Biology subjects

Deng, C.

Publications and source records attributed to Deng, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Yeast aging from a dynamic systems perspective: Analysis of single cell trajectories reveals significant interplay between nuclear size scaling, proteasome dynamics, and mitochondrial morphology

Yeast replicative aging is cell autonomous and thus a good model for mechanistic study from a dynamic systems perspective. Utilizing an engineered strain of yeast with a switchable genetic program to arrest daughter cells (without affecting mother cell divisions) and a high throughput microfluidic device, we systematically analyze the dynamic trajectories of thousands of single yeast mother cells throughout their lifespan, using fluorescent reporters that cover a range of biological processes, including some major aging hallmarks. We found that the markers of proteostasis stand out as most predictive of the lifespan of individual cells. In particular, nuclear proteasome concentration at middle age is a good predictor. We found that cell size (measured by area) grows linearly with time, and that nuclear size grows in proportion to maintain isometric scaling in young cells. As the cells become older, their nuclear size increases faster than linear and isometric size scaling breaks down. We observed that proteasome concentration in the nucleus exhibits dynamics very different from that in cytoplasm, with much more rapid decrease during aging; such dynamic behavior can be accounted for by the change of nuclear size in a simple mathematical model of transport. We hypothesize that the gradual increase of cell size and the associated nuclear size increase lead to the dilution of important nuclear factors (such as proteasome) that drives aging. We also show that perturbing proteasome changes mitochondria morphology and function, but not vice versa, potentially placing the change of proteosome upstream of the change of mitochondrial phenotypes. Our study produced large scale single cell dynamic data that can serve as a valuable resource for the aging research community to analyze the dynamics of other markers and potential causal relations between them. It is also a useful resource for building and testing physics/AI based models that identify early dynamics events predictive of lifespan and can be targets for longevity interventions.

bioinformatics↗

bioRxiv2024

The Arabidopsis amino acid transporter UmamiT20 confers susceptibility to B. cinerea

O_LIInduction of SWEET sugar transporters by bacterial pathogens via transcription activator-like (TAL) effectors is necessary for successful blight infection of rice, cassava and cotton, - likely providing sugars for bacterial propagation. C_LIO_LIHere, we show that infection of Arabidopsis by the necrotrophic fungus Botrytis cinerea causes increased accumulation of amino acid transporter UmamiT20 mRNA in leaves. UmamiT20 protein accumulates in leaf veins surrounding the lesions after infection. Consistent with a role during infection, umamiT20 knock-out mutants were less susceptible to B. cinerea. C_LIO_LIFunctional assays demonstrate that UmamiT20 mediates amino acid transport of a wide range of amino acid substrates. C_LIO_LIPathogen-induced UmamiT20 mRNA and protein accumulation support the hypothesis that transporter-mediated pathogen susceptibility is not unique to SWEETs in bacterial blight of rice but also for a necrotrophic fungus and implicate nutrients other than sucrose, i.e., amino acids, in nutrition or nutrient signaling related to immunity. We hypothesize that stacking of mutations in different types of susceptibility-related nutrient carriers to interfere with access to several nutrients may enable engineering robust pathogen resistance in a wide range of plant-pathogen systems. C_LI Lay AbstractPathogens infect plants to gain access to their nutrient resources, enabling the pathogens to cause disease and reproduce efficiently. Here we find that an amino acid transporter constitutes a susceptibility factor for the fungal pathogen B. cinerea.

