Gene therapy targeting SARM1 blocks pathological axon degeneration in mice

Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, an injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection and in models of neurological disease, suggesting that inhibiting SARM1 is a promising strategy to reduce pathological AxD. Unfortunately, no drugs exist to target SARM1. We, therefore, developed SARM1 dominant-negatives that potently block AxD in cellular models of axotomy and neuropathy. To assess efficacy in vivo, we used adeno-associated virus-mediated expression of the most potent SARM1 dominant-negative and nerve transection as a model of severe AxD. While axons of vehicle-treated mice degenerate rapidly, axons of mice expressing SARM1 dominant-negative can remain intact for \u3e10 d after transection, similar to the protection observed in SARM1-null mice. We thus developed a novel in vivo gene therapeutic to block pathological axon degeneration by inhibiting SARM1, an approach that may be applied clinically to treat manifold neurodegenerative diseases characterized by axon loss

Evaluation of short-term toxicity of ammonia and nitrite on the survival of whiteleg shrimp, Litopenaeus vannamei juveniles

The effects of short-term toxicity of total ammonia nitrogen (TAN) and nitrite were estimated in juveniles of Litopenaeus vannamei under laboratory conditions. In the first experiment, L. vannamei juveniles were exposed to different concentrations of ammonia (0, 5, 10, 15, 20, 30, and 40 mg of TAN L-1) or nitrite (0, 5, 10, 20, 30, 40, and 50 mg of NO2--N L-1), using the static renewal method at a salinity of 20 ppt and pH 8.2. The survival rates of juveniles significantly decreased when exposed to increased concentrations of ammonia or nitrite during the 96 h bioassays. The 24, 48, 72, and 96 h LC50 values of TAN in juveniles were 45.5, 30.1, 13.8, and 6.3 mg L-1, respectively, while the LC50 values of NO2--N at 24, 48, 72, and 96 h were 37.6, 16.7, 8.8, and 4.8 mg L-1, respectively. Experiment 2 evaluated the tolerance of L. vannamei juveniles at various salinities (5, 10, 15, and 20 ppt) under a high concentration of ammonia or nitrite (5 mg L-1). Results showed that the survival rates of L. vannamei at 5 ppt and 10 ppt were significantly lower than those at 20 ppt after 72 h and 96 h of exposure

LNK (SH2B3): paradoxical effects in ovarian cancer.

LNK (SH2B3) is an adaptor protein studied extensively in normal and malignant hematopoietic cells. In these cells, it downregulates activated tyrosine kinases at the cell surface resulting in an antiproliferative effect. To date, no studies have examined activities of LNK in solid tumors. In this study, we found by in silico analysis and staining tissue arrays that the levels of LNK expression were elevated in high-grade ovarian cancer. To test the functional importance of this observation, LNK was either overexpressed or silenced in several ovarian cancer cell lines. Remarkably, overexpression of LNK rendered the cells resistant to death induced by either serum starvation or nutrient deprivation, and generated larger tumors using a murine xenograft model. In contrast, silencing of LNK decreased ovarian cancer cell growth in vitro and in vivo. Western blot studies indicated that overexpression of LNK upregulated and extended the transduction of the mitogenic signal, whereas silencing of LNK produced the opposite effects. Furthermore, forced expression of LNK reduced cell size, inhibited cell migration and markedly enhanced cell adhesion. Liquid chromatography-mass spectroscopy identified 14-3-3 as one of the LNK-binding partners. Our results suggest that in contrast to the findings in hematologic malignancies, the adaptor protein LNK acts as a positive signal transduction modulator in ovarian cancers

Milk-Derived Exosomes and Metabolic Regulation

Exosomes are natural nanoparticles that play an important role in cell-to-cell communication. Communication is achieved through the transfer of cargos, such as microRNAs, from donor to recipient cells and binding of exosomes to cell surface receptors. Exosomes and their cargos are also obtained from dietary sources, such as milk. Exosome and cell glycoproteins are crucial for intestinal uptake. A large fraction of milk exosomes accumulates in the brain, whereas the tissue distribution of microRNA cargos varies among distinct species of microRNA. The fraction of milk exosomes that escapes absorption elicits changes in microbial communities in the gut. Dietary depletion of exosomes and their cargos causes a loss of circulating microRNAs and elicits phenotypes such as loss of cognitive performance, increase in purine metabolites, loss of fecundity, and changes in the immune response. Milk exosomes meet the definition of bioactive food compounds

Effects of combined rice flour and molasses use on the growth performance of Pacific white shrimp (<em>Litopenaeus vannamei</em> Boone, 1931) applied biofloc technology

