Biology subjects

Jang, J.

Publications and source records attributed to Jang, J..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Unveiling the enigma of Brain-resident immune cells

The immune system has been extensively studied in traditional immune hubs like the spleen and lymph nodes. However, recent advances in immunology highlight unique immune cell characteristics across anatomical compartments. In this study, we challenged conventional thinking by uncovering distinct immune cell populations within the brain parenchyma, separate from those in the blood, meninges, and choroid plexus, with unique transcriptional profiles. Brain-resident immune cells are not derived from maternal immune cells, and age-related changes, with an increase in CD8+ T cells in aged mice, are noted. Alzheimers disease (AD) alters microglias interaction with brain-resident immune cells, emphasizing immune-brain dynamics. Furthermore, we reveal dynamic immune cell interactions and essential cytokine roles in brain homeostasis, with stable cytokine expression but emerging signaling pathways in AD. In summary, this study advances our understanding of brain-resident immune cells in both normal and pathological conditions.

immunology↗

bioRxiv2023

Reproducing Left Ventricular Twist by Mimicking Myocardial Fiber Orientation Using 3D Bioprinting-assisted Tissue Assembly

BackgroundLeft ventricular twist, an opposite rotation of the apex and base, is caused by myocardial fiber orientation, a unique structural feature of the myocardium, and contributes to the effective ejection fraction of the native heart. Reproducing this structural-functional relationship in an in vitro heart model remains challenging due to the lack of synchrony between layers when mimicking the fiber orientations of each layer. MethodsWe employed a hierarchical approach for creating multilayered and multiaxial fibers in a chamber-like structure, as follows: 3D bioprinting-assisted tissue assembly, fabrication of uniaxially aligned engineered heart tissue as a building block, and assembly of them to create a myocardial fiber orientation in a chamber-like structure. ResultThe EHT module confirmed uniaxial alignment and cardiac functions such as contractility and electrophysiological properties. By fabricating the assembly platform by 3D bioprinting, it is possible to guide building blocks in various directions as intended, confirming the versatility of this method. The assembly platform allows structural and functional synchrony of assembled tissues while controlling and maintaining predefined cellular alignment. Furthermore, various shapes and sizes of EHT modules and assembly platform were fabricated for mimicking myocardial fiber orientation in a chamber-like structure. The resulting structure exhibited three layers and three orientations representing myocardial fiber orientation. Moreover, the left ventricular twist was confirmed by measuring basal and apical rotations. ConclusionsRecapitulation of the microscale structure of the left ventricle enabled the identification of information not discernible from the existing macroscale structure. This understanding of the structure-function relationship of the heart can provide insights into the mechanisms underlying cardiac structure, function, and related diseases. Furthermore, the versatility of the 3D bioprinting-assisted tissue assembly allows for the creation of organs and tissue collections with complex structural and functional features by fabricating and assembling modules that meet the specific requirements of target tissues and organs.

bioengineering↗

bioRxiv2023

Whole Transcriptome and Functional Analyses Identify Novel Genes Involved in Meiosis and Fertility in Drosophila melanogaster

Reproductive success requires the development of viable oocytes and the accurate segregation of chromosomes during meiosis. Failure to segregate chromosomes properly can lead to infertility, miscarriages, or developmental disorders. A variety of factors contribute to accurate chromosome segregation and oocyte development, such as spindle assembly and sister chromatid cohesion. However, many proteins required for meiosis remain unknown. In this study, we aimed to identify and characterize novel meiotic and fertility genes using the genome of Drosophila melanogaster. To accomplish this goal, genes upregulated within meiotically active tissues were identified. About 200 genes with no known function were silenced using RNA interference (RNAi), and the effects on meiosis and fertility were assessed. We identified 65 genes that when silenced caused infertility and/or high levels of chromosomal nondisjunction. The vast majority of these genes have human and mouse homologs that are also poorly studied. Through this screening process, we identified novel genes that are crucial for meiosis and oocyte development but have not been extensively studied in human or model organisms. Understanding the function of these genes will be an important step towards the understanding of their biological significance during reproduction. Author SummaryIn this study, we aimed to identify and characterize novel meiotic and fertility genes within the genome of Drosophila melanogaster. We identified 65 genes that when silenced caused infertility and/or high levels of chromosomal nondisjunction. The vast majority of these genes have human and mouse homologs that are also poorly studied. Through this screening process, we identified novel genes that are crucial for meiosis and oocyte development, making them strong candidates for future studies to characterize their functions.