plant biology↗

bioRxiv2024

A toolbox for ablating excitatory and inhibitory synapses

Recombinant optogenetic and chemogenetic proteins are potent tools for manipulating neuronal activity and controlling neural circuit function. However, there are few analogous tools for manipulating the structure of neural circuits. Here, we introduce three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to trigger the degradation of synaptic scaffolding proteins, leading to functional ablation of synapses. First, we developed a constitutive excitatory synapse ablator, PFE3, analogous to the inhibitory synapse ablator GFE3. PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses. In addition, we developed a light-inducible version of GFE3, paGFE3, using a novel photoactivatable complex based on the photocleavable protein PhoCl2c. paGFE3 degrades Gephyrin and ablates inhibitory synapses in response to 400 nm light. Finally, we developed a chemically inducible version of GFE3, chGFE3, which degrades inhibitory synapses when combined with the bio-orthogonal dimerizer HaloTag ligand-trimethoprim. Each tool is specific, reversible, and capable of breaking neural circuits at precise locations.

neuroscience↗

bioRxiv2024

Conditional Localization Pharmacology Manipulates the Cell Cycle with Spatiotemporal Precision

Traditional pharmacology has limited control of drug activity and localization in space and time. Herein, we described an approach for kinase regulation using conditional localization pharmacology (CLP), where an inactive caged inhibitor is localized to a site of interest in a dormant state using intracellular protein tethering. The activity of the inhibitor can be regulated with spatial and temporal precision in a live cellular environment using light. As a proof of concept, a photocaged MPS1 kinase inhibitor (reversine) bearing a Halo-tag ligand tether was designed to manipulate the cell cycle. We demonstrate that this new caged reversine halo probe (CRH) strategy is capable of efficient localization and exceptional spatiotemporal control over spindle assembly checkpoint (SAC) silencing and mitotic exit. Table of Contents artwork O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/612697v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@cd44f8org.highwire.dtl.DTLVardef@6b14f7org.highwire.dtl.DTLVardef@2d8945org.highwire.dtl.DTLVardef@18f4985_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Immune Cell Influence on Diffuse Large B-Cell Lymphoma: A Mendelian Randomization Analysis

ObjectiveTo elucidate the causal relationship between immune cells and diffuse large B-cell lymphoma (DLBCL), we conducted a Mendelian randomization analysis. MethodsMendelian randomization (MR) leverages genetic variants as instruments to infer causal effects from observational data. Here, we performed a two-sample MR analysis to assess the causal impact of 731 immune cell types on DLBCL. We employed various MR techniques, including the weighted median estimator (WME) and inverse variance weighting (IVW), and conducted sensitivity analyses to ensure result robustness. Additionally, reverse MR analysis was performed to explore the potential causal relationship between DLBCL and immune cells. ResultsWe identified seventeen immune features with causal links to DLBCL, categorized across various cellular groups: four in B cells, two in T cell maturation stages, six in Tregs, four in the TBNK group, and one in dendritic cells (DCs). Sensitivity analyses confirmed the absence of heterogeneity, horizontal pleiotropy, and bias in our findings. Reverse causal analysis revealed a causal association between DLBCL and one of the seventeen immune cell types identified. ConclusionsOur MR analysis of seventeen immune cell types uncovers the complex interactions between the immune system and DLBCL, providing crucial insights into the tumor microenvironment and potential avenues for targeted immunotherapy.

immunology↗

bioRxiv2024

MaskMol: Knowledge-guided Molecular Image Pre-Training Framework for Activity Cliffs with Pixel Masking

Activity cliffs, which refer to pairs of molecules that are structurally similar but show significant differences in their potency, can lead to model representation collapse and make the model challenging to distinguish them. Our research indicates that as molecular similarity increases, graph-based methods struggle to capture these nuances, whereas imagebased approaches effectively retain the distinctions. Thus, we developed MaskMol, a knowledge-guided molecular image selfsupervised learning framework. MaskMol accurately learns the representation of molecular images by considering multiple levels of molecular knowledge, such as atoms, bonds, and substructures. By utilizing pixel masking tasks, MaskMol extracts fine-grained information from molecular images, overcoming the limitations of existing deep learning models in identifying subtle structural changes. Experimental results demonstrate MaskMols high accuracy and transferability in activity cliff estimation and compound potency prediction across 20 different macromolecular targets, outperforming 25 state-of-the-art deep learning and machine learning approaches. Visualization analyses reveal MaskMols high biological interpretability in identifying activity cliff-relevant molecular substructures. Notably, through MaskMol, we identified candidate EP4 inhibitors that could be used to treat tumors. This study not only raises awareness about activity cliffs but also introduces a novel method for molecular image representation learning and virtual screening, advancing drug discovery and providing new insights into structure-activity relationships (SAR). Code is available at https://github.com/ZhixiangCheng/MaskMol.

