with diffuse lipid accumulation and focal inflammatory cell infiltration in the liver, assessed by hematoxylin and eosin staining. The indicators of intestinal barrier dysfunction, D-lactic acid and lipopolysaccharide, were significantly higher in alcohol-fed mice than in control mice. Alcohol exposure obviously caused high permeability in the ileum to fluorescein isothiocyanate-dextran (FD-4; molecular weight 4000). Transmission electron microscopy demonstrated that tight junctions and adherens junctions expanded noticeably in alcohol-fed mice. Although the tight junction (TJ) length of alcohol-fed mice had no significant difference compared with control mice, the adherens junction (AJ) length of alcohol-fed mice significantly decreased compared with control mice. Additionally, the ratios of both TJmax/TJmin and AJmax/AJmin were significantly larger in alcohol-fed mice than in control liquid-fed mice. In conclusion, high intestinal permeability caused by alcohol attributes to the irregular ultrastructure of the intestinal epithelial barrier. [ABSTRACT FROM AUTHOR]

High linear energy transfer (LET) radiation from space heavy charged particles or a heavier ion radiotherapy machine kills more cells than low LET radiation, mainly because high LET radiation-induced DNA damage is more difficult to repair. Relative biological effectiveness (RBE) is the ratio of the effects generated by high LET radiation to low LET radiation. Previously, our group and others demonstrated that the cell-killing RBE is involved in the interference of high LET radiation with non-homologous end joining but not homologous recombination repair. This effect is attributable, in part, to the small DNA fragments (≤40 bp) directly produced by high LET radiation, the size of which prevents Ku protein from efficiently binding to the two ends of one fragment at the same time, thereby reducing non-homologous end joining efficiency. Here we demonstrate that Ape1, an enzyme required for processing apurinic/apyrimidinic (known as abasic) sites, is also involved in the generation of small DNA fragments during the repair of high LET radiation-induced base damage, which contributes to the higher RBE of high LET radiation-induced cell killing. This discovery opens a new direction to develop approaches for either protecting astronauts from exposure to space radiation or benefiting cancer patients by sensitizing tumor cells to high LET radiotherapy. [ABSTRACT FROM AUTHOR]

Drosophila larval brain stem cells (neuroblasts) have emerged as an important model for the study of stem cell asymmetric division and the mechanisms underlying the transformation of neural stem cells into tumour-forming cancer stem cells. Each Drosophila neuroblast divides asymmetrically to produce a larger daughter cell that retains neuroblast identity, and a smaller daughter cell that is committed to undergo differentiation. Neuroblast self-renewal and differentiation are tightly controlled by a set of intrinsic factors that regulate ACD (asymmetric cell division). Any disruption of these two processes may deleteriously affect the delicate balance between neuroblast self-renewal and progenitor cell fate specification and differentiation, causing neuroblast overgrowth and ultimately lead to tumour formation in the fly. In this review, we discuss the mechanisms underlying Drosophila neural stem cell self-renewal and differentiation. Furthermore, we highlight emerging evidence in support of the notion that defects in ACD in mammalian systems, which may play significant roles in the series of pathogenic events leading to the development of brain cancers. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease that causes motor neuron degeneration, progressive motor dysfunction, paralysis, and death. Although multiple causes have been identified for this disease, >95% of ALS cases show aggregation of transactive response DNA binding protein (TDP-43) accompanied by its nuclear depletion. Therefore, the TDP-43 pathology may be a converging point in the pathogenesis that originates from various initial triggers. The aggregation is thought to result from TDP-43 misfolding, which could generate cellular toxicity. However, the aggregation as well as the nuclear depletion could also lead to a partial loss of TDP-43 function or TDP-43 dysfunction. To investigate the impact of TDP-43 dysfunction, we generated a transgenic mouse model for a partial loss of TDP-43 function using transgenic RNAi. These mice show ubiquitous transgene expression and TDP-43 knockdown in both the periphery and the central nervous system (CNS). Strikingly, these mice develop progressive neurodegeneration prominently in cortical layer V and spinal ventral horn, motor dysfunction, paralysis, and death. Furthermore, examination of splicing patterns of TDP-43 target genes in human ALS revealed changes consistent with TDP-43 dysfunction. These results suggest that the CNS, particularly motor neurons, possess a heightened vulnerability to TDP-43 dysfunction. Additionally, because TDP-43 knockdown predominantly occur in astrocytes in the spinal cord of these mice, our results suggest that TDP-43 dysfunction in astrocytes is an important driver for motor neuron degeneration and clinical phenotypes of ALS. [ABSTRACT FROM AUTHOR]

