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https://www.readbyqxmd.com/read/29458199/alpha-synuclein-oligomers-impair-memory-through-glial-cell-activation-and-via-toll-like-receptor-2
#1
Pietro La Vitola, Claudia Balducci, Milica Cerovic, Giulia Santamaria, Edoardo Brandi, Federica Grandi, Laura Caldinelli, Laura Colombo, Maria Grazia Morgese, Luigia Trabace, Loredano Pollegioni, Diego Albani, Gianluigi Forloni
Alpha-synuclein oligomers (α-synOs) are emerging as crucial factors in the pathogenesis of synucleinopathies. Although the connection between neuroinflammation and α-syn still remains elusive, increasing evidence suggests that extracellular moieties activate glial cells leading to neuronal damage. Using an acute mouse model, we explored whether α-synOs induce memory impairment in association to neuroinflammation, addressing Toll-like receptors 2 and 4 (TLR2 and TLR4) involvement. We found that α-synOs abolished mouse memory establishment in association to hippocampal glial activation...
February 16, 2018: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29457994/uric-acid-and-allopurinol-aggravate-absence-epileptic-activity-in-wistar-albino-glaxo-rijswijk-rats
#2
Renáta Krisztina Lakatos, Árpád Dobolyi, Zsolt Kovács
Uric acid has a role in several physiological and pathophysiological processes. For example, uric acid may facilitate seizure generalization while reducing uric acid level may evoke anticonvulsant/antiepileptic effects. Allopurinol blocks the activity of xanthine oxidase, by which allopurinol inhibits catabolism of hypoxanthine to xanthine and uric acid and, as a consequence, decreases the level of uric acid. Although the modulation of serum uric acid level is a widely used strategy in the treatment of certain diseases, our knowledge regarding the effects of uric acid on epileptic activity is far from complete...
February 16, 2018: Brain Research
https://www.readbyqxmd.com/read/29457375/evidence-for-alternate-modes-of-b-cell-activation-involving-fab-acquired-n-glycosylations-in-antibody-secreting-cells-infiltrating-the-labial-salivary-glands-of-sj%C3%A3-gren-s-syndrome-patients
#3
Kristi A Koelsch, Joshua Cavett, Kenneth Smith, Jacen S Moore, Sylvain D Lehoux, Nan Jia, Tim Mather, Syed M S Quadri, Astrid Rasmussen, C Erick Kaufman, David M Lewis, Lida Radfar, Teresa A Scordino, Christopher J Lessard, Biji T Kurien, Richard D Cummings, Judith A James, Kathy L Sivils, A Darise Farris, R Hal Scofield
OBJECTIVE: To better understand the role of B cells, potential mechanisms for their aberrant activation, and the production of autoantibodies in the pathogenesis of Sjögren's Syndrome (SS), we explored selection pressures and N-glycosylation acquired by somatic mutation (acN-glyc) in the immunoglobulin (Ig) variable regions (V-regions) of antibody secreting cells (ASCs) isolated from the minor salivary glands of SS patients and non-SS controls with sicca symptoms. METHODS: We report a novel method to produce and characterize recombinant monoclonal antibodies (mAbs) from SS patient and control labial salivary gland single-cell sorted ASC infiltrates that can be utilized to concurrently probe any other expressed genes...
February 18, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29456800/discovery-and-in-vitro-optimization-of-3-sulfamoylbenzamides-as-romk-inhibitors
#4
Matthew F Sammons, Sujay V Kharade, Kevin J Filipski, Markus Boehm, Aaron C Smith, Andre Shavnya, Dilinie P Fernando, Matthew S Dowling, Philip A Carpino, Neil A Castle, Shannon G Zellmer, Brett M Antonio, James R Gosset, Anthony Carlo, Jerod S Denton
Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS hit 4 , this series was optimized to provide ROMK inhibitors with good in vitro potencies and well-balanced ADME profiles. In contrast to previously reported small-molecule ROMK inhibitors, members of this series were demonstrated to be highly selective for inhibition of human over rat ROMK and to be insensitive to the N171D pore mutation that abolishes inhibitory activity of previously reported ROMK inhibitors...
February 8, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29456081/lysozyme-counteracts-%C3%AE-lactam-antibiotics-by-promoting-the-emergence-of-l-form-bacteria
#5
Yoshikazu Kawai, Katarzyna Mickiewicz, Jeff Errington
β-lactam antibiotics inhibit bacterial cell wall assembly and, under classical microbiological culture conditions that are generally hypotonic, induce explosive cell death. Here, we show that under more physiological, osmoprotective conditions, for various Gram-positive bacteria, lysis is delayed or abolished, apparently because inhibition of class A penicillin-binding protein leads to a block in autolytic activity. Although these cells still then die by other mechanisms, exogenous lytic enzymes, such as lysozyme, can rescue viability by enabling the escape of cell wall-deficient "L-form" bacteria...
