Biology subjects

Jin, N.

Publications and source records attributed to Jin, N..

14 recordsLinked to original sources

bioRxiv2026

Short-Term Plasticity of Contrast Surround Suppression During Repeated Psychophysical Measurement

Perceptual surround suppression is commonly treated as stable within a testing session, but recent evidence for normalization reweighting suggests that suppressive interactions can be modified by recent visual input. Here, we asked whether surround suppression changes over minutes of repeated measurement and whether such change varies with stimulus and sampling conditions. Across four psychophysical experiments, we tracked contrast and motion surround suppression while varying center-surround orientation and stimulus spatiotemporal properties. With static gratings, contrast surround suppression increased early and then approached a plateau, with no evidence that this change depended on center-surround orientation. With dynamic gratings, an increase emerged only under finer temporal sampling and more sustained stimulation, and model-based analyses suggested a faster increase than with static stimulation. Motion surround suppression measured with drifting gratings showed no systematic change. Together, these findings show that contrast surround suppression can change within a single psychophysical session without a separate adaptation phase, and that its measured time course varies with stimulus and sampling conditions. The results are consistent with rapid, experience-dependent reweighting of contextual normalization.

neuroscience↗

bioRxiv2026

Retinal electrical synapse plasticity is required for optimal visual performance

Most electrical synapses in the mammalian central nervous system are composed of Connexin 36 (Cx36). Electrical synapses are functionally plastic, changing their degree of coupling based on the activity of the cell or connected cells, or based on activation of neurotransmitter or neurohormone receptors. Plasticity can reach an extreme in which electrical synapses become functionally silent, which is a normal operational condition for some circuits. Cx36 coupling is regulated by phosphorylation, which opens the channels. In retinal circuits, Cx36 is often maintained in a poorly phosphorylated, poorly coupled state. We reasoned that phosphomimetic mutants of Cx36 could remain constitutively open and maintain circuits in a well-coupled state that will interrogate the need for plasticity. We developed a constitutively open Cx36 mutant by systematically replacing phosphorylatable residues that regulate coupling with acidic residues. Single mutants of serine 315 significantly modified functional regulation of coupling in HeLa cells, but mutation of four residues was required to produce a mutant that was constitutively open. This mutant, Cx36-S110D, T111E, S293D, S315D, called Cx36-DEDD, displayed high coupling in control conditions and only modest changes under phosphorylating and dephosphorylating conditions. We developed a conditional knockin mouse that expresses Cx36-DEDD and cytoplasmic tdTomato in cells that expressed Cre recombinase. When crossed with Six3-Cre mice, Cx36-DEDD expressed widely in the retina including in photoreceptors, bipolar, amacrine and ganglion cells. Rod-cone electrical coupling displayed the maximum of its physiological dynamic range, and photopic visual acuity and contrast sensitivity were significantly reduced in Cx36-DEDD homozygous animals. We conclude that reduction of coupling in some retinal circuits is required for optimal daylight vision. Significance StatementTwo types of synapses, chemical and electrical, work together throughout the central nervous system to perform neurological functions. While it is widely understood for chemical synapses that plasticity, changing the strength of synaptic connections, plays critical roles in many processes, this is far less understood for electrical synapses. By developing an electrical synapse protein mutant that locks channels in an open state, we have investigated retinal circuits that retain functional electrical synapses but lack their latitude for plasticity. This perturbation significantly compromises visual acuity and contrast sensitivity in the daylight, revealing that electrical synapse plasticity is necessary to tune retinal functions for optimal performance. Thus, electrical synapse plasticity along with chemical synapse plasticity is required for neural function.

