scholarly journals Ca2+-activated K+ channels reduce network excitability, improving adaptability and energetics for transmitting and perceiving sensory information

2018 ◽  
Author(s):  
Xiaofeng Li ◽  
Ahmad Abou Tayoun ◽  
Zhuoyi Song ◽  
An Dau ◽  
Diana Rien ◽  
...  
Keyword(s):  
Visual Information ◽  
Information Transfer ◽  
Ex Vivo ◽  
Adaptive Dynamics ◽  
Sensory Information ◽  
Fruit Fly ◽  
Bk Channel ◽  
Model Organisms ◽  
Novel Approach

AbstractCa2+-activated K+ channels (BK and SK) are ubiquitous in synaptic circuits, but their role in network adaptation and sensory perception remains largely unknown. Using electrophysiological and behavioral assays and biophysical modelling, we discover how visual information transfer in mutants lacking the BK channel (dSlo−), SK channel (dSK−) or both (dSK−;;dSlo−) is shaped in the female fruit fly (Drosophila melanogaster) R1-R6 photoreceptor-LMC circuits (R-LMC-R system) through synaptic feedforward-feedback interactions and reduced R1-R6 Shaker and Shab K+ conductances. This homeostatic compensation is specific for each mutant, leading to distinctive adaptive dynamics. We show how these dynamics inescapably increase the energy cost of information and promote the mutants’ distorted motion perception, determining the true price and limits of chronic homeostatic compensation in an in vivo genetic animal model. These results reveal why Ca2+-activated K+ channels reduce network excitability (energetics), improving neural adaptability for transmitting and perceiving sensory information.Significance statementIn this study, we directly link in vivo and ex vivo experiments with detailed stochastically operating biophysical models to extract new mechanistic knowledge of how Drosophila photoreceptor-interneuron-photoreceptor (R-LMC-R) circuitry homeostatically retains its information sampling and transmission capacity against chronic perturbations in its ion-channel composition, and what is the cost of this compensation and its impact on optomotor behavior. We anticipate that this novel approach will provide a useful template to other model organisms and computational neuroscience, in general, in dissecting fundamental mechanisms of homeostatic compensation and deepening our understanding of how biological neural networks work.

scholarly journals Marker for the pre-clinical development of bone substitute materials

2017 ◽  
Vol 3 (2) ◽  
pp. 711-715
Author(s):  
Michael de Wild ◽  
Simon Zimmermann ◽  
Marcel Obrecht ◽  
Michel Dard
Keyword(s):  
Bone Graft ◽  
Mechanical Stability ◽  
Clinical Performance ◽  
Ex Vivo ◽  
Region Of Interest ◽  
Defect Site ◽  
Novel Approach ◽  
Bone Substitute Materials ◽  
Clinical Experiments

AbstractThin mechanically stable Ti-cages have been developed for the in-vivo application as X-ray and histology markers for the optimized evaluation of pre-clinical performance of bone graft materials. A metallic frame defines the region of interest during histological investigations and supports the identification of the defect site. This standardization of the procedure enhances the quality of pre-clinical experiments. Different models of thin metallic frameworks were designed and produced out of titanium by additive manufacturing (Selective Laser Melting). The productibility, the mechanical stability, the handling and suitability of several frame geometries were tested during surgery in artificial and in ex-vivo bone before a series of cages was preclinically investigated in the female Göttingen minipigs model. With our novel approach, a flexible process was established that can be adapted to the requirements of any specific animal model and bone graft testing.

scholarly journals A method for single-neuron chronic recording from the retina in awake mice

Science ◽  
2018 ◽  
Vol 360 (6396) ◽  
pp. 1447-1451 ◽  
Author(s):  
Guosong Hong ◽  
Tian-Ming Fu ◽  
Mu Qiao ◽  
Robert D. Viveros ◽  
Xiao Yang ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Visual Information ◽  
Single Neuron ◽  
Ganglion Cells ◽  
Ex Vivo ◽  
Neural Circuitry ◽  
Retinal Ganglion ◽  
Chronic Recording ◽  
The Brain