The transcription factor NRF2 (NFE2L2) is a pivotal activator of genes encoding cytoprotective and detoxifying enzymes that limit the action of cytotoxic therapies in cancer. NRF2 acts by binding antioxidant response elements (ARE) in its target genes, but there is relatively limited knowledge about how it is negatively controlled. Here, we report that retinoic X receptor alpha (RXRα) is a hitherto unrecognized repressor of NRF2. RNAi-mediated knockdown of RXRα increased basal ARE-driven gene expression and induction of ARE-driven genes by the NRF2 activator tert-butylhydroquinone (tBHQ). Conversely, overexpression of RXRα decreased ARE-driven gene expression. Biochemical investigations showed that RXRα interacts physically with NRF2 in cancer cells and in murine small intestine and liver tissues. Furthermore, RXRα bound to ARE sequences in the promoters of NRF2-regulated genes. RXRα loading onto AREs was concomitant with the presence of NRF2, supporting the hypothesis that a direct interaction between the two proteins on gene promoters accounts for the antagonism of ARE-driven gene expression. Mutation analyses revealed that interaction between the two transcription factors involves the DNA-binding domain of RXRα and a region comprising amino acids 209-316 in human NRF2 that had not been defined functionally, but that we now designate as the NRF2-ECH homology (Neh) 7 domain. In non-small cell lung cancer cells where NRF2 levels are elevated, RXRα expression downregulated NRF2 and sensitized cells to the cytotoxic effects of therapeutic drugs. In summary, our findings show that RXRα diminishes cytoprotection by NRF2 by binding directly to the newly defined Neh7 domain in NRF2. [ABSTRACT FROM AUTHOR]

The adsorbed structures, Surface-enhanced Raman scattering (SERS) and pre-resonance Raman spectra of the U-Ag and U〈 〉U-Ag complexes are calculated using density-functional theory (DFT) method with B3LYP/6-311g (d, p) (C, H, O)/Lanl2dz (Ag) basis set. The uracil and uracil dimer prefer to a perpendicular orientation adsorbed on the Ag surface via atom O8 site. The SERS of the U-Ag and U〈 〉U-Ag complexes are similar with the normal Raman spectra of the isolated uracil and uracil dimer but with an enhancement factor less than 10. The enhancement mechanism is ascribed to the ground state static chemical enhancement from the static polarizability changes. The pre-resonance Raman spectra of the complexes are obtained at 316 nm and 315 nm, in which the enhancement factors are up to 103–104. The greatest enhancement factor is observed for the C2=O8 stretching vibration, caused by the electron transfer from the molecules to Ag atom. The charge transfer resonant enhancement plays the major role in the molecule–metal system. [ABSTRACT FROM AUTHOR]

Human metastasis-associated gene 1 (MTA1) is highly associated with the metastasis of prostate cancer; however, the molecular functions of MTA1 that facilitate metastasis remain unclear. In this study, we demonstrate that the silencing of MTA1 by siRNA treatment results in the upregulation of E-cadherin expression by the phosphorylation of AKT (p-AKT) and decreases the invasiveness of prostate cancer cells. We show that MTA1 is expressed in over 90% of prostate cancer tissues, especially metastatic prostate cancer tissue, comparing to non-expression in normal prostate tissue. RT-PCR analysis and Western blot assay showed that MTA1 expression is significantly higher in highly metastatic prostate cancer PC-3M-1E8 cells (1E8) than in poorly metastatic prostate cancer PC-3M-2B4 cells (2B4). Silencing MTA1 expression by siRNA treatment in 1E8 cells increased the cellular malignant characters, including the cellular adhesive ability, decreased the cellular invasive ability and changed the polarity of cellular cytoskeleton. 1E8 cells over-expressing MTA1 had a reduced expression of E-cadherin, while 1E8 cells treated with MTA1 siRNA had a higher expression of E-cadherin. The expression of phosphorylated AKT (p-AKT) or the inhibition of p-AKT by wortmannin treatment (100 nM) significantly altered the function of MTA1 in the regulation of E-cadherin expression. Alterations in E-cadherin expression changed the role of p-AKT in cellular malignant characters. All of these results demonstrate that MTA1 plays an important role in controlling the malignant transformation of prostate cancer cells through the p-AKT/E-cadherin pathway. This study also provides a new mechanistic role for MTA1 in the regulation of prostate cancer metastasis. [ABSTRACT FROM AUTHOR]

In this work, the SnO2/SiO2materials with various Sn loadings ranging from 1 to 16 wt % were prepared and used as heterogeneous acid catalysts for soybean oil transesterification to produce biodiesel. The catalyst with 8 wt % Sn loading and calcined at 873 K exhibited the best catalytic activity, giving an oil conversion of 81.7%. The dispersed amorphous SnO2species on the silica surface are considered to be active sites for the transesterification reaction. The effect of reaction parameters such as catalyst amount, reaction temperature, reaction time, and methanol-to-oil ratio was investigated to optimize the transesterification conditions. It is shown that the free fatty acid (FFA) and water have no significant influence on the catalytic activity to the transesterification reaction. In addition, the heterogeneous acid catalyst was found to have high activities toward the esterification of FFAs. Furthermore, the catalyst could be recovered with a better reusability. [ABSTRACT FROM AUTHOR]

