scholarly journals Differential effects of reduced glycoprotein VI levels on activation of murine platelets by glycoprotein VI ligands

2002 ◽  
Vol 368 (1) ◽  
pp. 293-300 ◽  
Author(s):  
Daniel C. SNELL ◽  
Valerie SCHULTE ◽  
Gavin E. JARVIS ◽  
Kanako ARASE ◽  
Daiju SAKURAI ◽  
...  
Keyword(s):  
Marked Effect ◽  
Protein Tyrosine Phosphorylation ◽  
Wild Type ◽  
Glycoprotein Vi ◽  
Coated Surface ◽  
The Right ◽  
Static Conditions ◽  
Blocking Antibodies ◽  
Snake Toxin ◽  
Stimulation Of

We have investigated the effects of decreased levels of the complex between glycoprotein VI (GPVI) and the Fc receptor γ-chain (FcRγ) on responses to collagen and GPVI-specific ligands in murine platelets. We show that levels of GPVI—FcRγ of the order of 50% and 20% of wild-type levels caused 2- and 5-fold shifts to the right respectively in the dose—response curve for aggregation in response to collagen, the snake toxin convulxin and the monoclonal antibody JAQ1. In addition, there is a delay in the onset of aggregation in response to collagen. In contrast, the stimulation of protein tyrosine phosphorylation by collagen (as measured after 150s) and adhesion to a collagen-coated surface under static conditions were unaffected in platelets with 50% and 20% of wild-type levels of GPVI. In contrast, responses to a collagen-related peptide (CRP), made up of repeat glycine-proline-hydroxyproline motifs, were markedly inhibited and abolished in platelets expressing 50% and 20% of wild-type levels of GPVI respectively. We suggest that the marked effect of a reduction in GPVI levels on the CRP-induced activation of platelets is due to the multivalent nature of CRP and the fact that GPVI is its sole receptor on platelets. Thus it appears that the interaction of CRP with GPVI is determined by a combination of affinity and avidity. The observation that collagen does not behave like CRP in platelets expressing reduced levels of GPVI, even in the combined presence of blocking antibodies against integrin α2β1 and GPV, suggests that collagen has a greater affinity than CRP for GPVI, and/or that other receptors are involved in its binding to platelets. The clinical significance of these results is discussed.

Critical Role for Cyclophilin D and the Mitochondrial Permeability Transition Pore (MPTP) in Platelet Activation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1508-1508 ◽  
Author(s):  
Shawn M. Jobe ◽  
Katina M. Wilson ◽  
Lori Leo ◽  
Jeffery D. Molkentin ◽  
Steven R. Lentz ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Mitochondrial Permeability Transition ◽  
Critical Role ◽  
In Vitro Tests ◽  
Cyclophilin D ◽  
Wild Type ◽  
Glycoprotein Vi ◽  
Stimulation Of