The retina, which processes visual information and sends it to the brain, is an excellent model for studying neural circuitry. It has been probed extensively ex vivo but has been refractory to chronic in vivo electrophysiology. We report a nonsurgical method to achieve chronically stable in vivo recordings from single retinal ganglion cells (RGCs) in awake mice. We developed a noncoaxial intravitreal injection scheme in which injected mesh electronics unrolls inside the eye and conformally coats the highly curved retina without compromising normal eye functions. The method allows 16-channel recordings from multiple types of RGCs with stable responses to visual stimuli for at least 2 weeks, and reveals circadian rhythms in RGC responses over multiple day/night cycles.

“The Balloon Plug Concept” for Tricuspid Valve Repair Ex Vivo Proof of Concept

2015 ◽  
Vol 10 (1) ◽  
pp. 27-32 ◽  
Author(s):  
Pietro Bajona ◽  
Stefano Salizzoni ◽  
Stijn Vandenberghe ◽  
Charles J. Bruce ◽  
Giovanni Speziali ◽  
...  
Keyword(s):  
Tricuspid Regurgitation ◽  
Ex Vivo ◽  
Tricuspid Valve Repair ◽  
Functional Tricuspid Regurgitation ◽  
Novel Approach ◽  
Annular Dilatation ◽  
Transvalvular Gradient ◽  
Antegrade Flow ◽  
The Right

Objective Functional tricuspid regurgitation (TR) is recognized as a significant cause of morbidity and mortality in cardiothoracic surgery. We hypothesized that a variably expandable, transvalvular balloon mounted on a catheter could be percutaneously inserted and fixed to the right ventricle apex. This novel approach could provide a minimally invasive way to eliminate clinically relevant TR caused by annular dilatation. This study was performed to test the ex vivo hemodynamic effects and the feasibility of the “balloon plug concept.” Methods Twenty harvested calf tricuspid valves were placed in a mechanical simulator. Tricuspid regurgitation was created by annular stretching and displacement of the papillary muscles so as to create central TR. A flexible catheter with a 4-cm–long, soft, fusiform balloon was positioned across the valve so that the balloon was suspended centrally across the valve annular plane. After activating the mechanical ventricle, data were collected with balloon inflation volumes of saline from 5 to 20 mL. Transvalvular pressure gradients and leaflet mechanics were evaluated with incremental inflation. Results In all cases, 5-mL inflation did not significantly reduce TR and 20-mL inflation caused obstruction to antegrade flow (mean transvalvular gradient > 4 mm Hg). Inflation between 10 and 15 mL caused significant reduction in TR with acceptable transvalvular gradients (<3 mm Hg). Conclusions The balloon plug concept showed promising ex vivo hemodynamic results. In vivo investigations are warranted to evaluate percutaneous techniques, thrombogenicity, and effects of repeated balloon-leaflet contact on valve integrity.

scholarly journals A projection specific logic to sampling visual inputs in mouse superior colliculus

2018 ◽  
Author(s):  
Katja Reinhard ◽  
Chen Li ◽  
Quan Do ◽  
Emily Burke ◽  
Steven Heynderickx ◽  
...  
Keyword(s):  
Superior Colliculus ◽  
Ganglion Cells ◽  
Ex Vivo ◽  
Sensory Information ◽  
Cell Types ◽  
Brain Regions ◽  
Visual Response ◽  
Retinal Ganglion ◽  
Parabigeminal Nucleus

