Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer.

Metabolic reprogramming and energetic rewiring are hallmarks of cancer that fuel disease progression and facilitate therapy evasion. The remodelling of oxidative phosphorylation and enhanced lipogenesis have previously been characterised as key metabolic features of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours, as well as upregulation of the enzymes associated with branched-chain amino acid (BCAA) catabolism. In this study, we hypothesised that the degradation of the BCAAs, particularly valine, may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool, as well as the maintenance of intracellular lipid metabolism. Through the suppression of BCAA availability, we report significantly reduced lipid content, strongly indicating that BCAAs are important lipogenic fuels in PCa. This work also uncovered a novel compensatory mechanism, whereby fatty acid uptake is increased in response to extracellular valine deprivation. Inhibition of valine degradation via suppression of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) resulted in a selective reduction of malignant prostate cell proliferation, decreased intracellular succinate and impaired cellular respiration. In combination with a comprehensive multi-omic investigation that incorporates next-generation sequencing, metabolomics, and high-content quantitative single-cell imaging, our work highlights a novel therapeutic target for selective inhibition of metabolic reprogramming in PCa

Preventing β-amyloid fibrillization and deposition: β-sheet breakers and pathological chaperone inhibitors

Central to the pathogenesis of Alzheimer's disease (AD) is the conversion of normal, soluble β-amyloid (sAβ) to oligomeric, fibrillar Aβ. This process of conformational conversion can be influenced by interactions with other proteins that can stabilize the disease-associated state; these proteins have been termed 'pathological chaperones'. In a number of AD models, intervention that block soluble Aβ aggregation, including β-sheet breakers, and compounds that block interactions with pathological chaperones, have been shown to be highly effective. When combined with early pathology detection, these therapeutic strategies hold great promise as effective and relatively toxicity free methods of preventing AD related pathology

Together forever? Explaining exclusivity in party-firm relations

Parties and firms are the key actors of representative democracy and capitalism respectively and the dynamic of attachment between them is a central feature of any political economy. This is the first article to systematically analyse the exclusivity of party-firm relations. We consider exclusivity at a point in time and exclusivity over time. Does a firm have a relationship with only one party at a given point in time, or is it close to more than one party? Does a firm maintain a relationship with only one party over time, or does it switch between parties? Most important, how do patterns of exclusivity impact on a firm’s ability to lobby successfully? We propose a general theory, which explains patterns of party-firm relations by reference to the division of institutions and the type of party competition in a political system. A preliminary test of our theory with Polish survey data confirms our predictions, establishing a promising hypothesis for future research

Hysteresis of Electronic Transport in Graphene Transistors

Graphene field effect transistors commonly comprise graphene flakes lying on SiO2 surfaces. The gate-voltage dependent conductance shows hysteresis depending on the gate sweeping rate/range. It is shown here that the transistors exhibit two different kinds of hysteresis in their electrical characteristics. Charge transfer causes a positive shift in the gate voltage of the minimum conductance, while capacitive gating can cause the negative shift of conductance with respect to gate voltage. The positive hysteretic phenomena decay with an increase of the number of layers in graphene flakes. Self-heating in helium atmosphere significantly removes adsorbates and reduces positive hysteresis. We also observed negative hysteresis in graphene devices at low temperature. It is also found that an ice layer on/under graphene has much stronger dipole moment than a water layer does. Mobile ions in the electrolyte gate and a polarity switch in the ferroelectric gate could also cause negative hysteresis in graphene transistors. These findings improved our understanding of the electrical response of graphene to its surroundings. The unique sensitivity to environment and related phenomena in graphene deserve further studies on nonvolatile memory, electrostatic detection and chemically driven applications.Comment: 13 pages, 6 Figure

Hexokinase 3 enhances myeloid cell survival via non-glycolytic functions.