Abstract Dual stimulation of platelets with thrombin and collagen results in the formation of a unique subpopulation of highly activated platelets. Characteristics of the highly activated platelet subpopulation includeincreased surface retention of procoagulant alpha granule proteins,high-level phosphatidylserine (PS) externalization, andmodulation of the fibrinogen receptor αIIbβ3 as evidenced by their decreased recognition by antibodies to activated αIIbβ3 such as PAC-1 and JON/A. Formation of the highly activated platelet subpopulation is closely correlated with a rapid loss of mitochondrial transmembrane potential (ΔΨm), a marker of MPTP formation. To test whether formation of the MPTP might regulate the development of the highly activated platelet subpopulation, platelet activation responses were examined in the presence of inhibitors and activators of MPTP formation. Cyclosporine, an inhibitor of MPTP formation, inhibited both PS externalization and αIIbβ3 modulation following dual stimulation with thrombin and the glycoprotein VI agonist convulxin (58 ± 4% vs. 9 ± 3%, p<0.01). Conversely, thrombin stimulation of platelets in the presence of H2O2 (100μM), an MPTP activator, increased PS externalization and αIIbβ3 modulation relative to platelets stimulated with thrombin alone (11 ± 3% vs. 48 ± 6%, p<0.05). Platelet activation responses were examined in cyclophilin D null (CypD −/−) mice, which have marked impairment of MPTP formation. Following dual agonist stimulation with thrombin and convulxin, both αIIbβ3 modulation and platelet PS externalization were significantly abrogated in CypD −/− platelets relative to wild type (7 ± 1% vs. 69 ± 1%, p<0.01). Alpha granule release, however, was unaffected in the absence of CypD. In vitro tests of platelet function similarly demonstrated that CypD −/− platelets had marked impairment of platelet prothrombinase activity relative to wild-type platelets after stimulation with thrombin and convulxin, but normal platelet aggregation responses. We then tested the hypothesis that CypD −/− mice would have an altered thrombotic response to arterial injury. Following photochemical injury of the carotid artery endothelium, a stable occlusive thrombus formed more rapidly in CypD −/− than in wild-type mice (16 ± 2 vs. 32 ± 7 min, p<0.05). Tail-bleeding time was unaffected. These results strongly implicate cyclophilin D and the MPTP as critical regulators of the subset of platelet activation responses occurring in the highly activated platelet subpopulation and suggest that activation of this novel platelet mitochondrial signaling pathway might play an important role in the regulation of the thrombotic response in vivo.

scholarly journals Hematopoietic lineage cell–specific protein 1 (HS1) is a functionally important signaling molecule in platelet activation

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2449-2456 ◽  
Author(s):  
Bryan N. Kahner ◽  
Robert T. Dorsam ◽  
Sripal R. Mada ◽  
Soochong Kim ◽  
Timothy J. Stalker ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Intracellular Signaling ◽  
Specific Protein ◽  
Null Mouse ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Glycoprotein Vi ◽  
Hematopoietic Lineage ◽  
Stimulation Of

Collagen activates platelets through an intracellular signaling cascade downstream of glycoprotein VI (GPVI). We have investigated the contribution of hematopoietic lineage cell–specific protein 1 (HS1) downstream of GPVI in platelet activation. Stimulation of GPVI leads to tyrosine phosphorylation of HS1, which is blocked by Src-family kinase inhibitors. Coimmunoprecipitation experiments revealed that HS1 associates with Syk and phosphatidylinositol 3-kinases. HS1-null mice displayed increased bleeding times and increased time to occlusion in the FeCl3 in vivo thrombosis model compared with their wild-type littermates. In addition, aggregation and secretion responses were diminished in HS1-null mouse platelets after stimulation of GPVI and protease-activated receptor 4 (PAR-4) agonists compared with wild-type littermate mouse platelets. Finally, Akt phosphorylation was diminished after GPVI or PAR-4 stimulation in platelets from HS1-null mice compared with their wild-type littermates. These results demonstrate that phosphorylation of the HS1 protein occurs downstream of GPVI stimulation and that HS1 plays a significant functional role in platelet activation downstream of GPVI and PARs.

Phosphene perceptions and safety of chronic visual cortex stimulation in a blind subject

2020 ◽  
Vol 132 (6) ◽  
pp. 2000-2007 ◽  
Author(s):  
Soroush Niketeghad ◽  
Abirami Muralidharan ◽  
Uday Patel ◽  
Jessy D. Dorn ◽  
Laura Bonelli ◽  
...  
Keyword(s):  
Visual Cortex ◽  
Adverse Events ◽  
Clinical Intervention ◽  
Occipital Cortex ◽  
Neuronal Population ◽  
Serious Adverse Events ◽  
Stimulation Parameters ◽  
The Right ◽  
Visual Cortical ◽  
Stimulation Of

