Biology subjects

Woo, J.

Publications and source records attributed to Woo, J..

47 records · Page 3Linked to original sources

bioRxiv2021

The African mosquito-borne diseasosome: Geographical patterns and range expansion

Mosquito-borne diseases (MBDs) such as malaria, dengue, and Rift Valley fever threaten public health and food security globally. Despite their cohesive nature, they are typically treated as distinct entities. Applying biological system analysis to the African MBDs from a One Health perspective, we provide the first biogeographic description of the African mosquito fauna corresponding with the pathogens they transmit. After compiling records accumulated over a century, we find that there are 677 mosquito species in Africa, representing 16 genera, and 151 mosquito-borne pathogens (MBPs) circulating primarily among wild tetrapods, dominated by viruses (95) and protozoans (47). We estimate that reported MBPs represent [~]1% of the actual number. Unlike mosquitoes, African arboviruses and mammalian plasmodia represent a higher share of the Worlds total based on the area - species richness relationship (P<0.0001), explaining the disproportional large share of global MBPs that originated from Africa. Species richness of African mosquitoes and MBPs are similarly concentrated along the equator, peaking in central Africa, with a secondary "ridge" along eastern Africa. Moderate diversity and low endemicity in mosquitoes across the Sahel reveals a fauna with high propensity for long-range migration. Regional differences in species richness, endemicity, and composition agreed with country-based results. The composition of mosquitoes and MBPs separates sub-Saharan Africa from north Africa, in accordance with the Palearctic and Afrotropical faunal realms, and west and central Africa are clustered together distinctly from the cluster of eastern and southern Africa. With [~]25% of the species occupying a single country, [~]50% in 1-3 countries and <5% found in >25 countries, the typical ranges of both mosquitoes and MBPs are surprisingly small. The striking similarity in diversity and especially in range distributions of mosquitoes and MBPs suggest that most MBPs are transmitted by one or few narrow-range mosquito vectors. Exceptionally widespread mosquito species (e.g., Ae. aegypti, Cx. quinquefasciatus, and 10 Anopheles species) feed preferentially on people and domestic animals, and nearly half are windborne migrants. Likewise, exceptionally widespread MBPs are transmitted between people or domestic animals and are vectored by one or more of the aforementioned widespread mosquitoes. Our results suggest that few MBPs have undergone a dramatic range expansion, after adapting to people or domestic animals as well as to exceptionally-widespread mosquitoes. During the intermediate phase of range expansion, MBPs extend their vector and vertebrate host ranges with a concomitant gradual increase in geographical range. Because range size may serve as a marker of the phase of range expansion, ranking the African MBPs according to range, we identified several MBPs that pose elevated risk for disease emergence (e.g., Wesselsbron virus). Taken together, our database, approach, and results can help improve MBD surveillance and lead to a better understanding of disease emergence. This knowledge has the potential to improve capacity to prevent and mitigate new and emerging MBD threats.

zoology↗

bioRxiv2021

HLA-dependent variation in SARS-CoV-2 CD8+ T cell cross-reactivity with human coronaviruses

Pre-existing T cell immunity to SARS-CoV-2 in individuals without prior exposure to SARS-CoV-2 has been reported in several studies. While emerging evidence hints toward prior exposure to common-cold human coronaviruses (HCoV), the extent of- and conditions for-cross-protective immunity between SARS-CoV-2 and HCoVs remain open. Here, by leveraging a comprehensive pool of publicly available functionally evaluated SARS-CoV-2 peptides, we report 126 immunogenic SARS-CoV-2 peptides with high sequence similarity to 285 MHC-presented target peptides from at least one of four HCoV, thus providing a map describing the landscape of SARS-CoV-2 shared and private immunogenic peptides with functionally validated T cell responses. Using this map, we show that while SARS-CoV-2 immunogenic peptides in general exhibit higher level of dissimilarity to both self-proteome and -microbiomes, there exist several SARS-CoV-2 immunogenic peptides with high similarity to various human protein coding genes, some of which have been reported to have elevated expression in severe COVID-19 patients. We then combine our map with a SARS-CoV-2-specific TCR repertoire data from COVID-19 patients and healthy controls and show that whereas the public repertoire for the majority of convalescent patients are dominated by TCRs cognate to private SARS-CoV-2 peptides, for a subset of patients, more than 50% of their public repertoires that show reactivity to SARS-CoV-2, consist of TCRs cognate to shared SARS-CoV-2-HCoV peptides. Further analyses suggest that the skewed distribution of TCRs cognate to shared and private peptides in COVID-19 patients is likely to be HLA-dependent. Finally, by utilising the global prevalence of HLA alleles, we provide 10 peptides with known cognate TCRs that are conserved across SARS-CoV-2 and multiple human coronaviruses and are predicted to be recognised by a high proportion of the global population. Overall, our work indicates the potential for HCoV-SARS-CoV-2 reactive CD8+ T cells, which is likely dependent on differences in HLA-coding genes among individuals. These findings may have important implications for COVID-19 heterogeneity and vaccine-induced immune responses as well as robustness of immunity to SARS-CoV-2 and its variants.