genetics↗

bioRxiv2023

Endocardial HDAC3 is required for myocardial trabeculation

Failure of proper ventricular trabeculation is often associated with congenital heart disease (CHD). Support from endocardial cells, including the secretion of extracellular matrix (ECM) and growth factors is critical for trabeculation. However, it is poorly understood how the secretion of ECM and growth factors is initiated and regulated by endocardial cells. We found that genetic knockout (KO) of histone deacetylase 3 (Hdac3) in the endocardium in mice resulted in early embryo lethality and ventricular hypotrabeculation. Single cell RNA sequencing identified significant downregulation of ECM components in Hdac3 KO endocardial cells. Secretome from cultured Hdac3 KO mouse cardiac endothelial cells lacked transforming growth factor {beta}3 (TGF{beta}3) and showed significantly reduced capacity in stimulating cultured cardiomyocyte proliferation, which was remarkably rescued by TGF{beta}3 supplementation. Mechanistically, we identified that HDAC3 induced Tgf{beta}3 expression through repressing microRNA (miR)-129-5p. Our findings provide novel insights into the pathogenesis of CHD and conceptual strategies to promote myocardial regeneration.

developmental biology↗

bioRxiv2022

One-step pipetting of barcoded planar microparticles into compact monolayer assembling chip for efficient readout of multiplexed immunoassay

Barcoded planar microparticles have many qualities suitable for developing cost-efficient multiplexed immunoassays. But at the translational research level, there are a number of technical aspects yet remain to be addressed which includes robustness and efficiency of the assay readout process. Assay readout process involves automated barcode identification and signal intensity values from each planar microparticle. For this, each microparticle has to be correctly aligned for correct barcode readout while being, ideally, compactly assembled for maximum microparticle imaging efficiency. To simultaneously achieve such alignment and assembly of microparticles but in a straightforward manner, we designed a microfluidic microparticle assembling chip that only requires a single pipetting step. Our design utilizes capillary flow based guided particle assembly, which allows maximum microparticle-based immunoassay readout efficiency. With the aid of image processing algorithms, we obtained good multiplex immunoassay readout accuracy similar to conventional imaging platforms. Our approach is applicable to both soft elastomer materials (e.g. PDMS) and rigid materials (e.g. polystyrene), the latter of which is frequently used for injection molding based mass production. We anticipate our device could help developing facile and user-friendly platform technologies based on barcoded planar microparticles.

bioengineering↗

bioRxiv2021

Epicardial HDAC3 promotes myocardial growth through a novel microRNA pathway

RationalEstablishment of the myocardial wall requires proper growth cues from nonmyocardial tissues. During heart development, the epicardium and epicardium-derived cells (EPDCs) instruct myocardial growth by secreting essential factors including fibroblast growth factor 9 (FGF9) and insulin-like growth factor 2 (IGF2). However, it is poorly understood how the epicardial secreted factors are regulated, in particular by chromatin modifications for myocardial formation. ObjectiveTo understand whether and how histone deacetylase 3 (HDAC3) in the developing epicardium regulates myocardial growth. Methods and ResultsWe deleted Hdac3 in the developing murine epicardium and mutant hearts showed ventricular myocardial wall hypoplasia with reduction of EPDCs. The cultured embryonic cardiomyocytes with supernatants from Hdac3 knockout (KO) mouse epicardial cells (MECs) also showed decreased proliferation. Genome-wide transcriptomic analysis revealed that Fgf9 and Igf2 were significantly down-regulated in Hdac3 KO MECs. We further found that Fgf9 and Igf2 expression is dependent on HDAC3 deacetylase activity. The supplementation of FGF9 or IGF2 can rescue the myocardial proliferation defects treated by Hdac3 KO supernatant. Mechanistically, we identified that microRNA (miR)-322 and miR-503 were upregulated in Hdac3 KO MECs and Hdac3 epicardial KO hearts. Overexpression of miR-322 or miR-503 repressed FGF9 and IGF2 expression, while knockdown of miR-322 or miR-503 restored FGF9 and IGF2 expression in Hdac3 KO MECs. ConclusionsOur findings reveal a critical signaling pathway in which epicardial HDAC3 promotes compact myocardial growth by stimulating FGF9 and IGF2 through repressing miR-322/miR-503, providing novel insights in elucidating etiology of congenital heart defects, and conceptual strategies to promote myocardial regeneration.