The trinuclear derivative Fe3(C8H8)3 was synthesized in 2009 by Lavallo and Grubbs via the reaction of Fe(C8H8)2 with a bulky heterocyclic carbene. This fascinating structure is the first example of a derivative of the well-known Fe3(CO)12 in which all 12 carbonyl groups have been replaced by hydrocarbon ligands. The density functional theory predicts a structure having a central Fe3 equilateral triangle with 2.9 Å Fe-Fe single bonded edges bridged by η5,η3-C8H8 ligands. This structure is close to the experimental structure, determined by X-ray crystallography. The related hypoelectronic MNi3(C8H8)3 derivatives (M = Cr, V, Ti) are predicted to have central scalene M3 triangles with edge lengths and Wiberg bond indices (WBIs) corresponding to one formal single M-M bond, one formal double M-M bond, and one formal triple M≡M bond. For Mn3(C8H8)3, both a doublet structure with one Mn-Mn double bond and two Mn-Mn single bonds in the Mn3 triangle, and a quartet structure with two Mn-Mn double bonds and one Mn-Mn single bond are predicted. The hyperelectronic derivatives MNi3(C8H8)3 have weaker direct M-M interactions in their M3 triangles, as indicated by both the M-M distances and the WBIs. Thus, NiNi3(C8H8)3 has bis(trihapto) η3,η3-C8H8 ligands bridging the edges of a central approximately equilateral Ni3 triangle with long Ni…Ni distances of ~3.7 Å. The WBIs indicate very little direct Ni-Ni bonding in this Ni3 triangle and thus a local nickel environment in the singlet Ni3(C8H8)3 similar to that observed for diallylnickel (η3-C3H5)2Ni. [ABSTRACT FROM AUTHOR]

The cell-cycle G2--Mphase gene UBE2C is overexpressed in various solid tumors including castration-resistant prostate cancer (CRPC). Our recent studies found UBE2C to be a CRPC-specific androgen receptor (AR) target gene that is necessary for CRPC growth, providing a potential novel target for therapeutic intervention. In this study, we showed that the G1--S cell-cycle inhibitor-779 (CCI-779), an mTOR inhibitor, inhibited UBE2C mRNA and protein expression in AR-positive CRPC cell models abl and C4-2B. Treatment with CCI-779 significantly decreased abl cell proliferation in vitro and in vivo through inhibition of cell-cycle progression of both G2--M and G1--S phases. In addition, exposure of abl and C4-2B cells to CCI-779 also decreased UBE2C-dependent cell invasion. The molecular mechanisms for CCI-779 inhibition of gene expression involved a decreased UBE2C binding of AR coactivators SRC1, SRC3, p300, and MED1 to the UBE2C enhancers, leading to a reduction in RNA polymerase II loading to the UBE2C promoter, and attenuation of UBE2C mRNA stability. Our data suggest that, in addition to its ability to block cell-cycle G1 to S-phase transition, CCI-779 causes a cell-cycle G2--M accumulation and an inhibition of cell invasion through a novel UBE2C-dependent mechanism, which contributes to antitumor activities of CCI-779 in UBE2C overexpressed AR-positive CRPC. Cancer Res; 71(14); 4866-76. ©2011 AACR. [ABSTRACT FROM AUTHOR]

Azulene is reported to react with Mn2(CO)10to give trans-C10H8Mn2(CO)6, which has been shown by X-ray crystallography to have a bis(pentahapto) structure with no metal-metal bond. This structure is found by density functional theory to be the lowest energy C10H8Mn2(CO)6structure. However, a corresponding bis(pentahapto) cis-C10H8Mn2(CO)6structure, also without an MnMn bond, lies within ∼1 kcal mol−1of this global minimum. The lowest energy C10H8Mn2(CO)5structure is singlet cis-η5,η5-C10H8Mn2(CO)5with an Mn→Mn dative bond from the Mn(CO)3group to the Mn(CO)2group. However, a singlet cis-η6,η4-C10H8Mn2(CO)5structure with a normal Mn–Mn single bond lies within ∼6 kcal mol−1of this global minimum. The lowest energy structures of the more highly unsaturated C10H8Mn2(CO)n(n= 4, 3, 2) systems all have cisgeometries and manganese-manganese bonds of various orders. The corresponding global minima are triplet cis-η5,η3-C10H8Mn2(CO)3(η2-μ-CO) for the tetracarbonyl with a four-electron donor bridging carbonyl group, singlet cis-η5,η5-C10H8Mn2(CO)3for the tricarbonyl, and triplet cis-η6,η4-C10H8Mn2(CO)(η2-μ-CO) for the dicarbonyl. [ABSTRACT FROM AUTHOR]

Soluble guanylate cyclase (sGC), as a nitric oxide (NO) sensor, is a critical heme-containing enzyme in NO-signaling pathway of eukaryotes. Human sGC is a heterodimeric hemoprotein, composed of a α-subunit (690 AA) and a heme-binding β-subunit (619 AA). Upon NO binding, sGC catalyzes the conversion of guanosine 5′-triphosphate (GTP) to 3′,5′-cyclic guanosine monophosphate (cGMP). cGMP is a second messenger and initiates the nitric oxide signaling, triggering vasodilatation, smooth muscle relaxation, platelet aggregation, and neuronal transmission etc. The breakthrough of the bottle neck problem for sGC-mediated NO singling was made in this study. The recombinant human sGC β1 subunit (HsGCβ619) and its truncated N-terminal fragments (HsGCβ195 and HsGCβ384) were efficiently expressed in Escherichia coli and purified successfully in quantities. The three proteins in different forms (ferric, ferrous, NO-bound, CO-bound) were characterized by UV–vis and EPR spectroscopy. The homology structure model of the human sGC heme domain was constructed, and the mechanism for NO binding to sGC was proposed. The EPR spectra showed a characteristic of five-coordinated heme-nitrosyl species with triplet hyperfine splitting of NO. The interaction between NO and sGC was investigated and the schematic mechanism was proposed. This study provides new insights into the structure and NO-binding of human sGC. Furthermore, the efficient expression system of E. coli will be beneficial to the further studies on structure and activation mechanism of human sGC. [ABSTRACT FROM AUTHOR]

