bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated Treatment of Co-Occurring Mental Illness and Addiction: Clinical Intervention, Program, and System Perspectives
Authors: Ziedonis Douglas M.
Published: August 2015

Individuals with mental illness and addiction comprise at least half of the patients in most mental health treatment systems. This combination results in increased risk for frequent psychiatric relapses, poor medication compliance, violence, suicide, legal problems, and high utilization of the emergency room or inpatient services. Traditional mental health and addiction treatments have not adequately addressed these co-occurring disorders due to clinical interventions, programs, and system flaws that have not addressed the individual's needs. Integrated treatment requires both an understanding of mental illness and addiction and the means to integrate and modify the traditional treatment approaches in both the mental health and addiction treatment fields. There is strong evidence to support the efficacy and effectiveness of integrated treatment in this population. All mental health clinicians should become experienced and skilled in the core psychotherapy approaches to treating substance use disorders, including motivational enhancement therapy, relapse prevention (cognitive-behavioral therapy), and 12-step facilitation. In addition, integrated treatment includes integrating medications for both addiction and mental illness with the behavioral therapies and other psychosocial interventions. This article reviews the clinical intervention, program, and system components of integrated treatment and specific clinical interventions for this population.
Silencing of RUNX2 enhances gemcitabine sensitivity of p53-deficient human pancreatic cancer AsPC-1 cells through the stimulation of TAp63-mediated cell death
Authors: Sugimoto H , Nakamura M , Yoda H , Hiraoka K , Shinohara K , Sang M , Fujiwara K , Shimozato O , Nagase H , Ozaki T
Published: August 2015

Runt-related transcription factor 2 (RUNX2) has been considered to be one of master regulators for osteoblast differentiation and bone formation. Recently, we have described that RUNX2 attenuates p53/TAp73-dependent cell death of human osteosarcoma U2OS cells bearing wild-type p53 in response to adriamycin. In this study, we have asked whether RUNX2 silencing could enhance gemcitabine (GEM) sensitivity of p53-deficient human pancreatic cancer AsPC-1 cells. Under our experimental conditions, GEM treatment increased the expression level of p53 family TAp63, whereas RUNX2 was reduced following GEM exposure, indicating that there exists an inverse relationship between the expression level of TAp63 and RUNX2 following GEM exposure. To assess whether TAp63 could be involved in the regulation of GEM sensitivity of AsPC-1 cells, small interfering RNA-mediated knockdown of TAp63 was performed. As expected, silencing of TAp63 significantly prohibited GEM-dependent cell death as compared with GEM-treated non-silencing cells. As TAp63 was negatively regulated by RUNX2, we sought to examine whether RUNX2 knockdown could enhance the sensitivity to GEM. Expression analysis demonstrated that depletion of RUNX2 apparently stimulates the expression of TAp63, as well as proteolytic cleavage of poly ADP ribose polymerase (PARP) after GEM exposure, and further augmented GEM-mediated induction of p53/TAp63-target genes, such as p21WAF1, PUMA and NOXA, relative to GEM-treated control-transfected cells, implying that RUNX2 has a critical role in the regulation of GEM resistance through the downregulation of TAp63. Notably, ablation of TAp63 gave a decrease in number of γH2AX-positive cells in response to GEM relative to control-transfected cells following GEM exposure. Consistently, GEM-dependent phosphorylation of ataxia telangiectasia-mutated protein was remarkably impaired in TAp63 knockdown cells. Collectively, our present findings strongly suggest that RUNX2-mediated repression of TAp63 contributes at least in part to GEM resistance of AsPC-1 cells, and thus silencing of RUNX2 may be a novel strategy to enhance the efficacy of GEM in p53-deficient pancreatic cancer cells.
Halobacteriovorax, an underestimated predator on bacteria: potential impact relative to viruses on bacterial mortality
Authors: Williams Henry N , Lymperopoulou Despoina S , Athar Rana , Chauhan Ashvini , Dickerson Tamar L , Chen Huan , Laws Edward , Berhane Timkhite-Kulu , Flowers Adrienne R , Bradley Nadine , Young Shanterial , Blackwood Denene , Murray Jacqueline , Mustapha Oladipupo , Blackwell Cory , Tung Yahsuan , Noble Rachel T
Published: August 2015

Predation on bacteria and accompanying mortality are important mechanisms in controlling bacterial populations and recycling of nutrients through the microbial loop. The agents most investigated and seen as responsible for bacterial mortality are viruses and protists. However, a body of evidence suggests that predatory bacteria such as the Halobacteriovorax (formerly Bacteriovorax), a Bdellovibrio-like organism, contribute substantially to bacterial death. Until now, conclusive evidence has been lacking. The goal of this study was to better understand the contributors to bacterial mortality by addressing the poorly understood role of Halobacteriovorax and how their role compares with that of viruses. The results revealed that when a concentrated suspension of Vibrio parahaemolyticus was added into microcosms of estuarine waters, the native Halobacteriovorax were the predators that responded first and most rapidly. Their numbers increased by four orders of magnitude, whereas V. parahaemolyticus prey numbers decreased by three orders of magnitude. In contrast, the extant virus population showed little increase and produced little change in the prey density. An independent experiment with stable isotope probing confirmed that Halobacteriovorax were the predators primarily responsible for the mortality of the V. parahaemolyticus. The results show that Halobacteriovorax have the potential to be significant contributors to bacterial mortality, and in such cases, predation by Halobacteriovorax may be an important mechanism of nutrient recycling. These conclusions add another dimension to bacterial mortality and the recycling of nutrients.
Core-satellite populations and seasonality of water meter biofilms in a metropolitan drinking water distribution system
Authors: Ling Fangqiong , Hwang Chiachi , LeChevallier Mark W , Andersen Gary L , Liu Wen-Tso
Published: August 2015