AbstractUsing sensory information to trigger different behaviours relies on circuits that pass-through brain regions. However, the rules by which parallel inputs are routed to different downstream targets is poorly understood. The superior colliculus mediates a set of innate behaviours, receiving input from ~30 retinal ganglion cell types and projecting to behaviourally important targets including the pulvinar and parabigeminal nucleus. Combining transsynaptic circuit tracing with in-vivo and ex-vivo electrophysiological recordings we observed a projection specific logic where each collicular output pathway sampled a distinct set of retinal inputs. Neurons projecting to the pulvinar or parabigeminal nucleus uniquely sampled 4 and 7 cell types, respectively. Four others innervated both pathways. The visual response properties of retinal ganglion cells correlated well with those of their disynaptic targets. These findings suggest that projection specific sampling of retinal inputs forms a mechanistic basis for the selective triggering of visually guided behaviours by the superior colliculus.

scholarly journals A projection specific logic to sampling visual inputs in mouse superior colliculus

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Katja Reinhard ◽  
Chen Li ◽  
Quan Do ◽  
Emily G Burke ◽  
Steven Heynderickx ◽  
...  
Keyword(s):  
Superior Colliculus ◽  
Ex Vivo ◽  
Sensory Information ◽  
Cell Types ◽  
Brain Regions ◽  
Biased Sampling ◽  
Visual Response ◽  
Retinal Ganglion ◽  
Parabigeminal Nucleus

Using sensory information to trigger different behaviors relies on circuits that pass through brain regions. The rules by which parallel inputs are routed to downstream targets are poorly understood. The superior colliculus mediates a set of innate behaviors, receiving input from >30 retinal ganglion cell types and projecting to behaviorally important targets including the pulvinar and parabigeminal nucleus. Combining transsynaptic circuit tracing with in vivo and ex vivo electrophysiological recordings, we observed a projection-specific logic where each collicular output pathway sampled a distinct set of retinal inputs. Neurons projecting to the pulvinar or the parabigeminal nucleus showed strongly biased sampling from four cell types each, while six others innervated both pathways. The visual response properties of retinal ganglion cells correlated well with those of their disynaptic targets. These findings open the possibility that projection-specific sampling of retinal inputs forms a basis for the selective triggering of behaviors by the superior colliculus.

scholarly journals Rational cotargeting of HDAC6 and BET proteins yields synergistic antimyeloma activity

2019 ◽  
Vol 3 (8) ◽  
pp. 1318-1329 ◽  
Author(s):  
Jennifer S. Carew ◽  
Claudia M. Espitia ◽  
Weiguo Zhao ◽  
Valeria Visconte ◽  
Faiz Anwer ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Family Members ◽  
Apoptosis Induction ◽  
Histone Deacetylase 6 ◽  
Novel Approach ◽  
Bet Inhibitors ◽  
Hdac6 Inhibitor ◽  
Bet Protein

Abstract Inhibition of bromodomain and extra terminal (BET) protein family members, including BRD4, decreases the expression of c-MYC and other key oncogenic factors and also significantly induces histone deacetylase 6 (HDAC6) expression. On the basis of the role of HDAC6 in malignant pathogenesis, we hypothesized that rational cotargeting of HDAC6 and BET family proteins may represent a novel approach that yields synergistic antimyeloma activity. We used genetic and pharmacologic approaches to selectively impair HDAC6 and BET function and evaluated the consequential impact on myeloma pathogenesis. These studies identified HDAC6 upregulation as an efficacy reducing mechanism for BET inhibitors because antagonizing HDAC6 activity synergistically enhanced the activity of JQ1 in a panel of multiple myeloma (MM) cell lines and primary CD138+ cells obtained from patients with MM. The synergy of this therapeutic combination was linked to significant reductions in c-MYC expression and increases in apoptosis induction. Administration of the clinical HDAC6 inhibitor ricolinostat was very well tolerated and significantly augmented the in vivo antimyeloma activity of JQ1. Ex vivo pharmacodynamic analyses demonstrated that the combination of JQ1 and ricolinostat led to significantly lower MM cell proliferation and increased apoptosis and diminished expression of c-MYC and BCL-2. These data demonstrate that cotargeting of HDAC6 and BET family members is a novel and clinically actionable approach to augment the efficacy of both classes of agents that warrants further investigation.