developmental biology↗

bioRxiv2021

Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi

BackgroundKra monkeys (Macaca fascicularis), a natural host of Plasmodium knowlesi, control parasitaemia caused by this parasite species and escape death without treatment. Knowledge of the disease progression and resilience in kra monkeys will aid the effective use of this species to study mechanisms of resilience to malaria. This longitudinal study aimed to define clinical, physiological and pathological changes in kra monkeys infected with P. knowlesi, which could explain their resilient phenotype. MethodsKra monkeys (n = 15, male, young adults) were infected intravenously with cryopreserved P. knowlesi sporozoites and the resulting parasitaemias were monitored daily. Complete blood counts, reticulocyte counts, blood chemistry and physiological telemetry data (n = 7) were acquired as described prior to infection to establish baseline values and then daily after inoculation for up to 50 days. Bone marrow aspirates, plasma samples, and 22 tissue samples were collected at specific time points to evaluate longitudinal clinical, physiological and pathological effects of P. knowlesi infections. ResultsAs expected, the kra monkeys controlled parasitaemia and remained with low-level, persistent parasitaemias without antimalarial intervention. Unexpectedly, early in the infection, fevers developed, which ultimately returned to baseline, as well as mild to moderate thrombocytopaenia, and moderate to severe anaemia. Mathematical modeling and the reticulocyte production index indicated that the anaemia was largely due to the removal of uninfected erythrocytes and not impaired production of erythrocytes. Mild tissue damage was observed, and tissue parasite load was associated with tissue damage even though parasite accumulation in the tissues was generally low. ConclusionsKra monkeys experimentally infected with P. knowlesi sporozoites presented with multiple clinical signs of malaria that varied in severity among individuals. Overall, the animals shared common mechanisms of resilience characterized by controlling parasitaemia 3-5 days after patency, and controlling fever, coupled with physiological and bone marrow responses to compensate for anaemia. Together, these responses likely minimized tissue damage while supporting the establishment of chronic infections, which may be important for transmission in natural endemic settings. These results provide new foundational insights into malaria pathogenesis and resilience in kra monkeys, which may improve understanding of human infections.

pathology↗

bioRxiv2021

JAG1 intracellular domain acts as a transcriptional cofactor that forms an oncogenic transcriptional complex with DDX17/SMAD3/TGIF2

Jagged1 (JAG1) is a Notch ligand that contact-dependently activates Notch receptors and regulates cancer progression. The JAG1 intracellular domain (JICD1) is generated from JAG1, such as the formation of NOTCH1 intracellular domain (NICD1), however, the role of JICD1 in tumorigenicity has not been comprehensively elucidated. Herein, we revealed that JICD1 induced astrocytes to acquire several cancer stem cell properties, including tumor formation, invasiveness, stemness, and resistance to chemotherapy and radiotherapy. The transcriptome, ChIP-sequencing, and proteomic analyses revealed that JICD1 increased SOX2 expression by forming a transcriptional complex with DDX17, SMAD3, and TGIF2. Furthermore, JICD1-driven tumorigenicity was directly regulated by SOX2. Therefore, our results demonstrated that, like NICD1, JICD1 acts as a transcriptional cofactor in the formation of the DDX17/SMAD3/TGIF2 transcriptional complex, leading to oncogenic transformation.