Drinking water distribution systems (DWDSs) harbor the microorganisms in biofilms and suspended communities, yet the diversity and spatiotemporal distribution have been studied mainly in the suspended communities. This study examined the diversity of biofilms in an urban DWDS, its relationship with suspended communities and its dynamics. The studied DWDS in Urbana, Illinois received conventionally treated and disinfected water sourced from the groundwater. Over a 2-year span, biomass were sampled from household water meters (n=213) and tap water (n=20) to represent biofilm and suspended communities, respectively. A positive correlation between operational taxonomic unit (OTU) abundance and occupancy was observed. Examined under a ‘core-satellite’ model, the biofilm community comprised 31 core populations that encompassed 76.7% of total 16 S rRNA gene pyrosequences. The biofilm communities shared with the suspended community highly abundant and prevalent OTUs, which related to methano-/methylotrophs (i.e., Methylophilaceae and Methylococcaceae) and aerobic heterotrophs (Sphingomonadaceae and Comamonadaceae), yet differed by specific core populations and lower diversity and evenness. Multivariate tests indicated seasonality as the main contributor to community structure variation. This pattern was resilient to annual change and correlated to the cyclic fluctuations of core populations. The findings of a distinctive biofilm community assemblage and methano-/methyltrophic primary production provide critical insights for developing more targeted water quality monitoring programs and treatment strategies for groundwater-sourced drinking water systems.
IL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis
Authors: Nakamura Rei , Sene Abdoulaye , Santeford Andrea , Gdoura Abdelaziz , Kubota Shunsuke , Zapata Nicole , Apte Rajendra S.
Published: August 2015

Macrophage dysfunction plays a pivotal role during neovascular proliferation in diseases of ageing including cancers, atherosclerosis and blinding eye disease. In the eye, choroidal neovascularization (CNV) causes blindness in patients with age-related macular degeneration (AMD). Here we report that increased IL10, not IL4 or IL13, in senescent eyes activates STAT3 signalling that induces the alternative activation of macrophages and vascular proliferation. Targeted inhibition of both IL10 receptor-mediated signalling and STAT3 activation in macrophages reverses the ageing phenotype. In addition, adoptive transfer of STAT3-deficient macrophages into eyes of old mice significantly reduces the amount of CNV. Systemic and CD163+ eye macrophages obtained from AMD patients also demonstrate STAT3 activation. Our studies demonstrate that impaired SOCS3 feedback leads to permissive IL10/STAT3 signalling that promotes alternative macrophage activation and pathological neovascularization. These findings have significant implications for our understanding of the pathobiology of age-associated diseases and may guide targeted immunotherapy.
Nanometre-scale probing of spin waves using single electron spins
Authors: van der Sar Toeno , Casola Francesco , Walsworth Ronald , Yacoby Amir
Published: August 2015

Pushing the frontiers of condensed-matter magnetism requires the development of tools that provide real-space, few-nanometre-scale probing of correlated-electron magnetic excitations under ambient conditions. Here we present a practical approach to meet this challenge, using magnetometry based on single nitrogen-vacancy centres in diamond. We focus on spin-wave excitations in a ferromagnetic microdisc, and demonstrate local, quantitative and phase-sensitive detection of the spin-wave magnetic field at ∼50 nm from the disc. We map the magnetic-field dependence of spin-wave excitations by detecting the associated local reduction in the disc’s longitudinal magnetization. In addition, we characterize the spin–noise spectrum by nitrogen-vacancy spin relaxometry, finding excellent agreement with a general analytical description of the stray fields produced by spin–spin correlations in a 2D magnetic system. These complementary measurement modalities pave the way towards imaging the local excitations of systems such as ferromagnets and antiferromagnets, skyrmions, atomically assembled quantum magnets, and spin ice.
Molecular metal–Nx centres in porous carbon for electrocatalytic hydrogen evolution
Authors: Liang Hai-Wei , Brüller Sebastian , Dong Renhao , Zhang Jian , Feng Xinliang , Müllen Klaus
Published: August 2015

Replacement of precious platinum with efficient and low-cost catalysts for electrocatalytic hydrogen evolution at low overpotentials holds tremendous promise for clean energy devices. Here we report a novel type of robust cobalt–nitrogen/carbon catalyst for the hydrogen evolution reaction (HER) that is prepared by the pyrolysis of cobalt–N4 macrocycles or cobalt/o-phenylenediamine composites and using silica colloids as a hard template. We identify the well-dispersed molecular CoNx sites on the carbon support as the active sites responsible for the HER. The CoNx/C catalyst exhibits extremely high turnover frequencies per cobalt site in acids, for example, 0.39 and 6.5 s−1 at an overpotential of 100 and 200 mV, respectively, which are higher than those reported for other scalable non-precious metal HER catalysts. Our results suggest the great promise of developing new families of non-precious metal HER catalysts based on the controlled conversion of homogeneous metal complexes into solid-state carbon catalysts via economically scalable protocols.
Germanium-Vacancy Single Color Centers in Diamond
Authors: Iwasaki Takayuki , Ishibashi Fumitaka , Miyamoto Yoshiyuki , Doi Yuki , Kobayashi Satoshi , Miyazaki Takehide , Tahara Kosuke , Jahnke Kay D. , Rogers Lachlan J. , Naydenov Boris , Jelezko Fedor , Yamasaki Satoshi , Nagamachi Shinji , Inubushi Toshiro , Mizuochi Norikazu , Hatano Mutsuko
Published: August 2015

