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On and Off Pathways

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https://www.readbyqxmd.com/read/28726522/steerable-induction-of-the-thymosin-%C3%A3-4-mrtf-a-pathway-via-aav-based-overexpression-induces-therapeutic-neovascularization
#1
Tilman Ziegler, Markus Kraus, Wira Husada, Florian Gesenhues, Qui Jiang, Olaf Pinkenburg, Teresa Trenkwalder, Karl-Ludwig Laugwitz, Ferdinand le Noble, Christian Weber, Christian Kupatt, Rabea Hinkel
Viral vectors have been frequently used in a variety of preclinical animal models to deliver genetic constructs into tissues. Among the vectors used, adeno-associated viral vectors (AAVs) may be targeted to specific tissues, depending on the serotype used. Moreover, they show robust expression for prolonged periods of time and have a low immunogenic potential. Furthermore, AAVs, unlike other vector systems, only display a low rate of genomic integration. However, to ensure efficient transgene production, expression is typically driven by constitutively active promoters, such as the CMV promotor...
July 20, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28724435/ww-domain-binding-protein-2-an-adaptor-protein-closely-linked-to-the-development-of-breast-cancer
#2
REVIEW
Shuai Chen, Han Wang, Yu-Fan Huang, Ming-Li Li, Jiang-Hong Cheng, Peng Hu, Chuan-Hui Lu, Ya Zhang, Na Liu, Chi-Meng Tzeng, Zhi-Ming Zhang
The WW domain is composed of 38 to 40 semi-conserved amino acids shared with structural, regulatory, and signaling proteins. WW domain-binding protein 2 (WBP2), as a binding partner of WW domain protein, interacts with several WW-domain-containing proteins, such as Yes kinase-associated protein (Yap), paired box gene 8 (Pax8), WW-domain-containing transcription regulator protein 1 (TAZ), and WW-domain-containing oxidoreductase (WWOX) through its PPxY motifs within C-terminal region, and further triggers the downstream signaling pathway in vitro and in vivo...
July 19, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28719061/tailored-engineering-of-an-unusual-c4h9nh3-2-ch3nh3-2pb3br10-two-dimensional-multilayered-perovskite-ferroelectric-for-high-performance-photodetectors
#3
Junhua Luo, Lina Li, Zhihua Sun, Peng Wang, Weida Hu, Sasa Wang, Chengmin Ji, Maochun Hong
Two-dimensional (2D) layered hybrid perovskites have shown great potentials in optoelectronics. However, although great efforts have been made, 2D hybrid perovskite ferroelectrics remain rare. Here, we constructed the first ferroelectric with 2D multilayered perovskite framework, (C4H9NH3)2(CH3NH3)2Pb3Br10 (1), by tailored alloying mixed-organic-cations into the prototype of CH3NH3PbBr3. For the first time, concrete ferroelectricity was created by molecular reorientation and synergic ordering of organic cations, which is unprecedented for the known 2D hybrid perovskites...
July 18, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28715957/the-transduction-cascade-in-retinal-on-bipolar-cells-signal-processing-and-disease
#4
Kirill A Martemyanov, Alapakkam P Sampath
Our robust visual experience is based on the reliable transfer of information from our photoreceptor cells, the rods and cones, to higher brain centers. At the very first synapse of the visual system, information is split into two separate pathways, ON and OFF, which encode increments and decrements in light intensity, respectively. The importance of this segregation is borne out in the fact that receptive fields in higher visual centers maintain a separation between ON and OFF regions. In the past decade, the molecular mechanisms underlying the generation of ON signals have been identified, which is unique in its use of a G-protein signaling cascade...
