Biology subjects

Gray, M.

Publications and source records attributed to Gray, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Rheumatoid Arthritis-associated IgG N-glycan agalactosylation diminishes neutrophilic inflammation by reducing FcgammaR binding and downstream signaling

The IgG Fc chain carries a single N-linked glycan which may undergo changes. Increased agalactosylated N-glycans are associated with rheumatoid arthritis (RA) and regarded as pro-inflammatory. Dysregulated neutrophils can make important contributions to host tissue damage. In RA, immune complexes (ICs) that have precipitated onto synovial joint surfaces activate neutrophils via Fc receptors, promoting localised inflammation. We engineered recombinant human monoclonal IgG with agalactosylated or galactosylated N-glycans, generated immobilised ICs and stimulated healthy donor and RA patient blood-derived neutrophils, comparing reactive oxygen species (ROS) production as read-out of neutrophilic inflammation. Both healthy donor and RA patient neutrophils generated less ROS when stimulated with ICs made from agalactosylated IgG. Mechanistically this was due to poorer binding of agalactosylated ICs to neutrophil Fc{gamma}Rs, causing lower activation of Akt and p38 MAPK. Both are required for immobilised IC-mediated stimulation of the neutrophil NADPH oxidase. Taken together, this suggests that disease-associated, agalactosylated IgG does not in fact promote inflammation and host tissue injury, at least not by acting on neutrophils. We propose that rather than promoting inflammation, agalactosylated IgG N-glycans that accompany inflammatory disease may arise as part of a compensatory mechanism that is aimed at reducing excessive inflammation and host tissue injury. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/735866v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@18a7178org.highwire.dtl.DTLVardef@1f8d75org.highwire.dtl.DTLVardef@1801a22org.highwire.dtl.DTLVardef@133e657_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

CaptureBody - an anti-CD45 x anti-IgG bispecific antibody enables accurate unmixing for spectral flow cytometry

Accurate spectral unmixing is a critical step for flow cytometry data analysis and requires a single stain control for every fluorescent parameter used in an experiment. Currently, compensation particles are often used for making single stain controls when a target protein is of low abundance or a cell type is of low frequency. However, compensation particles introduce incongruencies in emission spectra compared to cells resulting in spectral unmixing or compensation errors. To enable the use of cells regardless of the abundance of target proteins or immune cell type, we generated a bispecific antibody that links a human anti-CD45 and mouse anti-IgG variable region. We refer to this new bispecific tool as CaptureBody (CB) and highlight the benefits of its final nanobody-based design. We provide all sequences and methods necessary for the in-house expression of a CaptureBody to disseminate their use for spectral flow cytometry experiments.

immunology↗

bioRxiv2025

Low-intensity focused ultrasound to human amygdala reveals a causal role in ambiguous emotion processing and alters local and network-level activity

The amygdala is a core region changed in depression, a disorder characterized by compromised emotion, motivation and learning processes. However, lesion studies in humans examining amygdala function have largely focused on its role in processing fear. It currently remains unclear what causal role the human amygdala plays in more complex emotion, motivation and learning processes in daily life. This is because it has not been possible to reversibly modulate amygdala activity non-invasively in humans. Here, we used transcranial focused ultrasound stimulation (TUS) to bilaterally perturb neural activity in the basolateral amygdala (BLA). In separate sessions (n = 87), 29 healthy volunteers received offline-TUS to bilateral BLA, mid-insula or sham before playing a novel emotional learning task validated in an independent large cohort online (n = 210). 7T-resting-state and metabolite signals clearly demonstrated target engagement. BLA-TUS reduced the BLAs connectivity fingerprint and decreased its excitation/inhibition balance, suggesting an inhibitory effect of our TUS protocol on BLA activity. In behaviour, BLA-TUS caused a stimulation volume-dependent increase in the tendency to approach neutral, emotionally ambiguous faces, treating them more similarly to happy faces, and a slowing of reaction times for those two emotion categories. These effects were functionally and regionally specific and suggest a causal role for the amygdala in resolving emotional ambiguity. Our results provide important insights for future studies into mood disorders where ambiguous situations might be harder to resolve, which could contribute to existing emotional and learning biases.

neuroscience↗

bioRxiv2025

Astrocyte Store-Released Calcium Modulates Visual Cortex Synapse Development and Circuit Function.