neuroscience↗

bioRxiv2026

The in vivo inhibitory function of the MHC-I alpha3 domain/CD8alpha interaction

The interaction between the Major Histocompatibility Complex Class I (MHC-I) 3 domain and CD8 has classically been viewed as a positive coreceptor interaction that stabilizes TCR signaling during antigen recognition. However, its physiological function in mature peripheral CD8+ T cells in vivo remains incompletely understood. Here, we identify the MHC-I 3 domain-CD8 interaction as a previously unrecognized inhibitory pathway that tonically restrains peripheral CD8+ T-cell activation and maintains T-cell tolerance in vivo. Antibody-mediated disruption of the MHC-I 3 domain-CD8 interaction induced spontaneous activation of peripheral CD8+ T cells without impairing their survival, lowered the threshold for antigen-induced activation, and enhanced responsiveness to cognate peptide stimulation. In peptide-induced OT-I T-cell anergy models, blockade of either H-2Db or H-2Kb 3 domain interactions with CD8 prevented the induction of anergy and restored responsiveness of previously anergic T cells. Notably, blockade of the H-2Kb 3 domain enhanced OT-I responses despite simultaneously disrupting the classical positive coreceptor interaction within the TCR-peptide-MHC complex, indicating that tonic inhibitory signaling mediated by the MHC-I 3 domain predominates under these conditions. Together, these findings redefine the classical MHC-I-CD8 interaction as a bidirectional pathway that not only supports antigen recognition but also imposes tonic inhibitory control over peripheral CD8+ T cells. These results identify the MHC-I 3 domain-CD8 axis as a potential target for reversing T-cell tolerance and enhancing antitumor or antiviral immunity.

immunology↗

bioRxiv2026

Epigenetic and 3D Genome Changes Drive Primary Trastuzumab Resistance in HER2+ Breast Cancer

Primary trastuzumab resistance remains a major challenge in the treatment of HER2-positive breast cancer, with limited therapeutic options highlighting the need for deeper mechanistic insight. Here, integrative analysis of epigenomic and three-dimensional chromatin architecture reveals widespread remodeling of the regulatory landscape in resistant cells. Alterations in promoter-associated histone modifications?particularly H3K4me3 and H3K27me3?together with changes in active enhancer activity and promoter-enhancer interactions, appear to be key drivers of transcriptional reprogramming underlying resistance. As an illustrative example, SGK1 exhibits epigenetic activation in resistant cells, characterized by increased promoter H3K4me3 and enhanced chromatin interactions, consistent with its role in supporting cell survival, proliferation and metastasis. Overall, our findings highlight epigenetic and chromatin structural alterations as central mechanisms of primary trastuzumab resistance, providing a framework for novel therapeutic strategies development.

cancer biology↗

bioRxiv2025

Epigenetic Modulation, Intra-tumoral Microbiome and Immunity in Early Onset Colorectal Cancer

BackgroundThe incidence of colorectal cancer (CRC) in young adults (age of diagnosis < 50 years old) has been rapidly increasing. Although [~]20% of early-onset (EO) CRC cases are due to germline mutations, the etiology of the majority of EOCRC cases remains poorly understood. Non-genetic factors such as environmental exposure and lifestyle changes are likely to have a direct link to the increased incidence of sporadic EOCRC. We hypothesize that such factors may be observable as differences in the EOCRC epigenome, microbiome and immunome. We sought to address this by comparing differences in DNA methylation from the cohort of colorectal cancer patients in The Cancer Genome Atlas (TCGA). Further, we carefully identified intra-tumoral microbes from TCGA and two other datasets and then related the microbes to EOCRC status and deconvolved immune cell abundances. We found that DNA methylation (DNAm) age acceleration by12 years when compared with average-onset CRC (AOCRC) patients. Differentially methylated sites associated with genes are related to CREB signaling in neurons, G protein coupled receptor signaling, phagosome formation and S100 family signaling. These differences were validated in the gene expression from TCGA and a second, larger real-world dataset from the Oncology Research Information Exchange Network (ORIEN). However, no consistent differences were observed in the intra-tumor microbes between EOCRC and AOCRC. Interestingly, the most abundant microbes interacted with the immune systems differently between the EOCRC and AOCRC tumors, characterized by more, larger, positive correlations in EOCRC. These data suggest epigenetic modulation and accelerated aging may play a key role in the development of EOCRC. SIGNIFICANCEWe investigated whether environmentally driven factors contribute to early-onset colorectal cancer (EOCRC). We observed accelerated epigenetic aging in EOCRC and epigenetic changes associated with chronic inflammation. Tumor immune cell abundances correlated more strongly with microbes in EOCRC than average-onset CRC. These data suggest a dysregulation of immune response in EOCRC, driving chronic inflammation and tissue aging.

cancer biology↗

bioRxiv2024

A non-canonical CDK, Pho85 regulates the restart of the cell-cycle following stress