July 17, 2017: Annual Review of Vision Science
https://www.readbyqxmd.com/read/28715649/excellent-response-to-anti-pd-1-therapy-in-a-patient-with-hepatocellular-carcinoma-case-report-and-review-of-literature
#5
Hirva Mamdani, Howard Wu, Bert H O'Neil, Amikar Sehdev
Hepatocellular carcinoma (HCC) is an aggressive cancer associated with high mortality worldwide. HCC develops in the setting of underlying cirrhosis due to chronic liver disease. Surgery is usually considered the treatment of choice for early disease; however, most patients have locally advanced or metastatic HCC at diagnosis in which case treatments are limited. Immune checkpoint blockade of programmed death receptor-1 (PD-1) pathway offers a potential treatment strategy based on the encouraging results of the phase I/II trial of nivolumab (Checkmate 040 trial)...
May 2017: Discovery Medicine
https://www.readbyqxmd.com/read/28711146/drug-repositioning-strategies-for-the-identification-of-novel-therapies-for-rheumatic-autoimmune-inflammatory-diseases
#6
REVIEW
Amrie C Grammer, Peter E Lipsky
Rheumatic Autoimmune Inflammatory Diseases such as Sjögren's and lupus lack modern treatments. Less than 5% of drugs approved by the FDA from 2014 to mid-2016 had a RAID indication. Many RAID standard-of-care drugs were repurposed based on serendipitous observations, similarity-of-disease categorization, and/or off-target effects. Recently, drug repurposing has become more intentional, relying on an evolving awareness of molecular underpinnings, as well as a better understanding of drug-target interactions by computational modeling...
August 2017: Rheumatic Diseases Clinics of North America
https://www.readbyqxmd.com/read/28710275/a-ph-dependent-switch-promotes-%C3%AE-synuclein-fibril-formation-via-glutamate-residues
#7
Gina M Moriarty, Michael P Olson, Tamr B Atieh, Maria K Janowska, Sagar D Khare, Jean Baum
Alpha-synuclein (αS) is the primary protein associated with Parkinson's disease, and undergoes aggregation from its intrinsically disordered monomeric form to a cross-β fibrillar form. The closely related homolog beta-synuclein (βS) is essentially fibril resistant under cytoplasmic physiological conditions. Toxic gain of function by βS has been linked to dysfunction, but the aggregation behavior of βS under altered pH is not well understood. In this work, we compare fibril formation of αS and βS at pH 7...
July 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28709498/targeting-fyn-kinase-in-alzheimer-s-disease
#8
REVIEW
Haakon B Nygaard
The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research in AD, a deeper understanding of Aβ physiology has led to the recognition of distinct neuronal signaling pathways linking Aβ to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Aβ has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD...
June 13, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28709319/golf-course-and-funnel-energy-landscapes-protein-folding-concepts-in-martensites
#9
N Shankaraiah
We use protein folding energy landscape concepts such as golf course and funnel to study re-equilibration in athermal martensites under systematic temperature quench Monte Carlo simulations. On quenching below a transition temperature, the seeded high-symmetry parent-phase austenite that converts to the low-symmetry product-phase martensite, through autocatalytic twinning or elastic photocopying, has both rapid conversions and incubation delays in the temperature-time-transformation phase diagram. We find the rapid (incubation delays) conversions at low (high) temperatures arises from the presence of large (small) size of golf-course edge that has the funnel inside for negative energy states...
June 2017: Physical Review. E
https://www.readbyqxmd.com/read/28709293/fluorescence-correlation-spectroscopy-experiments-to-quantify-free-diffusion-coefficients-in-reaction-diffusion-systems-the-case-of-ca-2-and-its-dyes
#10
Lorena Sigaut, Cecilia Villarruel, María Laura Ponce, Silvina Ponce Dawson
Many cell signaling pathways involve the diffusion of messengers that bind and unbind to and from intracellular components. Quantifying their net transport rate under different conditions then requires having separate estimates of their free diffusion coefficient and binding or unbinding rates. In this paper, we show how performing sets of fluorescence correlation spectroscopy (FCS) experiments under different conditions, it is possible to quantify free diffusion coefficients and on and off rates of reaction-diffusion systems...