molecular biology↗

bioRxiv2021

Invasive Earthworms Alter Forest Soil Microbiomes and Nitrogen Cycling

Northern hardwood forests in formerly glaciated areas had been free of earthworms until exotic European earthworms were introduced by human activities. The invasion of exotic earthworms is known to dramatically alter soil physical, geochemical, and biological properties, but its impacts on soil microbiomes are still unclear. Here we show that the invasive earthworms alter soil microbiomes and ecosystem functioning, especially for nitrogen cycling. We collected soil samples at different depths from three sites across an active earthworm invasion chronosequence in a hardwood forest in Minnesota, USA. We analyzed the structures and the functional potentials of the soil microbiomes by using amplicon sequencing, high-throughput nitrogen cycle gene quantification (NiCE chip), and shotgun metagenomics. Both the levels of earthworm invasion and soil depth influenced the microbiome structures. In the most recently and minimally invaded soils, Nitrososphaera and Nitrospira as well as the genes related to nitrification were more abundant than in the heavily invaded soils. By contrast, genes related to denitrification and nitrogen fixation were more abundant in the heavily invaded than the minimally invaded soils. Our results suggest that the N cycling in forest soils is mostly nitrification driven before earthworm invasion, whereas it becomes denitrification driven after earthworm invasion.

microbiology↗

bioRxiv2020

Competition between parallel sensorimotor learning systems

Sensorimotor adaptation benefits from learning in two parallel systems: one that has access to explicit knowledge, and another that relies on implicit, unconscious correction. However, it is unclear how these systems interact: does enhancing one systems contributions, for example through instruction, impair the other, or do they learn independently? Here we illustrate that certain contexts can lead to competition between implicit and explicit learning. In some cases, each system is responsive to a task-related visual error. This shared error appears to create competition between these systems, such that when the explicit system increases its response, errors are siphoned away from the implicit system, thus reducing its learning. This model suggests that explicit strategy can mask changes in implicit error sensitivity related to savings and interference. Other contexts suggest that the implicit system can respond to multiple error sources. When these error sources conflict, a second type of competition occurs. Thus, the data show that during sensorimotor adaptation, behavior is shaped by competition between parallel learning systems.

neuroscience↗

bioRxiv2020

In-vivo histology of iron and myelin in the brain using magnetic susceptibility source separation in MRI

Obtaining a histological fingerprint from the in-vivo brain has been a long-standing target of magnetic resonance imaging (MRI). In particular, non-invasive imaging of iron and myelin, which are involved in normal brain functions and are histopathological hallmarks in neurodegenerative diseases, has practical utilities in neuroscience and medicine. Here, we propose a biophysical model that describes the individual contribution of paramagnetic (e.g., iron) and diamagnetic (e.g., myelin) susceptibility sources to the frequency shift and transverse relaxation of MRI signals. Using this model, we develop a method,{chi} -separation, that generates the voxel-wise distributions of the two sources. The method is validated using computer simulation and phantom experiments, and applied to ex-vivo and in-vivo brains. The results delineate the well-known histological features of iron and myelin in the specimen, healthy volunteers, and multiple sclerosis patients. This new technology may serve as a practical tool for exploring the microstructural information of the brain.

