Biology subjects

Park, J. S.

Publications and source records attributed to Park, J. S..

36 records · Page 2Linked to original sources

bioRxiv2024

The N-degron pathway governs autophagy to promote thermotolerance in Arabidopsis

Autophagy is a vital process that enables plants to adapt to various environmental changes. During heat stress (HS), misfolded and denatured proteins accumulate in cells, necessitating autophagy for their removal. Here, we show that a core autophagy component ATG8a is targeted for degradation via the Arg/N-degron pathway. ATG8a is expressed as two alternatively spliced transcripts encoding ATG8a isoforms, namely ATG8a(S) and ATG8a(L), with distinct N-termini. While ATG8a(S) remains stable, ATG8a(L) is N-terminally processed to expose the Arg/N-degron, leading to its degradation. UBR7, identified as an N-recognin, is responsible for ubiquitination and proteasomal degradation of ATG8a(L). Notably, ATG8a(S) and ATG8a(L) show dynamic expression patterns, fluctuating ATG8a levels during the HS and recovery periods. Our findings highlight the crucial role of ATG8a turnover in conferring thermotolerance, which is governed by Arg/N-degron-mediated regulation. Understanding the molecular basis of ATG8a stability will provide valuable insights into plant resilience to HS under changing climatic conditions.

plant biology↗

bioRxiv2024

Impact of PI3K pathway alterations on response to immune checkpoint inhibitors in HPV-negative head and neck squamous cell carcinoma

Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway (PI3K pathway) is a major intracellular regulatory pathway commonly involved in cancer survival, proliferation, migration, and metabolism. Activating mutations and amplifications of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) are frequent genomic features of head and neck squamous cell carcinoma (HNSCC). A growing body of evidence suggests that dysregulation of the PI3K pathway suppresses the anti-tumor immune response, thereby enabling tumor immune evasion. We retrospectively analyzed clinicopathologic and genomic data of patients with recurrent or metastatic (R/M) HNSCC treated with immune checkpoint inhibitors (ICI). PI3K pathway alterations were found in 44% and were associated with poor clinical outcomes in the human papillomavirus-negative (HPV-ve) HNSCC patients. PIK3CA expression was found to be inversely correlated with immune gene expression, decreased T-cell infiltration, and reduced CD8 T-cell cytotoxic activity. The pharmacologic inhibition of the PI3K pathway induced an increase in key immune-responsive gene expression in PIK3CA-mutant HPV-ve HNSCC cells. These findings suggest that the PI3K pathway activation promotes immune suppressive phenotype, and playing a role in conferring resistance to immune checkpoint inhibitors in HPV-ve subset of HNSCC patients. HighlightsAlterations in PI3K pathway are associated with poor clinical outcomes in HPV-negative HNSCC patients treated with immune checkpoint therapy. PI3K pathway activation correlates to immune suppressive tumor microenvironment in HNSCC. Pharmacologic inhibition of PI3K induces the expression of interferon-gamma responsive and antigen presentation machinery genes in HNSCC.

cancer biology↗

bioRxiv2024

Continent-wide drivers of spatial synchrony in age structure across wild great tit populations

Spatio-temporal variation in age structure influences population dynamics, yet we have limited understanding of the spatial scale at which its fluctuations are synchronised between populations. Using 32 great tit populations, spanning 3200km and >130,000 birds across 67 years, we quantify spatial synchrony in breeding age structure and its drivers. We show that larger clutch sizes, colder winters and summers, and larger beech crops lead to younger populations. We report distant-dependent spatial synchrony of age structure, which is maintained at approximately 650km. Despite covariation with age structure, reproductive and environmental variables do not influence the scale of synchrony, except for a moderate effect of beech masting. We suggest that local ecological and density-dependent dynamics impact how environmental variation interacts with age structure, influencing estimates of the environments effect on spatial synchrony. Our analyses demonstrate the operation of synchrony in age structure over large scales, with implications for age-dependent demography in populations.

ecology↗

bioRxiv2023

Transepithelial Electrical Impedance Increase Following Porous Substrate Electroporation Enables Label-Free Delivery