Stimulation of primary visual cortices has the potential to restore some degree of vision to blind individuals. Developing safe and reliable visual cortical prostheses requires assessment of the long-term stability, feasibility, and safety of generating stimulation-evoked perceptions.A NeuroPace responsive neurostimulation system was implanted in a blind individual with an 8-year history of bare light perception, and stimulation-evoked phosphenes were evaluated over 19 months (41 test sessions). Electrical stimulation was delivered via two four-contact subdural electrode strips implanted over the right medial occipital cortex. Current and charge thresholds for eliciting visual perception (phosphenes) were measured, as were the shape, size, location, and intensity of the phosphenes. Adverse events were also assessed.Stimulation of all contacts resulted in phosphene perception. Phosphenes appeared completely or partially in the left hemifield. Stimulation of the electrodes below the calcarine sulcus elicited phosphenes in the superior hemifield and vice versa. Changing the stimulation parameters of frequency, pulse width, and burst duration affected current thresholds for eliciting phosphenes, and increasing the amplitude or frequency of stimulation resulted in brighter perceptions. While stimulation thresholds decreased between an average of 5% and 12% after 19 months, spatial mapping of phosphenes remained consistent over time. Although no serious adverse events were observed, the subject experienced mild headaches and dizziness in three instances, symptoms that did not persist for more than a few hours and for which no clinical intervention was required.Using an off-the-shelf neurostimulator, the authors were able to reliably generate phosphenes in different areas of the visual field over 19 months with no serious adverse events, providing preliminary proof of feasibility and safety to proceed with visual epicortical prosthetic clinical trials. Moreover, they systematically explored the relationship between stimulation parameters and phosphene thresholds and discovered the direct relation of perception thresholds based on primary visual cortex (V1) neuronal population excitation thresholds.

INFLUENCE OF RIGHT VENTRICULAR LEAD IMPLANTATION SITE CHOICE ON PACING EFFICIENCY

2020 ◽  
pp. 13-17
Author(s):  
Dmitrii Aleksandrovich Lopyn ◽  
Stanislav Valerevich Rybchynskyi ◽  
Dmitrii Evgenevich Volkov
Keyword(s):  
Heart Failure ◽  
Right Ventricular ◽  
Longitudinal Strain ◽  
Treatment Options ◽  
Global Longitudinal Strain ◽  
Optimal Method ◽  
Cardiac Stimulation ◽  
Ventricular Lead ◽  
The Right ◽  
Stimulation Of

Currently the electrophysiological treatment options have been considered to be the most effective for many patients with arrhythmogenic cardiomyopathies, as well as in those with arrhythmias on the background of heart failure. Currently, the dependence of efficiency of the pacemakers on the location of the electrodes has been proven. In order to study the effect of a myocardial dysynchrony on the effectiveness of pacing depending on the location of the right ventricular electrode, an investigation has been performed. This study comprised the patients with a complete atrioventricular block, preserved ejection fraction of the left ventricle (more than 50 %), with no history of myocardial infarction, who were implanted with the two−chamber pacemaker. It has been established that the best results were achieved with a stimulation of the middle and lower septal zone of the right ventricle, the worst ones were obtained with a stimulation of its apex. It has been found that the dynamics of the magnitude of segmental strains and a global longitudinal strain coincided with the dynamics of other parameters of the pacemaker effectiveness, which indicated the pathogenetic value of myocardial dysynchrony in the progression of heart failure after implantation of the pacemaker. Therefore it could be concluded that the studying of myocardial mobility by determining a longitudinal strain for assessing the functional state of the myocardium and the effectiveness of pacing is highly advisable. It is emphasized that the use of the latest strains−dependent techniques for cardiac performance evaluation in the patients with bradyarrhythmia have a great potential to predict the development of chronic heart failure and to choose the optimal method of physiological stimulation of the heart. Key words: right ventricular lead, cardiac stimulation, myocardial dyssynchrony.