Integrin binding to ligand plays essential roles in the differentiation and function of mammalian cells. β2 integrins in leukocytes are needed for migration to sites of inflammation and in lymph nodes as well as for cellular events such as phagocytosis and the formation of the conjugates between T cells and antigen-presenting cells. In T cells, integrin adhesion is activated primarily by the antigen-receptor (TCR complex) and chemokines in a process known as ‘inside-out’ signalling. Great progress has been made in identifying mutations that are responsible for leukocyte adhesion deficiency (LAD) syndromes, a disorder that presents with an impaired ability to clear pathogens and recurrent life-threatening infections. LAD mutations have been identified with defects in integrins, fucosylation and in the new intracellular mediator kindlin-3. Here, we review the key players in the ‘inside-out’ and ‘outside-in’ signalling pathways that will serve as new potential targets in the design of novel therapeutics to treat various immunodeficiencies. [ABSTRACT FROM AUTHOR]

The mixed sandwich compounds (η5-C5H5)M(η7-C7H7) (M = Ti, V, Cr) have been known for approximately 50 years. The vanadium derivative ('trovacene') has recently been shown to be a useful precursor for the preparation of a variety of paramagnetic sandwich compounds. In this connection the structures of the complete series of the first row transition metal mixed sandwich compounds C5H5MC7H7 (M = Ti, V, Cr, Mn, Fe, Co, Ni) have been investigated by density functional theory. The experimentally known parallel ring sandwich structures (η5-C5H5)M(η7-C7H7) are found for the Ti, V, and Cr derivatives. Analysis of the frontier molecular orbitals of these complexes indicates that, for the metal d-orbitals, the z2 orbital is essentially non-bonding, the x2-y2 and xy orbitals are δ bonding to the seven-membered ring, and the xz and yz orbitals are π bonding to the five-membered ring. For the later transition metals, (η5-C5H5)M(η5-C7H7) structures with pentahapto seven-membered rings are preferred for iron and manganese and (η5-C5H5)M(η3-C7H7) structures with trihapto seven-membered rings are preferred for cobalt and nickel, leading to either 17- or 18-electron complexes in all cases. A higher energy parallel sandwich structure (η5-C5H5)Co(η7-C7H7) with a quartet spin state and a formal 21-electron cobalt configuration is also found for the cobalt derivative. [ABSTRACT FROM AUTHOR]

Background: It is widely recognized that interspecific hybridization may induce "genome shock", and lead to genetic and epigenetic instabilities in the resultant hybrids and/or backcrossed introgressants. A prominent component involved in the genome shock is reactivation of cryptic transposable elements (TEs) in the hybrid genome, which is often associated with alteration in the elements' epigenetic modifications like cytosine DNA methylation. We have previously reported that introgressants derived from hybridization between Oryza sativa (rice) and Zizania latifolia manifested substantial methylation re-patterning and rampant mobilization of two TEs, a copia retrotransposon Tos17 and a MITE mPing. It was not known however whether other types of TEs had also been transpositionally reactivated in these introgressants, their relevance to alteration in cytosine methylation, and their impact on expression of adjacent cellular genes. Results: We document in this study that the Dart TE family was transpositionally reactivated followed by stabilization in all three studied introgressants (RZ1, RZ2 and RZ35) derived from introgressive hybridization between rice (cv. Matsumae) and Z. latifolia, while the TEs remained quiescent in the recipient rice genome. Transposon-display (TD) and sequencing verified the element's mobility and mapped the excisions and reinsertions to the rice chromosomes. Methylation-sensitive Southern blotting showed that the Dart TEs were heavily methylated along their entire length, and moderate alteration in cytosine methylation patterns occurred in the introgressants relative to their rice parental line. Real-time qRT-PCR quantification on the relative transcript abundance of six single-copy genes flanking the newly excised or inserted Dart-related TE copies indicated that whereas marked difference in the expression of all four genes in both tissues (leaf and root) were detected between the introgressants and their rice parental line under both normal and various stress conditions, the difference showed little association with the presence or absence of the newly mobilized Dart-related TEs. Conclusion: Introgressive hybridization has induced transpositional reactivation of the otherwise immobile Dartrelated TEs in the parental rice line (cv. Matsumae), which was accompanied with a moderate alteration in the element's cytosine methylation. Significant difference in expression of the Dart-adjacent genes occurred between the introgressants and their rice parental line under both normal and various abiotic stress conditions, but the alteration in gene expression was not coupled with the TEs. [ABSTRACT FROM AUTHOR]