Environmental stress induces an arrest of the cell cycle. Thus, release from this arrest is essential for cell survival. The cell-cycle-arrest occurs via the down regulation of the cyclins that drive the main cyclin dependent kinase, CDK1/Cdc28. However, it was not clear how cells escape this potentially fatal arrest. Here we show that prior to the restoration of CDK1/Cdc28 cyclins, a non-canonical CDK, Pho85, initiates a cascade to restart the cell cycle. We demonstrate that following stress, Pho85 phosphorylates the Sch9 kinase, which in turn directly phosphorylates the transcriptional inhibitor Whi5, the yeast analog of RB1/retinoblastoma, and a CDK1 target. This promotes Whi5 translocation from the nucleus, and the release of the stress-induced arrest at G1 phase. In addition, we find that in parallel with Pho85, CDK1/Cdc28 also plays a role in the control of Whi5. Together, these findings provide insights into how cells re-enter the cell cycle during recovery from stress and reveal that a non-canonical CDK and cyclin takes on essential roles and acts via a pathway that functions in parallel with CDK1/Cdc28.

molecular biology↗

bioRxiv2024

Development of alcoholic liver disease model for drug evaluation from human induced pluripotent stem cell derived liver organoids

Alcoholic liver disease (ALD) poses a significant health challenge, demanding comprehensive research efforts to enhance our comprehension and treatment strategies. However, the development of effective treatments is hindered by the limitations of existing liver disease models. Liver organoids, characterized by their cellular complexity and three-dimensional (3D) tissue structure closely resembling the human liver, hold promise as ideal models for liver disease research. In this study, we employ a meticulously designed protocol involving the differentiation of human induced pluripotent stem cells (hiPSCs) into liver organoids. This process incorporates a precise combination of cytokines and small molecule compounds within a 3D culture system to guide the differentiation process. Subsequently, these differentiated liver organoids are subjected to ethanol treatment to induce ALD, thus establishing a disease model. Rigorous assessment through a series of experiments reveals that this model partially replicates key pathological features observed in clinical ALD, including cellular mitochondrial damage, elevated cellular reactive oxygen species (ROS) levels, fatty liver, and hepatocyte necrosis. In addition, this model offers potential utility in screening drugs for ALD treatment. Taken together, the liver organoids model of ALD, derived from hiPSCs differentiation, emerges as an invaluable platform for advancing our understanding and management of ALD in clinical settings.

cell biology↗

bioRxiv2023

The tumor microbiome reacts to hypoxia and can influence response to radiation treatment in colorectal cancer

Tumor hypoxia has been shown to predict poor patient outcomes in several cancer types, partially because it reduces radiations ability to kill cells. We investigated whether some of the clinical effects of hypoxia could also be due to its impact on the tumor microbiome. We examined the RNA-seq data from the Oncology Research Information Exchange Network (ORIEN) database of colorectal cancer (CRC) patients treated with radiotherapy. For each tumor, we identified microbial RNAs and related them to the hypoxic gene expression scores calculated from host mRNA. Our analysis showed that the hypoxia expression score predicted poor patient outcomes and identified tumors enriched with certain microbes such as Fusobacterium nucleatum. The presence of other microbes, such as Fusobacterium canifelinum, predicted poor patient outcomes, suggesting a potential interaction between hypoxia, the microbiome, and radiation response. To investigate this concept experimentally, we implanted CT26 CRC cells into both immune-competent BALB/c and immune-deficient athymic nude mice. After growth, where tumors passively acquired microbes from the gastrointestinal tract, we harvested tumors, extracted nucleic acids, and sequenced host and microbial RNAs. We stratified tumors based on their hypoxia score and performed metatranscriptomic analysis of microbial gene expression. In addition to hypoxia-trophic and -phobic microbial populations, analysis of microbial gene expression at the strain level showed expression differences based on the hypoxia score. Hypoxia appears to not only associate with different microbial populations but also elicit an adaptive transcriptional response in intratumoral microbes. SIGNIFICANCETumor hypoxia reduces radiations ability to kill cells. We explored whether some of the clinical effects of hypoxia could also be due to interaction with the tumor microbiome. Hypoxic expression scores associated with certain microbes and elicited an adaptive transcriptional response in others.

immunology↗

bioRxiv2023

Presence of the ER-Golgi intermediate compartment that matures into the Golgi in yeast