January 31, 2018: Cell
https://www.readbyqxmd.com/read/29455063/an-alanine-residue-in-human-parainfluenza-virus-type-3-phosphoprotein-is-critical-for-restricting-excessive-n-0-p-interaction-and-maintaining-n-solubility
#6
Shengwei Zhang, Qi Cheng, Chenxi Luo, Lei Yin, Yali Qin, Mingzhou Chen
The phosphoprotein (P) of human parainfluenza virus type 3 (HPIV3) plays a pivotal role in viral RNA synthesis, which interacts with the nucleoprotein (N) to form a soluble N0 -P complex (N0 , free of RNAs) to prevent the nonspecific RNA binding and illegitimate aggregation of N. Functional regions within P have been studied intensively. However, the precise site (s) within P directly involved in N0 -P interaction still remains unclear. In this study, using a series of deleted and truncated mutants of P of HPIV3, we demonstrate that amino-terminal 40 amino acids (aa) of P restrict and regulate N0 -P interaction...
February 15, 2018: Virology
https://www.readbyqxmd.com/read/29455004/role-of-rho-kinase-rock-in-tonic-but-not-phasic-contraction-in-the-frog-stomach-smooth-muscle
#7
Leyla Sahın, Ozge Selin Cevık, Dilan Deniz Koyuncu, Kansu Buyukafsar
AIMS: Rho/Rho-kinase (ROCK) signaling has extensively been shown to take part in mammalian smooth muscle contractions in response to diverse agents yet its role in the contraction of amphibian smooth muscle has not been investigated. Therefore, we aimed to explore any role of this pathway in the contractions of frog stomach smooth. MAIN METHODS: The strips were prepared and suspended in organ baths filled with Ringer solution. Changes in the circular strips of the frog stomach muscle length were recorded isotonically with a force transducer in organ baths...
February 15, 2018: Life Sciences
https://www.readbyqxmd.com/read/29454917/marine-derived-xyloketal-derivatives-exhibit-anti-stress-and-anti-ageing-effects-through-hsf-pathway-in-caenorhabditis-elegans
#8
Jie-Bin Zhou, Ying-Lin Zheng, Yi-Xuan Zeng, Jia-Wei Wang, Zhong Pei, Ji-Yan Pang
Ageing is a complex but universal phenomenon that progressively challenges the homeostasis network and finally leads to the dysfunction of organisms and even death. Previous studies demonstrated that xyloketal B and its derivatives, a series of marine novel ketone compounds, possessed unique antioxidative effects on endothelial and neuronal oxidative injuries. In this study, we examined the effects of xyloketal derivatives on extending lifespan and healthspan of Caenorhabditis elegans. The results showed that most selected xyloketals could protect Caenorhabditis elegans against heat stress and extend the lifespan of worms...
February 10, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29454037/melatonin-attenuates-%C3%AE-9-tetrahydrocannabinol-induced-reduction-in-rat-sperm-motility-and-kinematics-in-vitro
#9
Isiaka Abdullateef Alagbonsi, Luqman Aribidesi Olayaki
The use of Cannabis sativa (CS) has been widely demonstrated to have detrimental effect on male reproductive functions. Despite the well-known existence of endocannabinoid and melatonergic systems in semen, the physiological significance of their interaction is not understood. We recently showed that melatonin exacerbates the CS-induced gonadotoxicity in-vivo. To overcome the limitations associated with our in-vivo studies and further understand the role of cannabinoid-melatonin relationship in sperm functions, this study investigated the in-vitro effect of tetrahydrocannabinol (THC) and/or melatonin on motility and kinematics of capacitating rat sperms...
February 14, 2018: Reproductive Toxicology
https://www.readbyqxmd.com/read/29453862/insights-into-transcriptional-silencing-and-anti-silencing-in-shigella-flexneri-a-detailed-molecular-analysis-of-the-icsp-virulence-locus
#10
Natasha Weatherspoon-Griffin, Michael A Picker, Krystle L Pew, Hiromichi S Park, Daren Ginete, Monika M Karney, Pashtana Usufzy, Maria I Castellanos, Juan Carlos Duhart, Dustin J Harrison, Jillian N Socea, Alexander D Karabachev, Christopher T Hensley, Amber J Howerton, Rosa Ojeda-Daulo, Joy A Immak, Helen J Wing
Transcriptional silencing and anti-silencing mechanisms modulate bacterial physiology and virulence in many human pathogens. In Shigella species, many virulence plasmid genes are silenced by the histone-like nucleoid structuring protein H-NS and anti-silenced by the virulence gene regulator VirB. Despite the key role that these regulatory proteins play in Shigella virulence, their mechanisms of transcriptional control remain poorly understood. Here, we characterize the regulatory elements and their relative spacing requirements needed for the transcriptional silencing and anti-silencing of icsP, a locus that requires remotely located regulatory elements for both types of transcriptional control...