The formation of Ru microspheres by hydrothermal treated method in tungstosilicate acid H4SiW12O40, TSA solution is described. The particles are characterized by Xray diffraction analysis XRD and scanning electron microscopy SEM, respectively. The growth process of these microspheres has been examined. The results show that it is possible to synthesize and assemble other noble metal particles with unique superstructure. The characteristic catalytic behavior of the Ru microspheres is established by studying the decolorization of cango red in the presence of UV light. © 2009 WILEYVCH Verlag GmbH & Co. KGaA, Weinheim [ABSTRACT FROM AUTHOR]

AbstractRNA interference (RNAi) mediates sequence-specific gene silencing, which can be harnessed to silencing disease-causing genes for therapy. Particularly suitable diseases are those caused by dominant, gain-of-function type of gene mutations. In these diseases, the mutant gene generates a mutant protein or RNA product, which possesses toxic properties that harm cells. By silencing the mutant gene, the toxicity can be lessened because the amount of the toxic product is lowered in cells. In this report, we tested RNAi therapy in a mouse model for amyotrophic lateral sclerosis (ALS), which causes motor neuron degeneration, paralysis, and death. We used a transgenic model that overexpresses mutant Cu, Zn superoxide dismutase (SOD1G93A), which causes ALS by a gained toxic property. We delivered RNAi using recombinant adenovirus (RAd) and adeno-associated virus serotype 2 (AAV2). We compared the efficiency of RNAi delivery between injecting the viral vectors into muscle and into nerve, and found that nerve injetion is more efficient in delivering RNAi to motor neurons. Based on this data, we conducted therapeutic trials in the mouse model and found that nerve injection of RAd, but not AAV2, at the disease onset had a modest therapeutic efficacy. These results highlight the potential and the challenges in delivering RNAi therapy by gene therepy. Antioxid. Redox Signal.11, 1523–1534. [ABSTRACT FROM AUTHOR]

Abstract: A dilute surfactant–polymer (S–P) flooding system has been designed and developed for Gudong oilfield with Shengli petroleum sulfonate (SLPS) as the primary ingredient. The dynamic behavior of the system and the interactions of the system components have been investigated through various methods, including DPD molecular modeling technology and dynamic interfacial-tension analysis. The results have shown a significant synergistic effect between sulfonate and nonionic surfactant. The interfacial tension (IFT) and its time to reach equilibrium could be dramatically decreased, suggesting a fast diffusion–adsorption characteristic of ionic surfactants as well as the high surface activity of nonionic surfactants. The S–P flooding formulation was finalized as 0.3% (w/w) SLPS+0.1% (w/w) 1#+0.15% polyacrylamide (PAM), in which 1#, the secondary surfactant, is able to enhance the interfacial activity of SLPS and the flooding efficiency of the system. The S–P flooding system manifests a wide range of IFT with the lowest value of 2.95×10−3 mN/m. The pilot field trial of the system has exhibited outstanding performance to improve oil production and reduce water cut since the first injection of the main slug of the S–P flooding system started in June 2004. Until July 2008, the accumulated oil-production had risen by 17.8×104 tons, with the oil-recovery increase by 6.4%. The field trial provides useful information for the further large-scale application of the SP system in Shengli oilfield. [Copyright &y& Elsevier]

The structures and the relative energies of six possible tautomers of the thymine base have been studied by density functional theory (DFT) using the B3LYP and BP86 functionals. The keto-thymine (T1) is predicted to be the most stable thymine tautomer, which is consistent with the other theoretical results and experimental data. The corresponding thymine cations and anions are studied using the same level of theory with double-ζ plus polarization and diffuse functions (DZP++) basis sets. The ionization potentials (IPs), the electron affinities (EAs), and proton affinities (PAs) for different protonation sites in thymine base are obtained. T1 has the largest ionization potential and the lowest proton affinity among all the considered thymine tautomers. Faisant appel à la théorie de la fonctionnelle de la densité et utilisant des fonctions B3LP et BP86, on a étudié les structures et les énergies relatives de six tautomères potentiels de la thymine à l’été de base. Sur la base de ces calculs, il est prédit que la cétothymine (T1) est le tautomère le plus stable de la thymine; cette conclusion est en accord avec les autres calculs théoriques et avec les résultats expérimentaux. Les cations et anions correspondants à la thymine ont aussi été étudiés aux même niveaux de la théorie en utilisant comme ensembles de base des fonctions de polarisation double ζ plus et des fonctions diffuses (DZP++). On en a extrait les potentiels d’ionisation (PI), les affinités électroniques (AE) et les affinités protoniques (AP) pour les différents sites de protonation de la thymine. La cétothymine (T1) possède le potentiel d’ionisation le plus élevé et l’affinité protonique la plus faible parmi tous les tautomères considérés de la thymine. [ABSTRACT FROM AUTHOR]

