Biology subjects

Park, H.

Publications and source records attributed to Park, H..

209 records · Page 12Linked to original sources

bioRxiv2018

Predictive entrainment of natural speech through two fronto-motor top-down channels

Natural communication between interlocutors is enabled by the ability to predict upcoming speech in a given context. Previously we showed that these predictions rely on a fronto-motor top-down control of low-frequency oscillations in auditory-temporal brain areas that track intelligible speech. However, a comprehensive spatio-temporal characterisation of this effect is still missing. Here, we applied transfer entropy to source-localised MEG data during continuous speech perception. First, at low frequencies (1-4 Hz, brain delta phase to speech delta phase), predictive effects start in left fronto-motor regions and progress to right temporal regions. Second, at higher frequencies (14-18 Hz, brain beta power to speech delta phase), predictive patterns show a transition from left inferior frontal gyrus via left precentral gyrus to left primary auditory areas. Our results suggest a progression of prediction processes from higher-order to early sensory areas in at least two different frequency channels.

neuroscience↗

bioRxiv2018

Graphene-oxide quenching-based molecular beacon imaging of exosome-mediated transfer of neurogenic miR-193a on microfluidic platform

A microRNA (miR-193a) was found to be transferred in the exosomes of differentiated neural progenitors to undifferentiated clones. Graphene-oxide (GO) quenching-based molecular beacon was developed to detect RNAs in living cells and tissues quickly and sensitively. Here, we applied GO quencher-based molecular beacon sensor to visualize neurogenic miR-193a levels delivered via exosome during cell-non-autonomous neurogenesis of neural progenitor cells on microfluidic platform. Fluorescence signals of FAM-labeled peptide nucleic acid (PNA) against miR-193a quenched by GO nanosheets (FAM-PNA193a-GO) were recovered in undifferentiated recipient cells differentiated to the neuronal lineage by exosome-mediated neurogenesis 3 days after co-culture with differentiated donor cells. We propose that molecular beacon imaging using PNA-GO complex can be used to visualize individual cellular expression of mature microRNAs revealing their precise spatial localization and temporal sequences by the intercellular exosome delivery of messages to undergo processes such as cell-non-autonomous neurogenesis.

cell biology↗

bioRxiv2018

Lrfn2-mutant mice display suppressed synaptic plasticity and inhibitory synapse development and abnormal social communication and startle response

SALM1, also known as LRFN2, is a PSD-95-interacting synaptic adhesion molecule implicated in the regulation of NMDA receptor (NMDAR) clustering largely based on in vitro data, although its in vivo functions remain unclear. Here, we found that mice lacking SALM1/LRFN2 (Lrfn2-/- mice) show a normal density of excitatory synapses but altered excitatory synaptic function, including enhanced NMDAR-dependent synaptic transmission but suppressed NMDAR-dependent synaptic plasticity in the hippocampal CA1 region. Unexpectedly, SALM1 expression is detected in both glutamatergic and GABAergic neurons, and Lrfn2-/- CA1 pyramidal neurons show decreases in the density of inhibitory synapses and frequency of spontaneous inhibitory synaptic transmission. Behaviorally, ultrasonic vocalization was suppressed in Lrfn2-/- pups separated from their mothers, and acoustic startle was enhanced, but locomotion, anxiety-like behavior, social interaction, repetitive behaviors, and learning and memory were largely normal in adult Lrfn2-/- mice. These results suggest that SALM1/LRFN2 regulates excitatory synapse function, inhibitory synapse development, and social communication and startle behaviors in mice.\n\nSignificance StatementSynaptic adhesion molecules regulate synapse development and function, which govern neural circuit and brain functions. The SALM/LRFN family of synaptic adhesion proteins consists of five known members whose in vivo functions are largely unknown. Here we characterized mice lacking SALM1/LRFN2 (SALM1 knockout) known to associate with NMDA receptors and found that these mice showed altered NMDA receptor-dependent synaptic transmission and plasticity, as expected, but unexpectedly also exhibited suppressed inhibitory synapse development and synaptic transmission. Behaviorally, SALM1 knockout pups showed suppressed ultrasonic vocalization upon separation from their mothers, and SALM1 knockout adults showed enhanced responses to loud acoustic stimuli. These results suggest that SALM1/LRFN2 regulates excitatory synapse function, inhibitory synapse development, social communication, and acoustic startle behavior.

