Enhanced myocyte-based biosensing of the blood-borne signals regulating chronotropy

2002 ◽  
Vol 92 (2) ◽  
pp. 581-585 ◽  
Author(s):  
Jay M. Edelberg ◽  
Jason T. Jacobson ◽  
David S. Gidseg ◽  
Lilong Tang ◽  
David J. Christini
Keyword(s):  
Cardiac Myocyte ◽  
Cardiac Tissue ◽  
Critical Role ◽  
Excitable Tissue ◽  
Time Determination ◽  
Molecular Plasticity ◽  
Relationship Of ◽  
High Degree

Biosensors play a critical role in the real-time determination of relevant functional physiological needs. However, typical in vivo biosensors only approximate endogenous function via the measurement of surrogate signals and, therefore, may often lack a high degree of dynamic fidelity with physiological requirements. To overcome this limitation, we have developed an excitable tissue-based implantable biosensor approach, which exploits the inherent electropotential input-output relationship of cardiac myocytes to measure the physiological regulatory inputs of chronotropic demand via the detection of blood-borne signals. In this study, we report the improvement of this application through the modulation of host-biosensor communication via the enhancement of vascularization of chronotropic complexes in mice. Moreover, in an effort to further improve translational applicability as well as molecular plasticity, we have advanced this approach by employing stem cell-derived cardiac myocyte aggregates in place of whole cardiac tissue. Overall, these studies demonstrate the potential of biologically based biosensors to predict endogenous physiological dynamics and may facilitate the translation of this approach for in vivo monitoring.

scholarly journals Direct biologically based biosensing of dynamic physiological function

2001 ◽  
Vol 280 (5) ◽  
pp. H2006-H2010 ◽  
Author(s):  
David J. Christini ◽  
Jeff Walden ◽  
Jay M. Edelberg
Keyword(s):  
Real Time ◽  
Cardiac Tissue ◽  
Physiological Function ◽  
Physiological Activity ◽  
Functional Integration ◽  
Dynamic Regulation ◽  
Excitable Tissue ◽  
Alternative Approach

Dynamic regulation of biological systems requires real-time assessment of relevant physiological needs. Biosensors, which transduce biological actions or reactions into signals amenable to processing, are well suited for such monitoring. Typically, in vivo biosensors approximate physiological function via the measurement of surrogate signals. The alternative approach presented here would be to use biologically based biosensors for the direct measurement of physiological activity via functional integration of relevant governing inputs. We show that an implanted excitable-tissue biosensor (excitable cardiac tissue) can be used as a real-time, integrated bioprocessor to analyze the complex inputs regulating a dynamic physiological variable (heart rate). This approach offers the potential for long-term biologically tuned quantification of endogenous physiological function.

scholarly journals Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746

2016 ◽  
Vol 37 (3) ◽  
pp. 1095-1107 ◽  
Author(s):  
Jean-Dominique Gallezot ◽  
Beata Planeta ◽  
Nabeel Nabulsi ◽  
Donna Palumbo ◽  
Xiaoxi Li ◽  
...  
Keyword(s):  
Binding Sites ◽  
Human Subjects ◽  
Receptor Occupancy ◽  
Healthy Human ◽  
Positron Emission ◽  
Relationship Of ◽  
The Relationship ◽  
Pet Scans

Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds “tracer” levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant Kd of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo Kd. This method was applied in a study of healthy human subjects with the histamine H3 receptor radioligand [11C]GSK189254 to measure the PK-occupancy relationship of the H3 antagonist PF-03654746. From three test/retest studies, [11C]GSK189254 Kd was estimated to be 9.5 ± 5.9 pM. Oral administration of 0.1 to 4 mg of PF-03654746 resulted in occupancy estimates of 71%–97% and 30%–93% at 3 and 24 h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%–15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H3 binding sites ( ROmax = 100%), and its IC50 was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC50 was 26% higher.

scholarly journals Gamma-tubulin distribution in the neuron: implications for the origins of neuritic microtubules.

1992 ◽  
Vol 119 (1) ◽  
pp. 171-178 ◽  
Author(s):  
P W Baas ◽  
H C Joshi
Keyword(s):  
Immunoelectron Microscopy ◽  
Neuronal Development ◽  
Sympathetic Neurons ◽  
Critical Role ◽  
Explant Cultures ◽  
Gamma Tubulin ◽  
Cultured Sympathetic Neurons ◽  
High Degree ◽  
Tubulin Content

