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https://www.readbyqxmd.com/read/28635590/imbalance-between-innate-antiviral-and-pro-inflammatory-immune-responses-may-contribute-to-different-outcomes-involving-low-and-highly-pathogenic-avian-influenza-h5n3-infections-in-chickens
#1
John Pasick, Sandra Diederich, Yohannes Berhane, Carissa Embury-Hyatt, Wanhong Xu
In order to gain further insight into the early virus-host interactions associated with highly pathogenic avian influenza virus infections in chickens, genome-wide expression profiling of chicken lung and brain was carried out at 24 and 72 h post-inoculation (h p.i.). For this purpose two recombinant H5N3 viruses were utilized, each possessing a polybasic HA0 cleavage site but differing in pathogenicity. The original rH5N3 P0 virus, which has a low-pathogenic phenotype, was passaged six times through chickens to give rise to the derivative rH5N3 P6 virus, which is highly pathogenic (Diederich S, Berhane Y, Embury-Hyatt C, Hisanaga T, Handel K et al...
June 21, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28635355/aberrant-wnt-signaling-a-special-focus-in-cns-diseases
#2
Mercedes Arnés, Sergio Casas Tintó
Wnt signals regulate cell proliferation, migration and differentiation during development, as well as synaptic transmission and plasticity in the adult brain. Abnormal Wnt signaling is central to a number of brain pathologies. We review here, the significance of this pathway focused in the contribution of the most frequent alterations in receptors, secretable modulators and downstream targets in Alzheimer's disease (AD) and Glioblastoma (GBM). β-catenin and GSK3 levels are pivotal in the neurodegeneration associated to AD contributing to memory deficits, tau phosphorylation, increased β-amyloid production and modulation of Apolipoprotein E in the brain...
June 21, 2017: Journal of Neurogenetics
https://www.readbyqxmd.com/read/28634732/engineering-poly-lactic-co-glycolic-acid-plga-micro-and-nano-carriers-for-controlled-delivery-of-17%C3%AE-estradiol
#3
Alesia V Prakapenka, Heather A Bimonte-Nelson, Rachael W Sirianni
With menopause, circulating levels of 17β-estradiol (E2) markedly decrease. E2-based hormone therapy is prescribed to alleviate symptoms associated with menopause. E2 is also recognized for its beneficial effects in the central nervous system (CNS), such as enhanced cognitive function following abrupt hormonal loss associated with ovariectomy. For women with an intact uterus, an opposing progestogen component is required to decrease the risk of developing endometrial hyperplasia. While adding an opposing progestogen attenuates these detrimental effects on the uterus, it can attenuate the beneficial effects of E2 in the CNS...
June 20, 2017: Annals of Biomedical Engineering
https://www.readbyqxmd.com/read/28633897/discovery-and-optimization-of-3-4-aryl-heteroarylsulfonyl-piperazin-1-yl-6-piperidin-1-yl-pyridazines-as-novel-cns-penetrant-pan-muscarinic-antagonists
#4
Aaron M Bender, Rebecca L Weiner, Vincent B Luscombe, Sonia Ajmera, Hyekyung P Cho, Sichen Chang, Xiaoyan Zhan, Alice L Rodriguez, Colleen M Niswender, Darren W Engers, Thomas M Bridges, P Jeffrey Conn, Craig W Lindsley
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M4 (hM4 IC50s<200nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma Kp=2...
May 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28633005/autophagy-impairment-mediated-by-s-nitrosation-of-atg4b-leads-to-neurotoxicity-in-response-to-hyperglycemia
#5
Yazi Li, Yuying Zhang, Lei Wang, Ping Wang, Yanhong Xue, Xiaopeng Li, Xinhua Qiao, Xu Zhang, Tao Xu, Guanghui Liu, Peng Li, Chang Chen
The majority of diabetic patients develop neuropathy and there is an increasing prevalence of neurodegeneration in the central nervous system (CNS). However, the mechanism behind is poorly understood. Here we first observed that macroautophagy/autophagy was suppressed in the hippocampus of diabetic GK rats with hyperglycemia, whereas it was unchanged in ob/ob mice without hyperglycemia. Autophagy could be directly inhibited by high glucose in mouse primary hippocampal neurons. Moreover, autophagy was protective in high-glucose-induced neurotoxicity...
