Reversal of Hypertriglyceridemia, Fatty Liver Disease, and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler

SummaryNonalcoholic fatty liver disease (NAFLD) affects one in three Americans and is a major predisposing condition for the metabolic syndrome and type 2 diabetes (T2D). We examined whether a functionally liver-targeted derivative of 2,4-dinitrophenol (DNP), DNP-methyl ether (DNPME), could safely decrease hypertriglyceridemia, NAFLD, and insulin resistance without systemic toxicities. Treatment with DNPME reversed hypertriglyceridemia, fatty liver, and whole-body insulin resistance in high-fat-fed rats and decreased hyperglycemia in a rat model of T2D with a wide therapeutic index. The reversal of liver and muscle insulin resistance was associated with reductions in tissue diacylglycerol content and reductions in protein kinase C epsilon (PKCε) and PKCθ activity in liver and muscle, respectively. These results demonstrate that the beneficial effects of DNP on hypertriglyceridemia, fatty liver, and insulin resistance can be dissociated from systemic toxicities and suggest the potential utility of liver-targeted mitochondrial uncoupling agents for the treatment of hypertriglyceridemia, NAFLD, metabolic syndrome, and T2D

Comparing Brane Inflation to WMAP

We compare the simplest realistic brane inflationary model to recent cosmological data, including WMAP 3-year cosmic microwave background (CMB) results, Sloan Digital Sky Survey luminous red galaxies (SDSS LRG) power spectrum data and Supernovae Legacy Survey (SNLS) Type 1a supernovae distance measures. Here, the inflaton is simply the position of a $D3$-brane which is moving towards a $\bar{D}3$-brane sitting at the bottom of a throat (a warped, deformed conifold) in the flux compactified bulk in Type IIB string theory. The analysis includes both the usual slow-roll scenario and the Dirac-Born-Infeld scenario of slow but relativistic rolling. Requiring that the throat is inside the bulk greatly restricts the allowed parameter space. We discuss possible scenarios in which large tensor mode and/or non-Gaussianity may emerge. Here, the properties of a large tensor mode deviate from that in the usual slow-roll scenario, providing a possible stringy signature. Overall, within the brane inflationary scenario, the cosmological data is providing information about the properties of the compactification of the extra dimensions.Comment: 45 pages 11 figure

Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium

Several deleterious intra-acinar phenomena are simultaneously triggered on initiating acute pancreatitis. These culminate in acinar injury or inflammatory mediator generation in vitro and parenchymal damage in vivo. Supraphysiologic caerulein is one such initiator which simultaneously activates numerous signaling pathways including non-receptor tyrosine kinases such as of the Src family. It also causes a sustained increase in cytosolic calcium- a player thought to be crucial in regulating deleterious phenomena. We have shown Src to be involved in caerulein induced actin remodeling, and caerulein induced changes in the Golgi and post-Golgi trafficking to be involved in trypsinogen activation, which initiates acinar cell injury. However, it remains unclear whether an increase in cytosolic calcium is necessary to initiate acinar injury or if injury can be initiated at basal cytosolic calcium levels by an alternate pathway. To study the interplay between tyrosine kinase signaling and calcium, we treated mouse pancreatic acinar cells with the tyrosine phosphatase inhibitor pervanadate. We studied the effect of the clinically used Src inhibitor Dasatinib (BMS-354825) on pervanadate or caerulein induced changes in Src activation, trypsinogen activation, cell injury, upstream cytosolic calcium, actin and Golgi morphology. Pervanadate, like supraphysiologic caerulein, induced Src activation, redistribution of the F-actin from its normal location in the sub-apical area to the basolateral areas, and caused antegrade fragmentation of the Golgi. These changes, like those induced by supraphysiologic caerulein, were associated with trypsinogen activation and acinar injury, all of which were prevented by Dasatinib. Interestingly, however, pervanadate did not cause an increase in cytosolic calcium, and the caerulein induced increase in cytosolic calcium was not affected by Dasatinib. These findings suggest that intra-acinar deleterious phenomena may be initiated independent of an increase in cytosolic calcium. Other players resulting in acinar injury along with the Src family of tyrosine kinases remain to be explored. © 2013 Mishra et al

Hubble Space Telescope STIS Observations of GRB 000301C: CCD Imaging and Near-Ultraviolet MAMA Spectroscopy

We present Space Telescope Imaging Spectrograph observations of the optical transient (OT) counterpart of the γ-ray burster GRB 000301C obtained 5 days after the burst, on 2000 March 6. CCD clear-aperture imaging reveals a R ≃ 21.50 ± 0.15 source with no apparent host galaxy. An 8000 s, 1150 Å 18 on the line of sight to the OT. This measured redshift is conservatively a lower limit to the GRB redshift. However, as all other GRBs that have deep Hubble Space Telescope images appear to lie on the stellar field of a host galaxy, and as the large H I column density measured here and in later ground-based observations is unlikely on a random line of sight, we believe we are probably seeing absorption from H I in the host galaxy. In any case, this represents the largest direct redshift determination of a γ-ray burster to date. Our data are compatible with an OT spectrum represented by a power law with an intrinsic index α = 1.2 (f_ν ∝ ν^(-α)) and no extinction in the host galaxy, or with α = 0.5 and extinction by SMC-like dust in the OT rest frame with A_V = 0.15. The large N_(H I) and the lack of a detected host are similar to the situation for damped Lyα absorbers at z > 2