Cargo traffic through the Golgi apparatus is mediated by cisternal maturation, but it remains largely unclear how the cis-cisternae, the earliest Golgi sub-compartment, is generated. Here, we use high-speed, high-resolution confocal microscopy to analyze the spatiotemporal dynamics of a diverse set of proteins that reside in and around the Golgi in budding yeast. We find many mobile punctate structures that harbor yeast counterparts of mammalian endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) proteins, which we term "yeast ERGIC". It occasionally attaches onto the ER exit sites and gradually matures into the cis-Golgi. Upon treatment with the Golgi-disrupting agent brefeldin A, the ERGIC proteins form larger aggregates corresponding to the Golgi entry core compartment in plants, while cis- and medial-Golgi proteins are absorbed into the ER. We further analyze the dynamics of several late Golgi proteins. Together with our previous studies, we demonstrate a detailed spatiotemporal profile of the cisternal maturation process from ERGIC to Golgi and further to the trans-Golgi network. SummaryTojima et al. perform spatiotemporal mapping of a variety of proteins residing in and around the Golgi apparatus in budding yeast using super-resolution live imaging microscopy. They identified the ER-Golgi intermediate compartment that matures into the Golgi.

cell biology↗

bioRxiv2023

The tumor microbiome as a predictor of outcomes in patients with metastatic melanoma treated with immune checkpoint inhibitors

Emerging evidence supports the important role of the tumor microbiome in oncogenesis, cancer immune phenotype, cancer progression, and treatment outcomes in many malignancies. In this study, we investigated the metastatic melanoma tumor microbiome and potential roles in association with clinical outcomes, such as survival, in patients with metastatic disease treated with immune checkpoint inhibitors (ICIs). Baseline tumor samples were collected from 71 patients with metastatic melanoma before treatment with ICIs. Bulk RNA-seq was conducted on the formalin-fixed paraffin-embedded (FFPE) tumor samples. Durable clinical benefit (primary clinical endpoint) following ICIs was defined as overall survival [≥]24 months and no change to the primary drug regimen (responders). We processed RNA-seq reads to carefully identify exogenous sequences using the {exotic}tool. The 71 patients with metastatic melanoma ranged in age from 24 to 83 years, 59% were male, and 55% survived >24 months following the initiation of ICI treatment. Exogenous taxa were identified in the tumor RNA-seq, including bacteria, fungi, and viruses. We found differences in gene expression and microbe abundances in immunotherapy responsive versus non-responsive tumors. Responders showed significant enrichment of several microbes including Fusobacterium nucleatum, and non-responders showed enrichment of fungi, as well as several bacteria. These microbes correlated with immune-related gene expression signatures. Finally, we found that models for predicting prolonged survival with immunotherapy using both microbe abundances and gene expression outperformed models using either dataset alone. Our findings warrant further investigation and potentially support therapeutic strategies to modify the tumor microbiome in order to improve treatment outcomes with ICIs. SignificanceWe analyzed the tumor microbiome and interactions with genes and pathways in metastatic melanoma treated with immunotherapy, and identified several microbes associated with immunotherapy response and immune-related gene expression signatures. Machine learning models that combined microbe abundances and gene expression outperformed models using either dataset alone in predicting immunotherapy responses.

immunology↗

bioRxiv2023

A bioinformatics tool for identifying intratumoral microbes from the ORIEN dataset

Evidence supports significant interactions among microbes, immune cells, and tumor cells in at least 10-20% of human cancers, emphasizing the importance of further investigating these complex relationships. However, the implications and significance of tumor-related microbes remain largely unknown. Studies have demonstrated the critical roles of host microbes in cancer prevention and treatment responses. Understanding interactions between host microbes and cancer can drive cancer diagnosis and microbial therapeutics (bugs as drugs). Computational identification of cancer-specific microbes and their associations is still challenging due to the high dimensionality and high sparsity of intratumoral microbiome data, which requires large datasets containing sufficient event observations to identify relationships, and the interactions within microbial communities, the heterogeneity in microbial composition, and other confounding effects that can lead to spurious associations. To solve these issues, we present a bioinformatics tool, MEGA, to identify the microbes most strongly associated with 12 cancer types. We demonstrate its utility on a dataset from a consortium of 9 cancer centers in the Oncology Research Information Exchange Network (ORIEN). This package has 3 unique features: species-sample relations are represented in a heterogeneous graph and learned by a graph attention network; it incorporates metabolic and phylogenetic information to reflect intricate relationships within microbial communities; and it provides multiple functionalities for association interpretations and visualizations. We analyzed 2704 tumor RNA-seq samples and MEGA interpreted the tissue-resident microbial signatures of each of 12 cancer types. MEGA can effectively identify cancer-associated microbial signatures and refine their interactions with tumors. SIGNIFICANCEStudying the tumor microbiome in high-throughput sequencing data is challenging because of the extremely sparse data matrices, heterogeneity, and high likelihood of contamination. We present a new deep-learning tool, microbial graph attention (MEGA), to refine the organisms that interact with tumors.