June 20, 2017: Autophagy
https://www.readbyqxmd.com/read/28630333/boosting-cns-axon-regeneration-by-harnessing-antagonistic-effects-of-gsk3-activity
#6
Marco Leibinger, Anastasia Andreadaki, Renate Golla, Evgeny Levin, Alexander M Hilla, Heike Diekmann, Dietmar Fischer
Implications of GSK3 activity for axon regeneration are often inconsistent, if not controversial. Sustained GSK3 activity in GSK3(S/A) knock-in mice reportedly accelerates peripheral nerve regeneration via increased MAP1B phosphorylation and concomitantly reduces microtubule detyrosination. In contrast, the current study shows that lens injury-stimulated optic nerve regeneration was significantly compromised in these knock-in mice. Phosphorylation of MAP1B and CRMP2 was expectedly increased in retinal ganglion cell (RGC) axons upon enhanced GSK3 activity, but, surprisingly, no GSK3-mediated CRMP2 inhibition was detected in sciatic nerves, thus revealing a fundamental difference between central and peripheral axons...
June 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28630327/virus-induced-inflammasome-activation-is-suppressed-by-prostaglandin-d2-dp1-signaling
#7
Rahul Vijay, Anthony R Fehr, Ann M Janowski, Jeremiah Athmer, Dorthea L Wheeler, Matthew Grunewald, Ramakrishna Sompallae, Samarchith P Kurup, David K Meyerholz, Fayyaz S Sutterwala, Shuh Narumiya, Stanley Perlman
Prostaglandin D2 (PGD2), an eicosanoid with both pro- and anti-inflammatory properties, is the most abundantly expressed prostaglandin in the brain. Here we show that PGD2 signaling through the D-prostanoid receptor 1 (DP1) receptor is necessary for optimal microglia/macrophage activation and IFN expression after infection with a neurotropic coronavirus. Genome-wide expression analyses indicated that PGD2/DP1 signaling is required for up-regulation of a putative inflammasome inhibitor, PYDC3, in CD11b(+) cells in the CNS of infected mice...
June 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28630251/valnoctamide-inhibits-cytomegalovirus-infection-in-developing-brain-and-attenuates-neurobehavioral-dysfunctions-and-brain-abnormalities
#8
Sara Ornaghi, Lawrence S Hsieh, Angélique Bordey, Patrizia Vergani, Michael J Paidas, Anthony N van den Pol
Cytomegalovirus (CMV) is the most common infectious cause of brain defects and neurological dysfunction in developing human babies. Due to the teratogenicity and toxicity of available CMV antivirals, treatment options during early development are markedly limited. Valnoctamide (VCD), a neuroactive mood stabilizer with no known teratogenic activity, was recently demonstrated to have anti-CMV potential. However, it is not known whether this can be translated into an efficacious therapeutic effect to improve CMV-induced adverse neurological outcomes...
June 19, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28628860/in-silico-modeling-on-adme-properties-of-natural-products-classification-models-for-blood-brain-barrier-permeability-its-application-to-traditional-chinese-medicine-and-in-vitro-experimental-validation
#9
Xiuqing Zhang, Ting Liu, Xiaohui Fan, Ni Ai
In silico modeling of blood-brain barrier (BBB) permeability plays an important role in early discovery of central nervous system (CNS) drugs due to its high-throughput and cost-effectiveness. Natural products (NP) have demonstrated considerable therapeutic efficacy against several CNS diseases. However, BBB permeation property of NP is scarcely evaluated both experimentally and computationally. It is well accepted that significant difference in chemical spaces exists between NP and synthetic drugs, which calls into doubt on suitability of available synthetic chemical based BBB permeability models for the evaluation of NP...