The family of hexokinases (HKs) catalyzes the first step of glycolysis, the ATP-dependent phosphorylation of glucose to glucose-6-phosphate. While HK1 and HK2 are ubiquitously expressed, the less well-studied HK3 is primarily expressed in hematopoietic cells and tissues and is highly upregulated during terminal differentiation of some acute myeloid leukemia (AML) cell line models. Here we show that expression of HK3 is predominantly originating from myeloid cells and that the upregulation of this glycolytic enzyme is not restricted to differentiation of leukemic cells but also occurs during ex vivo myeloid differentiation of healthy CD34+ hematopoietic stem and progenitor cells. Within the hematopoietic system, we show that HK3 is predominantly expressed in cells of myeloid origin. CRISPR/Cas9 mediated gene disruption revealed that loss of HK3 has no effect on glycolytic activity in AML cell lines while knocking out HK2 significantly reduced basal glycolysis and glycolytic capacity. Instead, loss of HK3 but not HK2 led to increased sensitivity to ATRA-induced cell death in AML cell lines. We found that HK3 knockout (HK3-null) AML cells showed an accumulation of reactive oxygen species (ROS) as well as DNA damage during ATRA-induced differentiation. RNA sequencing analysis confirmed pathway enrichment for programmed cell death, oxidative stress, and DNA damage response in HK3-null AML cells. These signatures were confirmed in ATAC sequencing, showing that loss of HK3 leads to changes in chromatin configuration and increases the accessibility of genes involved in apoptosis and stress response. Through isoform-specific pulldowns, we furthermore identified a direct interaction between HK3 and the proapoptotic BCL-2 family member BIM, which has previously been shown to shorten myeloid life span. Our findings provide evidence that HK3 is dispensable for glycolytic activity in AML cells while promoting cell survival, possibly through direct interaction with the BH3-only protein BIM during ATRA-induced neutrophil differentiation

Properties of Graphene: A Theoretical Perspective

In this review, we provide an in-depth description of the physics of monolayer and bilayer graphene from a theorist's perspective. We discuss the physical properties of graphene in an external magnetic field, reflecting the chiral nature of the quasiparticles near the Dirac point with a Landau level at zero energy. We address the unique integer quantum Hall effects, the role of electron correlations, and the recent observation of the fractional quantum Hall effect in the monolayer graphene. The quantum Hall effect in bilayer graphene is fundamentally different from that of a monolayer, reflecting the unique band structure of this system. The theory of transport in the absence of an external magnetic field is discussed in detail, along with the role of disorder studied in various theoretical models. We highlight the differences and similarities between monolayer and bilayer graphene, and focus on thermodynamic properties such as the compressibility, the plasmon spectra, the weak localization correction, quantum Hall effect, and optical properties. Confinement of electrons in graphene is nontrivial due to Klein tunneling. We review various theoretical and experimental studies of quantum confined structures made from graphene. The band structure of graphene nanoribbons and the role of the sublattice symmetry, edge geometry and the size of the nanoribbon on the electronic and magnetic properties are very active areas of research, and a detailed review of these topics is presented. Also, the effects of substrate interactions, adsorbed atoms, lattice defects and doping on the band structure of finite-sized graphene systems are discussed. We also include a brief description of graphane -- gapped material obtained from graphene by attaching hydrogen atoms to each carbon atom in the lattice.Comment: 189 pages. submitted in Advances in Physic

Positron annihilation signatures associated with the outburst of the microquasar V404 Cygni

This document is the Accepted Manuscript version of the following article: Thomas Siegert, et al, ‘Positron annihilation signatures associated with the outburst of the microquasar V404 Cygni’, Nature: International Journal of Science, Vol. 531: 341-343, March 2016, DOI: https://doi.org/10.1038/nature16978. Content in the UH Research Archive is made available for personal research, educational, and non-commercial purposes only. Unless otherwise stated, all content is protected by copyright, and in the absence of an open license, permissions for further re-use should be sought from the publisher, the author, or other copyright holder.Microquasars1, 2, 3, 4 are stellar-mass black holes accreting matter from a companion star5 and ejecting plasma jets at almost the speed of light. They are analogues of quasars that contain supermassive black holes of 106 to 1010 solar masses. Accretion in microquasars varies on much shorter timescales than in quasars and occasionally produces exceptionally bright X-ray flares6. How the flares are produced is unclear, as is the mechanism for launching the relativistic jets and their composition. An emission line near 511 kiloelectronvolts has long been sought in the emission spectrum of microquasars as evidence for the expected electron–positron plasma. Transient high-energy spectral features have been reported in two objects7, 8, but their positron interpretation9 remains contentious. Here we report observations of γ-ray emission from the microquasar V404 Cygni during a recent period of strong flaring activity10. The emission spectrum around 511 kiloelectronvolts shows clear signatures of variable positron annihilation, which implies a high rate of positron production. This supports the earlier conjecture that microquasars may be the main sources of the electron–positron plasma responsible for the bright diffuse emission of annihilation γ-rays in the bulge region of our Galaxy11. Additionally, microquasars could be the origin of the observed megaelectronvolt continuum excess in the inner Galaxy.Peer reviewe