Porous substrate electroporation (PSEP) is a promising new method for intracellular delivery, yet fundamentals of the PSEP delivery process are not well understood, partly because most PSEP studies rely solely on imaging for evaluating delivery. Although effective, imaging alone limits understanding of intermediate processes leading to delivery. PSEP is an electrical process, so electrical impedance measurements naturally complement imaging for PSEP characterization. In this study, we developed a device capable of measuring impedance and performing PSEP and we monitored changes in transepithelial electrical impedance (TEEI). Our measurements show TEEI increases following PSEP, unlike other electroporation methods. We then demonstrated how cell culture conditions and electrical waveforms influence this response. More importantly, we correlated TEEI response features with viability and delivery efficiency, allowing prediction of outcomes without fluorescent cargo, imaging, or image processing. This label-free delivery also allows improved temporal resolution of transient processes following PSEP, which we expect will aid PSEP optimization for new cell types and cargos. TEASERElectrical impedance measurements were used to understand delivery and cellular response after porous substrate electroporation.

bioengineering↗

bioRxiv2023

A Normative Framework Dissociates Need and Motivation in Hypothalamic Neurons

Physiological needs evoke motivational drives to produce natural behaviours for survival. However, the temporally intertwined dynamics of need and motivation have made it challenging to differentiate these two components in previous experimental paradigms. Based on classic homeostatic theories, we established a normative framework to derive computational models of neural activity and behaviours for need-encoding and motivation-encoding neurons during events that induce predicted gain or loss. We further developed simple and intuitive experimental paradigms that enabled us to distinguish the distinct roles of subpopulations of neurons in the hypothalamus. Our results show that AgRP neurons and LHLepR neurons are consistent with need and motivation, respectively. Our study provides a parsimonious understanding of how distinct hypothalamic neurons separately encode need and motivation to produce adaptive behaviours for maintaining homeostasis.

neuroscience↗

bioRxiv2023

Characterization of Pik1 function in fission yeast reveals its conserved role in lipid synthesis and not cytokinesis

Phosphatidylinositol (PI)-4-phosphate (PI4P) is a lipid found at the plasma membrane (PM) and Golgi in cells from yeast to humans. PI4P is generated from PI by PI4-kinases and can be converted to PI-4,5-bisphosphate [PI(4,5)P2]. Schizosaccharomyces pombe have 2 essential PI4-kinases: Stt4 and Pik1. Stt4 localizes to the PM and its loss from the PM results in a decrease of PM PI4P and PI(4,5)P2. As a result, cells divide non-medially due to disrupted cytokinetic ring-PM anchoring. However, the localization and function of S. pombe Pik1 has not been thoroughly examined. Here, we found that Pik1 localizes exclusively to the trans-Golgi and is required for Golgi PI4P production. We determined that Ncs1 regulates Pik1, but unlike in other organisms, it is not required for Pik1 Golgi localization. When Pik1 function was disrupted, PM PI4P but not PI(4,5)P2 levels were reduced, a major difference with Stt4. We conclude that Stt4 is the chief enzyme responsible for producing the PI4P that generates PI(4,5)P2. Also, that cells with disrupted Pik1 do not divide asymmetrically highlights the specific importance of PM PI(4,5)P2 for cytokinetic ring-PM anchoring. Summary statementFission yeast Pik1 localizes exclusively to the trans-Golgi independently of Ncs1, where it contributes to PI4P but not PI(4,5)P2 synthesis. Pik1 does not affect cytokinesis.

cell biology↗

bioRxiv2022

Why the architecture of environmental fluctuation matters for fitness

The physical environment provides the very stage upon which the eco-evolutionary play unfolds. How fluctuations in the environment affect demographic fitness is thus central to selection predictions, life history analyses, and viability of populations. Treatment of fluctuating environments typically leverages the mathematics of random variability. However, environmental fluctuations in nature are almost always combinations of random and non-random components. For example, some fluctuations contain feedbacks which generate autocorrelation (e.g. disturbances such as floods, fires, and hurricanes), while others are driven by geophysical forces that create fixed cyclicality (e.g. seasonal, tidal, and diel). Despite theoretical developments, the consideration of non-random characteristics of fluctuations is still rare in empirical work on natural populations, mostly due to convention and partially due to difficulties in measuring and analyzing timeseries of environmental fluctuations. We show why non-randomness matters for fitness. Using a simple demographic model, we systematically compare four major categories of fluctuating environments: stochastic, positively autoregressive, negatively autoregressive, and periodic with error ("Noisy Clock"). The architectures of fluctuations influence the fitness of structured populations even when the modelled environments only differ in the timing of fluctuations, and not in their overall frequency. Importantly, we highlight two quantitative mechanisms through which fitness depends on fluctuation architecture--the consecutiveness of deviations from the environmental mean, and Jensens Inequality acting on nonlinear biological parameters--both relevant features in virtually all populations inhabiting variable environments. Our goal is to argue that non-random structures of environmental variability should be more seriously considered in empirical work. Such an endeavor would tap into the rich diversity of variable environments in nature to expand our understanding of the commensurate diversity of population dynamics.