Astrocytes, a major class of glial cells, are critical regulators of synapse development during early postnatal life. While dysregulation of this process is implicated in numerous neurological disorders, the precise mechanisms by which astrocytes guide synapse formation and maturation remain poorly understood. A central signaling pathway for astrocytes is the dynamic fluctuation of intracellular calcium (Ca2+), which can arise from various sources and modulate a wide range of downstream effects. A key astrocytic mechanism for integrating neuronal signals is the release of Ca2+ from endoplasmic reticulum stores mediated by the IP3 Receptor Type 2 (IP3R2). Although defects in this signaling pathway have been mainly linked to adult brain dysfunction, its role in shaping synaptic development, a period when astrocyte-neuronal communication is established, is largely unknown. Here, we investigated the role of IP3R2-mediated Ca2+ signaling in astrocyte-dependent regulation of synapse development in the mouse visual cortex. Using a combination of histological, molecular, and circuit-level approaches, we found that loss of astrocytic IP3R2 leads to significant deficits in the maturation of glutamatergic but not GABAergic synapses. These synaptic disruptions were accompanied by attenuated visually evoked neuronal activation and impaired behavioral responses to visual threat stimuli. We further show that astrocytic morphological complexity is diminished in the absence of IP3R2, suggesting that store-released Ca2+ is required for both the structural and functional maturation of astrocyte-neuron interactions. Our findings establish a critical role for astrocytic IP3R2-mediated Ca2+ signaling in shaping excitatory circuit development and the emergence of visually driven behaviors.

neuroscience↗

bioRxiv2025

Unlocking the Neuropeptidome using a Novel Endogenous Peptidomics Framework

Endogenous peptides have garnered increasing attention over the past decade driven by the development of advanced analytical methods. However, large-scale investigations of peptides as potential disease biomarkers or drug candidates are still hindered by their challenging biochemical properties and the scarcity of specialized analytical tools. Among these, neuropeptides are particularly challenging to study due to their low in vivo concentration, rapid turnover rate, and high structural variability. Data-independent acquisition (DIA) mass spectrometry (MS) has shown great ability in profiling low-abundance ions. Nevertheless, most available DIA analytical tools are designed for proteomics studies and are not suitable for endogenous peptides, as there is no set enzymatic cleavage for these peptides. Here, we introduce the novel EndoGenius platform, paired with DIA-NN, to achieve high-confidence neuropeptide identification using an updated spectral library for DIA MS analysis. By employing orthogonal offline fractionation, ion mobility instrumentation, and an optimized database searching algorithm specifically for neuropeptides, we have constructed the largest crustacean neuropeptide spectral library to date. With this library, in combination with neural networking technology, we report a 100-fold increase in the number of neuropeptides identified in all Cancer borealis tissues analyzed. We also cross-validated these findings with transcriptomics data to enhance identification confidence. This workflow presents a novel analytical framework for DIA peptidomics analysis, offering a robust approach to studying neuropeptides and other endogenous peptides. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/659356v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1bae342org.highwire.dtl.DTLVardef@9e26d8org.highwire.dtl.DTLVardef@1084f06org.highwire.dtl.DTLVardef@7c1371_HPS_FORMAT_FIGEXP M_FIG C_FIG SynopsisWe present a framework that capitalizes on robust analytical innovations and an optimized bioinformatics pipeline to provide the most comprehensive snapshot of the crustacean neuropeptidome to-date.