Axons and dendrites contain dense microtubule (MT) assays that are not attached to a traditional MT nucleating structure such as the centrosome. Nevertheless, the MTs within these neurites are highly organized with respect to their polarity, and consist of a regular 13-protofilament lattice, the two known characteristics of MTs nucleated at the centrosome. These observations suggest either that axonal and dendritic MTs arise at the centrosome, or that they are nucleated locally, following a redistribution of MT nucleating material from the centrosome during neuronal development. To begin distinguishing between these possibilities, we have determined the distribution of gamma-tubulin within cultured sympathetic neurons. gamma-tubulin, a newly discovered protein which is specifically localized to the pericentriolar region of nonneuronal cells (Zheng, Y., M. K. Jung, and B. R. Oakley. 1991. Cell. 65:817-823; Stearns, T., L. Evans, and M. Kirschner. 1991. Cell. 65:825-836), has been shown to play a critical role in MT nucleation in vivo (Joshi, H. C., M. J. Palacios, L. McNamara, and D. W. Cleveland. 1992. Nature (Lond.). 356:80-83). Because the gamma-tubulin content of individual cells is extremely low, we relied principally on the high degree of resolution and sensitivity afforded by immunoelectron microscopy. Our studies reveal that, like the situation in nonneuronal cells, gamma-tubulin is restricted to the pericentriolar region of the neuron. Furthermore, serial reconstruction analyses indicate that the minus ends of MTs in both axons and dendrites are free of gamma-tubulin immunoreactivity. The absence of gamma-tubulin from the axon was confirmed by immunoblot analyses of pure axonal fractions obtained from explant cultures. The observation that gamma-tubulin is restricted to the pericentriolar region of the neuron provides compelling support for the notion that MTs destined for axons and dendrites are nucleated at the centrosome, and subsequently released for translocation into these neurites.

In Vivo Determination of the Direction of Rotation and Moment-Angle Relationship of Individual Elbow Muscles

1998 ◽  
Vol 120 (5) ◽  
pp. 625-633 ◽  
Author(s):  
L. Zhang ◽  
J. Butler ◽  
T. Nishida ◽  
G. Nuber ◽  
H. Huang ◽  
...  
Keyword(s):  
Muscle Activation ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Elbow Flexion ◽  
Joint Movement ◽  
Flexion Extension ◽  
Relationship Of ◽  
Three Dimensional Space

The direction of rotation (DOR) of individual elbow muscles, defined as the direction in which a muscle rotates the forearm relative to the upper arm in three-dimensional space, was studied in vivo as a function of elbow flexion and forearm rotation. Electrical stimulation was used to activate an individual muscle selectively, and the resultant flexion-extension, supination-pronation, and varus-valgus moments were used to determine the DOR. Furthermore, multi-axis moment-angle relationships of individual muscles were determined by stimulating the muscle at a constant submaximal level across different joint positions, which was assumed to result in a constant level of muscle activation. The muscles generate significant moments about axes other than flexion-extension, which is potentially important for actively controlling joint movement and maintaining stability about all axes. Both the muscle DOR and the multi axis moments vary with the joint position systematically. Variations of the DOR and moment-angle relationship across muscle twitches of different amplitudes in a subject were small, while there were considerable variations between subjects.

scholarly journals Recombinant production, crystallization and crystal structure determination of dihydroorotate dehydrogenase fromLeishmania (Viannia) braziliensis

2015 ◽  
Vol 71 (5) ◽  
pp. 547-552 ◽  
Author(s):  
Renata Almeida Garcia Reis ◽  
Eder Lorenzato ◽  
Valeria Cristina Silva ◽  
Maria Cristina Nonato
Keyword(s):  
Crystal Structure ◽  
De Novo ◽  
Cell Metabolism ◽  
Dihydroorotate Dehydrogenase ◽  
Recombinant Production ◽  
High Degree ◽  
Respective Host

The enzyme dihydroorotate dehydrogenase (DHODH) is a flavoenzyme that catalyses the oxidation of dihydroorotate to orotate in thede novopyrimidine-biosynthesis pathway. In this study, a reproducible protocol for the heterologous expression of active dihydroorotate dehydrogenase fromLeishmania (Viannia) braziliensis(LbDHODH) was developed and its crystal structure was determined at 2.12 Å resolution.L. (V.) braziliensisis the species responsible for the mucosal form of leishmaniasis, a neglected disease for which no cure or effective therapy is available. Analyses of sequence, structural and kinetic features classifyLbDHODH as a member of the class 1A DHODHs and reveal a very high degree of structural conservation with the previously reported structures of orthologous trypanosomatid enzymes. The relevance of nucleotide-biosynthetic pathways for cell metabolism together with structural and functional differences from the respective host enzyme suggests that inhibition ofLbDHODH could be exploited for antileishmanicidal drug development. The present work provides the framework for further integratedin vitro,in silicoandin vivostudies as a new tool to evaluate DHODH as a drug target against trypanosomatid-related diseases.