ecology↗

bioRxiv2021

PoSTcode: Probabilistic image-based spatial transcriptomics decoder

Realising the full potential of novel image-based spatial transcriptomic (IST) technologies requires robust and accurate algorithms for decoding the hundreds of thousand fluorescent signals each derived from single molecules of mRNA. In this paper, we introduce PoSTcode, a probabilistic method for transcript decoding from cyclic multi-channel images, whose effectiveness is demonstrated on multiple large-scale datasets generated using different versions of the in situ sequencing protocols. PoSTcode is based on a re-parametrised matrix-variate Gaussian mixture model designed to account for correlated noise across fluorescence channels and imaging cycles. PoSTcode is shown to recover up to 50% more confidently decoded molecules while simultaneously decreasing transcript mislabeling when compared to existing decoding techniques. In addition, we demonstrate its increased stability to various types of noise and tuning parameters, which makes this new approach reliable and easy to use in practice. Lastly, we show that PoSTcode produces fewer doublet signals compared to a pixel-based decoding algorithm.

bioinformatics↗

bioRxiv2021

N-myc Downstream Regulated Gene 1 (NDRG1) functions as a molecular switch for cellular adaptation to hypoxia

Lack of oxygen (hypoxia and anoxia) is detrimental to cell function and survival and underlies many disease conditions. Hence, metazoans have evolved mechanisms to adapt to low oxygen. One such mechanism, metabolic suppression, decreases the cellular demand for oxygen by downregulating ATP-demanding processes. However, the molecular mechanisms underlying this adaptation are poorly understood. Here, we report on the role of ndrg1a in hypoxia adaptation of the anoxia-tolerant zebrafish embryo. ndrg1a is expressed in the kidney and ionocytes, cell types that use large amounts of ATP to maintain ion homeostasis. ndrg1a mutants are viable and develop normally when raised under normal oxygen. However, their survival and kidney function is reduced relative to WT embryos following exposure to prolonged anoxia. We further demonstrate that Ndrg1a binds to the energy-demanding sodium-potassium ATPase (NKA) pump under anoxia and is required for its degradation, which may preserve ATP in the kidney and ionocytes and contribute to energy homeostasis. Lastly, we show that sodium azide treatment, which increased lactate levels, was sufficient to trigger NKA degradation in an Ndrg1a-dependent manner. These findings support a model whereby Ndrg1a is essential for hypoxia adaptation and functions downstream of lactate signaling to induce NKA degradation, a process known to conserve cellular energy.

developmental biology↗

bioRxiv2021

Robust de novo design of protein binding proteins from target structural information alone

The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains an outstanding challenge. We describe a general solution to this problem which starts with a broad exploration of the very large space of possible binding modes and interactions, and then intensifies the search in the most promising regions. We demonstrate its very broad applicability by de novo design of binding proteins to 12 diverse protein targets with very different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of four of the binder-target complexes, and all four are very close to the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvement of both. Our approach now enables targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications.

synthetic biology↗

bioRxiv2021

Regulation of positive and negative selection and TCR signaling during thymic T cell development by capicua

Central tolerance is achieved through positive and negative selection of thymocytes mediated by T cell receptor (TCR) signaling strength. Thus, the dysregulation of the thymic selection process often leads to autoimmunity. Here, we show that capicua (CIC), a transcriptional repressor that suppresses autoimmunity, controls the thymic selection process. Loss of CIC prior to T-cell lineage commitment impaired both positive and negative selection of thymocytes. CIC deficiency attenuated TCR signaling in CD4+CD8+ double-positive (DP) cells, as evidenced by a decrease in CD5 and phospho-ERK levels and calcium flux. We identified Spry4, Dusp4, Dusp6, and Spred1 as CIC target genes that could inhibit TCR signaling in DP cells. Furthermore, impaired positive selection and TCR signaling were partially rescued in Cic and Spry4 double mutant mice. Our findings indicate that CIC is a transcription factor required for thymic T cell development and suggest that CIC acts at multiple stages of T cell development and differentiation to prevent autoimmunity.