Background: Inter-specific hybridization occurs frequently in plants, which may induce genetic and epigenetic instabilities in the resultant hybrids, allopolyploids and introgressants. It remains unclear however whether pollination by alien pollens of an incompatible species may impose a "biological stress" even in the absence of genome-merger or genetic introgression, whereby genetic and/or epigenetic instability of the maternal recipient genome might be provoked. Results: We report here the identification of a rice mutator-phenotype from a set of rice plants derived from a crossing experiment involving two remote and apparently incompatible species, Oryza sativa L. and Oenothera biennis L. The mutator-phenotype (named Tong211-LP) showed distinct alteration in several traits, with the most striking being substantially enlarged panicles. Expectably, gel-blotting by total genomic DNA of the pollen-donor showed no evidence for introgression. Characterization of Tong211-LP (S0) and its selfed progenies (S1) ruled out contamination (via seed or pollen) or polyploidy as a cause for its dramatic phenotypic changes, but revealed transgenerational mobilization of several previously characterized transposable elements (TEs), including a MITE (mPing), and three LTR retrotransposons (Osr7, Osr23 and Tos17). AFLP and MSAP fingerprinting revealed extensive, transgenerational alterations in cytosine methylation and to a less extent also genetic variation in Tong211-LP and its immediate progenies. mPing mobility was found to correlate with cytosine methylation alteration detected by MSAP but not with genetic variation detected by AFLP. Assay by q-RT-PCR of the steady-state transcript abundance of a set of genes encoding for the various putative DNA methyltransferases, 5-methylcytosine DNA glycosylases, and small interference RNA (siRNA) pathway-related proteins showed that, relative to the rice parental line, heritable perturbation in expression of 12 out of the 13 genes occurred in the mutator-phenotype and its sefled progenies. Conclusion: Transgenerational epigenetic instability in the form of altered cytosine methylation and its associated TE activity occurred in a rice mutator-phenotype produced by pollinating the rice stigma with pollens of O. biennis. Heritably perturbed homeostatic expression-state of genes involved in maintenance of chromatin structure is likely an underlying cause for the alien pollination-induced transgenerational epigenetic/genetic instability, and which occurred apparently without entailing genome merger or genetic introgression. [ABSTRACT FROM AUTHOR]

The structures, energies, and electron affinities of the tautomers of dehydrogenated thymine radicals (T-H) have been studied theoretically. Geometry optimizations were carried out utilizing the density functional theory (DFT) methods with double-ζ quality basis sets plus polarization and diffuse functions (DZP++). These methods have been carefully calibrated for the prediction of electron affinities. Significant structural differences were found among thymine 24 dehydrogenated radicals and their corresponding anions from thymine tautomers. The electron affinities for these radicals are in the range of 0.96 and 3.88 eV, contrasting with the much smaller electron affinities associated with the closed-shell thymine tautomers. Among these investigated radicals those with removal of a hydrogen atom from the nitrogen atoms present the larger electron affinities (EAs). [ABSTRACT FROM AUTHOR]

Binuclear cycloheptatrienylchromium carbonyls of the type (C7H7)2Cr2(CO)n (n = 6, 5, 4, 3, 2, 1, 0) have been investigated by density functional theory. Energetically competitive structures with fully bonded heptahapto η7-C7H7 rings are not found for (C7H7)2Cr2(CO)n structures having two or more carbonyl groups. This result stands in contrast to the related (CnHn)2M2(CO)n (M = Mn, n = 6; M = Fe, n = 5; M = Co, n = 4) systems. Most of the predicted (C7H7)2Cr2(CO)n structures have bent trihapto or pentahapto C7H7 rings and Cr≡Cr distances in the range 2.4–2.5 Å suggesting formal triple bonds. In some cases rearrangement of the heptagonal C7H7 ring to a tridentate cyclopropyldivinyl or tridentate bis(carbene)alkyl ligand is observed. In addition structures with CO insertion into the C7H7–Cr bond are predicted for (C7H7)2Cr2(CO)n (n = 6, 4, 2). The global minima found for the (C7H7)2Cr2(CO)n derivatives for n = 6, 5, and 4 are (η5-C7H7)(OC)2Cr≡Cr(CO)4(η1-C7H7), (η3-C7H7)(OC)2Cr≡Cr(CO)3(η2,1- C7H7), and (η5-C7H7)2Cr2(CO)4, respectively. The global minima for (C7H7)2Cr2(CO)n (n = 3, 2) have rearranged C7H7 groups. Singlet and triplet structures with heptahapto η7-C7H7 rings are found for the dimetallocenes (η7-C7H7)2Cr2(CO) and (η7-C7H7)2Cr2, with the singlet structures being of much lower energies in both cases. [Copyright &y& Elsevier]

The binuclear benzenemanganese carbonyls (η 6-C 6H 6) 2Mn 2(CO) n( n= 4, 3, 2, 1) have been studied by density functional theory (DFT) using the B3LYP and BP86 methods. The singlet doubly bridged and unbridged isomers of the saturated (η 6-C 6H 6) 2Mn 2(CO) 4are nearly degenerate, suggesting a highly fluxional system. The global minimum of (η 6-C 6H 6) 2Mn 2(CO) 3is a triplet electronic statea triply bridged isomer analogous to the known isoelectronic triplet Cp 2Fe 2(μ-CO) 3. The doubly bridged singlet structure (η 6-C 6H 6) 2Mn 2(CO)(μ-CO) 2lies 9 kcal/mol (B3LYP) or 7 kcal/mol (BP86) above this global minimum. The global minimum of (η 6-C 6H 6) 2Mn 2(CO) 2is a doubly bridged structure with a short manganese−manganese distance suggestive of a MnMn triple bond. Singlet and triplet structures are found for (η 6-C 6H 6) 2Mn 2(CO) with a two-electron donor CO group and metal−metal distances suggesting a M−M quadruple bond for the singlet state and a MM triple bond for the triplet state. [ABSTRACT FROM AUTHOR]