neuroscience↗

bioRxiv2018

Audio-tactile and peripersonal space processing around the trunk in human parietal and temporal cortex: an intracranial EEG study

Interactions with the environment happen by the medium of the body within ones peripersonal space (PPS) - the space surrounding the body. Studies in monkey and humans have highlighted a multisensory distributed cortical network representing the PPS. However, electrophysiological evidence for a multisensory encoding of PPS in humans is lacking. Here, we recorded for the first time intracranial electroencephalography (iEEG) in humans while administering tactile stimulation (T) on the trunk, approaching auditory stimuli (A), and the combination of the two (AT). To map PPS, in AT trials, tactile stimulation was delivered when the sound was far, at an intermediate location, or close to the body. We first identified electrodes showing AT multisensory integration (i.e., AT vs. A+T): 19% of the recording electrodes. Among those electrodes, we identified those showing a PPS effect (30% of the AT electrodes), i.e., a modulation of the evoked response to AT stimulation as a function of the distance between the sound and body. For most sites, AT multisensory integration and PPS effects had similar spatiotemporal characteristics, with an early response (~50ms) in the insular cortex, and later responses (~200ms) in pre- and post-central gyri. Superior temporal cortex showed a different response pattern with AT multisensory integration at ~100ms without PPS effect. These results, representing the first iEEG delineation of PPS processing in humans, show that PPS processing happens at neural sites where also multisensory integration occurs and at similar time periods, suggesting that PPS representation (around the trunk) is based on a spatial modulation of multisensory integration.

neuroscience↗

bioRxiv2017

Potent and Selective Antitumor Activity of a T-Cell Engaging Bispecific Antibody Targeting a Membrane-Proximal Epitope of ROR1

T-cell engaging bispecific antibodies present a promising strategy for cancer immunotherapy and numerous bispecific formats have been developed for retargeting cytolytic T cells toward tumor cells. To explore the therapeutic utility of T-cell engaging bispecific antibodies targeting the receptor tyrosine kinase ROR1, which is expressed by tumor cells of various hematologic and solid malignancies, we used a bispecific ROR1 x CD3 scFv-Fc format based on a heterodimeric and aglycosylated Fc domain designed for extended circulatory half-life and diminished systemic T-cell activation. A diverse panel of ROR1-targeting scFv derived from immune and naive rabbit antibody repertoires was compared in this bispecific format for target-dependent T-cell recruitment and activation. A ROR1-targeting scFv with a membrane-proximal epitope, R11, revealed potent and selective antitumor activity in vitro and in vivo and emerged as a prime candidate for further preclinical and clinical studies. To elucidate the precise location and engagement of this membrane-proximal epitope, which is conserved between human and mouse ROR1, the three-dimensional structure of scFv R11 in complex with the kringle domain of ROR1 was determined by X-ray crystallography at 1.6-[A] resolution.

immunology↗

bioRxiv2017

Entrained audiovisual speech integration implemented by two independent computational mechanisms: Redundancy in left posterior superior temporal gyrus and Synergy in left motor cortex

Information integration is fundamental to many aspects of human behavior, and yet its neural mechanism remains to be understood. For example, during face-to-face communication we know that the brain integrates the auditory and visual inputs but we do not yet understand where and how such integration mechanisms support speech comprehension. Here we show that two independent mechanisms forge audiovisual representations for speech comprehension in different brain regions. With a novel information theoretic measure, we found that theta (3-7 Hz) oscillations in the posterior superior temporal gyrus/sulcus (pSTG/S) code speech information that is common (i.e. redundant) to the auditory and visual inputs whereas the same oscillations in left motor and inferior temporal cortex code synergistic information between the same inputs. Importantly, redundant coding in the left pSTG/S and synergistic coding in the left motor cortex predict behavior - i.e. speech comprehension performance. Our findings therefore demonstrate that processes classically described as integration effectively reflect independent mechanisms that occur in different brain regions to support audiovisual speech comprehension.

neuroscience↗

bioRxiv2017

A Dynamic Bayesian Observer Model Reveals Origins of Bias in Visual Path Integration