immunology↗

bioRxiv2021

Spatial genomics maps the structure, character and evolution of cancer clones

Subclonality is a universal feature of cancers yet how clones grow, are spatially organised, differ phenotypically or influence clinical outcome is unclear. To address this, we developed base specific in situ sequencing (BaSISS). In fixed tissues, transcripts harbouring clone-defining mutations are detected, converted into quantitative clone maps and characterised through multi-layered data integration. Applied to 8 samples from key stages of breast cancer progression BaSISS localised 1.42 million genotype informative transcripts across 4.9cm2 of tissue. Microscopic clonal topographies are shaped by resident tissue architectures. Distinct transcriptional, histological and immunological features distinguish coexistent genetic clones. Spatial lineage tracing temporally orders clone features associated with the emergence of aggressive clinical traits. These results highlight the pivotal role of spatial genomics in deciphering the mechanisms underlying cancer progression.

cancer biology↗

bioRxiv2020

Comprehensive mapping of tissue cell architecture via integrated single cell and spatial transcriptomics

The spatial organization of cell types in tissues fundamentally shapes cellular interactions and function, but the high-throughput spatial mapping of complex tissues remains a challenge. We present [c]ell2location, a principled and versatile Bayesian model that integrates single-cell and spatial transcriptomics to map cell types in situ in a comprehensive manner. We show that [c]ell2location outperforms existing tools in accuracy and comprehensiveness and we demonstrate its utility by mapping two complex tissues. In the mouse brain, we use a new paired single nucleus and spatial RNA-sequencing dataset to map dozens of cell types and identify tissue regions in an automated manner. We discover novel regional astrocyte subtypes including fine subpopulations in the thalamus and hypothalamus. In the human lymph node, we resolve spatially interlaced immune cell states and identify co-located groups of cells underlying tissue organisation. We spatially map a rare pre-germinal centre B-cell population and predict putative cellular interactions relevant to the interferon response. Collectively our results demonstrate how [c]ell2location can serve as a versatile first-line analysis tool to map tissue architectures in a high-throughput manner.

genomics↗

bioRxiv2019

A Single-Cell Atlas and Lineage Analysis of the Adult Drosophila Ovary

The Drosophila ovary is a widely used model for germ cell and somatic tissue biology. We have used single-cell RNA-sequencing to build a comprehensive cell atlas of the adult Drosophila ovary containing unique transcriptional profiles for every major cell type in the ovary, including the germline and follicle stem cells. Using this atlas we identify novel tools for identification and manipulation of known and novel cell types and perform lineage tracing to test cellular relationships of previously unknown cell types. By this we discovered a new form of cellular plasticity in which inner germarial sheath cells convert to follicle stem cells in response to starvation.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC=\"FIGDIR/small/798223v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (60K):\norg.highwire.dtl.DTLVardef@b4c486org.highwire.dtl.DTLVardef@1d24e4aorg.highwire.dtl.DTLVardef@1217adorg.highwire.dtl.DTLVardef@1d09a63_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2019

Development of mouse and human cochlea at single cell resolution

Hearing loss is a common and disabling condition, yet our understanding of the physiologic workings of the inner ear has been limited by longstanding difficulty characterizing the function and characteristics of the many diverse, fragile, and rare cell types in the cochlea. Using single-cell RNA-sequencing and a novel clustering algorithm, CellFindR, we created a developmental map of the mouse and human cochlea, identifying multiple previously undescribed cell types, progenitor populations, and predicted lineage relationships. We additionally associated the expression of known hearing loss genes to the cell types and developmental timepoints in which they are expressed. This work will serve as a resource for understanding the molecular basis of hearing and designing therapeutic approaches for hearing restoration.