bioinformatics↗

bioRxiv2022

Fertilizer reduction with bio-organic fertilizer to regulate the root soil microbial community structure to improve Baby Chinese cabbage yield

Using high-throughput sequencing, this study aimed to explore the response of soil microbial community and Baby Chinese cabbage yield to the reduction of chemical fertilizers combined with bio-organic fertilizer in the Gansu plateau, China. Our experiments consisted of conventional fertilizer (CK), 30% chemical fertilizer reduction + 6,000 kg bio-organic fertilizer (T1), 30% chemical fertilizer reduction + 9,000 kg bio-organic fertilizer (T2), 40% chemical fertilizer reduction + 6,000 kg bio-organic fertilizer (T3), and 40% chemical fertilizer reduction + 9,000 kg bio-organic fertilizer (T4). Compared with CK, soil microbial diversity and richness were higher for all treatments with added bio-organic fertilizer. PCoA showed that the bacterial and fungal communities in T2 and T4 were similar to each other. Redundancy and Spearmans correlation analyses of microbial communities and soil physicochemical properties revealed that reductions in chemical fertilizer rate combined with bio-organic fertilizer had a stronger impact on the fungal than the bacterial community. They also increased the relative abundance of the dominant bacterial and fungal phyla. Baby Chinese cabbage yield was relatively higher under the combined bio-organic fertilizer plus reduced chemical fertilizer rate with T2 showing the highest yield. Therefore, this approach is feasible for sustainable agricultural, cost-effective and profitable crop production. ImportanceO_LIBio-organic + moderately reduced chemical fertilizer raised Chinese cabbage yield C_LIO_LIBio-organic + chemical fertilizer was more efficacious than either one alone C_LIO_LIPresence of bio-organic fertilizer enhanced overall rhizosphere physicochemistry C_LIO_LIBio-organic fertilizer improved beneficial bacterial & fungal abundance & diversity C_LIO_LIFertilizer combination sustainably & cost-effectively improves crop & soil quality C_LI

microbiology↗

bioRxiv2021

Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes

Throughout evolution, proinsulin has exhibited significant sequence variation in both C-peptide and insulin moieties. As the proinsulin coding sequence evolves, the gene product continues to be under selection pressure both for ultimate insulin bioactivity and for the ability of proinsulin to be folded for export through the secretory pathway of pancreatic {beta}-cells. The substitution proinsulin-R(B22)E is known to yield a bioactive insulin, although R(B22)Q has been reported as a mutation that falls within the spectrum of Mutant INS-gene induced Diabetes of Youth (MIDY). Here we have studied mice expressing heterozygous (or homozygous) proinsulin-R(B22)E knocked into the Ins2 locus. Neither females nor males bearing the heterozygous mutation develop diabetes at any age examined, but subtle evidence of increased proinsulin misfolding in the endoplasmic reticulum is demonstrable in isolated islets from the heterozygotes. Moreover, males have indications of glucose intolerance and within a few week exposure to a high-fat diet, they develop frank diabetes. Diabetes is more severe in homozygotes, and the development of disease parallels a progressive heterogeneity of {beta}-cells with increasing fractions of proinsulin-rich/insulin-poor cells, as well as glucagon-positive cells. Evidently, sub-threshold predisposition to proinsulin misfolding can go undetected, but provides genetic susceptibility to diet-induced {beta}-cell failure.

cell biology↗

bioRxiv2020

Retinal circuits driving a non-image forming visual behavior

Outer retinal circuits that drive non-image forming vision in mammals are unknown. Rods and cones signal light increments and decrements to the brain through the ON and OFF pathways, respectively. Although their contribution to image-forming vision is known, the contributions of the ON and OFF pathway to the pupillary light response (PLR), a non-image forming behavior, are unexplored. Here we use genetically modified mouse lines, to comprehensively define the outer retinal circuits driving the PLR. The OFF pathway, which mirrors the ON pathway in image-forming vision, plays no role in the PLR. We found that rods use the primary rod pathway to drive the PLR at scotopic light levels. At photopic light levels, the primary and secondary rod pathways drive normal PLR. Importantly, we find that cones are unable to compensate for rods. Thus, retinal circuit dynamics allow rods to drive the PLR across a wide range of light intensities.

neuroscience↗