Path integration is a navigation strategy by which animals track their position by integrating their self-motion velocity over time. To identify the computational origins of bias in visual path integration, we asked human subjects to navigate in a virtual environment using optic flow, and found that they generally travelled beyond the goal location. Such a behaviour could stem from leaky integration of unbiased self-motion velocity estimates, or from a prior expectation favouring slower speeds that causes underestimation of velocity. We tested both alternatives using a probabilistic framework that maximizes expected reward, and found that subjects biases were better explained by a slow-speed prior than imperfect integration. When subjects integrate paths over long periods, this framework intriguingly predicts a distance-dependent bias reversal due to build-up of uncertainty, which we also confirmed experimentally. These results suggest that visual path integration performance is limited largely by biases in processing optic flow rather than by suboptimal signal integration.

neuroscience↗

bioRxiv2017

The Rosetta all-atom energy function for macromolecular modeling and design

Over the past decade, the Rosetta biomolecular modeling suite has informed diverse biological questions and engineering challenges ranging from interpretation of low-resolution structural data to design of nanomaterials, protein therapeutics, and vaccines. Central to Rosettas success is the energy function: amodel parameterized from small molecule and X-ray crystal structure data used to approximate the energy associated with each biomolecule conformation. This paper describes the mathematical models and physical concepts that underlie the latest Rosetta energy function, beta_nov15. Applying these concepts,we explain how to use Rosetta energies to identify and analyze the features of biomolecular models.Finally, we discuss the latest advances in the energy function that extend capabilities from soluble proteins to also include membrane proteins, peptides containing non-canonical amino acids, carbohydrates, nucleic acids, and other macromolecules.

biophysics↗

bioRxiv2016

Generating in vivo somatic mouse mosaics with locus-specific, stably-integrated transgenic elements

Viral vectors and electroporation (EP)-mediated gene transfers are efficient means of inducing somatic mosaicism in mice, but they lack the exquisite control over transgene copy number, gene zygosity, and genomic-locus specificity that genetically engineered mouse models (GEMMs) provide. Here, we develop and demonstrate a simple and generalizable in vivo method, mosaic analysis by dual recombinase-mediated cassette exchange (MADR). MADR allows for stable labeling of mutant cells express transgenic elements from a precisely-defined chromosomal locus. To test our method, we generated reporter-labeled lineages from stem and progenitor cells in a well-defined Rosa26mTmG mouse. We demonstrate the power and versatility of MADR by creating novel glioma models with mixed, reporter-defined zygosity or with \"personalized\" driver mutations from pediatric glioma--each manipulation altering the profile of resulting tumors. Thus, MADR provides a high-throughput genetic platform for the dissection of development and disease, and this rapid method can be applied to the thousands of existing gene-trap mice.

neuroscience↗

bioRxiv2016

Melittin-induced alterations in morphology and deformability of human red blood cells using quantitative phase imaging techniques

Here, the actions of melittin, the active molecule of apitoxin or bee venom, were investigated on human red blood cells (RBCs) using quantitative phase imaging techniques. High-resolution realtime 3-D refractive index (RI) measurements and dynamic 2-D phase images of individual melittin-bound RBCs enabled in-depth examination of melittin-induced biophysical alterations of the cells. From the measurements, morphological, biochemical, and mechanical alterations of the RBCs were analyzed quantitatively. Furthermore, leakage of haemoglobin (Hb) inside the RBCs at high melittin concentration was also investigated.

biophysics↗

bioRxiv2016

Refractive index tomograms and dynamic membrane fluctuations of red blood cells from patients with diabetes mellitus

In this paper we present the optical characterisations of diabetic red blood cells (RBCs) in a non-invasive manner employing three-dimensional (3-D) quantitative phase imaging. By measuring 3-D refractive index tomograms and 2-D time-series phase images, the morphological (volume, surface area and sphericity), biochemical (haemoglobin concentration and content) and mechanical (membrane fluctuation) parameters were quantitatively retrieved at the individual cell level. With simultaneous measurements of individual cell properties, systematic correlative analyses on retrieved RBC parameters were also performed. Our measurements show that diabetic patients had RBCs of reduced cell sphericity and elevated intracellular haemoglobin concentration and content compared to healthy (non-diabetic) subjects. Furthermore, membrane deformability of diabetic RBCs is significantly lower than that of healthy, non-diabetic RBCs. Interestingly, non-diabetic RBCs exhibit strong correlations between the elevated glycated haemoglobin in RBC cytoplasm and decreased cell deformability, whereas diabetic RBCs do not show correlations. Our observations strongly support the idea that slow and irreversible glycation of haemoglobin and membrane proteins of RBCs by hyperglycaemia significantly compromises RBC deformability in diabetic patients.

biophysics↗