Effects of Bradykinin on Coagulation and Fibrinolysis Study in Vitro and in Vivo

1965 ◽  
Vol 14 (03/04) ◽  
pp. 508-518 ◽  
Author(s):  
G. G Neri Serneri ◽  
P. L Rossi Ferrini ◽  
P Paoletti ◽  
A Panti ◽  
G D’Ayala Valva
Keyword(s):  
Thrombin Generation ◽  
Thrombin Time ◽  
Lysis Time ◽  
Time Determination ◽  
Recalcification Time ◽  
Generation Test ◽  
Coagulation And Fibrinolysis

SummaryThe effects of bradykinin on coagulation and fibrinolysis have been studied both “in vitro” and “in vivo” in man. “In vitro” bradykinin employed at different concentrations does not affect the coagulation and fibrinolysis processes in any appreciable way. Bradykinin, intraarterially injected in man in the dose of 10 y, does not modify coagulation studied both with global investigations (thrombelastogram, recalcification time) and with analytical researches (Quick’s time, activation test of intrinsic thromboplastin, thrombin generation test and thromboplastin test, thrombin time, determination of antithrombin II and III). Bradykinin instead produces an activation of fibrinolysis both in the thrombelastographic investigation and in the lysis time of euglobulins. The decrease in the activity of the proactivator and of plasminogen supports our view that bradykinin produces an activation of the fibrinolytic system by liberating tissue kinases which act on the proactivator. The authors have discussed the physiological and physiopathological significance of the observed findings.

Dihydropyrimidinones scaffold as a promising nucleus for synthetic profile and various therapeutic targets: A Review

2020 ◽  
Vol 17 ◽  
Author(s):  
Shaik Khasimbi ◽  
Faraat Ali ◽  
Kiran Manda ◽  
Anjali Sharma ◽  
Garima Chauhan ◽  
...  
Keyword(s):  
Biginelli Reaction ◽  
Critical Role ◽  
Heterocyclic Ring ◽  
Biological Profile ◽  
Design Synthesis ◽  
Wide Range ◽  
Review Reports ◽  
Relationship Of ◽  
Anti Hiv

Background:: This review elaborates the updated synthetic and pharmacological approaches of a known group of dihydropyrimidinones/thiones from the multi-component reaction like Biginelli reaction was named Pietro Biginelli in 1891. This review consists of the reaction of an aromatic aldehyde, urea and ethyl acetoacetate leading to dihydropyrimidinone/thione. Currently, the scientific movement to develop economically viable green methods using compounds that are reusable, non-volatile, easily obtained, etc. Objective:: This review covers the recent synthesis and pharmacological advancement of dihydropyrimidinones/thiones moiety, along with covering the structure-activity relationship of the most potent compounds, which may prove to become better, more efficacious and safer agents. Thus, this review may help the researchers in drug designing and development of new Dihydropyrimidinones entities. Conclusion:: This review focuses on the wide application of dihydropyrimidinone/thione review reports the design, synthesis and pharmacological activities of nitrogen-sulphur containing dihydropyrimidinone moiety by using multi-component reaction. Dihydropyrimidinones (DHPM) pharmacophore is an important heterocyclic ring in medicinal chemistry. It is derived from multi-component reactions, “Biginelli reaction” and plays critical role as anticancer, antioxidant, antimicrobial, antiinflammatory, anti-HIV-1, antimalarial, anti-inflammatory, antihypertensive and anti-tubercular agents. Exhaustive research has led to the determination of its vast biological profile, with a wide range of therapeutic application.

Exacerbation of myocardial injury in transgenic mice overexpressing FGF-2 is T cell dependent

2002 ◽  
Vol 282 (2) ◽  
pp. H547-H555 ◽  
Author(s):  
Johanna T. A. Meij ◽  
Farah Sheikh ◽  
Sarah K. Jimenez ◽  
Peter W. Nickerson ◽  
Elissavet Kardami ◽  
...  
Keyword(s):  
T Cell ◽  
Myocardial Injury ◽  
Cardiac Myocyte ◽  
Cardiac Tissue ◽  
Isolated Heart ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Fgf Receptor ◽  
T Cell Infiltration

Fibroblast growth factor-2 (FGF-2) is cardioprotective when added exogenously, stimulates cardiac myocyte proliferation, and is a mediator of tissue repair after injury. Furthermore, transgenic (TG) mice overexpressing FGF-2 in cardiac muscle demonstrate increased resistance to injury in an isolated heart model of ischemia-reperfusion. We investigated how increasing the endogenous FGF-2 levels in the heart affects the extent of myocardial damage induced by isoproterenol in vivo. Histopathological evaluation of hearts after intraperitoneal injection of isoproterenol yielded significantly higher scores for myocardial damage in FGF-2 TG lines compared with non-TG mice. After 1 day, FGF-2 TG mouse hearts displayed more cellular infiltration correlating with increased tissue damage. Immunostaining of non-TG and FGF-2 TG mouse hearts showed the presence of leukocytes in the infiltrate, including T cells expressing FGF receptor-1. Treatment of mice with T cell suppressors cyclosporin A and anti-CD3ε significantly decreased the level of myocardial injury observed after isoproterenol and equalized the histopathology scores in FGF-2 TG and non-TG hearts. These data demonstrate a direct T cell involvement in the response to isoproterenol-induced injury in vivo. Moreover, the findings indicate that the exacerbation of myocardial damage in FGF-2 TG mice was dependent on T cell infiltration, implicating FGF-2 in the inflammatory response seen in cardiac tissue after injury in vivo.

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