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Botulinum neurotoxin (available commercially as BOTOX®) has been used successfully for treatment of several neuromuscular disorders including blepharospasm, dystonia, spasticity, and cerebral palsy in children. Our data demonstrate that injection of BOTOX® into the proximal intestinal wall of diet-induced obese (DIO) mice induces weight loss and reduces food intake. This was associated with amelioration of hyperglycemia, hyperlipidemia, and significant improvement of glucose tolerance without alteration of energy expenditure. We also observed accelerated gastrointestinal transit and significant reductions in glucose and lipid absorption which may account at least, in part to the observed weight loss and robust metabolic benefits, although possible systemic effects occurring as a consequence of central and/or peripheral signaling cannot be ignored. The observed metabolic benefits were found to be largely independent of weight loss as demonstrated by pair-feeding experiments. Effects lasted until about 8 weeks, for as long as the half-life of Botox as reported in prior rodent studies. These results have valuable clinical implications. If the observed effects are translatable in humans this approach could lay the foundation for therapeutic approaches geared toward robust and sustained weight loss, mimicking some of the benefits of bariatric surgeries without its cost and complications.

Current laboratory models of lymphatic metastasis generally require either genetically modified animals or are technically challenging. Herein, we have developed a robust protocol for the induction of intralymphatic metastasis in wild-type mice with reproducible outcomes. To determine an optimal injection quantity and timeline for tumorigenesis, C57Bl/6 mice were injected directly into the mesenteric lymph duct (MLD) with varying numbers of syngeneic murine colon cancer cells (MC38) or gastric cancer cells (YTN16) expressing GFP/luciferase and monitored over 2-4 weeks. Tumor growth was tracked via whole-animal in vivo bioluminescence imaging (IVIS). Our data indicate that the injection of tumor cells into the MLD is a viable model for lymphatic metastasis as necropsies revealed large tumor burdens and metastasis in regional lymph nodes. This protocol enables a closer study of the role of lymphatics in cancer metastasis and opens a window for the development of novel approaches for treatment of metastatic diseases.

Subarachnoid hemorrhage (SAH) due to rupture of an intracranial aneurysm leads to vasospasm resulting in delayed cerebral ischemia. Therapeutic options are currently limited to hemodynamic optimization and nimodipine, which have marginal clinical efficacy. Nitric oxide (NO) modulates cerebral blood flow through activation of the cGMP-Protein Kinase G (PKG) pathway. Our hypothesis is that SAH results in downregulation of signaling components in the NO-PKG pathway which could explain why treatments for vasospasm targeting this pathway lack efficacy and that treatment with a cell permeant phosphopeptide mimetic of downstream effector prevents delayed vasospasm after SAH. Using a rat endovascular perforation model, reduced levels of NO-PKG pathway molecules were confirmed. Additionally, it was determined that expression and phosphorylation of a PKG substrate: Vasodilator-stimulated phosphoprotein (VASP) was downregulated. A family of cell permeant phosphomimetic of VASP (VP) was wasdesigned and shown to have vasorelaxing property that is synergistic with nimodipine in intact vascular tissuesex vivo. Hence, treatment targeting the downstream effector of the NO signaling pathway, VASP, may bypass receptors and signaling elements leading to vasorelaxation and that treatment with VP can be explored as a therapeutic strategy for SAH induced vasospasm and ameliorate neurological deficits.

We report a direct fluorination method under fluorine gas atmosphere using a fluidized bed reactor for converting nanophase iron oxide (n-Fe2O3) to an electrochemically stable and higher energy density iron oxyfluoride/fluoride phase. Interestingly, no noticeable bulk iron oxyfluoride phase (FeOF) phase was observed even at fluorination temperature close to 300 °C. Instead, at fluorination temperatures below 250 °C, scanning transmission electron microscopy coupled with electron energy loss spectroscopy (STEM-EELS) and X-ray photoelectron spectroscopy (XPS) analysis showed surface fluorination with nominal composition, Fe2O3-xF2x (x1). At fluorination temperatures of 275 °C, STEM-EELS results showed porous interconnected nanodomains of FeF3 and Fe2O3 coexisting within the same particle, and overall the particles become less dense after fluorination. We performed potentiometric intermittent titration and electrochemical impedance spectroscopy studies to understand the lithium diffusion (or apparent diffusion) in both the oxyfluoride and mixed phase FeF3 + Fe2O3 composition, and correlate the results to their electrochemical performance. Further, we analyze from a thermodynamical perspective, the observed formation of the majority fluoride phase (77% FeF3) and the absence of the expected oxyfluoride phase based on the relative formation energies of oxide, fluoride, and oxyfluorides.