Atomic-sized fluorescent defects in diamond are widely recognized as a promising solid state platform for quantum cryptography and quantum information processing. For these applications, single photon sources with a high intensity and reproducible fabrication methods are required. In this study, we report a novel color center in diamond, composed of a germanium (Ge) and a vacancy (V) and named the GeV center, which has a sharp and strong photoluminescence band with a zero-phonon line at 602 nm at room temperature. We demonstrate this new color center works as a single photon source. Both ion implantation and chemical vapor deposition techniques enabled fabrication of GeV centers in diamond. A first-principles calculation revealed the atomic crystal structure and energy levels of the GeV center.
Superradiant Quantum Heat Engine
Authors: Hardal Ali Ü. C. , Müstecaplıoğlu Özgür E.
Published: August 2015

Quantum physics revolutionized classical disciplines of mechanics, statistical physics and electrodynamics. One branch of scientific knowledge however seems untouched: thermodynamics. Major motivation behind thermodynamics is to develop efficient heat engines. Technology has a trend to miniaturize engines, reaching to quantum regimes. Development of quantum heat engines (QHEs) requires emerging field of quantum thermodynamics. Studies of QHEs debate whether quantum coherence can be used as a resource. We explore an alternative where it can function as an effective catalyst. We propose a QHE which consists of a photon gas inside an optical cavity as the working fluid and quantum coherent atomic clusters as the fuel. Utilizing the superradiance, where a cluster can radiate quadratically faster than a single atom, we show that the work output becomes proportional to the square of the number of the atoms. In addition to practical value of cranking up QHE, our result is a fundamental difference of a quantum fuel from its classical counterpart.
Enhanced thermal properties of novel shape-stabilized PEG composite phase change materials with radial mesoporous silica sphere for thermal energy storage
Authors: Min Xin , Fang Minghao , Huang Zhaohui , Liu Yan’gai , Huang Yaoting , Wen Ruilong , Qian Tingting , Wu Xiaowen
Published: August 2015

Radial mesoporous silica (RMS) sphere was tailor-made for further applications in producing shape-stabilized composite phase change materials (ss-CPCMs) through a facile self-assembly process using CTAB as the main template and TEOS as SiO2precursor. Novel ss-CPCMs composed of polyethylene glycol (PEG) and RMS were prepared through vacuum impregnating method. Various techniques were employed to characterize the structural and thermal properties of the ss-CPCMs. The DSC results indicated that the PEG/RMS ss-CPCM was a promising candidate for building thermal energy storage applications due to its large latent heat, suitable phase change temperature, good thermal reliability, as well as the excellent chemical compatibility and thermal stability. Importantly, the possible formation mechanisms of both RMS sphere and PEG/RMS composite have also been proposed. The results also indicated that the properties of the PEG/RMS ss-CPCMs are influenced by the adsorption limitation of the PEG molecule from RMS sphere with mesoporous structure and the effect of RMS, as the impurities, on the perfect crystallization of PEG.
Decellularized human liver as a natural 3D-scaffold for liver bioengineering and transplantation
Authors: Mazza Giuseppe , Rombouts Krista , Rennie Hall Andrew , Urbani Luca , Vinh Luong Tu , Al-Akkad Walid , Longato Lisa , Brown David , Maghsoudlou Panagiotis , Dhillon Amar P. , Fuller Barry , Davidson Brian , Moore Kevin , Dhar Dipok , De Coppi Paolo , Malago Massimo , Pinzani Massimo
Published: August 2015

Liver synthetic and metabolic function can only be optimised by the growth of cells within a supportive liver matrix. This can be achieved by the utilisation of decellularised human liver tissue. Here we demonstrate complete decellularization of whole human liver and lobes to form an extracellular matrix scaffold with a preserved architecture. Decellularized human liver cubic scaffolds were repopulated for up to 21 days using human cell lines hepatic stellate cells (LX2), hepatocellular carcinoma (Sk-Hep-1) and hepatoblastoma (HepG2), with excellent viability, motility and proliferation and remodelling of the extracellular matrix. Biocompatibility was demonstrated by either omental or subcutaneous xenotransplantation of liver scaffold cubes (5 × 5 × 5 mm) into immune competent mice resulting in absent foreign body responses. We demonstrate decellularization of human liver and repopulation with derived human liver cells. This is a key advance in bioartificial liver development.
Simultaneous determination of acid-soluble biomass-derived compounds using high performance anion exchange chromatography coupled with pulsed amperometric detection
Authors: Anders N. , Humann H. , Langhans B. , Spieß A. C.
Published: August 2015

The described HPAEC-PAD method allows for the simultaneous determination of biomass derived compounds from cellulose, hemicellulose, lignin and pectin.
Simultaneous determination of 14 biogenic amines and metabolites in bullfrog blood using UFLC-MS/MS with SPE
Authors: Song Zhijun , Cai Meiqiang , Zhao Yonggang , Jin Micong , Deng Shaoping
Published: August 2015

A reliable, accurate, and sensitive method based on a simple extraction with trichloroacetic acid at 5% and a clean-up step by means of a Strata-X SPE cartridge prior to the analysis of 14 biogenic amines and metabolites by UFLC-MS/MS was developed.
A multi-stimuli responsive, self-assembling, boronic acid dipeptide
Authors: Jones Brad H. , Martinez Alina M. , Wheeler Jill S. , McKenzie Bonnie B. , Miller Lance L. , Wheeler David R. , Spoerke Erik D.
Published: August 2015

