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https://www.readbyqxmd.com/read/28437703/antiviral-treatment-strategies-based-on-gene-silencing-and-genome-editing
#1
REVIEW
Roger Badia, Ester Ballana, José A Esté, Eva Riveira-Muñoz
The ability of some viruses to establish latently infected chronic reservoirs that escape to immune control becomes a major roadblock that impedes the cure of these infections. Therefore, new alternatives are needed to pursuit the eradication of viral persistent infections. Gene silencing technologies are in constant evolution and provide an outstanding sequence specificity that allows targeting any coding sequence of interest. Here we provide an overview of the development of gene silencing technologies ranging from initially RNA interference to the recently developed CRISPR/Cas9 and their potential as new antiviral strategies focusing on the eradication of HIV...
April 21, 2017: Current Opinion in Virology
https://www.readbyqxmd.com/read/28437616/neural-network-and-nearest-neighbour-algorithms-for-enhancing-sampling-of-molecular-dynamics
#2
Raimondas Galvelis, Yuji Sugita
The free energy calculations of complex chemical and biological systems with molecular dynamics (MD) are inefficient due to multiple local minima separated by high-energy barriers. The minima can be escaped using an enhanced sampling method such as metadynamics, which apply bias (i.e. importance sampling) along a set of collective variables (CV), but the maximum number of CVs (or dimensions) is severely limited. We propose a high-dimensional bias potential method (NN2B) based on two machine learning algorithms: the nearest neighbour density estimator (NNDE) and the artificial neural network (ANN) for the bias potential approximation...
April 24, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28437611/dynamical-insights-in-the-decomposition-of-1-2-dioxetane
#3
Morgane Vacher, Anders M Brakestad, Hans O Karlsson, Ignacio Fdez Galván, Roland Lindh
Chemiluminescence in 1,2-dioxetane occurs via a thermally-activated decomposition reaction into two formaldehyde molecules. Both ground state and non-adiabatic dynamics (including singlet excited states) of the decomposition reaction have been simulated, starting from the first O-O bond breaking transition structure. The ground state dissociation occurs between t=30 fs and t=140 fs. The so-called entropic trap leads to frustrated dissociations, postponing the decomposition reaction. Specific geometrical conditions are necessary for the trajectories to escape from the entropic trap and for dissociation to be possible...
April 24, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28436947/dedifferentiation-into-blastomere-like-cancer-stem-cells-via-formation-of-polyploid-giant-cancer-cells
#4
N Niu, I Mercado-Uribe, J Liu
Our recent perplexing findings that polyploid giant cancer cells (PGCCs) acquired embryonic-like stemness and were capable of tumor initiation raised two important unanswered questions: how do PGCCs acquire such stemness, and to which stage of normal development do PGCCs correspond. Intriguingly, formation of giant cells due to failed mitosis/cytokinesis is common in the blastomere stage of the preimplantation embryo. However, the relationship between PGCCs and giant blastomeres has never been studied. Here, we tracked the fate of single PGCCs following paclitaxel-induced mitotic failure...
April 24, 2017: Oncogene
https://www.readbyqxmd.com/read/28436934/biopolymers-codelivering-engineered-t-cells-and-sting-agonists-can-eliminate-heterogeneous-tumors
#5
Tyrel T Smith, Howell F Moffett, Sirkka B Stephan, Cary F Opel, Amy G Dumigan, Xiuyun Jiang, Venu G Pillarisetty, Smitha P S Pillai, K Dane Wittrup, Matthias T Stephan
Therapies using T cells that are programmed to express chimeric antigen receptors (CAR T cells) consistently produce positive results in patients with hematologic malignancies. However, CAR T cell treatments are less effective in solid tumors for several reasons. First, lymphocytes do not efficiently target CAR T cells; second, solid tumors create an immunosuppressive microenvironment that inactivates T cell responses; and third, solid cancers are typified by phenotypic diversity and thus include cells that do not express proteins targeted by the engineered receptors, enabling the formation of escape variants that elude CAR T cell targeting...