СТИМУЛИРОВАНИЕ ПРАВОПОСЛУШНОГО ПОВЕДЕНИЯ ОСУЖДЕННЫХ В МЕСТАХ ЛИШЕНИЯ СВОБОДЫ В СОВЕТСКОМ И СОВРЕМЕННОМ РОССИЙСКОМ ЗАКОНОДАТЕЛЬСТВЕ

2020 ◽  
Author(s):  
Stanislav Kuzmin ◽  
Irina Polyanskaya
Keyword(s):  
Criminal Punishment ◽  
Personal Time ◽  
Labor Camps ◽  
Archival Documents ◽  
Legal Position ◽  
Executive System ◽  
The Right ◽  
Stimulation Of

Статья подготовлена на основе использования нормативных правовых актов и архивных документов различных исправительно-трудовых лагерей, указанных в сносках, что позволяет судить о территориальных рамках источников. Исследуется генезис становления и развития практики стимулирования правопослушного поведения осужденных посредством норм, не изменяющих их правовое положение в период отбывания уголовного наказания в виде лишения свободы на различных этапах функционирования исправительно-трудовой (уголовно-исполнительной) системы. На основе изученных документов можно сделать вывод, что в основу дифференциации поощрительных норм, распространявшихся на осужденных, положены следующие критерии: 1) поощрения, не изменяющие условия отбывания уголовного наказания в виде лишения свободы; 2) поощрения, изменяющие условия содержания осужденных. Из ранее применявшихся мер поощрений в современном уголовно-исполнительном законодательстве используются следующие: объявление благодарности с занесением в личное дело, материальное поощрение, право на дополнительную посылку, передачу и др. Среди других мер поощрения можно выделить увеличение времени ежедневной прогулки до двух часов для осужденных, содержащихся в строгих условиях отбывания наказания в колониях и тюрьмах. Также законодатель предусмотрел возможность проводить праздничные и выходные дни за пределами учреждения для осужденных, содержащихся в колониях-поселениях.The article is prepared on the basis of the use of normative legal acts and archival documents of various correctional labor camps mentioned in the footnotes, which allows to judge the territorial scope of the sources. The Genesis of formation and development of practice of stimulation of law-abiding behavior of condemned by means of the norms which are not changing their legal position during serving of criminal punishment in the form of imprisonment at various stages of functioning of correctional labor (criminal Executive) system is investigated. On the basis of the studied documents, it can be concluded that the basis for the differentiation of incentive norms that apply to convicts are the following criteria: 1) incentives that do not change the conditions of serving a criminal sentence in the form of imprisonment; 2) incentives that change the conditions of detention of convicts. Of the previously applied measures of incentives in the modern penal legislation the following are used: the announcement of gratitude with entering in personal time, material encouragement, the right to an additional parcel, transfer, etc. Among other measures of encouragement it is possible to allocate increase in time of daily walk to two hours for condemned detainees in strict conditions of serving of punishment in colonies and prisons. Also, the legislator provided the opportunity to spend holidays and weekends outside the institution for convicts held in colonies-settlements.

Impaired Platelet Function in Sept8-Deficient Mice In Vitro

2020 ◽  
Author(s):  
Kerstin Jurk ◽  
Katharina Neubauer ◽  
Victoria Petermann ◽  
Elena Kumm ◽  
Barbara Zieger
Keyword(s):  
Platelet Function ◽  
Thrombin Generation ◽  
Human Platelets ◽  
Platelet Surface ◽  
Integrin Αiibβ3 ◽  
Glycoprotein Vi ◽  
Fibrinogen Receptor ◽  
Static Conditions ◽  
The Impact

AbstractSeptins (Septs) are a widely expressed protein family of 13 mammalian members, recognized as a unique component of the cytoskeleton. In human platelets, we previously described that SEPT4 and SEPT8 are localized surrounding α-granules and move to the platelet surface after activation, indicating a possible role in platelet physiology. In this study, we investigated the impact of Sept8 on platelet function in vitro using Sept8-deficient mouse platelets. Deletion of Sept8 in mouse platelets caused a pronounced defect in activation of the fibrinogen receptor integrin αIIbβ3, α-granule exocytosis, and aggregation, especially in response to the glycoprotein VI agonist convulxin. In contrast, δ-granule and lysosome exocytosis of Sept8-deficient platelets was comparable to wild-type platelets. Sept8-deficient platelet binding to immobilized fibrinogen under static conditions was diminished and spreading delayed. The procoagulant activity of Sept8-deficient platelets was reduced in response to convulxin as determined by lactadherin binding. Also thrombin generation was decreased relative to controls. Thus, Sept8 is required for efficient integrin αIIbβ3 activation, α-granule release, platelet aggregation, and contributes to platelet-dependent thrombin generation. These results revealed Sept8 as a modulator of distinct platelet functions involved in primary and secondary hemostatic processes.