Central Exercise Action Increases the AMPK and mTOR Response to Leptin

AMP-activated protein kinase (AMPK) and mammalian Target of Rapamycin (mTOR) are key regulators of cellular energy balance and of the effects of leptin on food intake. Acute exercise is associated with increased sensitivity to the effects of leptin on food intake in an IL-6-dependent manner. To determine whether exercise ameliorates the AMPK and mTOR response to leptin in the hypothalamus in an IL-6-dependent manner, rats performed two 3-h exercise bouts, separated by one 45-min rest period. Intracerebroventricular IL-6 infusion reduced food intake and pretreatment with AMPK activators and mTOR inhibitor prevented IL-6-induced anorexia. Activators of AMPK and fasting increased food intake in control rats to a greater extent than that observed in exercised ones, whereas inhibitor of AMPK had the opposite effect. Furthermore, the reduction of AMPK and ACC phosphorylation and increase in phosphorylation of proteins involved in mTOR signal transduction, observed in the hypothalamus after leptin infusion, were more pronounced in both lean and diet-induced obesity rats after acute exercise. Treatment with leptin reduced food intake in exercised rats that were pretreated with vehicle, although no increase in responsiveness to leptin-induced anorexia after pretreatment with anti-IL6 antibody, AICAR or Rapamycin was detected. Thus, the effects of leptin on the AMPK/mTOR pathway, potentiated by acute exercise, may contribute to appetite suppressive actions in the hypothalamus

Dysregulated fibronectin trafficking by Hsp90 inhibition restricts prostate cancer cell invasion

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.The molecular chaperone Hsp90 is overexpressed in prostate cancer (PCa) and is responsible for the folding, stabilization and maturation of multiple oncoproteins, which are implicated in PCa progression. Compared to first-in-class Hsp90 inhibitors such as 17-allylamino-demethoxygeldanamycin (17-AAG) that were clinically ineffective, second generation inhibitor AUY922 has greater solubility and efficacy. Here, transcriptomic and proteomic analyses of patient-derived PCa explants identified cytoskeletal organization as highly enriched with AUY922 treatment. Validation in PCa cell lines revealed that AUY922 caused marked alterations to cell morphology, and suppressed cell motility and invasion compared to vehicle or 17-AAG, concomitant with dysregulation of key extracellular matrix proteins such as fibronectin (FN1). Interestingly, while the expression of FN1 was increased by AUY922, FN1 secretion was significantly decreased. This resulted in cytosolic accumulation of FN1 protein within late endosomes, suggesting that AUY922 disrupts vesicular secretory trafficking pathways. Depletion of FN1 by siRNA knockdown markedly reduced the invasive capacity of PCa cells, phenocopying AUY922. These results highlight a novel mechanism of action for AUY922 beyond its established effects on cellular mitosis and survival and, furthermore, identifies extracellular matrix cargo delivery as a potential therapeutic target for the treatment of aggressive PCa

Protocol for a home-based integrated physical therapy program to reduce falls and improve mobility in people with Parkinson’s disease

Background The high incidence of falls associated with Parkinson’s disease (PD) increases the risk of injuries and immobility and compromises quality of life. Although falls education and strengthening programs have shown some benefit in healthy older people, the ability of physical therapy interventions in home settings to reduce falls and improve mobility in people with Parkinson’s has not been convincingly demonstrated.Methods/design 180 community living people with PD will be randomly allocated to receive either a home-based integrated rehabilitation program (progressive resistance strength training, movement strategy training and falls education) or a home-based life skills program (control intervention). Both programs comprise one hour of treatment and one hour of structured homework per week over six weeks of home therapy. Blinded assessments occurring before therapy commences, the week after completion of therapy and 12 months following intervention will establish both the immediate and long-term benefits of home-based rehabilitation. The number of falls, number of repeat falls, falls rate and time to first fall will be the primary measures used to quantify outcome. The economic costs associated with injurious falls, and the costs of running the integrated rehabilitation program from a health system perspective will be established. The effects of intervention on motor and global disability and on quality of life will also be examined. Discussion This study will provide new evidence on the outcomes and cost effectiveness of home-based movement rehabilitation programs for people living with PD