April 24, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28436820/srna-mediated-activation-of-gene-expression-by-inhibition-of-5-3-exonucleolytic-mrna-degradation
#6
Sylvain Durand, Frédérique Braun, Anne-Catherine Helfer, Pascale Romby, Ciarán Condon
Post-transcriptional control by small regulatory RNA (sRNA) is critical for rapid adaptive processes. sRNAs can directly modulate mRNA degradation in Proteobacteria without interfering with translation. However, Firmicutes have a fundamentally different set of ribonucleases for mRNA degradation and whether sRNAs can regulate the activity of these enzymes is an open question. We show that Bacillus subtilis RoxS, a major trans-acting sRNA shared with Staphylococus aureus, prevents degradation of the yflS mRNA, encoding a malate transporter...
April 24, 2017: ELife
https://www.readbyqxmd.com/read/28436624/-mechanisms-of-histamine-ameliorating-memory-impairment-induced-by-pentylenetetrazole-kindling-epilepsy-in-rats
#7
Lisan Zhang, Guanfeng Chen, Jiefang Chen, Xudong He, Xingyue Hu
Objective: To investigate the effects of neuronal histamine on spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and to explore its mechanisms. Methods: A subconvulsive dose of pentylenetetrazole (35 mg/kg) was intraperitoneally injected in rats every 48 h to induce chemical kindling until fully kindled. Morris water maze was used to measure the spatial memory acquisition of the rats one week after fully pentylenetetrazole-kindled, and the histamine contents in different brain areas were measured spectrofluorometrically...
January 25, 2017: Zhejiang da Xue Xue Bao. Yi Xue Ban, Journal of Zhejiang University. Medical Sciences
https://www.readbyqxmd.com/read/28436620/arginine-rich-peptide-based-mrna-nanocomplexes-efficiently-instigate-cytotoxic-t-cell-immunity-dependent-on-the-amphipathic-organization-of-the-peptide
#8
Vimal K Udhayakumar, Ans De Beuckelaer, Joanne McCaffrey, Cian M McCrudden, Jonathan L Kirschman, Daryll Vanover, Lien Van Hoecke, Kenny Roose, Kim Deswarte, Bruno G De Geest, Stefan Lienenklaus, Philip J Santangelo, Johan Grooten, Helen O McCarthy, Stefaan De Koker
To date, the mRNA delivery field has been heavily dominated by lipid-based systems. Reports on the use of nonlipid carriers for mRNA delivery in contrast are rare in the context of mRNA vaccination. This paper describes the potential of a cell-penetrating peptide containing the amphipathic RALA motif to deliver antigen-encoding mRNA to the immune system. RALA condenses mRNA into nanocomplexes that display acidic pH-dependent membrane disruptive properties. RALA mRNA nanocomplexes enable mRNA escape from endosomes and thereby allow expression of mRNA inside the dendritic cell cytosol...
April 24, 2017: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/28436390/biomarkers-for-early-diagnosis-of%C3%A2-alzheimer-s-disease-in-the-oldest-old-yes-or-no
#9
Lucia Paolacci, David Giannandrea, Patrizia Mecocci, Lucilla Parnetti
In recent years, many efforts have been spent to identify sensitive biomarkers able to improve the accuracy of Alzheimer's disease (AD) diagnosis. Two different workgroups (NIA-AA and IWG) included cerebrospinal fluid (CSF) and neuroimaging findings in their sets of criteria in order to improve diagnostic accuracy as well as early diagnosis. The number of subjects with cognitive impairment increases with aging but the oldest old (≥85 years of age), the fastest growing age group, is still the most unknown from a biological point of view...
April 15, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28435972/-glp-1-gip-gcg-receptor-triagonist-improves-the-cognitive-behaviors-in-triple-transgenic-mice-of-alzheimer-s-disease
#10
Juan-Juan Jiao, Christian Hölscher, Tian Li, Xue-Fan Dong, Xue-Song Qu, Yue Cao, Mei-Na Wu, Zhao-Jun Wang, Jin-Shun Qi
Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health but is still irreversible up to now. Recent studies indicate that type 2 diabetes mellitus (T2DM) is an important risk factor for AD, and the drugs used for treatment of T2DM have shown some neuroprotective effects in the treatment of AD. Glucagon-like peptide-1 (GLP-1)/ glucose-dependent insulinotropic polypeptide (GIP)/glucagon (Gcg) receptor Triagonist is a new monomeric polypeptide equally activating the GLP-1/GIP/Gcg receptors, which is built on the basis of GLP-1/Gcg receptor coagonist core sequence, and incorporated with partial amino acids of GIP...
