Biology subjects

Ran, Y.

Publications and source records attributed to Ran, Y..

27 records · Page 2Linked to original sources

bioRxiv2022

Spike desensitisation as a mechanism for high-contrast selectivity in retinal ganglion cells

In the vertebrate retina, several dozens of parallel channels relay information about the visual world to the brain. These channels are represented by the different types of retinal ganglion cells (RGCs), whose responses are rendered selective for distinct sets of visual features by various mechanisms. These mechanisms can be roughly grouped into synaptic interactions and cell-intrinsic mechanisms, with the latter including dendritic morphology as well as ion channel complement and distribution. Here, we investigate how strongly ion channel complement can shape RGC output by comparing two mouse RGC types, the well-described ON alpha cell and a little-studied ON cell that is EGFP-labelled in the Igfbp5 mouse line and displays an unusual selectivity for high-contrast stimuli. Using patch-clamp recordings and computational modelling we show that in ON Igfbp5 cells - but not in the ON alpha cells - a higher activation threshold and a pronounced slow inactivation of the voltage-gated Na+ channels are responsible for the distinct contrast tuning and transient responses of ON Igfbp5 RGCs, respectively. This study provides an example for the powerful role that the last stage of retinal processing can play in shaping RGC responses. SIGNIFICANCE STATEMENTHere, we investigated, how voltage-gated sodium channels contribute to shaping the light responses of mouse retinal ganglion cells. Using single-cell electrophysiology and computational modelling, we studied a ganglion cell type that displays highly transient responses and an unusual selectivity for visual high-contrast stimuli. We found that the cells characteristic responses were largely determined by intrinsic mechanisms, notably, a high activation threshold and a pronounced slow inactivation of its voltage-gated sodium channels. Therefore, our study demonstrates how sodium channels at the last stage of retinal signal processing can contribute to shape retinal output to higher visual areas the brain; it also adds a rare example for how channel complement can be directly linked to feature selectivity.

neuroscience↗

bioRxiv2021

CFIm25 regulates human stem cell function independently of its role in mRNA alternative polyadenylation

It has recently been shown that CFIm25, a canonical mRNA 3 processing factor, could play a variety of physiological roles through its molecular function in the regulation of mRNA alternative polyadenylation (APA). Here, we used CRISPR/Cas9-mediated gene editing approach in human embryonic stem cells (hESCs) for CFIm25, and obtained three gene knockdown/mutant cell lines. CFIm25 gene editing resulted in higher proliferation rate and impaired differentiation potential for hESCs, with these effects likely to be directly regulated by the target genes, including the pluripotency factor rex1. Mechanistically, we unexpected found that perturbation in CFIm25 gene expression did not significantly affect cellular mRNA 3 processing efficiency and APA profile. Rather, we provided evidences that CFIm25 may impact RNA polymerase II (RNAPII) occupancy at the body of transcribed genes, and promote the expression level of a group of transcripts associated with cellular proliferation and/or differentiation. Further study indicated that CFIm25 association with LEO1, an RNAPII associated factor, might contribute to the effect. Taken together, these results reveal novel mechanisms underlying CFIm25s modulation in determination of cell fate, and provide evidence that the process of mammalian gene transcription may be regulated by an mRNA 3 processing factor.

molecular biology↗

bioRxiv2021

Center-surround interactions underlie bipolar cell motion sensing in the mouse retina

Motion is a critical aspect of vision. We studied the representation of motion in mouse retinal bipolar cells and found, surprisingly, that some bipolar cells possess motion-sensing capabilities that rely on their center-surround receptive fields. Using a glutamate sensor, we directly observed motion-sensitive bipolar cell synaptic output, which was strongest for local motion and dependent on the motions origin. We characterized bipolar cell receptive fields and found that there are motion and non-motion sensitive bipolar cell types, the majority being motion sensitive. Next, we used these bipolar cell receptive fields along with connectomics to design biophysical models of downstream cells. The models and experiments demonstrated that bipolar cells pass motion-sensitive excitation to starburst amacrine cells through direction-specific signals mediated by bipolar cells center-surround receptive field structure. As bipolar cells provide excitation to most amacrine and ganglion cells, their motion sensitivity may contribute to motion processing throughout the visual system.