neuroscience↗

bioRxiv2020

Successful Correction of ALD Patient-derived iPSCs Using CRISPR/Cas9

X-linked adrenoleukodystrophy (ALD) caused by the ABCD1 mutation, is the most common inherited peroxisomal disease. It is characterized by three phenotypes: inflammatory cerebral demyelination, progressive myelopathy, and adrenal insufficiency, but there is no genotype-phenotype correlation. Hematopoietic stem cell transplantation can only be used in a few patients in the early phase of cerebral inflammation; therefore, most affected patients have no curative option. Previously, we reported the generation of an ALD patient-derived iPSC model and its differentiation to oligodendrocytes. In this study, we have performed the first genome editing of ALD patient-derived iPSCs using homology-directed repair (HDR). The mutation site, c.1534G>A [GenBank: NM_000033.4], was corrected by introducing ssODN and the CRISPR/Cas9 system. The cell line exhibited normal ALD protein expression following genome editing. We differentiated the intermediate oligodendrocytes from mutation-corrected iPSCs and the metabolic derangement of ALD tended to correct but was not statistically significant. Mutation-corrected iPSCs from ALD patient can be used in research into the pathophysiology of and therapeutics for ALD.

neuroscience↗

bioRxiv2020

Projection of orthogonal tiling from the retina to the visual cortex

In higher mammals, the primary visual cortex (V1) is organized into diverse tuning maps of visual features such as orientation, spatial frequency and ocular dominance. The topography of these maps is observed to intersect orthogonally, implying that a developmental principle for efficient tiling of sensory modules may exist. However, it remains unclear how such a systematic relationship among cortical tuning maps could develop. Here, we show that the orthogonal organization of tuning modules already exist in retinal ganglion cell (RGC) mosaics, and that this provides a blueprint of the orthogonal organization in V1. Firstly, from the analysis of multi-electrode recording data in V1, we found that the ON-OFF subregion distance of receptive fields varies periodically across the cortical surface, strongly correlated to ocular dominance and spatial frequency in the area. Further, the ON-OFF alignment angle, that is orthogonal to the ON-OFF distance, appears to correlate with orientation tuning. These suggest that the orthogonal organization in V1 may originate from the spatial organization of the ON-OFF receptive fields in the bottom-up projections, and this scenario was tested from analysis of the RGC mosaics data in monkeys and cats. We found that the ON-OFF RGC distance and ON-OFF angle of neighbouring RGCs are organized into a topographic tiling across mosaics, analogous to the orthogonal intersection of cortical tuning maps. These findings suggest that the regularly structured ON-OFF patterns mirrored from a retina may initiate efficient tiling of functional domains in V1. HighlightsO_LIOrthogonal organization of visual tuning maps are observed in both V1 and the retina C_LIO_LICortical tuning maps are correlated with the profile of ON-OFF feedforward projections C_LIO_LIThe profile of ON-OFF receptive fields varies periodically across the V1 surface C_LIO_LIRegularly structured RGC patterns initiate the orthogonal tiling of sensory modules in V1 C_LI

neuroscience↗

bioRxiv2020

Ubiquitin ligase component LRS1 and transcription factor CrHy5 act as a light switch for photoprotection in Chlamydomonas

Survival under excess light conditions requires the light-induced accumulation of protein LHCSR3 and other photoprotection factors, to enable efficient energy-dependent quenching in the green microalga Chlamydomonas reinhardtii. Here, we demonstrate that the high light-tolerant phenotype of mutant hit1 is caused by a de-repression of promoters belonging to photoprotection genes, which in turn results from an inactivation of the E3 ubiquitin ligase substrate adaptor LRS1. Transcriptome analyses of hit1 revealed massive alterations of gene expression modulation as a consequence of perturbed LRS1 function, indicating its role as a crown regulator. In conjunction with random forest-based network modeling, these transcriptome analyses predicted that LRS1 controls photoprotection gene expression via an algal HY5 homolog as its prime transcription factor target. CrHY5 binds to T-box elements present in the promoters of these genes and its inactivation in the hit1 mutant via CRISPR-Cas9 genome editing, confirmed the regulatory connection between LRS1 and CrHY5, predicted by the network analysis.

