Liver-specific knockout of arginase-1 leads to a profound phenotype similar to inducible whole body arginase-1 deficiency

Arginase-1 (Arg1) converts arginine to urea and ornithine in the distal step of the urea cycle in liver. We previously generated a tamoxifen-inducible Arg1 deficient mouse model (Arg1-Cre) that disrupts Arg1 expression throughout the whole body and leads to lethality ≈ 2 weeks after gene disruption. Here, we evaluate if liver-selective Arg1 loss is sufficient to recapitulate the phenotype observed in global Arg1 knockout mice, as well as to gauge the effectiveness of gene delivery or hepatocyte transplantation to rescue the phenotype. Liver-selective Arg1 deletion was induced by using an adeno-associated viral (AAV)-thyroxine binding globulin (TBG) promoter-Cre recombinase vector administered to Arg1 "floxed" mice; Arg1(fl/fl) ). An AAV vector expressing an Arg1-enhanced green fluorescent protein (Arg1-eGFP) transgene was used for gene delivery, while intrasplenic injection of wild-type (WT) C57BL/6 hepatocytes after partial hepatectomy was used for cell delivery to "rescue" tamoxifen-treated Arg1-Cre mice. The results indicate that liver-selective loss of Arg1 (> 90% deficient) leads to a phenotype resembling the whole body knockout of Arg1 with lethality ≈ 3 weeks after Cre-induced gene disruption. Delivery of Arg1-eGFP AAV rescues more than half of Arg1 global knockout male mice (survival > 4 months) but a significant proportion still succumb to the enzyme deficiency even though liver expression and enzyme activity of the fusion protein reach levels observed in WT animals. Significant Arg1 enzyme activity from engrafted WT hepatocytes into knockout livers can be achieved but not sufficient for rescuing the lethal phenotype. This raises a conundrum relating to liver-specific expression of Arg1. On the one hand, loss of expression in this organ appears to be both necessary and sufficient to explain the lethal phenotype of the genetic disorder in mice. On the other hand, gene and cell-directed therapies suggest that rescue of extra-hepatic Arg1 expression may also be necessary for disease correction. Further studies are needed in order to illuminate the detailed mechanisms for pathogenesis of Arg1-deficiency

A Computational Approach to Understand \u3cem\u3eArabidopsis thaliana\u3c/em\u3e and Soybean Resistance to \u3cem\u3eFusarium solani\u3c/em\u3e (Fsg)

In this study, we reported the analysis of Arabidopsis thaliana microarray gene expression profile of root tissues after the plant was challenged with fungal pathogen Fusarium solani f. sp. glycines (Fsg). Our microarray analysis showed that the infection caused 130 transcript abundances (TAs) to increase by more than 2 fold and 32 out of 130 TAs were increased by more than 3 fold in the root tissues. However, only nineteen ESTs were observed with a decrease in TAs by more than 2 fold and 13 of them went down more than 3 fold due to the pathogen infection. In addition, the number of the up-regulated genes was nearly seven times more than that of downregulated genes. The coordinate regulation of adjacent genes was detected and the distance distribution of the nearest neighbor genes was less likely to be randomly scattered in genome. The results of this study enabled us to decipher the resistance mechanism to Fsg through an integrated computational approach

Ruthenium atomically dispersed in carbon outperforms platinum toward hydrogen evolution in alkaline media.

Hydrogen evolution reaction is an important process in electrochemical energy technologies. Herein, ruthenium and nitrogen codoped carbon nanowires are prepared as effective hydrogen evolution catalysts. The catalytic performance is markedly better than that of commercial platinum catalyst, with an overpotential of only -12 mV to reach the current density of 10 mV cm-2 in 1 M KOH and -47 mV in 0.1 M KOH. Comparisons with control experiments suggest that the remarkable activity is mainly ascribed to individual ruthenium atoms embedded within the carbon matrix, with minimal contributions from ruthenium nanoparticles. Consistent results are obtained in first-principles calculations, where RuCxNy moieties are found to show a much lower hydrogen binding energy than ruthenium nanoparticles, and a lower kinetic barrier for water dissociation than platinum. Among these, RuC2N2 stands out as the most active catalytic center, where both ruthenium and adjacent carbon atoms are the possible active sites