immunology↗

bioRxiv2021

Neural correlates of individual differences in speech-in-noise performance in a large cohort of cochlear implant users

ObjectivesUnderstanding speech in noise (SiN) is a complex task that recruits multiple cortical subsystems. Individuals vary in their ability to understand SiN. This cannot be explained by simple peripheral hearing profiles, but recent work by our group (Kim et al., 2021, Neuroimage) highlighted central neural factors underlying the variance in SiN ability in normal hearing (NH) subjects. The current study examined neural predictors of speech-in-noise ability in a large cohort of cochlear-implant (CI) users, with the long-term goal of developing a simple electrophysiological correlate that could be implemented in clinics. DesignWe recorded electroencephalography (EEG) in 114 post-lingually deafened CI users while they completed the California Consonant Test (CCT): a word-in-noise task. In many subjects, data were also collected on two other commonly used clinical measures of speech perception: a word-in-quiet task (Consonant-Nucleus-Consonant [CNC]) word and a sentence-in-noise task (AzBio sentences). Neural activity was assessed at a single vertex electrode (Cz), to maximize generalizability to clinical situations. The N1-P2 complex of event-related potentials (ERPs) at this location were included in multiple linear regression analyses, along with several other demographic and hearing factors as predictors of speech in noise performance. ResultsIn general, there was a good agreement between the scores on the three speech perception tasks. ERP amplitudes did not predict AzBio performance which was predicted by the duration of device use, low-frequency hearing thresholds, and age. However, ERP amplitudes were strong predictors for performance for both word recognition tasks: the CCT (which was conducted simultaneously with EEG recording), and the CNC (conducted offline). These correlations held even after accounting for known predictors of performance including residual low-frequency hearing thresholds. In CI-users, better performance was predicted by an increased cortical response to the target word, in contrast to previous reports in normal-hearing subjects in whom speech perception ability was accounted for by the ability to suppress noise. ConclusionsThese data indicate a neurophysiological correlate of speech-in-noise performance that can be relatively easily captured within the clinic, thereby revealing a richer profile of an individuals hearing performance than shown by psychoacoustic measures alone. These results also highlight important differences between sentence and word recognition measures of performance and suggest that individual differences in these measures may be underwritten by different mechanisms. Finally, the contrast with prior reports of NH listeners in the same task suggests CI-users performance may be explained by a different weighting of neural processes than NH listeners.

neuroscience↗

bioRxiv2021

Astrocytes render memory flexible

Cognitive flexibility is an essential ability to adapt to changing environment and circumstances. NMDAR has long been implicated in cognitive flexibility, but the precise molecular and cellular mechanism is not well understood. Here, we report that astrocytes regulate NMDAR tone through Best1-mediated glutamate and D-serine release, which is critical for cognitive flexibility. Co-release of D-serine and glutamate is required for not only homosynaptic LTD but also heterosynaptic LTD, which is induced at unstimulated synapses upon release of norepinephrine and activation of astrocytic 1-AR during homosynaptic LTP. Remarkably, heterosynaptic LTD at unstimulated synapses during memory acquisition is required for later repotentiation LTP during reversal learning, laying a foundation for flexible memory and cognitive flexibility. Our study sheds light on the pivotal role of astrocytes in orchestrating multiple synapses during memory formation and determining the fate of consolidated memory to be retained as a flexible memory. HighlightsO_LIAstrocytes regulate NMDAR tone via Best1-mediated glutamate and D-serine release C_LIO_LIActivation of astrocytic 1-AR induces heterosynaptic LTD via NMDAR tone C_LIO_LIHeterosynaptic LTD is required for repotentiation LTP and spatial reversal learning C_LIO_LIAstrocytic regulation of NMDAR tone is critical for metaplasticity and flexible memory C_LI

neuroscience↗

bioRxiv2021

High-throughput and high-efficiency sample preparation for single-cell proteomics using a nested nanowell chip