bioinformatics↗

bioRxiv2024

The central spindle drives anaphase chromosome segregation

Anaphase chromosome segregation depends on forces exerted by spindle microtubules. Current models propose two mechanisms of force generation: kinetochore microtubules (kMTs) depolymerize to pull chromosomes toward the spindle poles (anaphase A), while antiparallel microtubule sliding in the central spindle further separates the chromosomes by elongating the spindle (anaphase B). Experimental evidence in cells supports the sliding mechanism, but contributions of the depolymerization mechanism remain unclear. Here we show that kMT depolymerization limits spindle elongation rather than moving chromosomes apart. We developed a chemical optogenetic approach to recruit a microtubule depolymerase to kinetochores at anaphase onset, thereby increasing the rate of kMT depolymerization without perturbing earlier stages of mitosis. We find that increased depolymerization slows the velocity at which spindle poles move apart without changing kinetochore separation velocities. Our findings support a model in which kinetochores selectively couple to central spindle microtubules parallel to their kMTs, so that antiparallel sliding drives chromosome segregation while kMT depolymerization pulls poles inward.

cell biology↗

bioRxiv2024

A critical role of protein damage response in mediating cancer drug resistance

Multidrug resistance (MDR) frequently occurs during cancer therapy and remains a major obstacle for the cure of most cancers(1, 2). Drug resistance could exist intrinsically or be acquired by drug treatment(3-5), yet factors that regulate the resistance remain elusive. Here, we show that most anticancer drugs damage neosynthesized proteins prior to reaching their canonic targets and elicit profound cytotoxicity, which is largely compensated by protein damage response (PDR). We demonstrate that the PDR includes damage recognition and clearance that are mainly mediated by ubiquitin and proteasome systems, although some other factors, including cellular ATP levels and proliferation status, are also involved. We show that cancer stem cells (CSCs), which have lower protein synthesis, and drug resistance acquired cells (DRAC), which have higher proteasome activity, are more resistant than other cells. We further demonstrate that ATP promotes protein synthesis and suppresses proteasome activity, thus, increasing mitochondrial ATP production by PDK1 inhibition and using proteasome inhibitor to block protein damage clearance render CSCs and DRACs more vulnerable to anticancer drugs. Thus, patients with drug-resistant cancers and treatment-naive patients with low ATP levels and/or high proteasome activity can be identified and subtyped, and therapies containing PDK1-I and/or proteasome-I may be effective options for these patients.

cancer biology↗

bioRxiv2024

Ternary representation of contextual information along the CA1 transverse axis

Episodic memory refers to the recollection of personally experienced events anchored in spatial contexts. Salient objects within a navigation environment serve as both landmarks and event cues; however, the nuanced integration of these elements during episodic memory formation is not well understood. The mnemonic functions of the hippocampal CA1 region are partially organized along its transverse axis, with proximal and distal subregions preferentially processing spatial and non-spatial information, respectively. Based on comprehensive analysis of neuronal responses along the CA1 proximodistal axis to manipulations of environmental cues and object features, we identified an event-like population coding within CA1 following object displacement. In addition, the neuronal responses at both initial and relocated object locations were shaped by distinct convergent inputs. These findings highlight the specific roles that objects may play in spatial navigation and memory encoding, providing novel insights into the selective processing of object-related information within the entorhinal-hippocampal network. Significance StatementSalient objects within a navigation environment serve as both landmarks and event cues critical for episodic memory. However, the enigmatic contribution of objects to the "where" and "what" components of episodic memory remains poorly understood. Here we comprehensively analyzed the neuronal responses in the hippocampal CA1 region along its transverse axis, to manipulations of environmental cues and object features. Our results revealed an event-like population coding within CA1 following object displacement, suggesting a minimal landmark role these objects play during memory formation. This study provides novel insights into the selective and flexible processing of object-related information within the entorhinal-hippocampal network.