scholarly journals Drug discovery for psychiatric disorders using high-content single-cell screening of signaling network responses ex vivo

2019 ◽  
Vol 5 (5) ◽  
pp. eaau9093 ◽  
Author(s):  
Santiago G. Lago ◽  
Jakub Tomasik ◽  
Geertje F. van Rees ◽  
Hannah Steeb ◽  
David A. Cox ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Single Cell ◽  
Drug Targets ◽  
Ex Vivo ◽  
Signaling Network ◽  
Antipsychotic Treatment ◽  
Channel Blockers ◽  
Functional Responses ◽  
Novel Approach

There is a paucity of efficacious new compounds to treat neuropsychiatric disorders. We present a novel approach to neuropsychiatric drug discovery based on high-content characterization of druggable signaling network responses at the single-cell level in patient-derived lymphocytes ex vivo. Primary T lymphocytes showed functional responses encompassing neuropsychiatric medications and central nervous system ligands at established (e.g., GSK-3β) and emerging (e.g., CrkL) drug targets. Clinical application of the platform to schizophrenia patients over the course of antipsychotic treatment revealed therapeutic targets within the phospholipase Cγ1–calcium signaling pathway. Compound library screening against the target phenotype identified subsets of L-type calcium channel blockers and corticosteroids as novel therapeutically relevant drug classes with corresponding activity in neuronal cells. The screening results were validated by predicting in vivo efficacy in an independent schizophrenia cohort. The approach has the potential to discern new drug targets and accelerate drug discovery and personalized medicine for neuropsychiatric conditions.

TMOD-17. A NOVEL GLIOBLASTOMA INVASION MODEL USING HUMAN BRAIN SLICE CULTURES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi219-vi219
Author(s):  
Vidyha Ravi ◽  
Kevin Joseph ◽  
Jürgen Beck ◽  
Oliver Schnell ◽  
Ulrich Hofmann ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Tumour Microenvironment ◽  
Human Model ◽  
Model Organisms ◽  
Murine Models ◽  
Loss Of Function ◽  
High Concentration ◽  
Ample Evidence ◽  
Human Microglia

Abstract OBJECTIVE Glioblastoma (GBM) is among the most common of malignant brain tumours, with a median post-surgical survival of less than one year. Over the past several decades, therapies that appeared promising in mice models have failed during clinical trials due to the differences encountered during translation of research from model organisms to humans. To partially mitigate these difficulties in translation, we present a human cortical organotypic culture based GBM model, which allows us to manipulate individual components of the tumour environment in order to investigate the influence of different cell types in the immunosuppressive tumour microenvironment. METHODS Human neocortical tissue (at least 2 cm away from the tumour core) or entry cortex from epilepsy surgery guided by intraoperative neuro navigation, was cultured for up to 14 days post resection using an optimized medium. The cultured tissue was further injected with patient derived human GBM cells to create an ex vivo human model of glioblastoma model. The role of astrocytes in the tumour microenvironment was studied using microglia loss of function model. RESULTS Our established human neo-cortical slice model can recapitulate an in-vivo characteristics of glioblastoma from functional and imaging aspect. Our data corroborate differences between astrocytes in human and murine models in different reactive states, shows that the glioblastoma microenvironment can be difficult to be accurately modelled using murine models. Results from our human microglia depletion model, provided ample evidence that complex interaction of astrocytes and microglia cells, promotes an immunosuppressive environment in Glioblastoma by releasing high concentration of IL10 and TGFbeta (p&lt; 0.001). CONCLUSION Our model therefore has potential applications to the fields of neuroscience, neuro-oncology, and pharmacotherapy.