In silico comparison of transcript abundances during Arabidopsis thaliana and Glycine max resistance to Fusarium virguliforme

<p>Abstract</p> <p>Background</p> <p>Sudden death syndrome (SDS) of soybean (<it>Glycine max </it>L. Merr.) is an economically important disease, caused by the semi-biotrophic fungus <it>Fusarium solani </it>f. sp. <it>glycines</it>, recently renamed <it>Fusarium virguliforme </it>(Fv). Due to the complexity and length of the soybean-Fusarium interaction, the molecular mechanisms underlying plant resistance and susceptibility to the pathogen are not fully understood. <it>F. virguliforme </it>has a very wide host range for the ability to cause root rot and a very narrow host range for the ability to cause a leaf scorch. <it>Arabidopsis thaliana </it>is a host for many types of phytopathogens including bacteria, fungi, viruses and nematodes. Deciphering the variations among transcript abundances (TAs) of functional orthologous genes of soybean and <it>A. thaliana </it>involved in the interaction will provide insights into plant resistance to <it>F. viguliforme</it>.</p> <p>Results</p> <p>In this study, we reported the analyses of microarrays measuring TA in whole plants after <it>A. thaliana </it>cv 'Columbia' was challenged with fungal pathogen <it>F. virguliforme</it>. Infection caused significant variations in TAs. The total number of increased transcripts was nearly four times more than that of decreased transcripts in abundance. A putative resistance pathway involved in responding to the pathogen infection in <it>A. thaliana </it>was identified and compared to that reported in soybean.</p> <p>Conclusion</p> <p>Microarray experiments allow the interrogation of tens of thousands of transcripts simultaneously and thus, the identification of plant pathways is likely to be involved in plant resistance to Fusarial pathogens. Dissection of the set functional orthologous genes between soybean and <it>A. thaliana </it>enabled a broad view of the functional relationships and molecular interactions among plant genes involved in <it>F. virguliforme </it>resistance.</p

Methods and systems for submucosal implantation of a device for diagnosis and treatment with a therapeutic agent

Instruments, systems, implants, and methods are provided for performing submucosal medical procedures in a desired area of the digestive tract using endoscopy. Instruments include a safe access needle injection instrument, a submucosal tunneling instrument, a submucosal dissection instrument, and a mucosal resection device. A submucosal implant device for diagnosing and treating disorders of the body may be implanted. A passive submucosal implant device may take the form of a drug delivery depot in which a therapeutic agent within the depot elutes from the depot according to a predetermined elution profile. An active submucosal implant device may take the form of a drug delivery device that incorporates a self-contained diagnostic system to determine the appropriate delivery time and dosage of a therapeutic agent to be administered.Board of Regents, University of Texas Syste

Structural insights into RNA processing by the human RISC-loading complex.

Targeted gene silencing by RNA interference (RNAi) requires loading of a short guide RNA (small interfering RNA (siRNA) or microRNA (miRNA)) onto an Argonaute protein to form the functional center of an RNA-induced silencing complex (RISC). In humans, Argonaute2 (AGO2) assembles with the guide RNA-generating enzyme Dicer and the RNA-binding protein TRBP to form a RISC-loading complex (RLC), which is necessary for efficient transfer of nascent siRNAs and miRNAs from Dicer to AGO2. Here, using single-particle EM analysis, we show that human Dicer has an L-shaped structure. The RLC Dicer's N-terminal DExH/D domain, located in a short 'base branch', interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. A model generated by docking the available atomic structures of Dicer and Argonaute homologs into the RLC reconstruction suggests a mechanism for siRNA transfer from Dicer to AGO2

Masses and Ages for 230,000 LAMOST Giants, via Their Carbon and Nitrogen Abundances