neuroscience↗

bioRxiv2024

Cell Competition Eliminates Aneuploid Human Pluripotent Stem Cells

Human pluripotent stem cells (hPSCs) maintain diploid populations for generations despite a persistently high rate of mitotic errors that cause aneuploidy, or chromosome imbalances. Consequently, to maintain genome stability, aneuploidy must inhibit hPSC proliferation, but the mechanisms are unknown. Here, we surprisingly find that homogeneous aneuploid populations of hPSCs proliferate unlike aneuploid non-transformed somatic cells. Instead, in mosaic populations, cell non-autonomous competition between neighboring diploid and aneuploid hPSCs eliminates less fit aneuploid cells. Aneuploid hPSCs with lower Myc or higher p53 levels relative to diploid neighbors are outcompeted but conversely gain a selective advantage when Myc and p53 relative abundance switches. Thus, although hPSCs frequently missegregate chromosomes and inherently tolerate aneuploidy, Myc- and p53-driven cell competition preserves their genome integrity. These findings have important implications for the use of hPSCs in regenerative medicine and for how diploid human embryos are established despite the prevalence of aneuploidy during early development.

cell biology↗

bioRxiv2024

A conserved lysine/arginine-rich motif in potyviral 6K1 protein is key in engaging autophagy-mediated self-degradation for completing pepper veinal mottle virus infection

Potyviruses possess one positive-sense single-stranded RNA genome mainly with polyprotein processing as their gene expression strategy. The resulting polyproteins are proteolytically processed by three virus-encoded proteases into 11 or 12 mature proteins. One of such, 6-kDa peptide 1 (6K1), is an understudied viral factor. Its function in viral infection remains largely mysterious. This study is to reveal part of its roles by using pepper veinal mottle virus (PVMV) as a model virus. Alanine substitution screening analysis revealed that 15 out of 17 conserved residues across potyviral 6K1 sequences are essential for PVMV infection. However, 6K1 protein is less accumulated in virus-infected cells, even though P3-6K1 junction is efficiently processed by NIa-Pro for its release, indicating that 6K1 undergoes a self-degradation event. Mutating the cleavage site to prevent NIa-Pro processing abolishes viral infection, suggesting that the generation of 6K1 along with its degradation might be important for viral multiplication. We corroborated that cellular autophagy is engaged in 6K1s degradation. Individual engineering of the 15 6K1 variants into PVMV was performed to allow for their expression along with viral infection. Five of such variants, D30A, V32A, K34A, L36A, and L39A, significantly interfere with viral infection. The five residues are enclosed in a conserved lysine/arginine-rich motif; four of them appear to be crucial in engaging autophagy-mediated self-degradation. Based on these data, we envisaged a scenario that potyviral 6K1s interact with an unknown anti-viral component to be co-degraded by autophagy to promote viral infection. IMPORTANCEPotyvirus is the largest genus of plant-infecting RNA viruses, which encompasses socio-economically important virus species, such as Potato virus Y, Plum pox virus, and Soybean mosaic virus. Like all picorna-like viruses, potyviruses express their factors mainly via polyprotein processing. Theoretically, viral factors P3 through CP, including 6K1, should share an equivalent number of molecules. The 6K1 is small in size ([~]6 kDa) and conserved across potyviruses, but less accumulated in virus-infected cells. This study demonstrates that cellular autophagy is engaged in the degradation of 6K1 to promote viral infection. In particular, we found a conserved lysine/arginine-rich motif in 6K1s across potyviruses that is engaged in this degradation event. This finding reveals one facet of a small protein that help understand the pro-viral role of cellular autophagy in viral infection.