Inherited neurodegenerative diseases, such as Huntington disease and subset of Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis, are caused by the mutant genes that have gained undefined properties that harm cells in the nervous system, causing neurodegeneration and clinical phenotypes. Lowering the mutant gene expression is preäicted to slow the disease progression and produce clinical benefit. Administration of small interfering RNA (siRNA) can silence specific genes. However, long term delivery of siRNA to silence the mutant genes, a requirement for treatment of these chronic central nervous system (CNS) diseases, remains a critical unsolved issue. Here we designed and tested a chemically stabilized siRNA against human Cu,Zn-superoxide dismutase (SOD1) in a mouse model for amyotrophic lateral sclerosis. We show that the modified siRNA has enhanced stability and retains siRNA activity. Administration of this siRNA at the disease onset by long term infusion into the CNS resulted in widespread distribution of this siRNA, knocked down the mutant SOD1 expression, slowed the disease progression, and extended the survival. These results bring RNA interference therapy one step closer to its clinical application for treatment of chronic, devastating, and fatal CNS disorders. [ABSTRACT FROM AUTHOR]

In view of experimental work on (η 4-C 4H 4) 2Fe 2(μ-CO) 3the full range of binuclear cyclobutadieneiron carbonyls (η 4-C 4H 4) 2Fe 2(CO) n( n= 5, 4, 3, 2, 1) have been studied by density functional theory using the B3LYP and BP86 functionals. The pentacarbonyl (η 4-C 4H 4) 2Fe 2(CO) 5is predicted to have a singly bridged (η 4-C 4H 4) 2Fe 2(CO) 4(μ-CO) structure with an Fe−Fe single-bond distance of 2.743 Å (BP86). For (η 4-C 4H 4) 2Fe 2(CO) 4cisand transdoubly CO-bridged singlet structures are found as well as two types of doubly CO-bridged triplet structures. One type has Fe−Fe bond distances in the single-bond range 2.64−2.66 Å and 17-electron iron configurations. The other type of triplet structure has FeFe bond distances in the range 2.38−2.39 Å for a σ + 2/ 2π double bond like that in dioxygen and 18-electron iron configurations. For (η 4-C 4H 4) 2Fe 2(CO) 3the global minimum is the experimentally observed triply CO-bridged structure with an FeFe distance of 2.148 Å (BP86), corresponding to the triple bond required for 18-electron iron configurations. For (η 4-C 4H 4) 2Fe 2(CO) 2the doubly CO-bridged triplet structure with an FeFe distance of 2.216 Å is the lowest energy structure. For (η 4-C 4H 4) 2Fe 2(CO) the lowest lying singlet, triplet, and quintet structures have four-electron-donor bridging η 2-μ-CO groups, as indicated by Fe−O distances around 2.0−2.1 Å. Higher energy perpendicular or near-perpendicular structures with bridging C 4H 4ligands are found in addition to coaxial structures for both (η 4-C 4H 4) 2Fe 2(CO) 2and (η 4-C 4H 4) 2Fe 2(CO). [ABSTRACT FROM AUTHOR]

The iron carbonyl nitrosyls Fe2(NO)2(CO)n (n = 7, 6, 5, 4, 3) have been studied by density functional theory (DFT) using the B3LYP and BP86 methods, for comparison of their predicted structures with those of isoelectronic cobalt carbonyl derivatives. The lowest energy structures for Fe2(NO)2(CO)7 and Fe2(NO)2(CO)6 have two NO bridges, and the lowest energy structure for Fe2(NO)2(CO)5 has a single NO bridge with metal-metal distances (BP86) of 3.161, 2.598, and 2.426 Å, respectively, corresponding to the formal metal-metal bond orders of zero, one, and two, respectively, required for the favored 18-electron configuration for the iron atoms. The heptacarbonyl Fe2(NO)2(CO)7 is thermodynamically unstable with respect to CO loss to give Fe2(NO)2(CO)6. The favored structures for the more highly unsaturated Fe2(NO)2(CO)4 and Fe2(NO)2(CO)3 also have bridging NO groups but avoid iron-iron bond orders higher than two by formal donation of five electrons from bridging NO groups with relatively short Fe-O distances. The lowest energy structures of the unsaturated Fe2(NO)2(CO)n derivatives (n = 5, 4, 3) are significantly different from the isoelectronic cobalt carbonyls Co2(CO),n+2 owing to the tendency for Fe2(NO)2(CO)n to form structures with bridging NO groups and metal-metal formal bond orders no higher than two. [ABSTRACT FROM AUTHOR]

