Biology subjects

Ding, M.

Publications and source records attributed to Ding, M..

4 recordsLinked to original sources

bioRxiv2018

Targeting RyR2 with a phosphorylation site-specific nanobody Reverses Dysfunction of Failing Cardiomyocytes in Rat

Chronic PKA phosphorylation of RyR2 has been shown to increased diastolic SR Ca2+ leak and lead to cardiac dysfunction. Since the change of phosphorylation level of RyR2 is a biomarker of failing heart, we attempted to verify the hypothesis that intracellular gene delivery of a RyR2 targeting phosphorylation site-specific nanobody could preserve contractility of failing myocardium. In present study, we acquired the RyR2-specific nanobodies from a phage display library which are variable domains of camellidae heavy chain-only antibodies (VHH). One of the monoclonal nanobodies, AR185, inhibiting RyR2 phosphorylation in an in vitro assay was then chosen for further investigation. We investigated the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of AR185 against post-ischemic heart failure. Adeno-associated virus gene delivery elevated the intracellular expression AR185 protein in the ischemic heart failure model of rats, and this treatment normalized the systolic and diastolic dysfunction of the failing myocardium in vivo and in vitro by reversing myocardial Ca2+ handling. Furthermore, AR185 gene transfer to failing cardiomyocytes reduced the frequency of sarcoplasmic reticulum (SR) calcium leak, thereby restoring the attenuated intracellular calcium transients and SR calcium load. Moreover, AR185 gene transfer inhibited PKA phosphorylation of RyR2 in failing cardiomyocytes. Our results provided strong pre-clinical experimental evidence of the cardiac expression of RyR2 nanobody with AAV9 vectors as a promising therapeutic strategy for ischemic heart failure.

pathology↗

bioRxiv2017

Temporal coupling of field potentials and action potentials in the neocortex

The local field potential (LFP) is an aggregate measure of group neuronal activity and is often correlated with the action potentials of single neurons. In recent years investigators have found that action potential firing rates increase during elevations in power high-frequency band oscillations (50-200 Hz range). However action potentials also contribute to the LFP signal itself, making the spike-LFP relationship complex. Here we examine the relationship between spike rates and LFPs in varying frequency bands in rat neocortical recordings. We find that 50-180Hz oscillations correlate most consistently with high firing rates, but that other LFPs bands also carry information relating to spiking, including in some cases anti-correlations. Relatedly, we find that spiking itself and electromyographic activity contribute to LFP power in these bands. The relationship between spike rates and LFP power varies between brain states and between individual cells. Finally, we create an improved oscillation-based predictor of action potential activity by specifically utilizing information from across the entire recorded frequency spectrum of LFP. The findings illustrate both caveats and improvements to be taken into account in attempts to infer spiking activity from LFP.

neuroscience↗

bioRxiv2017

Transcranial alternating current stimulation induces long-term augmentation of neural connectivity and sustained anxiety reduction

Although transcranial alternating current stimulation (tACS) has demonstrated short-term effects in modulating neural oscillations, potential clinical efficacy of tACS for treating \"oscillopathies\" (disorders associated with aberrant neural oscillations) hinges on its ability to generate long-term neural plasticity, which can translate into lasting behavioral changes. Administering alpha-frequency tACS over 4 consecutive days, we evaluated short- and long-term (> 24 hours) effects of -tACS on local alpha power and oscillatory connectivity, along with behavioral outcomes in anxious arousal and affective sensory perception. The -tACS (vs. sham stimulation) group exhibited increases in posterior alpha power immediately and 30 minutes post-stimulation but not 24 hours post-stimulation, suggesting transient effects on local neuronal synchrony. Strikingly, long-range alpha-frequency Granger causal connectivity (posterior[->]frontal) increased not only immediately and 30 minutes but also 24 hours post-stimulation, paralleled by sustained reductions in anxious arousal and aversion to auditory stimuli. Therefore, tACS is capable of eliciting long-term plasticity in long-range oscillatory connectivity with direct, lasting behavioral consequences, while leaving endogenous local oscillations unaltered. This temporal disparity in local and network effects favors the view of large-scale network strengthening by tACS, calling for research attention to the circuit and network impacts of tACS. Critically, with the growing recognition of large-scale network dysfunctions as a transdiagnostic pathophysiology of psychiatric disorders, this connectivity plasticity advocates for the clinical application of tACS with its unique advantage in tackling network pathologies.

neuroscience↗

bioRxiv2017

Intestinal cell kinase regulates chondrocyte proliferation and maturation during skeletal development

An autosomal recessive loss-of-function mutation R272Q in human ICK (intestinal cell kinase) gene causes profound multiplex developmental defects in human ECO (endocrine-cerebro-osteodysplasia) syndrome. ECO patients exhibit a wide variety of skeletal abnormalities, yet the underlying cellular and molecular mechanisms by which ICK regulates skeletal development remain largely unknown. The goal of this study is to understand the structural and mechanistic basis underlying skeletal anomalies caused by ICK dysfunction. Ick R272Q knock in transgenic mouse model not only recapitulated major ECO skeletal defects such as short limbs and polydactyly but also revealed a deformed spine with deficient intervertebral disc. Loss of ICK functions markedly reduces mineralization in the spinal column, ribs, and long bones. Ick mutants show a significant decrease in the number of proliferating chondrocytes and type X collagen-expressing hypertrophic chondrocytes in the spinal column and the growth plate of long bones. Our results demonstrate that ICK plays an important role in bone and intervertebral disc development by promoting chondrocyte proliferation and maturation, and thus provide novel mechanistic insights into the skeletal phenotypes of human ECO syndrome.

developmental biology↗