bioinformatics↗

bioRxiv2019

The first finding of lichen Solorina saccata at an algific talus slope in Korea

An algific talus slope is composed of broken rocks with vents connected to an ice cave, releasing cool air in summer and relatively warmer air in winter to maintain a more stable microclimate all year round. Such geological features create a very unusual and delicate ecosystem. Although there are around 25 algific talus slopes in Korea, lichen ecology of these areas had not been investigated to date. In this study, we report the first exploration of lichen ecology at an algific talus slope, Jangyeol-ri, in Korea. A total of 37 specimens were collected over 2017-2018. Morphological and sequencing analysis revealed 27 species belonging to 18 genera present in the area. Of particular interest among these species was Solorina saccata, as it has previously not been reported in Korea and most members of genus Solorina are known to inhabit alpine regions of the Northern Hemisphere. We provide here a taxonomic key for S. saccata alongside molecular phylogenetic analyses and prediction of potential habitats in South Korea. Sequences were generated from all S. saccata specimens collected in this study, together with three S. saccata specimens from China for comparison. Phylogenetic analysis based on nuclear small subunit (nuSSU) showed that all the S. saccata specimens are tightly grouped into one clade with high support values (P=0.99) and showed close relatedness to S. spongiosa than S. crocea. Additional analyses were carried out using concatenated sequences: 65 sequences of mitochondrial small subunit (mtSSU) combined with nuLSU and 66 sequences of RPB1 with nuLSU. In these analyses, genus Peltigera was found to be the closest genus to S. saccata. Furthermore, regions in South Korea potentially suitable for Solorina spp. were predicted based on climatic features of known habitats around the globe. Our results showed that the suitable areas are mostly at high altitudes in mountainous areas where the annual temperature range doesnt exceed 26.6{degrees}C. Further survey of other environmental conditions determining the suitability of Solorina spp. should lead to a more precise prediction of suitable habitats and trace the origin of Solorina spp. in Korea.

ecology↗

bioRxiv2019

Ecological and evolutionary patterns in the enigmatic protist genus Percolomonas (Heterolobosea; Discoba) from diverse habitats

The heterotrophic flagellate Percolomonas cosmopolitus (Heterolobosea) is often observed in saline habitats worldwide that range from coastal waters to saturated brines. However, only two cultures assigned to this morphospecies have been examined using molecular methods, and their 18S rRNA gene sequences are extremely different. Further the salinity tolerances of individual strains are unknown. Thus, our knowledge on the autecology and diversity in this morphospecies is deficient. Here, we report 18S rRNA gene data on seven strains similar to P. cosmopolitus from seven geographically remote locations (New Zealand, Kenya, Korea, Poland, Russia, Spain, and the USA) with sample salinities ranging from 4{per thousand} to 280{per thousand}, and compare morphology and salinity tolerance of the nine available strains. Percolomonas cosmopolitus-like strains show few-to-no consistent morphological differences, and form six clades separated by often extremely large 18S rDNA divergences (up to 42.4%). Some strains grew best at salinities from 75 to 125{per thousand} and represent halophiles. All but one of these belonged to two geographically heterogeneous clusters that formed a robust monophyletic group in phylogenetic trees; this likely represents an ecologically specialized subclade of halophiles. Our results suggest that P. cosmopolitus is a cluster of several cryptic species (at least), which are unlikely to be distinguished by geography. Interestingly, the 9 Percolomonas strains formed a clade in 18S rDNA phylogenies, unlike most previous analyses based on two sequences.

microbiology↗

bioRxiv2018

Cyclical environments drive variation in life history strategies: a general theory of cyclical phenology

Cycles, such as seasons or tides, characterize many systems in nature. Overwhelming evidence shows that climate change-driven alterations to environmental cycles--such as longer seasons-- are associated with phenological shifts around the world, suggesting a deep link between environmental cycles and life cycles. However, general mechanisms of life history evolution in cyclical environments are still not well understood. Here I build a demographic framework and ask how life history strategies optimize fitness when the environment perturbs a structured population cyclically, and how strategies should change as cyclicality changes. I show that cycle periodicity alters optimality predictions of classic life history theory because repeated cycles have rippling selective consequences over time and generations. Notably, fitness landscapes that relate environmental cyclicality and life history optimality vary dramatically depending on which trade-offs govern a given species. The model tuned with known life history trade-offs in a marine intertidal copepod T. californicus successfully predicted the shape of life history variation across natural populations spanning a gradient of tidal periodicities. This framework shows how environmental cycles can drive life history variation--without complex assumptions of individual responses to cues such as temperature--thus expanding the range of life history diversity explained by theory and providing a basis for adaptive phenology.

ecology↗