microbiology↗

bioRxiv2024

TLR9 activation in large wound induces tissue repair and hair follicle regeneration via gamma delta T cells

The mechanisms underlying tissue repair in response to damage have been one of main subjects of investigation. In this study, we leveraged the wound-induced hair neogenesis (WIHN) models in adult mice to explore the inner correlation. Our investigation revealed that heightened release of mitochondrial DNA (mtDNA) accompanying tissue damage activated the toll-like receptor 9 (TLR9) pathway, influencing the repair process and the ultimate number of regenerated hair follicles. Furthermore, our analysis of single-cell RNA sequencing comparisons demonstrated increased TLR9 activation was associated with the recruitment of gamma delta T cells ({gamma}{delta}T). Inhibition of {gamma}{delta}T cell recruitment led to a reduction in the population of {gamma}{delta}T cells and a more fibrotic healing outcome. Notably, these {gamma}{delta}T cells exhibited distinctive high production of AREG, contributing to the rapid increase of local AREG levels around the epidermis and influencing the fate commitment of keratinocytes. These findings provide new insights into the roles of TLRs as critical mediators in the sense of tissue damage, the modulation of immune cell activity, and the ultimate influence on healing outcomes. TeaserStarting with how tissue injury stimulates downstream tissue repair and regeneration through relevant signals, this study explored the phenomenon and correlation between tissue damage and TLR9, and the effect of TLR9 on {gamma}{delta}T, keratinocytes and the healing outcomes.

cell biology↗

bioRxiv2024

Identifying new cancer genes based on the integration of annotated gene sets via hypergraph neural networks

MotivationIdentifying cancer genes remains a significant challenge in cancer genomics research. Annotated gene sets encode functional associations among multiple genes, and cancer genes have been shown to cluster in hallmark signaling pathways and biological processes. The knowledge of annotated gene sets is critical for discovering cancer genes but remains to be fully exploited. ResultsHere, we present the DIsease-Specific Hypergraph neural network (DISHyper), a hypergraph-based computational method that integrates the knowledge from multiple types of annotated gene sets to predict cancer genes. First, our benchmark results demonstrate that DISHyper outperforms the existing state-of-the-art methods and highlight the advantages of employing hypergraphs for representing annotated gene sets. Second, we validate the accuracy of DISHyper-predicted cancer genes using functional validation results and multiple independent functional genomics data. Third, our model predicts 44 novel cancer genes, and subsequent analysis shows their significant associations with multiple types of cancers. Overall, our study provides a new perspective for discovering cancer genes and reveals previously undiscovered cancer genes. AvailabilityDISHyper is freely available for download at https://github.com/genemine/DISHyper. Contactjxwang@mail.csu.edu.cn

systems biology↗

bioRxiv2023

'Off-pore' nucleoporins relocalize heterochromatic breaks through phase separation

Phase separation forms membraneless compartments in the nuclei, including by establishing heterochromatin "domains" and repair foci. Pericentromeric heterochromatin mostly comprises repeated sequences prone to aberrant recombination, and "safe" homologous recombination (HR) repair of these sequences requires the movement of repair sites to the nuclear periphery before Rad51 recruitment and strand invasion. How this mobilization initiates is unknown, and the contribution of phase separation to these dynamics is unclear. Here, we show that Nup98 nucleoporin is recruited to heterochromatic repair sites before relocalization through Sec13 or Nup88 nucleoporins, and downstream from the Smc5/6 complex and SUMOylation. Remarkably, the phase separation properties of Nup98 are required and sufficient to mobilize repair sites and exclude Rad51, thus preventing aberrant recombination while promoting HR repair. Disrupting this pathway results in heterochromatin repair defects and widespread chromosome rearrangements, revealing a novel "off-pore" role for nucleoporins and phase separation in nuclear dynamics and genome integrity in a multicellular eukaryote. HighlightsO_LINup88 and Sec13 recruit Nup98 to heterochromatic DSBs downstream from Smc5/6 C_LIO_LINup88, Sec13 and Nup98 promote repair focus mobilization in heterochromatin off-pore C_LIO_LINup98 excludes Rad51 from repair sites inside the heterochromatin domain C_LIO_LIPhase separation by Nup98 is required and sufficient for relocalization and Rad51 exclusion C_LI