Boronic acid-modified phenylalanine dipeptide reversibly assembles into nanoribbon gels, triggered through variations in pH, ionic strength, and unique polyol interactions.
A new label-free strategy for a highly efficient chemiluminescence immunoassay
Authors: Yang Zhanjun , Cao Yue , Li Juan , Wang Juntao , Du Dan , Hu Xiaoya , Lin Yuehe
Published: August 2015

A new label-free chemiluminescence (CL) immunoassay method which is based on the co-immobilization of a capture antibody and horseradish peroxidase (HRP) on the Au nanoparticle–chitosan composite interface is proposed for the cheap, fast and convenient detection of proteins.
A surface-adaptive nanocarrier to prolong circulation time and enhance cellular uptake
Authors: Cheng Tangjian , Ma Rujiang , Zhang Yumin , Ding Yuxun , Liu Jinjian , Ou Hanlin , An Yingli , Liu Jianfeng , Shi Linqi
Published: August 2015

Mixed-shell micelles (MSMs) with adaptive surfaces could rapidly and reversibly change surface properties to prolong circulation time and enhance cellular uptake.
Bidentate nitroxide ligands stable toward oxidative redox cycling and their complexes with cerium and lanthanum
Authors: Kim Jee Eon , Carroll Patrick J. , Schelter Eric J.
Published: August 2015

A redox non-innocent bidentate nitroxide ligand stabilizes a tetravalent cerium cation and subsequently an electron–hole upon the oxidation on the electrochemical time scale.
An asymmetric allylic alkylation reaction of 3-alkylidene oxindoles
Authors: Feng Junjun , Li Xin , Cheng Jin-Pei
Published: August 2015

An efficient asymmetric allylic alkylation reaction with respect to 3-alkylidene oxindoles and racemic MBH carbonate has been achieved.
Are stabilizing osmolytes preferentially excluded from the protein surface? FTIR and MD studies
Authors: Bruździak P. , Adamczak B. , Kaczkowska E. , Czub J. , Stangret J.
Published: August 2015

Stabilizing osmolytes are not always preferentially excluded and can interact with the protein surface in two ways: indirectly or directly.
Mesoporous pores impregnated with Au nanoparticles as effective dielectrics for enhancing triboelectric nanogenerator performance in harsh environments
Authors: Chun Jinsung , Kim Jin Woong , Jung Woo-suk , Kang Chong-Yun , Kim Sang-Woo , Wang Zhong Lin , Baik Jeong Min
Published: August 2015

A facile synthesis of mesoporous films impregnated with Au nanoparticles as effective dielectrics for enhancing the TENG's performance based on vertical contact-separation mode is demonstrated.
Renewable fuels from concentrated solar power: towards practical artificial photosynthesis
Authors: Bonke Shannon A. , Wiechen Mathias , MacFarlane Douglas R. , Spiccia Leone
Published: August 2015

A solar-to-fuel conversion efficiency of 22% was achieved by using concentrated solar power to run a matched electrolyser based on Earth-abundant materials.
Methylated derivatives of myricetin enhance life span in Caenorhabditis elegans dependent on the transcription factor DAF-16
Authors: Büchter C. , Ackermann D. , Honnen S. , Arnold N. , Havermann S. , Koch K. , Wätjen W.
Published: August 2015

Methylated derivatives of myricetin enhance the life span of the nematodeCaenorhabditis eleganscomparable to the non-methylated flavonoid myricetin. The life-prolonging effects are dependent on the transcription factor DAF-16.
Bithiophene-based polybenzofulvene derivatives with high stacking and hole mobility
Authors: Cappelli Andrea , Razzano Vincenzo , Paolino Marco , Grisci Giorgio , Giuliani Germano , Donati Alessandro , Mendichi Raniero , Samperi Filippo , Battiato Salvatore , Boccia Antonella Caterina , Mura Andrea , Bongiovanni Giovanni , Mróz Wojciech , Botta Chiara
Published: August 2015

The insertion of bithiophene chromophores in the phenylindene scaffold produced stacked polybenzofulvenes showing high hole mobility.
Precise synthesis of thermoreversible block copolymers containing reactive furfuryl groups via living anionic polymerization: the countercation effect on block copolymerization behavior
Authors: Kang Beom-Goo , Pramanik Nabendu B. , Singha Nikhil K. , Lee Jae-Suk , Mays Jimmy
Published: August 2015

Well-defined block copolymers containing furan groups were anionically synthesized in the presence of NaBPh4and used for the formation of thermoreversible networksviaa Diels–Alder click reaction.
Treatment of pharmaceutical wastewater for reuse by coupled membrane-aerated biofilm reactor (MABR) system
Authors: Tian Hailong , Zhang Huimin , Li Peng , Sun Linquan , Hou Feifei , Li Baoan
Published: August 2015

The pharmaceutical intermediate wastewater treatment was studied by using a coupled membrane-aerated biofilm reactor (MABR) system, which included ozone oxidation, MABR biochemical method, and improved coagulation–flocculation technology.
Response surface optimization and artificial neural network modeling of biodiesel production from crude mahua (Madhuca indica) oil under supercritical ethanol conditions using CO2 as co-solvent
Authors: Sarve Antaram N. , Varma Mahesh N. , Sonawane Shriram S.
Published: August 2015