neuroscience↗

bioRxiv2025

DEVELOPMENT OF A POTENT MONOCLONAL ANTIBODY FOR TREATMENT OF HUMAN METAPNEUMOVIRUS INFECTIONS

Human metapneumovirus (HMPV) is a major cause of respiratory infections, particularly among vulnerable populations, yet effective therapeutics remain unavailable. Monoclonal antibodies (mAbs) offer a promising approach for both treatment and prevention. Here, we describe the discovery and characterization of 4F11, a highly potent and broadly neutralizing mAb with demonstrated in vitro and in vivo efficacy against HMPV. Using cryo-electron microscopy, we defined a unique mechanism of binding HMPV employed by 4F11, which distinguishes it from previously characterized RSV and HMPV mAbs. 4F11 targets an epitope located at the apex of the prefusion F protein (site O) with a 1:1 stoichiometry, distinct from the 3:1 stoichiometry observed with other HMPV site O antibodies. Unlike other site O antibodies, which penetrate the glycan shield between Asn57 and Asn172, 4F11 binds vertically and directly interacts with the Asn172 glycan, representing a unique glycan-dependent mode of recognition. In vitro, 4F11 displayed high potency and broad neutralization across diverse HMPV strains. It also showed a low propensity for resistance development, with only a single escape mutation (K179E) identified, a mutation not found in any published HMPV sequence to date. Viruses rescued with the K179E escape mutation had significantly decreased fitness in vitro compared to wild-type virus. In a hamster challenge model, 4F11 significantly reduced viral loads in both the lungs and nasal turbinates. These findings highlight 4F11 as a promising candidate for therapeutic development, particularly for immunocompromised individuals and other high-risk groups.

immunology↗

bioRxiv2025

Cochlin-Expressing Memory B (COMB) Cells Are Enriched in Autoimmune Diseases and Display a Distinct Activation Profile

Rheumatoid arthritis (RA) is the most common chronic autoimmune arthritis, causing joint damage and affecting multiple organs over time. B cells play a key role in driving the disease by producing autoantibodies, releasing cytokines, and presenting antigens to T cells. While B cell depletion therapies can help reduce inflammation, they remove all CD20+B cells indiscriminately, which can increase infection risk and interfere with important regulatory immune functions. To better define pathogenic B cell subsets, we performed single-cell RNA and ATAC sequencing on circulating and synovial B cells from patients with early, untreated RA. We identified a novel population of memory B cells expressing cochlin (COCH), termed cochlin - expressing memory B (COMB) cells. While detectable at low levels in healthy controls, COMB cells are significantly expanded in RA and exhibit a distinct transcriptional profile indicative of immune activation. Epigenetic analysis showed that COMB cells have more open chromatin at key immune regulatory regions, including sites bound by NF-{kappa}B family transcription factors like RELA and REL. This suggests that these cells are primed to respond to inflammatory signals. We also looked at publicly available datasets and found COMB-like cells in the blood of people with systemic lupus erythematosus (SLE) and Sjogrens syndrome (SjS), as well as in inflamed kidney tissue from patients with SLE. COMB cells across these diseases share a conserved gene expression signature, pointing to a common memory B cell programme associated with autoimmunity. These findings define COMB cells as a previously unrecognised, transcriptionally and epigenetically distinct memory B cell subset enriched across autoimmune diseases, offering new insights into B cell-mediated pathology and potential therapeutic targets.

immunology↗

bioRxiv2024

Polymorphic tandem repeats shape single-cell gene expression across the immune landscape

