Biology subjects

Patterson, K.

Publications and source records attributed to Patterson, K..

12 recordsLinked to original sources

bioRxiv2026

Building an Interoperable Rare Disease Multi-omic Resource: The GREGoR Data Model and Dataset

Rare disease research and diagnosis rely on the integration of genomic and phenotypic data generated across diverse clinical sites; however, the absence of widely adopted standards for representing genomic data and associated metadata has limited data interoperability, reuse, and cross-study analysis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was established to investigate challenging rare disease cases and evaluate emerging multi-omic technologies for clinical translation. To support coordinated data integration across distributed research sites, we developed a common Consortium Data Model in partnership with domain experts to standardize the capture of participant-, family-, phenotype- and assay-level metadata, with a particular emphasis on using a modular architecture to support linking of multiple data versions from multiple omic technologies to a single individual and attribution of a genetic finding to the specific technology used for its initial discovery. Adoption of the GREGoR Data Model has enabled continued generation and public release of a harmonized, analysis-ready Consortium Dataset. The most recent release includes phenotypic, family and multi-omic data from 12,292 participants in 5,029 families. Other rare disease data sharing efforts are beginning to adopt this data model which will facilitate cross consortium analyses and empower rare disease research. This work demonstrates that a collaborative, flexible, and scalable data model can enable large-scale rare disease research, facilitate cross-center data harmonization, and enable data interoperability.

genomics↗

bioRxiv2025

Ex Vivo Testing of Inflatable Penile Prosthesis in Human Cadaveric Penis with Paired in Silico Model offering Surgical and Biomechanical Insights

BackgroundInflatable penile prostheses (IPPs) are a critical solution for patients with erectile dysfunction refractory to medical therapy. However, a detailed understanding of their mechanical interaction with penile tissues remains limited. AimTo develop and validate an innovative experimental-computational framework for studying IPP behaviour through ex vivo implantation and inflation testing in human cadaveric penile tissue, paired with a finite element-based (FE-based) computational model. MethodsAn AMS 700 IPP was surgically implanted into a human cadaveric penis (including the glans and [~]15 cm of shaft) using standard clinical techniques. The cylinders were placed within the corpora cavernosa, with the pump and reservoir positioned externally in a closed hydraulic loop. An inflation test was performed ex vivo, with real-time ultrasound imaging used to monitor cylinder expansion. Internal pressure was recorded using a digital barometer. Following inflation, sectional analysis enabled 3D approximation of penile shaft geometry. A representative FE-based computational model was developed, incorporating anatomically accurate tissue layers--tunica albuginea (TA), corpus cavernosa (CC), corpus spongiosum (CS), and fascia--with realistic material properties to simulate the inflation process. OutcomesThis study enabled the mechanical response of penile tissues to IPP inflation to be quantified using both experimental and computational modalities. ResultsThe combined use of ultrasound imaging and digital pressure monitoring successfully captured dynamic IPP behaviour during inflation. The FE model reproduced experimental outcomes with good fidelity, providing a detailed understanding of stress distribution and tissue deformation. Clinical ImplicationsThis integrated approach can inform future IPP design improvements and aid surgeons in preoperative planning by offering predictive insights into prosthesis-tissue interaction. Strengths & LimitationsA major strength of this study is the novel integration of cadaveric experimentation with computational modelling. However, limitations include the absence of active physiological responses and potential variability due to cadaveric tissue properties. ConclusionThis pioneering work establishes a robust platform for studying IPP mechanics in realistic anatomical contexts, with promising implications for optimising device design and improving patient outcomes in urologic surgery.

bioengineering↗

bioRxiv2025

Hidden hematological, biochemical and immune costs of asymptomatic malaria infections in semi-wild chimpanzees