The present study describes the renewable, environment-friendly approach for the production of biodiesel from low cost, high acid value mahua oil under supercritical ethanol conditions using carbon dioxide (CO2) as a co-solvent.
Amorphous carbon modified nano-sized tungsten carbide as a gas diffusion electrode catalyst for the oxygen reduction reaction
Authors: Liu Zhiwei , Li Ping , Zhai Fuqiang , Wan Qi , Volinsky Alex A. , Qu Xuanhui
Published: August 2015

Nanostructured tungsten carbide is used as the catalyst in a gas diffusion electrode. The presence of the appropriate amorphous carbon is beneficial for improving the conductivity and dispersibility of the tungsten carbide catalyst.
Managing the retro-pathway in direct catalytic asymmetric aldol reactions of thioamides
Authors: Bao Youmei , Kumagai Naoya , Shibasaki Masakatsu
Published: August 2015

Thioamides are the preferred pronucleophiles for direct catalytic asymmetric aldol reactions in the context of soft Lewis acid/hard Brønsted base cooperative catalysis.
A vertical and cross-linked Ni(OH)2 network on cellulose-fiber covered with graphene as a binder-free electrode for advanced asymmetric supercapacitors
Authors: Zhang Lin-Lin , Li Huan-Huan , Fan Chao-Ying , Wang Kang , Wu Xing-Long , Sun Hai-Zhu , Zhang Jing-Ping
Published: August 2015

A vertical and cross-linked Ni(OH)2 network on cellulose-fiber covered with graphene as a binder-free electrode for asymmetric supercapacitors exhibits excellent electrochemical performance.
Antibacterial and photochemical properties of cellulose nanofiber–titania nanocomposites loaded with two different types of antibiotic medicines
Authors: Galkina O. L. , Önneby K. , Huang P. , Ivanov V. K. , Agafonov A. V. , Seisenbaeva G. A. , Kessler V. G.
Published: August 2015

Nano TiO2 grafted onto nano cellulose was used both for regulation of drug release and for UV-protection of the drugs.
The molecular basis of lysosomal storage diseases and their treatment
Authors: Winchester B. , Vellodi A. , Young E.
Published: August 2015

The lysosomal system is the main intracellular mechanism for the catabolism of naturally occurring endogenous and exogenous macromolecules and the subsequent recycling of their constituent monomeric components. It also plays an important part in processing essential metabolites. A genetic defect in a protein responsible for maintaining the lysosomal system results in the accumulation within lysosomes of partially degraded molecules, the initial step in the process leading to a lysosomal storage disease. The defective protein can be a luminal lysosomal enzyme or protein cofactor, a lysosomal membrane protein or a protein involved in the post-translational modification or transport of lysosomal proteins. Over 40 lysosomal storage diseases are known and they have a collective incidence of ≈ 1 in 7000–8000 live births. Most of the genes for the lysosomal proteins have been cloned, permitting mutation analysis in individual cases. This information can be used for genotype/phenotype correlation, genetic counselling and the selection of patients for novel forms of therapy, such as substrate deprivation or dispersal, enzyme replacement, bone-marrow transplantation and gene transfer.
Searching for the ideal forms of proteins
Authors: Taylor W. R.
Published: August 2015

A modification of the Structure Alignment Program (SAP), combined with a novel automatic method for the definition of structural elements, correctly identified the core folds of a variety of small β/α proteins when compared with a series of ideal architectures. This approach opens the possibility of not just determining whether one structure is like another, but given a range of ideal forms, determining what the protein is. Preliminary studies have shown it to work equally well on the all dα-class and the all-β class of protein, each of which have corresponding ideal forms. Given the speed of the algorithm, it will be possible to compare all of these against the Protein Structure Database and determine the extent to which the current ideal forms can account for the variety of protein structure. Analysis of the remainder should provide a base for the development of further forms.
Androgen-receptor-interacting nuclear proteins
Authors: Jänne O. A. , Moilanen A.-M. , Poukka H. , Rouleau N. , Karvonen U. , Kotaja N. , Häkli M. , Palvimo J.J.
Published: August 2015

Androgen receptor (AR) belongs to the super-family of nuclear hormone receptors that employ complex molecular mechanisms to guide the development and physiological functions of their target tissues. Our recent work has led to the identification of four novel proteins that recognize AR zinc-finger region (ZFR) both in vivo and in vitro. One is a small nuclear RING-finger protein that possesses separate interaction interfaces for AR and for other transcription activators such as Spl. The second is a nuclear serine/threonine protein kinase (androgen-receptor-interacting nuclear protein kinase; ANPK); however, the receptor itself does not seem to be a substrate for this kinase. The third one is dubbed androgen-receptor-interacting protein 3 (ARIP3) and is a novel member of the PIAS (protein inhibitor of activated STAT) protein family. The fourth protein, termed ARIP4, is a nuclear ATPase that belongs to the SNF2-like family of chromatin remodelling proteins. All four proteins exhibit a punctate nuclear pattern when expressed in cultured cells. Each protein modulates AR-dependent transactivation in co-transfection experiments; their activating functions are not restricted to AR. Current work is aimed at elucidating the biochemical and functional properties of these AR-interacting proteins and at finding the partner proteins that form complexes with them in vivo.
Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, has a key role in central control of arterial blood pressure
Authors: Reaux A. , Iturrioz X. , Vazeux G. , Fournie-Zaluski M.-C. , David C. , Roques B. P. , Corvol P. , Llorens-Cortes C.
Published: August 2015

Overactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental animal models. We have recently reported that, in the murine brain RAS, angiotensin II (AngII) is converted by aminopeptidase A (APA) into angiotensin III (AngIII), which is itself degraded by aminopeptidase N (APN), both peptides being equipotent to increase vasopressin release and arterial blood pressure when injected by the intracerebroventricular (i.c.v.) route. Because AngII is converted in vivo into AngIII, the exact nature of the active peptide is not precisely known. To delineate their respective roles in the central control of cardiovascular functions, specific and selective APA and APN inhibitors are needed to block the metabolic pathways of AngII and AngIII respectively. In the absence of such compounds for APA, we first explored the organization of the APA active site by site-directed mutagenesis. This led us to propose a molecular mechanism of action for APA similar to that proposed for the bacterial enzyme thermolysin deduced from X-ray diffraction studies. Secondly, we developed a specific and selective APA inhibitor, compound EC33 [(S)-3-amino-4-mercaptobutylsulphonic acid], as well as a potent and selective APN inhibitor, PC18 (2-amino-4-methylsulphonylbutane thiol). With these new tools we examined the respective roles of AngII and AngIII in the central control of arterial blood pressure. A central blockade of APA with the APA inhibitor EC33 suppressed the pressor effect of exogenous AngII, suggesting that brain AngII must be converted into AngIII to increase arterial blood pressure. Furthermore, EC33, injected alone i.c.v. but not intravenously, caused a dose-dependent decrease in arterial blood pressure by blocking the formation of brain AngIII but not systemic AngIII. This is corroborated by the fact that the selective APN inhibitor PC 18 administered alone via the i.c.v. route increased arterial blood pressure. This pressor response was blocked by prior treatment with the angiotensin type 1 receptor antagonist losartan, showing that blocking the action of APN on AngIII metabolism leads to an increase in endogenous AngIII levels, resulting in arterial blood pressure increase through an interaction with angiotensin type 1 receptors. These results demonstrate that AngIII is a major effector peptide of the brain RAS, exerting a tonic stimulatory control over arterial blood pressure. Thus APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors, crossing the blood-brain barrier, as central anti-hypertensive agents.
Complexity of transcriptional control in neuropeptide gene expression; enkephalin gene regulation during neurodevelopment
Authors: Agoston D. v. , Dobi A.
Published: August 2015

The gene for enkephalin is expressed only in specific subsets of neurons in the mammalian central nervous system (CNS), whereas the large majority of neurons do not express the gene. This restricted expression is the result of a developmental process during which some of the multi-potent neural progenitors express the gene for enkephalin and thereby become enkephalinergic neurons. The regulation of this process is not well understood. We have used a novel approach to identify DNA-protein interactions that regulate the developmental expression of the gene for enkephalin. We have identified four novel DNA regulatory sites and their binding proteins that are expressed in the developing mammalian CNS. These protein-DNA interactions regulate DNA and nuclear structures through DNA bending, DNA sliding, chromatin remodelling and far-distant DNA interactions. The concerted and coordinated interactions of these four DNA elements and their binding proteins contribute to the guiding of multipotent neural progenitors into enkephalinergic neurons. The provided examples suggest an important role for architectural transcriptional regulation during CNS development.
Protective peptides derived from novel glial proteins
Authors: Brenneman D. E. , Spong C. Y. , Gozes I.
Published: August 2015

In studying the mediators of VIP neurotrophism in the central nervous system, two glial proteins have been discovered. Both of these proteins contain short peptides that exhibit femtomolar potency in preventing neuronal cell death from a wide variety of neurotoxic substances. Extension of these peptides to models of oxidative stress or neurodegeneration in vivo have indicated significant efficacy in protection. These peptides, both as individual agents and in combination, have promise as possible protective agents in the treatment of human neurodegenerative disease and in pathologies involving oxidative stress.
Ca2+ signalling in stomatal guard cells
Authors: McAinsh M. R. , Gray J. E. , Hetherington A. M. , Leckie C. P. , Ng C.
Published: August 2015

Ca2+ is a ubiquitous second messenger in the signal transduction pathway(s) by which stomatal guard cells respond to external stimuli. Increases in guard-cell cytosolic free Ca2+ concentration ([Ca2+]cyt) have been observed in response to stimuli that cause both stomatal opening and closure. In addition, several important components of Ca2+-based signalling pathways have been identified in guard cells, including the cADP-ribose and phospholipase C/Ins(1,4,5)P3-mediated Ca2+-mobilizing pathways. The central role of stimulus-induced increases in [Ca2+]cyt in guard-cell signal transduction has been clearly demonstrated in experiments examining the effects of modulating increases in [Ca2+]cyt on alterations in guard-cell turgor or the activity of ion channels that act as effectors in the guard-cell turgor response. In addition, the paradox that Ca2+ is involved in the transduction of signals that result in opposite end responses (stomatal opening and closure) might be accounted for by the generation of stimulus-specific Ca2+ signatures, such that increases in [Ca2+]cyt exhibit unique spatial and temporal characteristics.
Genomic organization and gene function in Leishmania
Authors: Myler P. J. , Sisk E. , McDonagh P. D. , Martinez-Calvillo S. , Schnaufer A. , Sunkin S. M. , Yan S. , Madhubala R. , Ivens A. , Stuart K.
Published: August 2015