While the adaptor SKAP-55 mediates LFA-1 adhesion on T-cells, it is not known whether the adaptor regulates other aspects of signaling. SKAP-55 could potentially act as a node to coordinate the modulation of adhesion with downstream signaling. In this regard, the GTPase p21ras and the extracellular signal-regulated kinase (ERK) pathway play central roles in T-cell function. In this study, we report that SKAP-55 has opposing effects on adhesion and the activation of the p21ras -ERK pathway in T-cells. SKAP-55 deficient primary T-cells showed a defect in LFA-1 adhesion concurrent with the hyperactivation of the ERK pathway relative to wild-type cells. RNAi knock down (KD) of SKAP-55 in T-cell lines also showed an increase in p21ras activation, while over-expression of SKAP-55 inhibited activation of ERK and its transcriptional target ELK. Three observations implicated the p21ras activating exchange factor RasGRP1 in the process. Firstly, SKAP-55 bound to RasGRP1 via its C-terminus, while secondly, the loss of binding abrogated SKAP-55 inhibition of ERK and ELK activation. Thirdly, SKAP-55-/- primary T-cells showed an increased presence of RasGRP1 in the trans-Golgi network (TGN) following TCR activation, the site where p21ras becomes activated. Our findings indicate that SKAP-55 has a dual role in regulating p21ras-ERK pathway via RasGRP1, as a possible mechanism to restrict activation during T-cell adhesion. [ABSTRACT FROM AUTHOR]

Background: Transgenic RNAi holds promise as a simple, low-cost, and fast method for reverse genetics in mammals. It may be particularly useful for producing animal models for hypomorphic gene function. Inducible RNAi that permits spatially and temporally controllable gene silencing in vivo will enhance the power of transgenic RNAi approach. Furthermore, because microRNA (miRNA) targeting specific genes can be expressed simultaneously with protein coding genes, incorporation of fluorescent marker proteins can simplify the screening and analysis of transgenic RNAi animals. Results: We sought to optimally express a miRNA simultaneously with a fluorescent marker. We compared two construct designs. One expressed a red fluorescent protein (RFP) and a miRNA placed in its 3' untranslated region (UTR). The other expressed the same RFP and miRNA, but the precursor miRNA (pre-miRNA) coding sequence was placed in an intron that was inserted into the 3'-UTR. We found that the two constructs expressed comparable levels of miRNA. However, the intron-containing construct expressed a significantly higher level of RFP than the intron-less construct. Further experiments indicate that the 3'-UTR intron enhances RFP expression by its intrinsic gene-expression-enhancing activity and by eliminating the inhibitory effect of the premiRNA on the expression of RFP. Based on these findings, we incorporated the intron-embedded pre-miRNA design into a conditional expression construct that employed the Cre-loxP system. This construct initially expressed EGFP gene, which was flanked by loxP sites. After exposure to Cre recombinase, the transgene stopped EGFP expression and began expression of RFP and a miRNA, which silenced the expression of specific cellular genes. Conclusion: We have designed and tested a conditional miRNA-expression construct and showed that this construct expresses both the marker genes strongly and can silence the target gene efficiently upon Cre-mediated induction of the miRNA expression. This construct can be used to increase the efficiency [ABSTRACT FROM AUTHOR]

Crystals of NaLa(WO4)2 : Ho3+ were grown by the Czochralski method. The spectroscopic properties have been investigated at room temperature. Intensity parameters, radiative lifetimes and branching ratios have been calculated in the framework of Judd-Ofelt theory. The luminescence spectra measured under 450 nm pumping are dominated by a strong green emission in the 550 nm region connected with the 5S2 + 5F4 - 5I8 transition. The stimulated emission cross-section for this transition was estimated. The luminescence decay curve of the 5S2 + 5F4 level was also measured at room temperature. [ABSTRACT FROM AUTHOR]

Self-renewal and differentiation are cardinal features of stem cells. Asymmetric cell division provides one fundamental mechanism by which stem cell self-renewal and differentiation are balanced. A failure of this balance could lead to diseases such as cancer. During asymmetric division of stem cells, factors controlling their self-renewal and differentiation are unequally segregated between daughter cells. Numb is one such factor that is segregated to the differentiating daughter cell during the stem-cell-like neuroblast divisions in Drosophila melanogaster, where it inhibits self-renewal. The localization and function of Numb is cell-cycle-dependent. Here we show that Polo (ref. 13), a key cell cycle regulator, the mammalian counterparts of which have been implicated as oncogenes as well as tumour suppressors, acts as a tumour suppressor in the larval brain. Supernumerary neuroblasts are produced at the expense of neurons in polo mutants. Polo directly phosphorylates Partner of Numb (Pon, ref. 16), an adaptor protein for Numb, and this phosphorylation event is important for Pon to localize Numb. In polo mutants, the asymmetric localization of Pon, Numb and atypical protein kinase C are disrupted, whereas other polarity markers are largely unaffected. Overexpression of Numb suppresses neuroblast overproliferation caused by polo mutations, suggesting that Numb has a major role in mediating this effect of Polo. Our results reveal a biochemical link between the cell cycle and the asymmetric protein localization machinery, and indicate that Polo can inhibit progenitor self-renewal by regulating the localization and function of Numb. [ABSTRACT FROM AUTHOR]