Biology subjects

Jansen, K.

Publications and source records attributed to Jansen, K..

7 recordsLinked to original sources

bioRxiv2024

Apnoea suppresses brain activity in infants

Apnoea - the cessation of breathing - is commonly observed in premature infants. These events can reduce cerebral oxygenation and are associated with poorer neurodevelopmental outcomes. However, relatively little is known about how apnoea and shorter pauses in breathing impact brain function in infants, which will provide greater mechanistic understanding of how apnoea affects brain development. We analysed simultaneous recordings of respiration, electroencephalography (EEG), heart rate, and peripheral oxygen saturation in 124 recordings from 118 infants (post-menstrual age: 38.6 {+/-} 2.7 weeks [mean {+/-} standard deviation]) during apnoeas (pauses in breathing greater than 15 seconds) and shorter pauses in breathing between 5 and 15 seconds. EEG amplitude significantly decreased during both apnoeas and shorter pauses in breathing compared with normal breathing periods. Change in EEG amplitude was significantly associated with change in heart rate during apnoea and breathing pauses and, during apnoeas only, with oxygen saturation change. No associations were found between EEG amplitude and pause duration or post-menstrual age. The decrease in EEG amplitude may be a result of the changing metabolism and/or homeostasis following changes in oxygen and carbon dioxide concentrations, which alters the release of neurotransmitters. As apnoeas often occur in premature infants, frequent disruption to brain activity may impact neural development and result in long-term neurodevelopmental consequences.

neuroscience↗

bioRxiv2023

Brain age as an estimator of neurodevelopmental outcome: A deep learning approach for neonatal cot-side monitoring

The preterm neonate can experience stressors that affect the rate of brain maturation and lead to long-term neurodevelopmental deficits. However, some neonates who are born early follow normal developmental trajectories. Extraction of data from electroencephalography (EEG) signals can be used to calculate the neonates brain age which can be compared to their true age. Discrepancies between true age and brain age (the brain age delta) can then be used to quantify maturational deviation, which has been shown to correlate with long-term abnormal neurodevelopmental outcomes. Nevertheless, current brain age models that are based on traditional analytical techniques are less suited to clinical cot-side monitoring due to their dependency on long-duration EEG recordings, the need to record activity across multiple EEG channels, and the manual calculation of predefined EEG features which is time-consuming and may not fully capture the wealth of information in the EEG signal. In this study, we propose an alternative deep-learning approach to determine brain age, which operates directly on the EEG, using a Convolutional Neural Network (CNN) block based on the Inception architecture (called Sinc). Using this deep-learning approach on a dataset of preterm infants with normal neurodevelopmental outcomes (where we assume brain age = postmenstrual age), we can calculate infant brain age with a Mean Absolute Error (MAE) of 0.78 weeks (equivalent to a brain age estimation error for the infant within +/- 5.5 days of their true age). Importantly, this level of accuracy can be achieved by recording only 20 minutes of EEG activity from a single channel. This compares favourably to the degree of accuracy that can be achieved using traditional methods that require long duration recordings (typically >2 hours of EEG activity) recorded from a higher density 8-electrode montage (MAE = 0.73 weeks). Importantly, the deep learning models brain age deltas also distinguish between neonates with normal and severely abnormal outcomes (Normal MAE = 0.71 weeks, severely abnormal MAE = 1.27 weeks, p=0.02, one-way ANOVA), making it highly suited for potential clinical applications. Lastly, in an independent dataset collected at an independent site, we demonstrate the models generalisability in age prediction, as accurate age predictions were also observed (MAE of 0.97 weeks). HighlightsO_LIPreterm stress exposure leads to long-term neurodevelopmental deficits C_LIO_LIDeficits are quantifiable using EEG-based brain age prediction errors C_LIO_LIOur deep-learning solution for brain age prediction outperforms previous approaches C_LIO_LIPredictions are achieved with only 20 mins EEG and a single bipolar channel C_LIO_LIPrediction errors correlate with long-term Bayley scale neurodevelopmental outcomes C_LI

neuroscience↗

bioRxiv2023

Primed to resolve: A single cell atlas of the shoulder capsule reveals a cellular basis for resolving inflammatory fibrosis

Fibrotic conditions are a significant global disease burden. While some therapies delay disease progression, none reverse fibrosis. To gain insights into how fibrosis might resolve, we developed a comparative single cell atlas of frozen shoulder capsule tissue; a chronic inflammatory fibrotic human disease that resolves spontaneously. We identified both a population of pro-inflammatory MERTKlowCD48+ macrophages (M{varphi}) and a population of MERTK+LYVE1+MRC1+M{varphi} enriched for negative regulators of inflammation. Micro-cultures of patient-derived cells identified cell-matrix interactions between MERTK+M{varphi} and DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in the resolution of frozen shoulder. Cross-tissue analysis revealed a shared gene expression cassette between MERTK+M{varphi} in the shoulder capsule and a similar cell population enriched in synovial tissues from rheumatoid arthritis patients in disease remi ssion, supporting the concept that MERTK+M{varphi} provide a cellular basis for the resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identified MERTK+LYVE1+MRC1+M{varphi} and DKK3+ and POSTN+ fibroblast populations analogous to those identified in adult shoulder capsule, suggesting that the template to resolve fibrosis is established during development. Therapeutic enhancement of crosstalk between MerTK+M{varphi} and pro-resolving DKK3+ and POSTN+ fibroblasts could accelerate resolution of frozen shoulder and resolve persistent inflammatory fibrotic disease in other tissues.