Sequencing of the Leishmania major Friedlin genome is well underway with chromosome 1 (Chr1) and Chr3 having been completely sequenced, and Chr4 virtually complete. Sequencing of several other chromosomes is in progress and the complete genome sequence may be available as soon as 2003. A large proportion (≈ 70%) of the newly identified genes remains unclassified, with many of these being potentially Leishmania (or kinetoplastid-) specific. Most interestingly, the genes are organized into large (> 100–300 kb) polycistronic clusters of adjacent genes on the same DNA strand. Chrl contains two such clusters organized in a ‘divergent’ manner, i.e. the mRNAs for the two sets of genes are both transcribed towards the telomeres. Chr3 contains two ‘convergent’ clusters, with a single ‘divergent’ gene at one telomere, with the two large clusters separated by a tRNA gene. We have characterized several genes from the LD1 (Leishmania DNA 1) region of Chr35. BT1 (formerly ORFG) encodes a biopterin transporter and ORFF encodes a nuclear protein of unknown function. Immunization of mice with recombinant antigens from these genes results in significant reduction in parasite burden following Leishmania challenge. Recombinant ORFF antigen shows promise as a serodiagnostic. We have also developed a tetracycline-regulated promoter system, which allows us to modulate gene expression in Leishmania.
3′-Untranslated regions are important in mRNA localization and translation: lessons from selenium and metallothionein
Authors: Hesketh J.
Published: August 2015

There is increasing evidence that 3′-UTRs (3′-untranslated regions) of mRNAs contain regulatory elements that have important roles in post-transcriptional control of gene expression. For example, 3′-UTRs are important in determining mRNA localization and directing selenocysteine insertion during selenoprotein synthesis. Metallothionein mRNA is localized around the nucleus and associated with the cytoskeleton; this is determined by the 3′-UTR. Deletion and mutagenesis studies are defining the nature of the signal. Incorrect mRNA localization prevents subsequent nuclear localization of metallothionein protein and affects its function. Selenium (Se) is incorporated as selenocysteine into approx. 30 mammalian proteins by a mechanism that requires a specific structure within the 3′-UTR of the corresponding mRNAs. When Se supply is low the effect on selenoprotein expression is not uniform but shows differential effects that are tissue- and protein-specific; there is a ‘prioritization’ of selenoprotein synthesis that is partly influenced by the 3′-UTRs of the different mRNAs. Single-nucleotide polymorphisms in the gene regions corresponding to 3′-UTRs could potentially influence gene regulation. We have discovered a common polymorphism in a part of the glutathione peroxidase 4 gene which corresponds to the 3′-UTR, and our recent results suggest that this single-nucleotide polymorphism has functional and physiological effects, as well as altered frequency in disease.
Novel tissue remodelling roles for human recombinant erythropoietin
Authors: Coussons P.J. , Baig S. , Fanutti C. , Grant R.
Published: August 2015

rHuEPO (recombinant human erythropoietin) is a haemopoietic growth factor and a primary regulator of erythropoiesis that is used for the treatment of chronic anaemia associated with RA (rheumatoid arthritis). Erythropoietin also appears to modulate a broad array of cellular processes, including progenitor stem-cell development, cellular integrity, angiogenesis and oxidative damage. These diverse activities suggest the exciting possibility of multiple roles for rHuEPO therapy in a variety of disorders other than RA, including cerebral ischaemia, myocardial infarction, chronic congestive heart failure and cancer. Thus it appears that rHuEPO may be a pleiotropic agent, capable of influencing tissue remodelling independently of its established erythropoietic role. Whereas these effects may be largely beneficial, dose-related side effects could have implications for the safe therapeutic use of rHuEPO and its illegal use as a performance-enhancing agent in endurance sports.
Centaurin β4 in cancer
Authors: Martin R.K. , Jackson T.R.
Published: August 2015

Centaurin β4 proteins are products of the DDEF1 (development and differentiation-enhancing factor 1) locus on human chromosome 8q24.1-24.2. Recent reports have indicated that this region and its products are amplified during development of several human cancers. Centaurins are GAPs (GTPase-activating proteins) that, together with GEFs (guanine nucleotide-exchange factors), regulate cyclic activation of Arfs (ADP-ribosylation factors), members of the Ras GTPase superfamily. Centaurin β4 proteins associate with a variety of cellular signalling components implicated in control of growth, survival and movement and may act to direct assembly and/or disassembly of molecular complexes in concert with Arf, lipid and protein phosphorylation signalling pathways.
Roles of the Bloom's syndrome helicase in the maintenance of genome stability
Authors: Cheok C.F. , Bachrati C.Z. , Chan K.L. , Ralf C. , Wu L. , Hickson I.D.
Published: August 2015

The RecQ family of DNA helicases is highly conserved in evolution from bacteria to humans. Of the five known human RecQ family members, three (BLM, WRN and RECQ4, which cause Bloom's syndrome, Werner's syndrome and Rothmund–Thomson syndrome respectively) are mutated in distinct clinical disorders associated with cancer predisposition and/or premature aging. BLM forms part of a multienzyme complex including topoisomerase IIIα, replication protein A and a newly identified factor called BLAP75. Together, these proteins play a role in the resolution of DNA structures that arise during the process of homologous recombination repair. In the absence of BLM, cells show genomic instability and a high incidence of sister-chromatid exchanges. In addition to a DNA structure-specific helicase activity, BLM also catalyses Holliday-junction branch migration and the annealing of complementary single-stranded DNA molecules.
The Type IIB restriction endonucleases
Authors: Marshall Jacqueline J.T. , Halford Stephen E.
Published: August 2015