neuroscience↗

bioRxiv2021

Estimating smooth and sparse neural receptive fields with a flexible spline basis

Spatio-temporal receptive field (STRF) models are frequently used to approximate the computation implemented by a sensory neuron. Typically, such STRFs are assumed to be smooth and sparse. Current state-of-the-art approaches for estimating STRFs based empirical Bayes estimation encode such prior knowledge into a prior covariance matrix, whose hyperparameters are learned from the data, and thus provide STRF estimates with the desired properties even with little or noisy data. However, empirical Bayes methods are often not computationally efficient in high-dimensional settings, as encountered in sensory neuroscience. Here we pursued an alternative approach and encode prior knowledge for estimation of STRFs by choosing a set of basis function with the desired properties: a natural cubic spline basis. Our method is computationally efficient, and can be easily applied to Linear-Gaussian and Linear-Nonlinear-Poisson models as well as more complicated Linear-Nonlinear-Linear-Nonlinear cascade model or spike-triggered clustering methods. We compared the performance of spline-based methods to no-spline ones on simulated and experimental data, showing that spline-based methods consistently outperformed the no-spline versions. We provide a Python toolbox for all suggested methods (https://github.com/berenslab/RFEst/).

neuroscience↗

bioRxiv2020

Rhamnolipid production from waste cooking oil using newly isolated halotolerant Pseudomonas aeruginosa M4

This study isolated a novel halotolerant Pseudomonas aeruginosa M4, that was able to degrade oil and produce rhamnolipids. Various carbon sources, nitrogen sources, inoculum ratio, pH, and temperature were tested to optimize the oil degradation conditions. The highest oil degradation rate of 85.20 % and lipase activity of 23.86 U/mL were obtained under the optimal conditions (5% inoculum at 35 {degrees}C and pH 8). The components of degradation products at different times were analyzed to explore the mechanism of oil degradation by GC-MS. Short chain fatty acid of acetic and n-butyric acids were the primary degradation intermediates. P. aeruginosa M4 had good salt tolerance up to 70 g/L. The maximum rhamnolipid concentration of 1119.87 mg/L was produced when P. aeruginosa M4 used waste cooking oil as the sole carbon source. Rhamnose precursors were synthesized from glycerol, a hydrolysis product of waste cooking oil. R-3-hydroxyalkanoate precursors were synthesized de novo using acetyl-CoA produced from {beta}-oxidation of fatty acids. The findings show that P. aeruginosa M4 is a valuable biosurfactant producer in the treatment of waste cooking oil. Key PointsP. aeruginosa isolation, oil degradation mechanism, rhamnolipid production from WCO

microbiology↗

bioRxiv2019

A new long-acting GLP-1 derivative 6- KTP ameliorates body weight and lipid metabolism in DIO mice

As a global epidemic, obesity has become the biggest challenge facing global and public health. Glucagon-like peptide-1(GLP-1) has been able to inhibit appetite, slow gastric emptying and reduce body weight. We designed a novel long-acting GLP-1 derivative 6-KTP based on wild-type GLP-1 and performed its pharmacodynamics study on obesity in DIO mice. DIO mice were treated once daily with subcutaneous injections of 6-KTP (1.8 mg/kg body weight), Liraglutide (0.4 mg/kg body weight) or vehicle (phosphate buffered saline (PBS), pH 7.4) for 12 weeks. The results show that 6-KTP decreased food intake, induced anorexia and weight loss, and improved blood lipid and lipid metabolism in DIO mice.