February 17, 2018: Molecular Microbiology
https://www.readbyqxmd.com/read/29453691/effect-of-phosphorylation-and-single-nucleotide-polymorphisms-on-caspase-substrates-processing
#11
Sonu Kumar, Piotr Cieplak
Posttranslational modifications that involve either reversible covalent modification of proteins or irreversible proteolysis are central to the regulation of key cellular mechanisms, including apoptosis, cell-cycle regulation and signal transduction. There is mounting evidence suggesting cross-talk between proteases and kinases. For instance: caspases, a class of proteases involved in programmed cell death-apoptosis, cleave a large set of various types of proteins. Simultaneously, kinases restrict caspase activity by phosphorylating their protein substrates in the vicinity of cleavage site...
February 16, 2018: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/29453458/il-2-inducible-kinase-itk-is-critical-for-hiv-1-infection-of-jurkat-t-cells
#12
Anika Hain, Melanie Krämer, René M Linka, Saeideh Nakhaei-Rad, Mohammad Reza Ahmadian, Dieter Häussinger, Arndt Borkhardt, Carsten Münk
Successful replication of Human immunodeficiency virus (HIV)-1 depends on the expression of various cellular host factors, such as the interleukin-2 inducible T-cell kinase (ITK), a member of the protein family of TEC-tyrosine kinases. ITK is selectively expressed in T-cells and coordinates signaling pathways downstream of the T-cell receptor and chemokine receptors, including PLC-1 activation, Ca 2+ -release, transcription factor mobilization, and actin rearrangements. The exact role of ITK during HIV-1 infection is still unknown...
February 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29453401/endothelial-smoothened-dependent-hedgehog-signaling-is-not-required-for-sonic-hedgehog-induced-angiogenesis-or-ischemic-tissue-repair
#13
Rajesh Gupta, Alexander R Mackie, Sol Misener, Lijun Liu, Douglas W Losordo, Raj Kishore
Sonic Hedgehog (Shh) signaling induces neovascularization and angiogenesis. It is not known whether the hedgehog signaling pathway in endothelial cells is essential to angiogenesis. Smoothened (Smo) transduces hedgehog signaling across the cell membrane. This study assessed whether endothelial Smoothened-dependent Shh signaling is required for Shh-mediated angiogenesis and ischemic tissue repair. Endothelial-specific smoothened knockout mice, eSmo Null were created using Cre-lox recombination system. eSmo Null mice had no observable phenotype at baseline and showed normal cardiac function...
February 16, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29452828/glutamatergic-ventral-pallidal-neurons-modulate-activity-of-the-habenula-tegmental-circuitry-and-constrain-reward-seeking
#14
Jessica Tooley, Lauren Marconi, Jason Bondoc Alipio, Bridget Matikainen-Ankney, Polymnia Georgiou, Alexxai V Kravitz, Meaghan C Creed
BACKGROUND: The ability to appropriately integrate and respond to rewarding and aversive stimuli is essential for survival. The ventral pallidum (VP) plays a critical role in processing both rewarding and aversive stimuli. However, the VP is a heterogeneous structure, and how VP subpopulations integrate into larger reward networks to ultimately modulate these behaviors is not known. We identify a noncanonical population of glutamatergic VP neurons that play a unique role in responding to aversive stimuli and constraining inappropriate reward seeking...
January 12, 2018: Biological Psychiatry
https://www.readbyqxmd.com/read/29452377/discordance-in-the-dependence-on-kisspeptin-signaling-in-mini-puberty-vs-adolescent-puberty-human-genetic-evidence
#15
Muhammad Shahab, Margaret Lippincott, Yee-Ming Chan, Addie Davies, Paulina M Merino, Lacey Plummer, Veronica Mericq, Stephanie Seminara
Context: Hypothalamic kisspeptin signaling plays a critical role in the initiation and maintenance of reproductive function. Biallelic mutations in the coding sequence of KISS1R (GPR54) have been identified in patients with idiopathic hypogonadotropic hypogonadism (IHH), but it is unknown whether biallelic variants can also be associated with related reproductive disorders. Case description: A missense homozygous variant (c.890G>T p.R297L) in KISS1R was identified in a child who presented with microphallus and bilateral cryptorchidism...