Background Neuregulin‐1β ( NRG ‐1β) is a growth factor critical for cardiac development and repair with therapeutic potential for heart failure. We previously showed that the glial growth factor 2 ( GGF 2) isoform of NRG ‐1β improves cardiac function in rodents after myocardial infarction ( MI ), but its efficacy in a large animal model of cardiac injury has not been examined. We therefore sought to examine the effects of GGF 2 on ventricular remodeling, cardiac function, and global transcription in post‐ MI swine, as well as potential mechanisms for anti‐remodeling effects. Methods and Results MI was induced in anesthetized swine (n=23) by intracoronary balloon occlusion. At 1 week post‐ MI , survivors (n=13) received GGF 2 treatment (intravenous, biweekly for 4 weeks; n=8) or were untreated (n=5). At 5 weeks post‐ MI , fractional shortening was higher (32.8% versus 25.3%, P =0.019), and left ventricular ( LV ) end‐diastolic dimension lower (4.5 versus 5.3 cm, P =0.003) in GGF 2‐treated animals. Treatment altered expression of 528 genes, as measured by microarrays, including collagens, basal lamina components, and matricellular proteins. GGF 2‐treated pigs exhibited improvements in LV cardiomyocyte mitochondria and intercalated disk structures and showed less fibrosis, altered matrix structure, and fewer myofibroblasts (myoFbs), based on trichrome staining, electron microscopy, and immunostaining. In vitro experiments with isolated murine and rat cardiac fibroblasts demonstrate that NRG ‐1β reduces myoFbs, and suppresses TGF β‐induced phospho‐ SMAD 3 as well as α SMA expression. Conclusions These results suggest that GGF 2/ NRG ‐1β prevents adverse remodeling after injury in part via anti‐fibrotic effects in the heart.

Pancreatic islet transplantation has shown great success in the treatment of diabetic patients. However, the required immunosuppressive therapy exposes patients to serious side effects.We have designed a novel five-component/three-membrane capsule and encapsulation system to protect the transplanted islet cells from immune system attack while allowing the influx of molecules and nutrients necessary for cell function/survival and efflux of the desired cellular product, specifically insulin, for making recipients healthy.We transplanted encapsulated canine pancreatic islets into the peritoneal cavity of pancreatectomized canines. Transplantation normalized fasting blood glucose levels in nine out of nine dogs for up to 214 days with a single transplantation. Retransplantation was assessed in three animals and encapsulated islets were effective in providing fasting glycemic control after the initial transplantation had run its course. No immunosuppression or anti-inflammatory therapy was used.This advancement in transplantation may lead to an alternative approach for islet transplantation treatment for diabetic patients. This approach may also benefit patients suffering from other hormone deficiency diseases including liver disease and Parkinson's disease.

Multivalent conversion-based binary transition metal (TM) compounds have recently gained significant attention due to their higher specific capacity compared to conventional intercalation-based lithium-ion materials, due to their multiple red-ox states contributing towards transfer of > 1 lithium per transition metal atom. 1-2 However, harvesting reversible multi-electron capacity from multivalent systems presents many challenges, such as poor electronic conductivity, poor transport and interfacial charge transfer kinetics, and structural instability during multi-electron charge transfer, which leads to poor cyclability and huge voltage hysteresis during the charge-discharge cycles.3 Many approaches are tried by us to solve these issues. Initially, we investigated the role of electrode architecture on the capacity retention and hysteresis.4 A electrode architecture consists of nanometer sized iron fluoride particles (~25-50nm) coated with multilayer graphitic platelets and bound to an electronic backbone comprising of an interconnected network of carbon fibers (5-9 µm diameter) was specially designed. This unique combination of reduced particle size and electrode architecture significantly improves the local electronic conductivity and enhances the electrochemical performance such as better capacity retention and C-rate performance. At the same time, the voltage hysteresis was significantly reduced from 1.5 V to ~0.9V, compared to normal slurry electrodes. The reaction transport kinetics was further improved at elevated temperature (60oC), yielding almost theoretical specific capacity (700 mAhg-1) with reasonably good cycle life (Figure 1). We also explored alternate 3D architectures through a colloidal templating strategy to produce inverse opal scaffolds for fabricating iron fluorides as well as oxides electrode that could provide a bicontinuous channels for facilitating ion and electron transport, to greatly improve the kinetics and voltage hysterisis.5The overall performance of such 3D templated structures are impressive, and may provide a new architectural concept for next generation high energy density batteries. In addition, we proposed a novel molecular approach for conversion compounds by converting iron oxides to oxyfluorides/fluorides through a controlled fluorination process.6 Our study suggests that the fluorination process occurs from surface to core of the oxide particles with increased fluorinating temperatures. This is supported by electrochemical capacity enhancement along with a concomitant increase in voltage plateau of the fluorinated samples as demonstrated in the electrochemical cycling (Figure 2), differential capacity and cyclic voltammetry results. Acknowledgement This research is sponsored by the Laboratory Directed Research and Development Program of Oak Ridge National Laboratory, managed by UT-Battelle, LLC, for the U. S. Department of Energy. Electrode and materials characterization work is supported by Vehicle Technologies Program for the Office of Energy Efficiency and Renewable Energy, Department of Energy. References: P. Poizot, S. Lauruelle, S. Grugeon, L. Dupont and J. -M. Tarascon , Nature, 407, 496 (2000). H. Li, P. Balaya and J. Maier, J Electrochem. Soc. 151, A1878, (2004). J. Cabana, L. Monconduit, D. Larcher and M. R. Palacin, Adv. Mater. 22, E170, (2010). S. K. Martha, J. Nanda, H. Zhou, J. C. Idrobo, N. J. Dudney, S. Pannala, S. Dai, J. Wang, and P. V. Braun, RSC Advances. 4, 6730, (2014) J. Wang, P. V. Braun, H. Zhou and J. Nanda (to be submitted) H. Zhou, J. Nanda, S. K. Martha, J. Adcock, J. C. Idrobo, L. Baggetto, G. M. Veith, S. Dai, S. Pannala and N. J. Dudney, The Journal of Physical Chemistry Letters , 4(21), 3798, (2013)

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