physiology↗

bioRxiv2019

Type-specific dendritic integration in mouse retinal ganglion cells

Neural computation relies on the integration of synaptic inputs across a neurons dendritic arbour. However, the fundamental rules that govern dendritic integration are far from understood. In particular, it is still unclear how cell type-specific differences in dendritic integration arise from general features of neural morphology and membrane properties. Here, retinal ganglion cells (RGCs), which relay the visual systems first computations to the brain, represent an exquisite model. They are functionally and morphologically diverse yet defined, and they allow studying dendritic integration in a functionally relevant context. Here, we show how four morphologically distinct types of mouse RGC with shared excitatory synaptic input (transient Off alpha, transient Off mini, sustained Off, and F-miniOff) exhibit distinct dendritic integration rules. Using two-photon imaging of dendritic calcium signals and biophysical modelling, we demonstrate that these RGC types strongly differ in their spatio-temporal dendritic integration: In transient Off alpha cells, dendritic receptive fields displayed little spatial overlap, indicative of a dendritic arbour that is partitioned in largely isolated regions. In contrast, dendritic receptive fields in the other three RGCs overlapped greatly and were offset to the soma, suggesting strong synchronization of dendritic signals likely due to backpropagation of somatic signals. Also temporal correlation of dendritic signals varied extensively among these types, with transient Off mini cells displaying the highest correlation across their dendritic arbour. Modelling suggests that morphology alone cannot explain these differences in dendritic integration, but instead specific combinations of dendritic morphology and ion channel densities are required. Together, our results reveal how neurons exhibit distinct dendritic integration profiles tuned towards their type-specific computations in their circuits, with the interplay between morphology and ion channel complement as a key contributor.

neuroscience↗

bioRxiv2019

Neural circuits in the mouse retina support color vision in the upper visual field

Color vision is essential to the survival of most animals. Its neural basis lies in the retina, where chromatic signals from different photoreceptor types sensitive to distinct wavelengths are locally compared by neural circuits. Mice, like most mammals, are generally dichromatic and have two cone photoreceptor types. However, in the ventral retina most cones display the same spectral preference, impairing spectral comparisons necessary for color vision. This conflicts with behavioral evidence showing that mice can discriminate colors only in the corresponding upper visual field. Here, we systematically investigated the neural circuits underlying mouse color vision across three processing stages of the retina by recording the output of cones, bipolar and ganglion cells using two-photon imaging. Surprisingly, we found that across all retinal layers most color-opponent cells were located in the ventral retina. This started at the level of the cone output, where color-opponency was mediated by horizontal cells and likely involving rod photoreceptors. Next, bipolar cells relayed the chromatic information to ganglion cells in the inner retina, where type-specific, non-linear center-surround interactions resulted in specific color-opponent output channels to the brain. This suggests that neural circuits in the mouse retina are specifically tuned to extract color information from the upper visual field, aiding robust detection of aerial predators and ensuring the animals survival.

neuroscience↗

bioRxiv2018

High affinity interactions and signal transduction between Aβ oligomers and TREM2

Rare coding variant in the Triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimers disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD associated TREM2 variants to various forms of A{beta} and APOE in multiple assays. TREM2 interacts directly with various forms of A{beta}, with highest affinity interactions observed between TREM2 and soluble A{beta}42 oligomers. We confirm the previous interaction between APOE3 and APOE4 and TREM2. High affinity binding of TREM2 to A{beta} oligomers is characterized by very slow dissociation. Pre-incubation with A{beta} is shown to block the interaction of APOE. In cellular assays, AD-associated variants of TREM2 reduced the amount of A{beta}42 internalized, and in NFAT assay the R47H variant decreased NFAT signaling activity in response to A{beta}42. These studies demonstrate i) a high affinity interaction between TREM2 and A{beta} oligomers that can block interaction with another ligand and ii) that AD-associated TREM2 variants bind A{beta} with equivalent affinity but show loss of function in terms of signaling and A{beta} internalization.

cell biology↗