Tandem repeats (TRs) - highly polymorphic, repetitive sequences across the human genome - are important regulators of gene expression but remain underexplored due to challenges in accurate genotyping and analysis1. Here, we generate new whole genome and single-cell RNA sequencing from >5.4 million blood-derived cells across 1,925 individuals in two cohorts [Cuomo et al., accompanying manuscript], and perform meta-analysis to characterize the impact of variation in >1.7 million TR loci on immune cell type-specific gene expression. We identify >69,000 single-cell expression TR loci (sc-eTRs), 30.7% of which are specific to one of 28 immune cell types, and reveal dynamic regulatory effects using cell-state inference. Matched single-cell ATAC sequencing profiles from >3.4 million nuclei in 922 individuals [Xue et al., accompanying manuscript]. uncover chromatin accessibility QTLs for nearly one-third of expression-associated TRs, supporting coordinated effects on cis-regulatory architecture. Fine-mapping implicates 1,490 TRs as candidate causal drivers of gene expression in 6.1% of tested genes, and colocalization analyses highlight >200 genes in which TRs likely mediate genetic associations with immune and hematological traits. Together, these results provide a genome-wide, multiomic view of TR-mediated regulation in the human immune system, establishing TRs as key contributors to cell type-specific regulatory variation and complex trait architecture.

genomics↗

bioRxiv2024

The distribution of the hemlock woolly adelgid in Canada.

The hemlock woolly adelgid, Adelges tsugae Annand (Hemiptera: Adelgidae) has distinct native and invasive populations in Canada. On Canadas west coast the adelgid is a native insect feeding on western hemlock, Tsuga heterophylla (Raf.) Sarg. and mountain hemlock, Tsuga mertensiana (Bong.) Carriere (Pinaceae). In eastern Canada, the adelgid is an invasive species that attacks and kills eastern hemlock, Tsuga canadensis (L.) Carriere (Pinaceae). We obtained all records of A. tsugae in institutional and public databases and develop updated range maps, phenologies and dispersal estimates for the species in British Columbia and eastern Canada In British Columbia A. tsugaes distribution is centred around the lower mainland and on Vancouver Island but with populations in the interior and along the Pacific coast that have been poorly explored and which could be sources of biological control agents to manage invasive populations in the east. In eastern Canada, the adelgid has invaded all of southern Nova Scotia, portions of the Niagara region in Ontario as far west as Hamilton, and at least one site on the north shore of Lake Ontario. No populations have been found in New Brunswick, Quebec or Prince Edward Island. Finaly, we estimated the rate of spread in Nova Scotia at 12.6 {+/-} 8.2 to 20.5 {+/-} 27.21 km/year.

ecology↗

bioRxiv2024

Runaway resorption of microcracks contributes to age-related hip-fracture patients

Microdefects, including microcracks and resorption trenches, may be important contributors to bone fragility. 3D microdefect morphology was imaged using synchrotron micro-CT to develop a classification system for investigating the relationship with bone mechanics and hip-fractures. Femoral heads from ageing hip-fracture patients (n=5, 74-82 years) were compared to ageing non-fracture controls (n=5, 72-84 years). Two trabecular cores were prepared from the chiasma; one was imaged using synchrotron micro-CT to measure microdefects and one was mechanically tested to measure tensile strength. Morphological and mechanical data were compared and correlated using Mann Whitney U test and Pearsons rank correlation. Microdefects varied and were classified into four categories based on shape and measurable parameters. Hip-fracture donors exhibited significantly higher density of all microdefects (p<0.05). Microdefect volume was strongly negatively correlated with ultimate tensile strength (p<0.05) and stiffness (p<0.05). Microdefects might contribute to loss of bone strength and fragility fracture via runaway resorption. Microcracks could promote focussed osteoclastic resorption and the formation of resorption pits which create stress risers leading to the re-formation of microcracks under continued load. CT-based classification methods should be used to explore the complex interaction between microdefects, metabolism, and bone fracture mechanics.

bioengineering↗

bioRxiv2024

Airway succinate chemosensing induces CFTR-dependent anion secretion and mucus clearance which is impaired in cystic fibrosis.