The endonucleases from the Type IIB restriction–modification systems differ from all other restriction enzymes. The Type IIB enzymes cleave both DNA strands at specified locations distant from their recognition sequences, like Type IIS nucleases, but they are unique in that they do so on both sides of the site, to liberate the site from the remainder of the DNA on a short duplex. The fact that these enzymes cut DNA at specific locations mark them as Type II systems, as opposed to the Type I enzymes that cut DNA randomly, but in terms of gene organization and protein assembly, most Type IIB restriction–modification systems have more in common with Type I than with other Type II systems. Our current knowledge of the Type IIB systems is reviewed in the present paper.
Dendritic trafficking for neuronal growth and plasticity
Authors: Ehlers Michael D.
Published: August 2015

Among the largest cells in the body, neurons possess an immense surface area and intricate geometry that poses many unique cell biological challenges. This morphological complexity is critical for neural circuit formation and enables neurons to compartmentalize cell–cell communication and local intracellular signalling to a degree that surpasses other cell types. The adaptive plastic properties of neurons, synapses and circuits have been classically studied by measurement of electrophysiological properties, ionic conductances and excitability. Over the last 15 years, the field of synaptic and neural electrophysiology has collided with neuronal cell biology to produce a more integrated understanding of how these remarkable highly differentiated cells utilize common eukaryotic cellular machinery to decode, integrate and propagate signals in the nervous system. The present article gives a very brief and personal overview of the organelles and trafficking machinery of neuronal dendrites and their role in dendritic and synaptic plasticity.
Aberrant palmitoylation in Huntington disease
Authors: Sanders Shaun S. , Hayden Michael R.
Published: August 2015

Huntington disease (HD) is an adult-onset neurodegenerative disease caused by a CAG expansion in the HTT gene. HD is characterized by striatal atrophy and is associated with motor, cognitive and psychiatric deficits. In the presence of the HD mutation, the interactions between huntingtin (HTT) and huntingtin interacting protein 14 (HIP14 or DHHC17) and HIP14-like (DHHC13, a HIP14 orthologue), palmitoyl acyltransferases for HTT, are disturbed, resulting in reduced palmitoylation of HTT. Genetic ablation of either Hip14 or Hip14l recapitulates many features of HD, including striatal atrophy and motor deficits. However, there are no changes in palmitoylation of HTT in either mouse model and, subsequently, the similarities between the phenotypes of these two mouse models and the HD mouse model are believed to result from underpalmitoylation of other HIP14 and HIP14L substrates. HTT acts as a modulator of HIP14 activity such that in the presence of the HD mutation, HIP14 is less active. Consequently, HIP14 substrates are less palmitoylated, leading to neuronal toxicity. This suggests that altered HIP14–HTT and HIP14L–HTT interactions in the presence of the HD mutation reduces palmitoylation and promotes mislocalization of HTT and other HIP14/HIP14L substrates. Ultimately, HD may be, in part, a disease of altered palmitoylation.
Post-translational myristoylation at the cross roads of cell death, autophagy and neurodegeneration
Authors: Martin Dale D.O. , Hayden Michael R.
Published: August 2015

In a little more than a decade, post-translational myristoylation (PTMyr) has become an established post-translational modification during cell death. It involves the addition of the fatty acid myristate to newly exposed N-terminal glycines following caspase cleavage. It promotes membrane binding and relocalization of functional protein domains released by caspase cleavage during apoptosis, or programmed cell death. However, as the requirement of caspase cleavage has expanded beyond just cell death, it has become apparent that PTMyr may play a role in cell survival, differentiation and now autophagy. Herein, we describe how myristoylation may play a role in autophagy with an emphasis on PTMyr.
Peptide and small molecule inhibitors of the Keap1–Nrf2 protein–protein interaction
Authors: Wells Geoff
Published: August 2015

The transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) up-regulates the expression of a range of cytoprotective enzymes with antioxidant response elements in their promoter regions and thus can protect cells against oxidative damage. Increasing Nrf2 activity has been proposed as a therapeutic intervention in a range of chronic neurodegenerative conditions and cancer chemoprevention. One of the main mechanisms by which Nrf2 is negatively regulated involves an interaction with the ubiquitination facilitator protein, Kelch-like ECH-associated protein 1 (Keap1) that facilitates degradation of Nrf2. Inhibition of this process underlies the mode of action of a broad group of compounds that increase Nrf2 activity. A number of natural products, including the isothiocyanate sulforaphane, up-regulate Nrf2 by interacting with Keap1 in a covalent manner to stall its activity. Recently, a number of peptide and small molecule inhibitors of the protein-protein interaction (PPI) between Keap1 and Nrf2 have been described. These classes of compound have contrasting modes of action at the molecular level and there is emerging evidence that their biological activities have similarities and differences. This review describes the various classes of PPI inhibitor that have been described in the literature and the biological evaluations that have been performed.
Glomerular Permeability during Proteinuria Induced by Plasma Infusion
Authors: Petrie J. J. B. , Cleland J. F. , MacLean Pamela R. , Robson J. S.
Published: August 2015

1. Glomerular permeability to protein and dextran was studied in four patients with bleeding disorders who had normal renal function and in whom proteinuria occurred during the large infusions of plasma needed for treatment of the primary disorder.

2. Results are expressed in terms of selectivity indices which relate clearance to molecular weight.

3. Dextran selectivity was high both in the presence and absence of proteinuria and protein selectivity during proteinuria was also high.

4. Proteinuria induced by plasma infusion is likely to be glomerular in origin and the results indicate that the normal glomerulus is highly selective to plasma protein as well as to dextran.