Global quantification of protein abundances in single cells would provide more direct information on cellular function phenotypes and complement transcriptomics measurements. However, single-cell proteomics (scProteomics) is still immature and confronts technical challenges, including limited proteome coverage, poor reproducibility, as well as low throughput. Here we describe a nested nanoPOTS (N2) chip to dramatically improve protein recovery, operation robustness, and processing throughput for isobaric-labeling-based scProteomics workflow. The N2 chip allows reducing cell digestion volume to <30 nL and increasing processing capacity to > 240 single cells in one microchip. In the analysis of [~]100 individual cells from three different cell lines, we demonstrate the N2 chip-based scProteomics platform can robustly quantify [~]1500 proteins and reveal functional differences. Our analysis also reveals low protein abundance variations (median CVs < 16.3%), highlighting the utility of such measurements, and also suggesting the single-cell proteome is highly stable for the cells cultured under identical conditions.

systems biology↗

bioRxiv2021

Robust, sensitive, and quantitative single-cell proteomics based on ion mobility filtering

Unbiased single-cell proteomics (scProteomics) promises to advance our understanding of cell functions within complex biological systems. However, a major challenge for current methods is their ability to identify and provide accurate quantitative information for low abundance proteins. Herein, we describe an ion mobility-enhanced mass spectrometry acquisition and peptide identification method, TIFF (Transferring Identification based on FAIMS Filtering), designed to improve the sensitivity and accuracy of label-free scProteomics. TIFF significantly extends the ion accumulation times for peptide ions by filtering out singly charged background ions. The peptide identities are then assigned by a 3-dimensional MS1 feature matching approach (retention time, accurate mass, and FAIMS compensation voltage). The TIFF method enabled unbiased proteome analysis to a depth of >1,700 proteins in single HeLa cells with >1,100 proteins consistently quantified. As a demonstration, we applied the TIFF method to obtain temporal proteome profiles of >150 single murine macrophage cells during a lipopolysaccharide stimulation experiment and identified time-dependent proteome profiles.

systems biology↗

bioRxiv2020

Evaluating performance of existing computational models in predicting CD8+ T cell pathogenic epitopes and cancer neoantigens

T cell recognition of a cognate peptide-MHC complex (pMHC) presented on the surface of infected or malignant cells, is of utmost importance for mediating robust and long-term immune responses. Accurate predictions of cognate pMHC targets for T Cell Receptors (TCR) would greatly facilitate identification of vaccine targets for both pathogenic diseases as well as personalized cancer immunotherapies. Predicting immunogenic peptides therefore has been at the centre of intensive research for the past decades but has proven challenging. Although numerous models have been proposed, performance of these models has not been systematically evaluated and their success rate in predicting epitopes in the context of human pathology, has not been measured and compared. In this study, we evaluated the performance of several publicly available models, in identifying immunogenic CD8+ T cell targets in the context of pathogens and cancers. We found that for predicting immunogenic peptides from an emerging virus such as SARS-CoV-2, none of the models perform substantially better than random or offer considerable improvement beyond HLA ligand prediction. We also observed suboptimal performance for predicting cancer neoantigens. Through investigation of potential factors associated with ill performance of models, we highlight several data- and model-associated issues. In particular, we observed that cross-HLA variation in the distribution of immunogenic and non-immunogenic peptides in training data of the models seem to substantially confound the predictions. We additionally compared key parameters associated with immunogenicity between pathogenic peptides and cancer neoantigens and observed evidence for differences in the thresholds of binding affinity and stability, which suggested the need to modulate different features in identifying immunogenic pathogen vs. cancer peptides. Overall, we demonstrate that accurate and reliable prediction of immunogenic CD8+ T cell targets remains unsolved, thus we hope our work will guide users and model developers regarding potential pitfalls and unsettled questions in existing immunogenicity predictors.

immunology↗

bioRxiv2020

Thermosensitivity of the voltage-dependent activation of calcium homeostasis modulator 1 (calhm1) ion channel

Calcium homeostasis modulator 1 (calhm1) proteins form an outwardly rectifying nonselective ion channel having exceedingly slow kinetics and low sensitivity to voltage that is shifted by lowering extracellular Ca2+ ([Ca2+]e). Here we found that physiological temperature dramatically facilitates the voltage-dependent activation of the calhm1 current (Icalhm1); increased amplitude (Q10, 7-15) and fastened speed of activation. Also, the leftward shift of the half-activation voltage (V1/2) was similary observed in the normal and lower [Ca2+]e. Since calhm1 is highly expressed in the brain and taste cells, the thermosensitivity should be considered in their electrophysiology.