The respiratory tract possesses a highly regulated innate defense system which includes efficient cilia-mediated mucus transport or mucociliary clearance (MCC). This essential process relies on appropriate hydration of airway surfaces which is controlled by a blend of transepithelial sodium and liquid absorption via the epithelial sodium channel (ENaC), and anion and liquid secretion, primarily regulated by the cystic fibrosis transmembrane conductance regulator (CFTR) channel. MCC is tightly regulated by second messenger signalling pathways. Succinate is derived from parasites, microorganisms and inflammatory cells, and its concentration increases in the airway surface liquid (ASL) during infections. Increases in ASL succinate activates the G-protein coupled succinate receptor (SUCNR1), which acts as a succinate sensor. Here, we tested the hypothesis that succinate signalling was linked to CFTR activity, ASL hydration and increased MCC. We observed that SUCNR1 activation stimulated anion secretion, increased mucus transport and induced bronchoconstriction in mouse airways. In parallel, stimulation of human bronchial epithelial cells (HBEC) with succinate activated anion secretion and increased ASL height. All functions activated by succinate/SUCNR1 were impeded when working with tissues and cells isolated from animal models or individuals affected cystic fibrosis (CF) or when CFTR was inhibited. Moreover, when HBECs derived from {Delta}F508 individuals were incubated with the triple drug combination of elexacaftor/tezacaftor/ivacaftor (ETI), succinate-induced anion secretion was restored, confirming the tight relationship between SUCNR1 signalling and CFTR function. Our results identify a novel activation pathway for CFTR that participates in the defence response of the airways, which is defective in CF. We propose that succinate acts as a danger molecule that alerts the airways to the presence of pathogens leading to a flushing out of the airways.

physiology↗

bioRxiv2023

Geographic risk assessment of Batrachochytrium salamandrivorans invasion in Costa Rica as a means of informing emergence management and mitigation

Remotely-sensed risk assessments of emerging, invasive pathogens are key to targeted surveillance and outbreak responses. The recent emergence and spread of the fungal pathogen, Batrachochytrium salamandrivorans (Bsal), in Europe has negatively impacted multiple salamander species. Scholars and practitioners are increasingly concerned about the potential consequences of this lethal pathogen in the Americas, where salamander biodiversity is higher than anywhere else in the world. Although Bsal has not yet been detected in the Americas, certain countries have already proactively implemented monitoring and detection plans in order to identify areas of greatest concern and enable efficient contingency planning in the event of pathogen detection. To predict areas in Costa Rica with a high Bsal transmission risk, we employed ecological niche modeling combined with biodiversity and tourist visitation data to ascertain the specific risk to a country with world renowned biodiversity. Our findings indicate that approximately 23% of Costa Ricas landmass provides suitable conditions for Bsal, posing a threat to 37 salamander species. The Central and Talamanca mountain ranges, in particular, have habitats predicted to be highly suitable for the pathogen. To facilitate monitoring and mitigation efforts, we identified eight specific protected areas that we believe are at the greatest risk due to a combination of high biodiversity, tourist visitation, and suitable habitat for Bsal. We advise regular monitoring utilizing remotely-sensed data and ecological niche modeling to effectively target in-situ surveillance and as places begin implementing educational efforts.