plant biology↗

bioRxiv2019

Asymptotic limits of sensorimotor adaptation

After extended practice, motor adaptation reaches a limit in which learning appears to stop, despite the fact that residual errors persist. What prevents the brain from eliminating the residual errors? Here we found that the adaptation limit was causally dependent on the second order statistics of the perturbation; when variance was high, learning was impaired and large residual errors persisted. However, when learning relied solely on explicit strategy, both the adaptation limit and its dependence on perturbation variability disappeared. In contrast, when learning depended entirely, or in part on implicit learning, residual errors developed. Residual errors in implicit performance were caused by variance-dependent modifications to error sensitivity, not forgetting. These observations are consisted with a model of learning in which the implicit system becomes more sensitive to error when errors are consistent, but forgets this memory of errors over time. Thus, residual errors in motor adaptation are a signature of the implicit learning system, caused by an error sensitivity that depends on the history of past errors.

neuroscience↗

bioRxiv2019

Spontaneous generation of face recognition in untrained deep neural networks

Face-selective neurons are observed in the primate visual pathway and are considered the basis of facial recognition in the brain. However, it is debated whether this neuronal selectivity can arise spontaneously, or requires training from visual experience. Here, we show that face-selective neurons arise spontaneously in random feedforward networks in the absence of learning. Using biologically inspired deep neural networks, we found that face-selective neurons arise under three different network conditions: one trained using non-face natural images, one randomized after being trained, and one never trained. We confirmed that spontaneously emerged face-selective neurons show the biological view-point-invariant characteristics observed in monkeys. Such neurons suddenly vanished when feedforward weight variation declined to a certain level. Our results suggest that innate face-selectivity originates from statistical variation of the feedforward projections in hierarchical neural networks.

neuroscience↗

bioRxiv2019

Spontaneous generation of innate number sense in untrained deep neural networks

Number-selective neurons are observed in numerically naive animals, but it was not understood how this innate function emerges in the brain. Here, we show that neurons tuned to numbers can arise in random feedforward networks, even in the complete absence of learning. Using a biologically inspired deep neural network, we found that number tuning arises in three cases of networks: one trained to non-numerical natural images, one randomized after trained, and one never trained. Number-tuned neurons showed characteristics that were observed in the brain following the Weber-Fechner law. These neurons suddenly vanished when the feedforward weight variation decreased to a certain level. These results suggest that number tuning can develop from the statistical variation of bottom-up projections in the visual pathway, initializing innate number sense.

neuroscience↗

bioRxiv2019

Local Glutamate-Mediated Dendritic Plateau Potentials Change the State of the Cortical Pyramidal Neuron

Dendritic spikes in thin dendritic branches (basal and oblique dendrites) of pyramidal neurons are traditionally inferred from spikelets measured in the cell body. Here, we used laser-spot voltage-sensitive dye imaging in cortical pyramidal neurons (rat brain slices) to investigate the voltage waveforms of dendritic potentials occurring in response to spatially-restricted glutamatergic inputs. Local dendritic potentials lasted 200-500 ms and propagated to the cell body where they caused sustained 10-20 mV depolarizations. Plateau potentials propagating from dendrite to soma, and action potentials propagating from soma to dendrite, created complex voltage waveforms in the middle of the thin basal dendrite, comprised of local sodium spikelets, local plateau potentials, and back-propagating action potentials, superimposed on each other. Our model replicated these experimental observations and made predictions, which were tested in experiments. Dendritic plateau potentials occurring in basal and oblique branches put pyramidal neurons into an activated neuronal state ("prepared state"), characterized by depolarized membrane potential and faster membrane responses. The prepared state provides a time window of 200-500 ms during which cortical neurons are particularly excitable and capable of following afferent inputs. At the network level, this predicts that sets of cells with simultaneous plateaus would provide cellular substrate for the formation of functional neuronal ensembles. New & NoteworthyIn cortical pyramidal neurons, we recorded glutamate-mediated dendritic plateau potentials using voltage imaging, and created a computer model that recreated experimental measures from dendrite and cell body. Our model made new predictions, which were then tested in experiments. Plateau potentials profoundly change neuronal state -- a plateau potential triggered in one basal dendrite depolarizes the soma and shortens membrane time constant, making the cell more susceptible to firing triggered by other afferent inputs.

neuroscience↗