The health consequences of Plasmodium infections in wild great apes, particularly in asymptomatic animals, remain poorly understood. This study investigated the hematological and immune impacts of natural malaria infections in 27 semi-wild chimpanzees (Pan troglodytes troglodytes) from Gabon. Using MinION sequencing and species-specific PCR, results showed a 48.15% overall Plasmodium infection rate, with frequent multi-species co-infections involving Plasmodium gaboni, Plasmodium reichenowi, and Plasmodium vivax-like parasites. In addition, younger animals were significantly more infected and exhibited higher parasitemia levels, especially those with triple infections involving P. vivax-like. Profiling of 15 hematological markers and 8 cytokines/chemokines known to be associated with malarial infections in humans revealed significant alterations in infected chimpanzees, including elevated urea, reduced creatinine, and increased systemic concentrations of pro-inflammatory (TNF, IL-1{beta}, CCL3) and anti-inflammatory (IL-10) cytokines. Ex vivo PBMC stimulation yielded higher IL-10 in infected than non-infected individuals, indicating a regulatory-skewed cytokine response at the time of sampling. These results suggest that malaria in chimpanzees is associated with systemic immune modulation and accompanied by signs of physiological stress, including potential renal dysfunction. This study challenges the assumption that chronic Plasmodium infections are entirely benign in great apes and highlight the need to integrate immunological health indicators into conservation strategies. Broader immune profiling and longitudinal studies will be essential in the future to assess long-term health outcomes and resilience in these endangered populations.

evolutionary biology↗

bioRxiv2025

Cell modeling and rescue of a novel non-coding genetic cause of Glycogen Storage Disease IX

Delayed diagnosis of Mendelian disease substantially prevents early therapeutic intervention that could improve symptoms and prognosis. One major contributing challenge is the functional interpretation of non-coding variants that cause disease by altering splicing and/or gene expression. We identified two siblings with glycogen storage disease (GSD) type IX {gamma}2, both of whom had a classic clinical presentation, enzyme deficiency, and a known pathogenic splice acceptor variant on one allele of PHKG2. Despite the autosomal recessive nature of the disease, no variant on the second allele was identified by gene panel sequencing. To identify a potential missing second pathogenic variant, we completed whole genome sequencing (WGS) and detected putative deep intronic splicing variant in PHKG2 in both siblings. We confirmed the functional splicing effects of this variant using short-read and long-read RNA-seq on patient blood and a HEK293T cell model in which we installed the variant using CRISPR editing. Using the cell model, we demonstrated multiple biochemical and cellular impacts that are consistent with GSD IX {gamma}2, and a reversal of aberrant splicing using antisense splice-switching oligonucleotides. In doing so, we demonstrate a novel and robust pathway for detecting, validating, and reversing the impacts of novel non-coding causes of rare disease.

genetics↗

bioRxiv2020

Targeted long-read sequencing resolves complex structural variants and identifies missing disease-causing variants

BACKGROUNDDespite widespread availability of clinical genetic testing, many individuals with suspected genetic conditions do not have a precise diagnosis. This limits their opportunity to take advantage of state-of-the-art treatments. In such instances, testing sometimes reveals difficult-to-evaluate complex structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in specific genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. METHODSTargeted long-read sequencing (T-LRS) was performed on 33 individuals using Read Until on the Oxford Nanopore platform. This method allowed us to computationally target up to 100 Mbp of sequence per experiment, resulting in an average of 20x coverage of target regions, a 500% increase over background. We analyzed patient DNA for pathogenic substitutions, structural variants, and methylation differences using a single data source. RESULTSThe effectiveness of T-LRS was validated by detecting all genomic aberrations, including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences, previously identified by prior clinical testing. In 6/7 individuals who had complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, which led, in one case, to a change in clinical management. In nine individuals with suspected Mendelian conditions who lacked a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in five and variants of uncertain significance in two others. CONCLUSIONST-LRS can accurately predict pathogenic copy number variants and triplet repeat expansions, resolve complex rearrangements, and identify single-nucleotide variants not detected by other technologies, including short-read sequencing. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority candidate genes and regions or to further evaluate complex clinical testing results. The application of T-LRS will likely increase the diagnostic rate of rare disorders.

genomics↗

bioRxiv2020

Technical Note: Quantifying music-dance synchrony with the application of a deep learning-based 2D pose estimator