April 25, 2017: Sheng Li Xue Bao: [Acta Physiologica Sinica]
https://www.readbyqxmd.com/read/28435462/a-programmed-nanoparticle-with-self-adapting-for-accurate-cancer-cell-eradication-and-therapeutic-self-reporting
#11
Yingping Luo, Liwei Huang, Ye Yang, Xianfei Zhuang, Siyao Hu, Huangxian Ju, Bo-Yang Yu, Jiangwei Tian
To achieve the best therapeutic efficacy and good prognosis, the drugs necessitate tailored profiles of excellent spatiotemporal control and therapeutic monitoring. Here we introduce a programmed theranostic nanoparticle with self-adapting properties for tumor-specific systemic treatment, including stealthy surface to prolong circulation time in blood, surface charge-reversion for tumor targeting, receptor-mediated internalization to increase intracellular accumulation, "proton sponge effect" for controllable drug release and escape from endo/lysosome...
2017: Theranostics
https://www.readbyqxmd.com/read/28435125/the-blockage-of-ventromedial-hypothalamus-crf-type-2-receptors-impairs-escape-responses-in-the-elevated-t-maze
#12
Mariana S C F Silva, Thaissa M O Souza, Bruno A Pereira, Daniel A Ribeiro, Isabel C Céspedes, Jackson C Bittencourt, Milena B Viana
In a previous study, the administration of corticotrophin-releasing factor (CRF) into the dorsomedial hypothalamus (DMH), a region that modulates defensive reactions, was shown to facilitate elevated T-maze (ETM) avoidance responses, an anxiogenic-like effect. Intra-DMH administration of the CRF type 1 receptor (CRFR1) antagonist antalarmin induced anxiolytic-like effects and counteracted the anxiogenic effects of CRF. The present study further investigates the role played by CRF receptors of the medial hypothalamus in anxiety...
April 20, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28434585/translating-dynamic-defense-patterns-from-rodents-to-people
#13
REVIEW
D Caroline Blanchard
Specific defensive behaviors of rodents are shaped by features of the eliciting threat stimuli and situation. Threat scenarios confirmed these relationships in people, with results substantially replicated in 4 additional scenario studies. Subsequent human studies involve computer games measuring fear as flight from threat stimuli and anxiety as alternation between two threats. Stabilometric studies have shown reduction in sway (freezing) to inescapable (e.g. with gun pointed at subject) threatening photographs; but enhanced lateral sway (flight attempts) to escapable threats; (gun pointed away from subject)...
May 2017: Neuroscience and Biobehavioral Reviews
https://www.readbyqxmd.com/read/28434399/the-next-generation-of-immunotherapy-keeping-lung-cancer-in-check
#14
REVIEW
Ashwin Somasundaram, Timothy F Burns
Lung cancer is the deadliest malignancy with more cancer deaths per year than the next three cancers combined. Despite remarkable advances in targeted therapy, advanced lung cancer patients have not experienced a significant improvement in mortality. Lung cancer has been shown to be immunogenic and responsive to checkpoint blockade therapy. Checkpoint signals such as CTLA-4 and PD-1/PD-L1 dampen T cell activation and allow tumors to escape the adaptive immune response. Response rates in patients with pretreated, advanced NSCLC were much higher and more durable with PD-1 blockade therapy compared to standard-of-care, cytotoxic chemotherapy...
April 24, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28434031/fkbp51s-signature-in-peripheral-blood-mononuclear-cells-of-melanoma-patients-as-a-possible-predictive-factor-for-immunotherapy
#15
Simona Romano, Ester Simeone, Anna D'Angelillo, Paolo D'Arrigo, Michele Russo, Mario Capasso, Vito Alessandro Lasorsa, Nicola Zambrano, Paolo A Ascierto, Maria Fiammetta Romano
The inhibitory immune checkpoint PD-L1/PD1 promotes the alternative splicing of the FKBP5 gene, resulting in increased expression of its variant 4 in the peripheral blood mononuclear cells of melanoma patients. The variant 4 transcript is translated into the truncated FKBP51s protein. Given the importance of co-inhibitory signalling in tumour immune escape, here we tested the potential for using FKBP51s expression to predict immunotherapy outcomes. To do this, we immunophenotyped PBMCs from 118 melanoma patients and 77 age- and sex-matched healthy controls...