February 14, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29452253/remote-limb-ischemic-postconditioning-protects-against-cerebral-ischemia-reperfusion-injury-by-activating-ampk-dependent-autophagy
#16
Hao Guo, Lei Zhao, Bodong Wang, Xia Li, Hao Bai, Haixiao Liu, Liang Yue, Wei Guo, Zhenyuan Bian, Li Gao, Dayun Feng, Yan Qu
Remote limb ischemic postconditioning (RIPoC) is a promising adjunct treatment for cerebral ischemia-reperfusion (IR) injury. However, the underlying mechanisms have not been fully elucidated yet. The present study aims to investigate potential involvement and regulatory mechanisms of autophagy in RIPoC treatment against cerebral IR injury in mice. Mice were subjected to 2 h middle cerebral artery occlusion (MCAO) then treated with vehicle, 3-methyladenine (3-MA, an autophagy inhibitor), or compound C (an AMPK inhibitor) at the onset of reperfusion...
February 13, 2018: Brain Research Bulletin
https://www.readbyqxmd.com/read/29452158/protein-kinase-c-epsilon-mediates-the-inhibition-of-angiotensin-ii-on-the-slowly-activating-delayed-rectifier-potassium-current-through-channel-phosphorylation
#17
Xiangbo Gou, Wenying Wang, Sihao Zou, Yajuan Qi, Yanfang Xu
The slowly activating delayed rectifier K + current (I Ks ) is one of the main repolarizing currents in the human heart. Evidence has shown that angiotensin II (Ang II) regulates I Ks through the protein kinase C (PKC) pathway, but the related results are controversial. This study was designed to identify PKC isoenzymes involved in the regulation of I Ks by Ang II and the underlying molecular mechanism. The whole-cell patch-clamp technique was used to record I Ks in isolated guinea pig ventricular cardiomyocytes and in human embryonic kidney (HEK) 293 cells co-transfected with human KCNQ1/KCNE1 genes and Ang II type 1 receptor genes...
February 13, 2018: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29452146/the-hippo-yap1-pathway-interacts-with-fgfr1-signaling-to-maintain-stemness-in-lung-cancer
#18
Tingting Lu, Ziming Li, Ying Yang, Wenxiang Ji, Yongfeng Yu, Xiaomin Niu, Qingyu Zeng, Weiliang Xia, Shun Lu
The Hippo pathway plays a critical role in organ size control, tissue homeostasis and tumor genesis through its key transcription regulator Yes-associated protein1 (YAP1), but the mechanism underlying its role in lung cancer is unclear. We hypothesized that YAP1 influences FGFR1 signaling to maintain cancer stem-like cell (CSC) properties in FGFR1-amplified lung cancer. In support of this, our data confirms that expression levels of YAP1 are positively associated with those of FGFR1 in clinical lung carcinoma samples as measured by real-time PCR, western blot, and immunohistochemistry (IHC) staining...
February 13, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29451819/protection-from-chronic-stress-and-depressive-symptom-induced-vascular-endothelial-dysfunction-in-female-rats-is-abolished-by-pre-existing-metabolic-disease
#19
Steven D Brooks, Stan Hileman, Paul D Chantler, Samantha Milde, Kent C Lemaster, Stephanie Frisbee, J Kevin Shoemaker, Dwayne N Jackson, Jefferson C Frisbee
While it is known that chronic stress and clinical depression are powerful predictors of poor cardiovascular outcomes, recent clinical evidence has identified correlations between the development of metabolic disease and that for depressive symptoms; creating a combined condition of severely elevated cardiovascular disease risk. In this companion manuscript, we determine the impact of pre-existing metabolic disease on the relationship between chronic stress//depressive symptoms and vascular function, using the obese Zucker (OZR) and the unpredictable chronic mild stress UCMS models...
February 16, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29451703/mechanisms-of-imidazoline-i-2-receptor-agonist-induced-antinociception-in-rats-involvement-of-monoaminergic-neurotransmission
#20
Justin N Siemian, Kaixuan Wang, Yanan Zhang, Jun-Xu Li
BACKGROUND AND PURPOSE: Although studies have established the antinociceptive efficacies of imidazoline I2 receptor (I2 R) agonists, its exact post-receptor mechanism remains unknown. This study tested the hypothesis that monoaminergic transmission is critical for I2 R agonist-induced antinociception. EXPERIMENTAL APPROACH: The von Frey filament test was used to examine the antinociceptive effects of the I2 R agonists 2-BFI and CR4056 on chronic constriction injury (CCI)-induced neuropathic pain or complete Freund's adjuvant (CFA)-induced inflammatory pain in rats...
February 16, 2018: British Journal of Pharmacology
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