Dance interventions are more effective at improving gait and balance outcomes than other rehabilitation interventions. Repeated training may culminate in superior motor performance compared to other interventions without synchronization. This technical note will describe a novel method using a deep learning-based 2D pose estimator: OpenPose, alongside beat analysis of music to quantify movement-music synchrony during salsa dancing. This method has four components: i) camera setup and recording, ii) tempo/downbeat analysis and waveform cleanup, iii) OpenPose estimation and data extraction, and iv) synchronization analysis. Two trials were recorded: one in which the dancer danced synchronously to the music and one where they did not. The salsa dancer performed a solo basic salsa step continuously for 90 seconds to a salsa track while their movements and the music were recorded with a webcam. This data was then extracted from OpenPose and analyzed. The mean synchronization value for both feet was significantly lower in the synchronous condition than the asynchronous condition, indicating that this is an effective means to track and quantify a dancers movement and synchrony while performing a basic salsa step.

neuroscience↗

bioRxiv2020

Transposable element mobilization in interspecific yeast hybrids

Barbara McClintock first hypothesized that interspecific hybridization could provide a "genomic shock" that leads to the mobilization of transposable elements. This hypothesis is based on the idea that regulation of transposable element movement is potentially disrupted in hybrids. However, the handful of studies testing this hypothesis have yielded mixed results. Here, we set out to identify if hybridization can increase transposition rate and facilitate colonization of transposable elements in Saccharomyces cerevisiae x Saccharomyces uvarum interspecific yeast hybrids. S. cerevisiae have a small number of active long terminal repeat (LTR) retrotransposons (Ty elements), while their distant relative S. uvarum have lost the Ty elements active in S. cerevisiae. While the regulation system of Ty elements is known in S. cerevisiae, it is unclear how Ty elements are regulated in other Saccharomyces species, and what mechanisms contributed to the loss of most classes of Ty elements in S. uvarum. Therefore, we first assessed whether transposable elements could insert in the S. uvarum sub-genome of a S. cerevisiae x S. uvarum hybrid. We induced transposition to occur in these hybrids and developed a sequencing technique to show that Ty elements insert readily and non-randomly in the S. uvarum genome. We then used an in vivo reporter construct to directly measure transposition rate in hybrids, demonstrating that hybridization itself does not alter rate of mobilization. However, we surprisingly show that species-specific mitochondrial inheritance can change transposition rate by an order of magnitude. Overall, our results provide evidence that hybridization can facilitate the introduction of transposable elements across species boundaries and alter transposition via mitochondrial transmission, but that this does not lead to unrestrained proliferation of transposable elements suggested by the genomic shock theory.

genetics↗

bioRxiv2019

Graded, multi dimensional intragroup and intergroup variations in primary progressive aphasia and post stroke aphasia.

Language impairments caused by stroke (post-stroke aphasia) and neurodegeneration (primary progressive aphasia) have overlapping symptomatology, nomenclature and are classically divided into categorical subtypes. Surprisingly, primary progressive aphasia (PPA) and post-stroke aphasia (PSA) have rarely been directly compared in detail. Rather previous studies have compared certain subtypes (e.g., semantic variants) or have focussed on a specific cognitive/linguistic task (e.g., reading). This study assessed a large range of linguistic and cognitive tasks across the full spectra of PSA and PPA. We applied varimax-rotated principal component analysis to explore the underlying structure of the variance in the assessment scores. Similar phonological, semantic and fluency-related components were found for PSA and PPA. A combined principal component analysis across the two aetiologies revealed graded intragroup and intergroup variations on all four extracted components. Classification analysis was employed to test, formally, whether there were any categorical boundaries for any subtypes of PPA or PSA. Semantic dementia proved to form a true diagnostic category (i.e., within group homogeneity and distinct between group differences), whereas there was considerable overlap and graded variations within and between other subtypes of PPA and PSA. These results suggest that (a) a multi-dimensional rather than categorical classification system may be a better conceptualisation of aphasia from both causes, and (b) despite the very different types of pathology, these broad classes of aphasia have considerable features in common.

neuroscience↗

bioRxiv2019

Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum.