cell biology↗

bioRxiv2023

Nitrite deteriorates bioreactor performance by reducing growth of Ca. Brocadia sapporoensis instead of inhibiting the anammox activity

Effects of nitrite on anammox activities have been of widespread concern. However, the molecular mechanisms of specific microorganisms in anammox systems responding to nitrite remain unexplored. This study investigated the effects of excess nitrite on core metabolism of AnAOB and symbiotic bacteria, and further elucidated the response mechanism of these effects on microbial growth and nitrogen removal performance. Specifically, nitrogen removal process in a continuous-flow anaerobic ammonia oxidation membrane bioreactor completely collapsed when the nitrite concentration reached 243 mg N/L. Integrated meta-omics analyses demonstrated that excess nitrite disrupted the energy metabolism of Ca. Brocadia sapporoensis (AMXB1), reducing the energy available for establishing tolerance. It disrupted cell replication by impairing biosynthesis process of AMXB1, especially DNA replication and the formation of vital cell structures, e.g., cell membrane and cell wall, as well as the cellular protection system, leading to the collapse of the anammox system. In addition, the cross-feeding of glycogen, lipopolysaccharide and amino acid between AMXB1 and symbiotic bacteria was hindered by excess nitrite, which also contributed to the anomalous cell proliferation and metabolism of AMXB1. These findings contribute to our understanding of the ability of anammox consortia to respond to nitrite stress and process stability in engineered ecosystems. HighlightsO_LINO --N concentration of 243 mg N/L caused the performance collapse of a continuous-flow anammox MBR. C_LIO_LIExcess nitrite likely disrupted the energy metabolism of AMXB1, reducing the energy availability for mitigating nitrite toxicity. C_LIO_LIThe cross-feeding between AMXB1 and symbiotic bacteria was hindered by excess nitrite. C_LIO_LIThe hindrance of cross-feeding was reversed as the concentration of nitrite decreased. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/568540v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@6b199forg.highwire.dtl.DTLVardef@15f2a74org.highwire.dtl.DTLVardef@dc2d8eorg.highwire.dtl.DTLVardef@132deb1_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2023

Bioinfo-Bench: A Simple Benchmark Framework for LLM Bioinformatics Skills Evaluation

AO_SCPLOWBSTRACTC_SCPLOWLarge Language Models (LLMs) have garnered significant recognition in the life sciences for their capacity to comprehend and utilize knowledge. The contemporary expectation in diverse industries extends beyond employing LLMs merely as chatbots; instead, there is a growing emphasis on harnessing their potential as adept analysts proficient in dissecting intricate issues within these sectors. The realm of bioinformatics is no exception to this trend. In this paper, we introduce BO_SCPLOWIOINFOC_SCPLOW-BO_SCPLOWENCHC_SCPLOW, a novel yet straightforward benchmark framework suite crafted to assess the academic knowledge and data mining capabilities of foundational models in bioinformatics. BO_SCPLOWIOINFOC_SCPLOW-BO_SCPLOWENCHC_SCPLOW systematically gathered data from three distinct perspectives: knowledge acquisition, knowledge analysis, and knowledge application, facilitating a comprehensive examination of LLMs. Our evaluation encompassed prominent models ChatGPT, Llama, and Galactica. The findings revealed that these LLMs excel in knowledge acquisition, drawing heavily upon their training data for retention. However, their proficiency in addressing practical professional queries and conducting nuanced knowledge inference remains constrained. Given these insights, we are poised to delve deeper into this domain, engaging in further extensive research and discourse. It is pertinent to note that project BO_SCPLOWIOINFOC_SCPLOW-BO_SCPLOWENCHC_SCPLOW is currently in progress, and all associated materials will be made publicly accessible.1

bioinformatics↗

bioRxiv2023

The Application of Label-free Detection Using a Tapered Optical Fiber System for Head and Neck Cancer and Infectious Biomolecules