physiology↗

bioRxiv2020

Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters

SARS-CoV-2 infection results in viral burden in the upper and lower respiratory tract, enabling transmission and often leading to substantial lung pathology. Delivering the antiviral treatment directly to the lungs has the potential to improve lung bioavailability and dosing efficiency. As the SARS-CoV-2 Receptor Binding Domain (RBD) of the Spike (S) is increasingly deemed to be a clinically validated target, RBD-specific B cells were isolated from patients following SARS-CoV-2 infection to derive a panel of fully human monoclonal antibodies (hmAbs) that potently neutralize SARS-CoV-2. The most potent hmAb, 1212C2 was derived from an IgM memory B cell, has high affinity for SARS-CoV-2 RBD which enables its direct inhibition of RBD binding to ACE2. The 1212C2 hmAb exhibits in vivo prophylactic and therapeutic activity against SARS-CoV-2 in hamsters when delivered intraperitoneally, achieving a meaningful reduction in upper and lower respiratory viral burden and lung pathology. Furthermore, liquid nebulized inhale treatment of SARS-CoV-2 infected hamsters with as low as 0.6 mg/kg of inhaled dose, corresponding to approximately 0.03 mg/kg of lung deposited dose, mediated a reduction in respiratory viral burden that is below the detection limit, and mitigated lung pathology. The therapeutic efficacy achieved at an exceedingly low-dose of inhaled 1212C2 supports the rationale for local lung delivery and achieving dose-sparing benefits as compared to the conventional parenteral route of administration. Taken together, these results warrant an accelerated clinical development of 1212C2 hmAb formulated and delivered via inhalation for the prevention and treatment of SARS-CoV-2 infection.

immunology↗

bioRxiv2020

TRANsCre-DIONE transdifferentiates scar-forming reactive astrocytes into functional motor neurons

In spinal cord injury (SCI), the scar-forming reactive astrocytes with upregulated GFAP proliferate aberrantly near the injury site, allowing themselves as a prime target for transdifferentiation into neurons to replenish dead neurons. However, the conventional use of GFAP promoter to target reactive astrocytes has two inherent problems: inadvertent conversion of normal astrocytes and low efficiency due to progressive weakening of promoter activity during transdifferentiation. Here, we report that the scar-forming reactive astrocytes are selectively transdifferentiated into neurons with 87% efficiency and 96% specificity via TRANsCre-DIONE, a combination of the split-Cre system under two different promoters of GFAP and Lcn2 and a Cre-loxP-dependent inversion and expression of Neurog2 under the strong EF1 promoter. After SCI, TRANsCre-DIONE caused transdifferentiation into Isl1-positive motor neurons, reduced astrogliosis, enhanced regeneration in surrounding cells, and a significant motor recovery. Our study proposes TRANsCre-DIONE as the next-generation therapeutic approach for patients suffering from SCI. HighlightsTRANsCre-DIONE converts reactive astrocyte into neuron by over-expression of Neurog2 Reactive astrocytes are targeted using split-Cre under two promoters, GFAP and Lcn2 TRANsCre-DIONE reduces reactivity, replaces dead neurons and alleviates symptom of SCI Transdifferentiated-neurons are GABA+ in the striatum and Isl1+ in the spinal cord

neuroscience↗

bioRxiv2019

Genomic programming of antigen cross-presentation in IRF4-expressing human Langerhans cells

Langerhans cells (LCs) in the epidermis present MHC I and MHC II-restricted antigens thereby priming either CD8 or CD4 T cell immune responses. The genomic programs and transcription factors regulating antigen presentation in LCs remain to be elucidated. We show human LCs are highly efficient in MHC I-antigen cross-presentation but lack the transcription factor IRF8 that is critical in dendritic cells. LC migration from the epidermis enhances their ability to cross-present antigens and is accompanied by the induction of the transcription factor IRF4, whose expression is correlated by scRNA-seq with genes involved in ubiquitin-dependent protein degradation. Chromatin profiling reveals enrichment of EICE and AICE composite DNA binding motifs in regulatory regions of antigen-presentation genes, which can be recognized by IRF4 in conjunction with PU.1 or BATF3 expressed in LCs. Thus, the genomic programming of human LCs including inducible expression of IRF4 with enhanced cross-presentation distinguishes them from conventional dendritic cells.

immunology↗