We measure carbon and nitrogen abundances to a precision of ≾0.1 dex for 450,000 giant stars from their low-resolution (R ~ 1800) LAMOST DR2 survey spectra. We use these [C/M] and [N/M] measurements, together with empirical relations based on the APOKASC sample, to infer stellar masses and implied ages for 230,000 of these objects to 0.08 dex and 0.2 dex respectively. We use The Cannon, a data-driven approach to spectral modeling, to construct a predictive model for LAMOST spectra. Our reference set comprises 8125 stars observed in common between the APOGEE and LAMOST surveys, taking seven APOGEE DR12 labels (parameters) as ground truth: T_(eff), log g, [M/H], [α/M], [C/M], [N/M], and A_k. We add seven colors to the Cannon model, based on the g, r, i, J, H, K, W1, W2 magnitudes from APASS, 2MASS, and WISE, which improves our constraints on T_(eff) and log g by up to 20% and on A_k by up to 70%. Cross-validation of the model demonstrates that, for high-S/N objects, our inferred labels agree with the APOGEE values to within 50 K in temperature, 0.04 mag in A_k, and <0.1 dex in log g, [M/H], [C/M], [N/M], and [α/M]. We apply the model to 450,000 giants in LAMOST DR2 that have not been observed by APOGEE. This demonstrates that precise individual abundances can be measured from low-resolution spectra and represents the largest catalog to date of homogeneous stellar [C/M], [N/M], masses, and ages. As a result, we greatly increase the number and sky coverage of stars with mass and age estimates

Radiation-induced Assembly of Rad51 and Rad52 Recombination Complex Requires ATM and c-Abl

Cells from individuals with the recessive cancer-prone disorder ataxia telangiectasia (A-T) are hypersensitive to ionizing radiation (I-R). ATM (mutated in A-T) is a protein kinase whose activity is stimulated by I-R. c-Abl, a nonreceptor tyrosine kinase, interacts with ATM and is activated by ATM following I-R. Rad51 is a homologue of bacterial RecA protein required for DNA recombination and repair. Here we demonstrate that there is an I-R-induced Rad51 tyrosine phosphorylation, and this induction is dependent on both ATM and c-Abl. ATM, c-Abl, and Rad51 can be co-immunoprecipitated from cell extracts. Consistent with the physical interaction, c-Abl phosphorylates Rad51 in vitro and in vivo. In assays using purified components, phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. After I-R, an increase in association between Rad51 and Rad52 occurs in wild-type cells but not in cells with mutations that compromise ATM or c-Abl. Our data suggest signaling mediated through ATM, and c-Abl is required for the correct post-translational modification of Rad51, which is critical for the assembly of Rad51 repair protein complex following I-R

Methods and systems for performing submucosal medical procedures

Instruments, systems and methods are provided for performing submucosal medical procedures in a desired area of the digestive tract using endoscopy. Instruments include a safe access needle injection instrument, a submucosal tunneling instrument, a submucosal dissection instrument, a mucosal resection device. Systems include a combination of one or more of such instruments with or without injectable agents. Embodiments of various methods for performing the procedures are also provided.Board of Regents, University of Texas Syste

Janus monolayers of transition metal dichalcogenides.

Structural symmetry-breaking plays a crucial role in determining the electronic band structures of two-dimensional materials. Tremendous efforts have been devoted to breaking the in-plane symmetry of graphene with electric fields on AB-stacked bilayers or stacked van der Waals heterostructures. In contrast, transition metal dichalcogenide monolayers are semiconductors with intrinsic in-plane asymmetry, leading to direct electronic bandgaps, distinctive optical properties and great potential in optoelectronics. Apart from their in-plane inversion asymmetry, an additional degree of freedom allowing spin manipulation can be induced by breaking the out-of-plane mirror symmetry with external electric fields or, as theoretically proposed, with an asymmetric out-of-plane structural configuration. Here, we report a synthetic strategy to grow Janus monolayers of transition metal dichalcogenides breaking the out-of-plane structural symmetry. In particular, based on a MoS2 monolayer, we fully replace the top-layer S with Se atoms. We confirm the Janus structure of MoSSe directly by means of scanning transmission electron microscopy and energy-dependent X-ray photoelectron spectroscopy, and prove the existence of vertical dipoles by second harmonic generation and piezoresponse force microscopy measurements