June 2017: Physical Review. E
https://www.readbyqxmd.com/read/28706179/nilotinib-induced-recurrent-gastric-polyps-case-report-and-review-of-literature
#11
Nancy Kassem, Omar M Ismail, Halima Elomri, Mohamad A Yassin
BACKGROUND Tyrosine kinase inhibitors (TKIs) are currently an important targeted drug class in the treatment of chronic myeloid leukemia (CML). Imatinib was the first approved TKI for CML in 2001. Nilotinib is a second-generation TKI, approved in 2007; it inhibits BCR-ABL, PDGFR, and c-KIT, and is 30 times more potent than imatinib. Tyrosine kinase enzymes are expressed in multiple tissues and are involved in several signaling pathways; they have been shown to have several off-target side effects. CASE REPORT We report a case of an elderly male with CML and no history of gastrointestinal diseases, treated with nilotinib, and developed recurrent gastric polyps after three years of treatment...
July 14, 2017: American Journal of Case Reports
https://www.readbyqxmd.com/read/28702523/implications-of-peptide-assemblies-in-amyloid-diseases
#12
REVIEW
Pu Chun Ke, Marc-Antonie Sani, Feng Ding, Aleksandr Kakinen, Ibrahim Javed, Frances Separovic, Thomas P Davis, Raffaele Mezzenga
Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology - much of which are poorly understood - these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer's, Parkinson's, type 2 diabetes and prion diseases...
July 12, 2017: Chemical Society Reviews
https://www.readbyqxmd.com/read/28702012/community-composition-of-nitrous-oxide-consuming-bacteria-in-the-oxygen-minimum-zone-of-the-eastern-tropical-south-pacific
#13
Xin Sun, Amal Jayakumar, Bess B Ward
The ozone-depleting and greenhouse gas, nitrous oxide (N2O), is mainly consumed by the microbially mediated anaerobic process, denitrification. N2O consumption is the last step in canonical denitrification, and is also the least O2 tolerant step. Community composition of total and active N2O consuming bacteria was analyzed based on total (DNA) and transcriptionally active (RNA) nitrous oxide reductase (nosZ) genes using a functional gene microarray. The total and active nosZ communities were dominated by a limited number of nosZ archetypes, affiliated with bacteria from marine, soil and marsh environments...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28701543/novel-channel-mediated-choline-transport-in-cholinergic-neurons-of-the-mouse-retina
#14
Toshiyuki Ishii, Kohei Homma, Asuka Mano, Takumi Akagi, Yasuhide Shigematsu, Yukio Shimoda, Hiroyoshi Inoue, Yoshihiko Kakinuma, Makoto Kaneda
Choline uptake into the presynaptic terminal of cholinergic neurons is mediated by the high affinity choline transporter and is essential for acetylcholine synthesis. In a previous study, we reported that P2X2 purinoceptors are selectively expressed in OFF-cholinergic amacrine cells of the mouse retina. Under specific conditions, P2X2 purinoceptors acquire permeability to large cations, such as N-methyl-D-glucamine, and therefore potentially could act as a non-canonical pathway for choline entry into neurons...
July 12, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28700203/mechanisms-of-atmospherically-relevant-cluster-growth
#15
Bryan R Bzdek, Joseph W DePalma, Murray V Johnston
Atmospheric aerosols impact global climate either directly by scattering solar radiation or indirectly by serving as cloud condensation nuclei, which influence cloud albedo and precipitation patterns. Our scientific understanding of these impacts is poor relative to that of, for instance, greenhouse gases, in part because it is difficult to predict particle number concentrations. One important pathway by which particles are added to the atmosphere is new particle formation, where gas phase precursors form molecular clusters that subsequently grow to the climatically relevant size range (50-100 nm diameter)...