June 7, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28626522/study-of-para-quinone-methide-precursors-toward-the-realkylation-of-aged-acetylcholinesterase
#10
Ryan J Yoder, Qinggeng Zhuang, Jeremy M Beck, Andrew Franjesevic, Travis G Blanton, Sydney Sillart, Tyler Secor, Leah Guerra, Jason D Brown, Carolyn Reid, Craig A McElroy, Özlem Doğan Ekici, Christopher S Callam, Christopher M Hadad
Acetylcholinesterase (AChE) is an essential enzyme that can be targeted by organophosphorus (OP) compounds, including nerve agents. Following exposure to OPs, AChE becomes phosphylated (inhibited) and undergoes a subsequent aging process where the OP-AChE adduct is dealkylated. The aged AChE is unable to hydrolyze acetylcholine, resulting in accumulation of the neurotransmitter in the central nervous system (CNS) and elsewhere. Current therapeutics are only capable of reactivating inhibited AChE. There are no known therapeutic agents to reverse the aging process or treat aged AChE...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626388/increasing-n-acetylaspartate-in-the-brain-during-postnatal-myelination-does-not-cause-the-cns-pathologies-of-canavan-disease
#11
Abhilash P Appu, John R Moffett, Peethambaran Arun, Sean Moran, Vikram Nambiar, Jishnu K S Krishnan, Narayanan Puthillathu, Aryan M A Namboodiri
Canavan disease is caused by mutations in the gene encoding aspartoacylase (ASPA), a deacetylase that catabolizes N-acetylaspartate (NAA). The precise involvement of elevated NAA in the pathogenesis of Canavan disease is an ongoing debate. In the present study, we tested the effects of elevated NAA in the brain during postnatal development. Mice were administered high doses of the hydrophobic methyl ester of NAA (M-NAA) twice daily starting on day 7 after birth. This treatment increased NAA levels in the brain to those observed in the brains of Nur7 mice, an established model of Canavan disease...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28626016/the-mtor-substrate-s6-kinase-1-s6k1-is-a-negative-regulator-of-axon-regeneration-and-a-potential-drug-target-for-central-nervous-system-injury
#12
Hassan Al-Ali, Ying Ding, Tatiana Slepak, Wei Wu, Yan Sun, Yania Martinez, Xiao-Ming Xu, V P Lemmon, J L Bixby
The mammalian target of Rapamycin (mTOR) positively regulates axon growth in the mammalian central nervous system (CNS). Though axon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 Kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR's positive effect on axon growth. In contrast to this expectation, we demonstrate that inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by 2-3 fold...
June 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28624361/low-intensity-rtms-has-sex-dependent-effects-on-the-local-response-of-glia-following-a-penetrating-cortical-stab-injury
#13
Darren Clarke, Marissa A Penrose, Alan R Harvey, Jennifer Rodger, Kristyn A Bates
Repetitive transcranial magnetic stimulation (rTMS), a non-invasive form of brain stimulation, has shown experimental and clinical efficacy in a range of neuromodulatory models, even when delivered at low intensity (i.e. subthreshold for action potential generation). After central nervous system (CNS) injury, studies suggest that reactive astrocytes and microglia can have detrimental but also beneficial effects; thus modulating glial activity, for example through application of rTMS, could potentially be a useful therapeutic tool following neurotrauma...
June 14, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28623435/the-brain-behaves-as-a-muscle
#14
Marinella Coco
It is known that lactate accumulates in the skeletal muscle during intense anaerobic exercise but is rapidly cleared from the muscles when they resume aerobic metabolism; however, at least some lactate reaches the blood stream. It has been observed that during maximal exercise, blood lactate increases with transport of the blood to the brain. This could be interpreted as a mechanism to protect against possible "central fatigue" in times of maximal activity during the course of which the lactate would preserve the functionality of the primary cortical motor and sensory areas, even at the expense of the efficiency of the other structures...
June 16, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28621566/glutamate-dehydrogenase-is-essential-to-sustain-neuronal-oxidative-energy-metabolism-during-stimulation
#15
Michaela C Hohnholt, Vibe H Andersen, Jens V Andersen, Sofie K Christensen, Melis Karaca, Pierre Maechler, Helle S Waagepetersen
The enzyme glutamate dehydrogenase (GDH; Glud1) catalyzes the (reversible) oxidative deamination of glutamate to α-ketoglutarate accompanied by a reduction of NAD(+) to NADH. GDH connects amino acid, carbohydrate, neurotransmitter and oxidative energy metabolism. Glutamine is a neurotransmitter precursor used by neurons to sustain the pool of glutamate, but glutamine is also vividly oxidized for support of energy metabolism. This study investigates the role of GDH in neuronal metabolism by employing the Cns- Glud1(-/-) mouse, lacking GDH in the brain (GDH KO) and metabolic mapping using (13)C-labelled glutamine and glucose...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28621563/reduced-mastication-impairs-memory-function
#16
Y Fukushima-Nakayama, Takehito Ono, M Hayashi, M Inoue, H Wake, Takashi Ono, T Nakashima
Mastication is an indispensable oral function related to physical, mental, and social health throughout life. The elderly tend to have a masticatory dysfunction due to tooth loss and fragility in the masticatory muscles with aging, potentially resulting in impaired cognitive function. Masticatory stimulation has influence on the development of the central nervous system (CNS) as well as the growth of maxillofacial tissue in children. Although the relationship between mastication and cognitive function is potentially important in the growth period, the cellular and molecular mechanisms have not been sufficiently elucidated...