HST/STIS observations of GRB000301C: CCD imaging and NUV MAMA spectroscopy

We present HST/STIS observations of the optical counterpart (OT) of the gamma-ray burster GRB 000301C obtained on 2000 March 6, five days after the burst. CCD clear aperture imaging reveals a R ~ 21.50+/-0.15 source with no apparent host galaxy. An 8000 s, 1150 < lambda/A < 3300 NUV-MAMA prism spectrum shows a relatively flat continuum (in f_lambda) between 2800 and 3300 A, with a mean flux 8.7 (+0.8,-1.6)+/- 2.6 10^(-18) ergs/s/cm^2/A, and a sharp break centered at 2797+/-25 A. We interpret it as HI Lyman break at z = 2.067+/-0.025 indicating the presence of a cloud with a HI column density log(HI) > 18 on the line-of-sight to the OT. This value is conservatively a lower limit to the GRB redshift. However, the facts that large N(HI) system are usually considered as progenitors of present day galaxies and that other OTs are found associated with star forming galaxies strongly suggest that it is the GRB redshift. In any case, this represents the largest direct redshift determination of a gamma-ray burster to date. Our data are compatible with an OT spectrum represented by a power-law with an intrinsic index \alpha = 1.2((f_nu \propto nu^-alpha) and no extinction in the host galaxy or with alpha = 0.5 and extinction by a SMC-like dust in the OT rest-frame with A_V = 0.15. The large N(HI) and the lack of detected host is similar to the situation for damped Ly-alpha absorbers at z > 2.Comment: Replaced by final version. 10 p., 2 fig. Scheduled to appear in ApJ 555 n2 Jul 10, 2001. Minor changes, both redshift and mean near UV flux are revised with slightly larger values, due to a wrong offset sign in the wavelength calibratio

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

An Antiretroviral/Zinc Combination Gel Provides 24 Hours of Complete Protection against Vaginal SHIV Infection in Macaques

Repeated use, coitus-independent microbicide gels that do not contain antiretroviral agents also used as first line HIV therapy are urgently needed to curb HIV spread. Current formulations require high doses (millimolar range) of antiretroviral drugs and typically only provide short-term protection in macaques. We used the macaque model to test the efficacy of a novel combination microbicide gel containing zinc acetate and micromolar doses of the novel non-nucleoside reverse transcriptase inhibitor MIV-150 for up to 24 h after repeated gel application.Rhesus macaques were vaginally challenged with SHIV-RT up to 24 h after repeated administration of microbicide versus placebo gels. Infection status was determined by measuring virologic and immunologic parameters. Combination microbicide gels containing 14 mM zinc acetate dihydrate and 50 µM MIV-150 afforded full protection (21 of 21 animals) for up to 24 h after 2 weeks of daily application. Partial protection was achieved with the MIV-150 gel (56% of control at 8 h after last application, 11% at 24 h), while the zinc acetate gel afforded more pronounced protection (67% at 8-24 h). Marked protection persisted when the zinc acetate or MIV-150/zinc acetate gels were applied every other day for 4 weeks prior to challenge 24 h after the last gel was administered (11 of 14 protected). More MIV-150 was associated with cervical tissue 8 h after daily dosing of MIV-150/zinc acetate versus MIV-150, while comparable MIV-150 levels were associated with vaginal tissues and at 24 h.A combination MIV-150/zinc acetate gel and a zinc acetate gel provide significant protection against SHIV-RT infection for up to 24 h. This represents a novel advancement, identifying microbicides that do not contain anti-viral agents used to treat HIV infection and which can be used repeatedly and independently of coitus, and underscores the need for future clinical testing of their safety and ability to prevent HIV transmission in humans

Midline Signalling Systems Direct the Formation of a Neural Map by Dendritic Targeting in the Drosophila Motor System

During embryonic development of the motor system of Drosophila, motorneurons target their dendrites to different regions along the body axis in response to midline guidance cues

Albendazole and antibiotics synergize to deliver short-course anti-Wolbachiacurative treatments in preclinical models of filariasis

Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period. Here we have identified a synergy between the anthelmintic albendazole (ABZ) and drugs depleting the filarial endosymbiont Wolbachia, a proven macrofilaricide target, which reduces treatment from several weeks to 7 days in preclinical models. ABZ had negligible effects on Wolbachia but synergized with minocycline or rifampicin (RIF) to deplete symbionts, block embryogenesis, and stop microfilariae production. Greater than 99% Wolbachia depletion following 7-day combination of RIF+ABZ also led to accelerated macrofilaricidal activity. Thus, we provide preclinical proof-of-concept of treatment shortening using antibiotic+ABZ combinations to deliver anti-Wolbachia sterilizing and macrofilaricidal effects. Our data are of immediate public health importance as RIF+ABZ are registered drugs and thus immediately implementable to deliver a 1-wk macrofilaricide. They also suggest that novel, more potent anti-Wolbachia drugs under development may be capable of delivering further treatment shortening, to days rather than weeks, if combined with benzimidazoles

Fourteen Recommendations to Create a More Inclusive Environment for LGBTQ+ Individuals in Academic Biology

Individuals who identify as lesbian, gay, bisexual, transgender, queer, and otherwise non-straight and/or non-cisgender (LGBTQ+) have often not felt welcome or represented in the biology community. Additionally, biology can present unique challenges for LGBTQ+ students because of the relationship between certain biology topics and their LGBTQ+ identities. Currently, there is no centralized set of guidelines to make biology learning environments more inclusive for LGBTQ+ individuals. Rooted in prior literature and the collective expertise of the authors who identify as members and allies of the LGBTQ+ community, we present a set of actionable recommendations to help biologists, biology educators, and biology education researchers be more inclusive of individuals with LGBTQ+ identities. These recommendations are intended to increase awareness of LGBTQ+ identities and spark conversations about transforming biology learning spaces and the broader academic biology community to become more inclusive of LGBTQ+ individuals