ecology↗

bioRxiv2023

SparseRNAFolD: Sparse RNA pseudoknot-free Folding including Dangles

MotivationComputational RNA secondary structure prediction by free energy minimization is indispensable for analyzing structural RNAs and their interactions. These methods find the structure with the minimum free energy (MFE) among exponentially many possible structures and have a restrictive time and space complexity (O(n3) time and O(n2) space for pseudoknot-free structures) for longer RNA sequences. Furthermore, accurate free energy calculations including dangles contributions can be difficult and costly to implement, particularly when optimizing for time and space requirements. ResultsHere we introduce a fast and efficient sparsified MFE pseudoknot-free structure prediction algorithm, SparseRNAFolD, that utilizes an accurate energy model that accounts for dangles contributions. While sparsification technique was previously employed to improve time and space complexity of a pseudoknot-free structure prediction method with a realistic energy model, SparseMFEFold, it was not extended to include dangles contributions due to complexity of computation. This may be at the cost of prediction accuracy. In this work, we compare three different sparsified implementations for dangles contributions and provide pros and cons of each method. As well, we compare our algorithm to LinearFold, a linear time and space algorithm, where we find in practice, SparseRNAFolD has lower memory consumption across all lengths of sequence and a faster time for lengths up to 1000 bases. ConclusionOur SparseRNAFolD algorithm is an MFE-based algorithm that guarantees optimality of result and employs the most general energy model including dangles contributions. We provide basis for applying dangles to sparsified recursion in a pseudoknot-free model which has the ability to be extended to pseudoknots. AvailabilitySparseRNAFolDs algorithm and detailed results are available at https://github.com/mateog4712/SparseRNAFolD.

bioinformatics↗

bioRxiv2023

A comprehensive analysis of rheumatoid arthritis B cells reveals the importance of CD11c+ve double-negative-2 B cells as the major synovial plasma cell precursor.

B cells are key pathogenic drivers of chronic inflammation in rheumatoid arthritis (RA). There is limited understanding of the relationship between synovial B cell subsets and pathogenic antibody secreting cells (ASCs). This knowledge is crucial for the development of targeted therapies. Here, we combine flow cytometry of circulating B cells with single-cell RNA and paired repertoire sequencing of over 27,000 synovial B cells from patients with established RA. Twelve B cell clusters were identified including previously recognised subsets, and a novel cluster that strongly expressed heat shock proteins. All lineages identified by trajectory analysis contribute to the DN2 B cell population, which is the major precursor to synovial ASCs. This was further supported by B cell receptor (BCR) lineage analysis, which revealed clonal relationships between DN2 cells and ASCs. This study advances our understanding of B cells in RA and reveals the origin of pathogenic ASCs in the RA synovium.

immunology↗

bioRxiv2021

Inhibition of the sodium-dependent HCO3 -transporter SLC4A4, produces a cystic fibrosis-like airway disease phenotype.

Bicarbonate secretion is a fundamental process involved in maintaining acid-base homeostasis. Disruption of bicarbonate entry into airway lumen, as has been observed in cystic fibrosis, produces several defects in lung function due to thick mucus accumulation. Bicarbonate is critical for correct mucin deployment and there is increasing interest in understanding its role in airway physiology, particularly in the initiation of lung disease in children affected by cystic fibrosis, in the absence of detectable bacterial infection. The current model of anion secretion in mammalian airways consists of CFTR and TMEM16A as apical anion exit channels, with limited capacity for bicarbonate transport compared to chloride. However, both channels can couple to SLC26A4 anion exchanger to maximise bicarbonate secretion. Nevertheless, current models lack any details about the identity of the basolateral protein(s) responsible for bicarbonate uptake into airway epithelial cells. We report herein that the electrogenic, sodium-dependent, bicarbonate cotransporter, SLC4A4, is expressed in the basolateral membrane of human and mouse airways, and that its pharmacological inhibition or genetic silencing reduces bicarbonate secretion. In fully differentiated primary human airway cells, SLC4A4 inhibition induced an acidification of the airways surface liquid and markedly reduced the capacity of cells to recover from an acid load. Studies in the Slc4a4-null mice revealed a previously unreported lung phenotype, characterized by mucus accumulation and reduced mucociliary clearance. Collectively, our results demonstrate that the reduction of SLC4A4 function induced a CF-like phenotype, even when chloride secretion remained intact, highlighting the important role SLC4A4 plays in bicarbonate secretion and mammalian airway function.

physiology↗

bioRxiv2020

Decreased calmodulin recruitment triggers PMCA4 dysfunction and pancreatic injury in cystic fibrosis