May 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28620840/quality-of-life-impairment-in-beh%C3%A3-et-s-disease-and-relationship-with-disease-activity-a-prospective-study
#17
Claudia Fabiani, Antonio Vitale, Ida Orlando, Jurgen Sota, Marco Capozzoli, Rossella Franceschini, Mauro Galeazzi, Gian Marco Tosi, Bruno Frediani, Luca Cantarini
Our aim was to prospectively investigate the impact of Behçet's disease (BD), disease activity, and clinical and demographic characteristics on different aspects of quality of life (QoL) measured by the short-form (SF)-36 QoL scale. We administered the SF-36 to 37 consecutive BD patients in different moments of disease activity, and to 23 healthy controls (HC). The eight subcategories of the SF-36 underwent statistical analysis for identifying differences and correlations. Compared to HC, BD patients showed significantly lower mean scores in all SF-36 QoL subscales except mental health and role-emotional...
June 15, 2017: Internal and Emergency Medicine
https://www.readbyqxmd.com/read/28620314/orexin-system-the-key-for-a-healthy-life
#18
REVIEW
Sergio Chieffi, Marco Carotenuto, Vincenzo Monda, Anna Valenzano, Ines Villano, Francesco Precenzano, Domenico Tafuri, Monica Salerno, Nicola Filippi, Francesco Nuccio, Maria Ruberto, Vincenzo De Luca, Luigi Cipolloni, Giuseppe Cibelli, Maria P Mollica, Diego Iacono, Ersilia Nigro, Marcellino Monda, Giovanni Messina, Antonietta Messina
The orexin-A/hypocretin-1 and orexin-B/hypocretin-2 are neuropeptides synthesized by a cluster of neurons in the lateral hypothalamus and perifornical area. Orexin neurons receive a variety of signals related to environmental, physiological and emotional stimuli, and project broadly to the entire CNS. Orexin neurons are "multi-tasking" neurons regulating a set of vital body functions, including sleep/wake states, feeding behavior, energy homeostasis, reward systems, cognition and mood. Furthermore, a dysfunction of orexinergic system may underlie different pathological conditions...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28619981/ibrutinib-unmasks-critical-role-of-bruton-tyrosine-kinase-in-primary-cns-lymphoma
#19
Christian Grommes, Alessandro Pastore, Nicolaos Palaskas, Sarah S Tang, Carl Campos, Derrek Schartz, Paolo Codega, Donna Nichol, Owen Clark, Wan-Ying Hsieh, Daniel Rohle, Marc K Rosenblum, Agnes Viale, Viviane Tabar, Cameron W Brennan, Igor T Gavrilovic, Thomas J Kaley, Craig Nolan, Antonio M P Omuro, Elena Pentsova, Alissa A Thomas, Elina Tsyvkin, Ariela Noy, M Lia Palomba, Paul A Hamlin, Craig Sauter, Craig H Moskowitz, Julia Wolfe, Ahmet Dogan, Minhee Won, Jon Glass, Scott Peak, Enrico C Lallana, Vaios Hatzoglou, Anne S Reiner, Philip Gutin, Jason T Huse, Katherine Panageas, Thomas G Graeber, Nikolaus Schultz, Lisa M DeAngelis, Ingo K Mellinghoff
Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with Nuclear factor kappa B (NF-κB). The role of BTK in primary CNS lymphoma (PCNSL) is unknown. We performed a Phase 1 clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS Lymphoma. Clinical responses to ibrutinib occurred in 10/13 (77%) PCNSL patients, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of Caspase Recruitment Domain Family Member 11, a known ibrutinib resistance mechanism...
June 15, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28619678/april-taci-axis-is-dispensable-for-the-immune-response-to-rabies-vaccination
#20
Shannon L Haley, Evgeni P Tzvetkov, Andrew G Lytle, Kishore R Alugupalli, Joseph R Plummer, James P McGettigan
There is significant need to develop a single-dose rabies vaccine to replace the current multi-dose rabies vaccine regimen and eliminate the requirement for rabies immune globulin in post-exposure settings. To accomplish this goal, rabies virus (RABV)-based vaccines must rapidly activate B cells to secrete antibodies which neutralize pathogenic RABV before it enters the CNS. Increased understanding of how B cells effectively respond to RABV-based vaccines may improve efforts to simplify post-exposure prophylaxis (PEP) regimens...
June 12, 2017: Antiviral Research
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