April 22, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28433662/iron-and-thiol-redox-signaling-in-cancer-an-exquisite-balance-to-escape-ferroptosis
#16
REVIEW
Shinya Toyokuni, Fumiya Ito, Kyoko Yamashita, Yasumasa Okazaki, Shinya Akatsuka
Epidemiological data indicate a constant worldwide increase in cancer mortality, although the age of onset is increasing. Recent accumulation of genomic data on human cancer via next-generation sequencing confirmed that cancer is a disease of genome alteration. In many cancers, the Nrf2 transcription system is activated via mutations either in Nrf2 or Keap1 ubiquitin ligase, leading to persistent activation of the genes with antioxidative functions. Furthermore, deep sequencing of passenger mutations is clarifying responsible cancer causative agent(s) in each case, including aging, APOBEC activation, smoking and UV...
April 19, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28433469/delayed-effect-of-early-life-corticosterone-treatment-on-adult-anti-predator-behavior-in-a-common-passerine
#17
Jacquelyn K Grace, Laure Martin-Gousset, Frédéric Angelier
Acute, short-term effects of early-life stress and associated glucocorticoid upregulation on behavior are widely documented across vertebrates. However, the persistence and severity of these effects are largely unknown, especially through the adult stage and in wild species. Here, we investigate long-term effects of experimental post-natal increases in a circulating glucocorticoid on antipredator behavior in wild house sparrows (Passer domesticus) tested in captivity. We manipulate circulating corticosterone concentration in wild, free-living nestlings, transfer fledglings to captivity, and test juveniles and adults for two measures of antipredator behavior: evasiveness during a direct human encounter, and propensity to escape from a risky environment...
April 19, 2017: Physiology & Behavior
https://www.readbyqxmd.com/read/28433039/diffusion-in-quasi-one-dimensional-channels-a-small-system-n-p-t-transition-state-theory-for-hopping-times
#18
Sheida Ahmadi, Richard K Bowles
Particles confined to a single file, in a narrow quasi-one-dimensional channel, exhibit a dynamic crossover from single file diffusion to Fickian diffusion as the channel radius increases and the particles begin to pass each other. The long time diffusion coefficient for a system in the crossover regime can be described in terms of a hopping time, which measures the time it takes for a particle to escape the cage formed by its neighbours. In this paper, we develop a transition state theory approach to the calculation of the hopping time, using the small system isobaric-isothermal ensemble to rigorously account for the volume fluctuations associated with the size of the cage...
April 21, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28432986/the-effects-of-thymoquinone-on-hippocampal-cytokine-level-brain-oxidative-stress-status-and-memory-deficits-induced-by-lipopolysaccharide-in-rats
#19
Rahimeh Bargi, Fereshteh Asgharzadeh, Farimah Beheshti, Mahmoud Hosseini, Hamid Reza Sadeghnia, Majid Khazaei
OBJECTIVE: The study objective was to determine the protective effects of thymoquinone (TQ) on brain tissues oxidative stress status, hippocampal cytokine level, and learning and memory deficits induced by lipopolysaccharide (LPS) in rats. METHODS: Animals were randomly divided into the following groups and treated: (1) Control (saline), (2) LPS (1mg/kg i.p.), (3-5) 2, 5 or 10mg/kg TQ extract 30min before LPS injection. The treatment was started since two weeks before the behavioral experiments and continued during the behavioral tests (LPS injected 2h before each behavioral experiment)...
April 19, 2017: Cytokine
https://www.readbyqxmd.com/read/28432280/small-molecules-targeting-histone-demethylase-genes-kdms-inhibit-growth-of-temozolomide-resistant-glioblastoma-cells
#20
Barbara Banelli, Antonio Daga, Alessandra Forlani, Giorgio Allemanni, Daniela Marubbi, Maria Pia Pistillo, Aldo Profumo, Massimo Romani
In glioblastoma several histone demethylase genes (KDM) are overexpressed compared to normal brain tissue and the development of Temozolomide (TMZ) resistance is accompanied by the transient further increased expression of KDM5A and other KDMs following a mechanism that we defined as "epigenetic resilience". We hypothesized that targeting KDMs may kill the cells that survive the cytotoxic therapy.We determined the effect of JIB 04 and CPI-455, two KDM inhibitors, on glioblastoma cells and found that both molecules are more effective against TMZ-resistant rather than native cells...
April 4, 2017: Oncotarget
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