The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the aggregation of Tau and TDP-43 in frontotemporal dementia, and to the heterogeneity of clinical disease. We used positron emission tomography in vivo with (a) [11C]PK-11195, a marker of activated microglia and a proxy index of neuroinflammation, and (b) [18F]AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and diseases associated with TDP-43 protein aggregation, and which is used as a surrogate marker of non-{beta}-amyloid protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant frontotemporal dementia, 11 with the semantic variant of primary progressive aphasia and 10 with the non-fluent variant of primary progressive aphasia), 28 of whom underwent both [18F]AV-1451 and [11C]PK-11195 PET, and matched controls (14 for [18F]AV-1451 and 15 for [11C]PK-11195). We used univariate region-of-interest analyses, and multivariate analysis of the distribution of binding that explicitly control for individual differences in ligand affinity for TDP-43 and different Tau isoforms. We found differences between patients and controls in frontotemporal regions for both neuroinflammation and protein aggregation, and a strong positive correlation between these two processes in all disease groups. Despite this regional co-localisation, the multivariate distribution of [11C]PK-11195 binding related better to clinical heterogeneity than did the distribution of [18F]AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate group classification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.

neuroscience↗

bioRxiv2019

Left anterior temporal lobe is necessary for efficient lateralised processing of spoken word identity

In the healthy human brain, the processing of spoken words is strongly left-lateralised, while the processing of complex non-linguistic sounds recruits brain regions bilaterally. Here we asked whether the left anterior temporal lobe, strongly implicated in semantic processing, is critical to this special treatment of linguistic stimuli. Nine patients with semantic dementia (SD) and fourteen age-matched controls underwent magnetoencephalography and structural MRI. Voxel based morphometry demonstrated the stereotypical pattern of SD: severe grey matter loss restricted to the left anterior temporal lobe. During magnetoencephalography, participants listened to word sets in which identity and meaning were ambiguous until utterance completion, for example played vs plate. Whereas left-hemispheric responses were similar across groups, patients demonstrated increased right hemisphere activity 174-294ms after stimulus disambiguation. Source reconstructions confirmed recruitment of right-sided analogues of language regions in SD: atrophy of left anterior temporal lobe was associated with increased activity in right temporal pole, middle temporal gyrus, inferior frontal gyrus and supramarginal gyrus. Moreover only healthy controls had differential responses to words versus non-words in right auditory cortex and planum temporale. Overall, the results indicate that anterior temporal lobe is necessary for normal and efficient processing of word identity in the rest of the language network.

neuroscience↗

bioRxiv2018

Temperature preference biases parental genome retention during hybrid evolution

Interspecific hybridization can introduce genetic variation that aids in adaptation to new or changing environments. Here we investigate how the environment, and more specifically temperature, interacts with hybrid genomes to alter parental genome representation over time. We evolved Saccharomyces cerevisiae x Saccharomyces uvarum hybrids in nutrient-limited continuous culture at 15{degrees}C for 200 generations. In comparison to previous evolution experiments at 30{degrees}C, we identified a number of temperature specific responses, including the loss of the S. cerevisiae allele in favor of the cryotolerant S. uvarum allele for several portions of the hybrid genome. In particular, we discovered a genotype by environment interaction in the form of a reciprocal loss of heterozygosity event on chromosome XIII. Which species haplotype is lost or maintained is dependent on the parental species temperature preference and the temperature at which the hybrid was evolved. We show that a large contribution to this directionality is due to temperature sensitivity at a single locus, the high affinity phosphate transporter PHO84. This work helps shape our understanding of what forces impact genome evolution after hybridization, and how environmental conditions may favor or disfavor hybrids over time.

evolutionary biology↗

bioRxiv2017

Control of Genetic Parasites Mediated Through Nucleoporin Evolution

Yeasts serve as long-term hosts to several types of genetic parasites. Few studies have addressed the evolutionary trajectory of yeast genes that control the stable co-existence of these parasites with their host cell. In Saccharomyces yeasts, the retrovirus-like Ty retrotransposons must access the nucleus. We show that several genes encoding components of the yeast nuclear pore complex have experienced natural selection for substitutions that change the encoded protein sequence. By replacing these S. cerevisiae genes with orthologs from other Saccharomyces species, we discovered that natural sequence changes have affected the control of Ty retrotransposons. Specifically, changing the genetic sequence of NUP84 or NUP82 to what is found in other Saccharomyces species alters the retrotransposition of S. cerevisiae Ty1 and Ty3, respectively. Importantly, all tested housekeeping functions of NUP84 and NUP82 remained equivalent across species. The nuclear pore complex is the gatekeeper of the nucleus. It appears that nucleoporins are adapting to modulate the control of genetic parasites which access the nucleus, which is achieved despite the strict constraints imposed by host nuclear pore complex function.

evolutionary biology↗