cell biology↗

bioRxiv2022

Neutralization of Omicron BA.1, BA.2, and BA.3 SARS-CoV-2 by 3 doses of BNT162b2 vaccine

The newly emerged Omicron SARS-CoV-2 has 3 distinct sublineages: BA.1, BA.2, and BA.3. BA.1 accounts for the initial surge and is being replaced by BA.2, whereas BA.3 is at a low prevalence at this time. Here we report the neutralization of BNT162b2-vaccinated sera (collected at 1 month after dose 3) against the three Omicron sublineages. To facilitate the neutralization testing, we engineered the complete BA.1, BA.2, or BA.3 spike into an mNeonGreen USA-WA1/2020 SRAS-CoV-2. All BNT162b2-vaccinated sera neutralized USA-WA1/2020, BA.1-, BA.2-, and BA.3-spike SARS-CoV-2s with titers of >20; the neutralization geometric mean titers (GMTs) against the four viruses were 1211, 336, 300, and 190, respectively. Thus, the BA.1-, BA.2-, and BA.3-spike SARS-CoV-2s were 3.6-, 4.0-, and 6.4-fold less efficiently neutralized than the USA-WA1/2020, respectively. Our data have implications in vaccine strategy and understanding the biology of Omicron sublineages.

microbiology↗

bioRxiv2020

Topographic Guidance in Melt-Electrowritten Tubular Scaffolds Enhances Engineered Kidney Tubule Performance

To advance the engineering of kidney tubules for future implantation, constructs should be both self-supportive and yet small-sized and highly porous. Here, we hypothesize that the fabrication of small-sized porous tubular scaffolds with a highly organized fibrous microstructure by means of melt-electrowriting (MEW) allows the development of self-supported kidney proximal tubules with enhanced properties. A custom-built MEW device was used to fabricate tubular fibrous scaffolds with small diameter sizes (O = 0.5, 1, 3 mm) and well-defined, porous microarchitectures (rhombus, square, and random). Human umbilical vein endothelial cells (HUVEC) and human conditionally immortalized proximal tubular epithelial cells (ciPTEC) were seeded into the scaffolds and tested for monolayer formation, integrity, and organization, as well as for extracellular matrix (ECM) production and renal transport functionality. Tubular scaffolds were successfully manufactured by fine control of MEW instrument parameters. A minimum inner diameter of 0.5 mm and pore sizes of 0.2 mm were achieved. CiPTEC formed tight monolayers in all scaffold microarchitectures tested, but well-defined rhombus-shaped pores outperformed and facilitated unidirectional cell orientation, increased collagen type IV deposition, and expression of the renal transporters and differentiation markers organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp). To conclude, we present smaller diameter engineered kidney tubules with microgeometry-directed cell functionality. Due to the well-organized tubular fiber scaffold microstructure, the tubes are mechanically self-supported, and the self-produced ECM constitutes the only barrier between the inner and outer compartment, facilitating rapid and active solute transport.

bioengineering↗

bioRxiv2020

Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells

Thymic epithelial cells (TEC) control the selection of a T-cell repertoire reactive to pathogens but tolerant of self. While this process is known to involve the promiscuous expression of virtually the entire protein-coding gene repertoire the extent to which TEC recapitulate peripheral isoforms, and the mechanisms by which they do so, have remained largely unknown. We performed the first assembly-based transcriptomic census of transcript structures and splicing factor (SF) expression in mouse medullary TEC (mTEC) and 21 peripheral tissues. Mature mTEC expressed 60.1% of all protein-coding transcripts, more than was detected in any of the peripheral tissues. However, for genes with tissue-restricted expression, we found that mTEC produced fewer isoforms than did the relevant peripheral tissues. Analysis of exon inclusion revealed an absence of brain-specific micro-exons in mTEC. We did not find unusual numbers of novel transcripts in TEC and show that Aire, the facilitator of promiscuous gene expression, promotes usage of long transcripts but has only a limited impact on alternative splicing in mTEC. Comprehensive assessment of SF expression in mTEC identified a small set of non-promiscuously expressed SF genes amongst which we confirmed RBFOX to be present with AIRE in mTEC nuclei. Using a conditional loss of function approach, we show that Rbfox2 promotes mTEC development and regulates the alternative splicing of promiscuously expressed genes. These data indicate that TEC recommission a small number of peripheral SFs, including members of the Rbfox family, to generate a broad but selective representation of the peripheral splice isoform repertoire.

immunology↗

bioRxiv2018

Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis

The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune mediated inflammatory diseases (IMIDs). However it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue driven processes observed in IMIDs such as inflammation and damage. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of FAP+ synovial cells suppressed both inflammation and bone erosions in murine models of resolving and persistent arthritis. Single cell transcriptional analysis identified two distinct fibroblast subsets: FAP+ THY1+ immune effector fibroblasts located in the synovial sub-lining, and FAP+ THY1- destructive fibroblasts restricted to the synovial lining. When adoptively transferred into the joint, FAP + THY1- fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation whereas transfer of FAP + THY1+ fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell based therapies aimed at modulating inflammation and tissue damage.

immunology↗