July 12, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28699516/induction-of-synthetic-lethality-by-natural-compounds-targeting-cancer-signaling
#16
Lee Farrand, Sanguine Byun
Despite the breakthroughs that have been achieved, significant unmet needs relating to the inadequate efficacy and toxicity of currently-available cancer therapies remain. Kinase inhibitors are a class of agents that target signaling factors responsible for the survival of malignant cells, and may address at least some of these issues. The concept of synthetic lethality provides a potential solution to counteract pathway redundancies, and refers to situations in which a mutation in one of two particular genes alone permits cell survival, while simultaneous mutation in both results in cell death...
July 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28695520/use-of-inosine-monophosphate-dehydrogenase-activity-assay-to-determine-the-specificity-of-parp-1-inhibitors
#17
Sajitha Anthony, Jeffrey R Peterson, Yingbiao Ji
Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme involved in purine nucleotide biosynthesis. It is responsible for catalyzing the oxidation of inosine monophosphate (IMP) into xanthosine monophosphate (XMP). Concurrently, the cofactor NAD(+) is reduced to NADH. Poly(ADP-ribose) polymerase 1 (PARP-1) also utilizes NAD(+) as a substrate to synthesize poly(ADP-ribose). It has been demonstrated that inhibition of PARP-1 activity can be an effective cancer therapeutic. However, most PARP-1 inhibitors, including olaparib, were developed as NAD(+) analogs...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28684784/probing-the-missing-mature-%C3%AE-cell-proteomic-landscape-in-differentiating-patient-ipsc-derived-cells
#18
Heidrun Vethe, Yngvild Bjørlykke, Luiza M Ghila, Joao A Paulo, Hanne Scholz, Steven P Gygi, Simona Chera, Helge Ræder
MODY1 is a maturity-onset monogenic diabetes, caused by heterozygous mutations of the HNF4A gene. To date the cellular and molecular mechanisms leading to disease onset remain largely unknown. In this study, we demonstrate that insulin-positive cells can be generated in vitro from human induced pluripotent stem cells (hiPSCs) derived from patients carrying a non-sense HNF4A mutation, proving for the first time, that a human HNF4A mutation is neither blocking the expression of the insulin genes nor the development of insulin-producing cells in vitro...
July 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28684277/nlrp3-inflammasome-activation-mediates-fatigue-like-behaviors-in-mice-via-neuroinflammation
#19
Ziteng Zhang, Xiujuan Ma, Zhenna Xia, Jikuai Chen, Yangang Liu, Yongchun Chen, Jiangbo Zhu, Jinfeng Li, Huaiyu Yu, Ying Zong, Guocai Lu
Numerous experimental and clinical studies have suggested that the interaction between the immune system and the brain plays an important role in the pathophysiology of chronic fatigue syndrome (CFS). The NLRP3 inflammasome is an important part of the innate immune system. This complex regulates proinflammatory cytokine interleukin-1β (IL-1β) maturation, which triggers different kinds of immune-inflammatory reactions. We employed repeated forced swims to establish a model of CFS in mice. NLRP3 knockout (KO) mice were also used to explore NLRP3 inflammasome activation in the mechanisms of CFS, using the same treatment...
July 3, 2017: Neuroscience
https://www.readbyqxmd.com/read/28683789/circulating-osteoprotegerin-is-associated-with-chronic-kidney-disease-in-hypertensive-patients
#20
Stella Bernardi, Barbara Toffoli, Fleur Bossi, Riccardo Candido, Elisabetta Stenner, Renzo Carretta, Fabio Barbone, Bruno Fabris
BACKGROUND: Osteoprotegerin (OPG) is a glycoprotein that plays an important regulatory role in the skeletal, vascular, and immune system. It has been shown that OPG predicts chronic kidney disease (CKD) in diabetic patients. We hypothesized that OPG could be a risk marker of CKD development also in non-diabetic hypertensive patients. METHODS: A case-control study was carried out to measure circulating OPG levels in 42 hypertensive patients with CKD and in 141 hypertensive patients without CKD...
July 6, 2017: BMC Nephrology
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