Exocrine pancreatic damage is a common complication of cystic fibrosis (CF), which can significantly debilitate the quality of life and life expectancy of CF patients. The cystic fibrosis transmembrane conductance regulator (CFTR) has a major role in pancreatic ductal ion secretion, however, it presumably has an influence on intracellular signaling as well. Here we describe in multiple model systems, including iPSC-derived human pancreatic organoids from CF patients, that the activity of PMCA4 is impaired by the decreased expression of CFTR in ductal cells. The regulation of PMCA4, which colocalizes and physically interacts with CFTR on the apical membrane of the ductal cells, is dependent on the calmodulin binding ability of CFTR. Moreover, CFTR seems to be involved in the process of the apical recruitment of calmodulin, which enhances its role in calcium signaling and homeostasis. Sustained intracellular Ca2+ elevation in CFTR KO cells undermined the mitochondrial function and increased apoptosis. Based on these, the prevention of sustained intracellular Ca2+ overload may improve the exocrine pancreatic function and may have a potential therapeutic aspect in CF.

cell biology↗

bioRxiv2020

Detection of a multi-disease biomarker in Salivawith Graphene Field Effect Transistors

Human carbonic anhydrase 1 (CA1) has been suggested as a biomarker for identification of several diseases including cancers, pancreatitis, diabetes, and Sjogrens syndrome. However, the lack of a rapid, cheap, accurate, and easy-to-use quantification technique has prevented widespread utilization of CA1 for practical clinical applications. To this end, we present a label-free electronic biosensor for detection of CA1 utilizing highly sensitive graphene field effect transistors (G-FETs) as a transducer and specific RNA aptamers as a probe. The binding of CA1 with aptamers resulted in a positive shift in Dirac voltage VD of the G-FETs, the magnitude of which depended on target concentration. These aptameric G-FET biosensors showed the binding affinity (KD) of [~] 2.3 ng/ml (70 pM), which is four orders lower than that reported using a gel shift assay. This lower value of KD enabled us to achieve a detection range (10 pg/ml - 100 ng/ml) which is well in line with the clinically relevant range. These highly sensitive devices allowed us to further prove their clinical relevance by successfully detecting the presence of CA1 in human saliva samples. Utilization of this label-free biosensor could facilitate the early stage identification of various diseases associated with changes in concentration of CAs.

biophysics↗

bioRxiv2020

Deaf intermarriage does not increase the prevalence of deafness alleles

The idea that deaf intermarriage increases deafness was forcefully pushed in the late 19th century by Alexander Graham Bell, in proceedings published by the National Academy of Science. Bells hypothesis was not supported by a 19th century study by Edward Allen Fay, which was funded by Bells own organization, the Volta Bureau. The Fay study showed through an analysis of 4,471 deaf marriages that the chances of having deaf children did not increase significantly when both parents were deaf. In light of an apparent increase in non-complementary pairings when a recent dataset of Gallaudet alumni was compared with the 19th century Fay dataset, Bells argument has been resurrected that residential schools for the deaf, which concentrate signing deaf individuals together, have promoted assortative mating and increased the prevalence of both phenotypic deafness and the commonest recessive deafness allele. Because this hypothesis persists, even though it contradicts classical models introduced by R.A. Fisher and Sewell Wright, it is critically important that this hypothesis be thoroughly re-investigated. In this study, we used an established forward-time genetics simulator with parameters and measurements collected from the published literature. Compared to mathematical equations, simulations allowed for more complex modeling, operated without assumptions of parametricity, and captured ending distributions and variances. Our simulation results affirm predictions from classical equations and show that assortative mating only modestly increases the prevalence of phenotypically deaf individuals, with this effect mostly completed by the third generation. Most importantly, our data show that even intense assortative mating does not increase allelic frequency under reported conditions. These results are not locus-specific and are generalizable to other forms of recessive deafness. We offer alternative explanations for the higher rate of non-complementary pairings measured in the contemporary Gallaudet alumni sample as compared to the Fay dataset.

genetics↗