Abstract 381: Ex vivo Heart Function Analysis in Adult Zebrafish

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Alexey V Dvornikov ◽  
Hong Zhang ◽  
Xiaolei Xu
Keyword(s):  
Ex Vivo ◽  
Function Analysis ◽  
Heart Function ◽  
Heart Diseases ◽  
Genetic Modifiers ◽  
Adult Zebrafish ◽  
Inherited Cardiomyopathy ◽  
Novel Approach ◽  
Vertebrate Model

Zebrafish ( Danio rerio ) is an efficient vertebrate model of human cardiomyopathy which is amenable to the medium throughput screening approaches opening opportunities to search new genetic modifiers via mutagenesis screening and assessing compound-based therapies at larger scale. The advent of genome editing technology enables the generation of a panel of genetic models of cardiomyopathy with mutations in leading cardiomyopathy genes. However, one of the major bottlenecks for adult zebrafish as a cardiomyopathy model is the lack of appropriate cardiac functional assays. Due to small heart size, in vivo methods such as those based on echocardiography, are limited by their insufficient resolution. Here, we report the development of an ex vivo approach aimed to facilitate phenotyping in adult zebrafish. We show that our method is able to quantify parameters of pump function of the heart, including end-diastolic/systolic length/volumes, ejection and shortening fractions, and velocities of contraction/relaxation. We defined the basic parameters of these indices using different wild-type strains, age, and sex, and then demonstrated that our method can be useful in definition of progression of pathogenesis of both acquired (doxorubicin-injected) and inherited cardiomyopathy models. We conclude that our novel approach shall facilitate cardiac phenotyping in adult zebrafish models of heart diseases.

TTP889, a Novel Orally Active Partial Inhibitor of FIXa Inhibits Clotting in Two A/V Shunt Models without Prolonging Bleeding Times.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1886-1886 ◽  
Author(s):  
Robert Rothlein ◽  
Jane M. Shen ◽  
Najih Naser ◽  
Devi R. Gohimukkula ◽  
Thomas B. Caligan ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Anticoagulant Activity ◽  
Clot Formation ◽  
Once Daily ◽  
Post Surgery ◽  
Novel Approach ◽  
Clotting Cascade ◽  
Orally Active ◽  
Coagulation Pathway

Abstract Based on previous studies showing the efficacy of FactorIXa (FIXa) blockade using an active site-blocked form of this coagulation enzyme, we speculated that partial inhibition of the intrinsic coagulation pathway would offer a novel approach to attenuate intravascular clot formation without promoting untoward bleeding. Here we describe the anticoagulant activity of TTP889, a small molecule partial inhibitor of FIXa activity. TTP889 is orally absorbed with a PK profile that is conducive to once daily dosing. It is selective for FIXa in that it shows little to no activity against several other proteases in the clotting cascade including FXa, FXIa, FXIIa or FVIIa in a unique clotting assay. In vivo, TTP889 inhibited fibrin deposition in a rat arteriovenous (A/V) shunt model. In this model, vehicle treated rats had 104mg ± 43 of fibrin deposited on a silk thread after a 15 minute shunt while TTP889 treated rats had significantly less fibrin deposited (39mg ± 18 p=<0.001). Furthermore, TTP889 inhibited clotting in a porcine A/V shunt model where pressure across a hemodialysis filter that was shunting the carotid artery to the jugular vein was used as an indirect marker of clot formation. In this model, TTP889 at 0.3mg/kg performed as well as 150U/kg of heparin over the 90-minute shunt. Of additional importance, TTP889 has no effect on bleeding times as measured by APTT or ACT assays ex-vivo or by bleeding time and volume from incisions in the skin or spleen in vivo. Together, these data support that TTP889 is a selective partial inhibitor of FIXa activity that offers a novel approach to attenuate clot formation associated with intravascular clotting without promoting untoward bleeding. TTP 889 is currently in Phase II and is being evaluated for the prevention of DVT in hip fracture patients with treatment starting one week post surgery and continued for 3 weeks.

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