scholarly journals Stimulation of the right entorhinal white matter enhances visual memory encoding in humans

2021 ◽  
Vol 14 (1) ◽  
pp. 131-140
Author(s):  
Emily A. Mankin ◽  
Zahra M. Aghajan ◽  
Peter Schuette ◽  
Michelle E. Tran ◽  
Natalia Tchemodanov ◽  
...  
Keyword(s):  
White Matter ◽  
Visual Memory ◽  
Memory Encoding ◽  
The Right ◽  
Stimulation Of

scholarly journals Natural Zeitgebers Under Temperate Conditions Cannot Compensate for the Loss of a Functional Circadian Clock in Timing of a Vital Behavior in Drosophila

2021 ◽  
pp. 074873042199811
Author(s):  
Franziska Ruf ◽  
Oliver Mitesser ◽  
Simon Tii Mungwa ◽  
Melanie Horn ◽  
Dirk Rieger ◽  
...  
Keyword(s):  
Molecular Clock ◽  
Time Window ◽  
Fruit Fly ◽  
Diel Activity ◽  
Wild Type ◽  
Statistical Measures ◽  
Clock Mutant ◽  
Full Complement ◽  
The Right

The adaptive significance of adjusting behavioral activities to the right time of the day seems obvious. Laboratory studies implicated an important role of circadian clocks in behavioral timing and rhythmicity. Yet, recent studies on clock-mutant animals questioned this importance under more naturalistic settings, as various clock mutants showed nearly normal diel activity rhythms under seminatural zeitgeber conditions. We here report evidence that proper timing of eclosion, a vital behavior of the fruit fly Drosophila melanogaster, requires a functional molecular clock under quasi-natural conditions. In contrast to wild-type flies, period01 mutants with a defective molecular clock showed impaired rhythmicity and gating in a temperate environment even in the presence of a full complement of abiotic zeitgebers. Although period01 mutants still eclosed during a certain time window during the day, this time window was much broader and loosely defined, and rhythmicity was lower or lost as classified by various statistical measures. Moreover, peak eclosion time became more susceptible to variable day-to-day changes of light. In contrast, flies with impaired peptidergic interclock signaling ( Pdf01 and han5304 PDF receptor mutants) eclosed mostly rhythmically with normal gate sizes, similar to wild-type controls. Our results suggest that the presence of natural zeitgebers is not sufficient, and a functional molecular clock is required to induce stable temporal eclosion patterns in flies under temperate conditions with considerable day-to-day variation in light intensity and temperature. Temperate zeitgebers are, however, sufficient to functionally rescue a loss of PDF-mediated clock-internal and -output signaling

scholarly journals COMPLEMENTATION ANALYSIS OF LINKED CIRCADIAN CLOCK MUTANTS OF NEUROSPORA CRASSA

Genetics ◽  
1976 ◽  
Vol 82 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Jerry F Feldman ◽  
Marian N Hoyle
Keyword(s):  
Linkage Group ◽  
Circadian Clock ◽  
Neurospora Crassa ◽  
Period Length ◽  
Complementation Analysis ◽  
Wild Type ◽  
The Right

ABSTRACT A fourth mutant of Neurospora crassa, designated frq-4, has been isolated in which the period length of the circadian conidiation rhythm is shortened to 19.3 ± 0.3 hours. This mutant is tightly linked to the three previously isolated frq mutants, and all four map to the right arm of linkage group VII about 10 map units from the centromere. Complementation tests suggest, but do not prove, that all four mutations are allelic, since each of the four mutants is co-dominant with the frq  + allele—i.e., heterokaryons have period lengths intermediate between the mutant and wild-type—and since heterokaryons between pairs of mutants also have period lengths intermediate between those of the two mutants.

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