IntroductionHead and neck squamous cell carcinoma (HNSCC) is associated with high morbidity and mortality due to late detection. Tapered optical fiber sensors (TOFS) are biosensors with the potential application as a point-of-care device for detection of HNSCC biomarkers. TOFS uses optical fibers as transduction elements and antigen-antibody binding for the detection of target biomolecules. The present TOFS system was designed to achieve high specificity, sensitivity, and repeatability. To explore its application in HNSCC, we targeted the proinflammatory cytokine IL-8, known for its role in promoting tumorigenicity, metastasis, and angiogenesis in HNSCC. To validate our proof-of-concept experiment, a viral surrogate of SARS-CoV-2, Human Coronavirus OC43 (HCoV-OC43), was also tested. MethodsOur TOFS system contains four main parts: the tapered optical fiber, reservoir (cell), laser light source, and photodetector. The fiber is bitapered with a narrow waist region that anchors antibodies to detect target biomolecules. Light is transduced by the laser to the fiber where it travels through the down-taper region to the tapered waist followed by the up-tapered region and ultimately transmitted to the photodetector. The tapered waist facilitates the transformation of a single mode light to multiple modes, which reverts to a single mode of light as it continues through the up-taper region. Biomolecules introduced to the waist region alter the effective refractive index, which is reflected in the phase change of the wavelength. This is detected by the photodetector and quantified using Fouier analysis. Our tapered fibers were designed with antigen-antibody complexes targeting IL-8 and HCoV-OC43 to validate our TOFS design across two different antigens. ResultsTOFS with tethered mouse anti-human IgG (28nm) bound to dissolved IL-8 (14 nm) produces a measurable phase shift. As little as 10pg/ml or 7.1X105 IL-8 molecules/l was detected by the prototype device and the phase change represented in real-time the binding dynamic of IL-8 to the tethered IgG. To validate our proof-of-concept experiment, HCoV-OC43 dissolved in saliva was detected with a sensitivity of 50 viruses/mL. ConclusionsTOFS device is a highly sensitive system capable of detecting proteins, viruses, and other biomolecules. Selectivity of the system is guaranteed by specific antigen-antibody binding, supported by the detection of IL-8 and HCoV-OC43 at the femtomolar level. The long-term goal for TOFS is its application as a point-of-care device used for detection, monitoring, and surveillance of HNSCC as well as detection of other pathogens in the clinical setting.

cancer biology↗

bioRxiv2023

Genetic regulation of cell-type specific chromatin accessibility shapes the etiology of brain diseases

Nucleotide variants in cell type-specific gene regulatory elements in the human brain are major risk factors of human disease. We measured chromatin accessibility in sorted neurons and glia from 1,932 samples of human postmortem brain and identified 34,539 open chromatin regions with chromatin accessibility quantitative trait loci (caQTL). Only 10.4% of caQTL are shared between neurons and glia, supporting the cell type specificity of genetic regulation of the brain regulome. Incorporating allele specific chromatin accessibility improves statistical fine-mapping and refines molecular mechanisms underlying disease risk. Using massively parallel reporter assays in induced excitatory neurons, we screened 19,893 brain QTLs, identifying the functional impact of 476 regulatory variants. Combined, this comprehensive resource captures variation in the human brain regulome and provides novel insights into brain disease etiology. One sentence summaryCell-type specific chromatin accessibility QTL reveals regulatory mechanisms underlying brain diseases.

genomics↗