A 63-day completely random experiment with three replications was carried out to compare the effects of five different combination ratios of rice flour (R) and molasses (M) on the growth and survival rates of Pacific white shrimp (Litopenaeus vannamei Boone, 1931) postlarvae applied biofloc technology. Five biofloc (BF) treatments, including R90-M10, R70-M30, R50-M50, R30-M70, and R10-M90, formed with the addition of different combination ratios of rice flour and molasses, i.e., 90% R+10% M, 70% R+30% M, 50% R+50% M, 30% R+70% M, and 10% R+90% M, respectively, with C/N ratios of 15:1, and a control (neither rice flour nor molasses applied) was randomly arranged into the 18 plastic tanks of 1.0 m3 volume (with 0.5 m3 of water) each tank and salinity of 15‰. The postlarvae (0.095 g) were stocked into the tanks at a 150 ind. m−3 density and fed pelleted feed (40% protein). There was an improvement in growth (FMW, WG, DWG, and SGR) for all treatments. Besides, treatments with more than or equal to 30% molasses have improved SR, FCR, and FB. Especially the highest SR (94.2%) was obtained at the R70-M30, which perhaps created the highest FB (1.435 kg m−3) in this treatment. The lowest FCR (1.28) was also observed in the R70-M30 and significantly differed from the control and other treatments. Besides, water quality parameters were within the ranges recommended for Pacific white shrimp health during the experimental period. Our findings indicated the benefits of shrimp culture using the BF system when different combined ratios of rice flour and molasses were applied, of which a ratio of 70% rice flour and 30% molasses was considered as the best

Stress Induced Structural Transformations in Au Nanocrystals

Nanocrystals can exist in multiply twinned structures like the icosahedron, or single crystalline structures like the cuboctahedron or Wulff-polyhedron. Structural transformation between these polymorphic structures can proceed through diffusion or displacive motion. Experimental studies on nanocrystal structural transformations have focused on high temperature diffusion mediated processes. Thus, there is limited experimental evidence of displacive motion mediated structural transformations. Here, we report the high-pressure structural transformation of 6 nm Au nanocrystals under nonhydrostatic pressure in a diamond anvil cell that is driven by displacive motion. In-situ X-ray diffraction and transmission electron microscopy were used to detect the transformation of multiply twinned nanocrystals into single crystalline nanocrystals. High-pressure single crystalline nanocrystals were recovered after unloading, however, the nanocrystals quickly reverted back to multiply twinned state after redispersion in toluene solvent. The dynamics of recovery was captured using transmission electron microscopy which showed that the recovery was governed by surface recrystallization and rapid twin boundary motion. We show that this transformation is energetically favorable by calculating the pressure-induced change in strain energy. Molecular dynamics simulations showed that defects nucleated from a region of high stress region in the interior of the nanocrystal, which make twin boundaries unstable. Deviatoric stress driven Mackay transformation and dislocation/disclination mediated detwinning are hypothesized as possible mechanisms of high-pressure structural transformation.Comment: 32 pages, 14 figures, and 1 movie (please open pdf with Adobe Acrobat Reader to see the embedded movie

Re-examining the consumption-wealth relationship : the role of model uncertainty

This paper discusses the consumption-wealth relationship. Following the recent influential workof Lettau and Ludvigson [e.g. Lettau and Ludvigson (2001), (2004)], we use data on consumption, assets andlabor income and a vector error correction framework. Key …ndings of their work are that consumption doesrespond to permanent changes in wealth in the expected manner, but that most changes in wealth are transitoryand have no e¤ect on consumption. We investigate the robustness of these results to model uncertainty andargue for the use of Bayesian model averaging. We …nd that there is model uncertainty with regards to thenumber of cointegrating vectors, the form of deterministic components, lag length and whether the cointegratingresiduals a¤ect consumption and income directly. Whether this uncertainty has important empirical implicationsdepends on the researcher's attitude towards the economic theory used by Lettau and Ludvigson. If we workwith their model, our findings are very similar to theirs. However, if we work with a broader set of models andlet the data speak, we obtain somewhat di¤erent results. In the latter case, we …nd that the exact magnitudeof the role of permanent shocks is hard to estimate precisely. Thus, although some support exists for the viewthat their role is small, we cannot rule out the possibility that they have a substantive role to play

Nucleation of Dislocations in 3.9 nm Nanocrystals at High Pressure

As circuitry approaches single nanometer length scales, it is important to predict the stability of metals at these scales. The behavior of metals at larger scales can be predicted based on the behavior of dislocations, but it is unclear if dislocations can form and be sustained at single nanometer dimensions. Here, we report the formation of dislocations within individual 3.9 nm Au nanocrystals under nonhydrostatic pressure in a diamond anvil cell. We used a combination of x-ray diffraction, optical absorbance spectroscopy, and molecular dynamics simulation to characterize the defects that are formed, which were found to be surface-nucleated partial dislocations. These results indicate that dislocations are still active at single nanometer length scales and can lead to permanent plasticity.Comment: 33 pages, 12 figure