Biology subjects

Kerr, G.

Publications and source records attributed to Kerr, G..

11 recordsLinked to original sources

bioRxiv2026

IMU-based upper limb kinematics validation: sensor fusion optimisation, sensor-to-segment alignment, and joint angle accuracy.

Conventional clinical assessment of upper limb kinematics relies on goniometry or visual estimation, methods that provide limited information on multi-segment 3D kinematics and can have poor inter-rater reliability. Inertial measurement units (IMUs) represent a viable alternative; however, extracting anatomically meaningful joint angles from skin-mounted sensors remains challenging owing to sensor-to-segment misalignment, soft-tissue artefact, and suboptimal orientation estimation under dynamic conditions. This study developed and validated a multi-segment IMU-based framework for upper limb kinematic assessment, addressing three stages of the measurement pipeline: (i) sensor fusion gain optimisation as a function of task mean segment angular velocity; (ii) accuracy of an anatomical landmark registration-based alignment method; and (iii) comparative evaluation of landmark-based alignment against manual and neutral-pose alignment approaches. Twenty participants with typical shoulder function performed clinical and functional upper limb tasks, recorded simultaneously with an optoelectronic motion capture system and six IMUs tracking the thorax, clavicle, scapula, humerus, forearm, and hand. Orientation estimation used a gradient-descent complementary filter with velocity-dependent gain modulation. Sensor-to-segment alignment was achieved via manual, neutral-pose, and landmark registration methods. Mean sensor orientation errors ranged from 1.5 to 3 degrees across segments/tasks and increased with angular velocity. Landmark registration produced substantially lower joint angle errors than manual and neutral-pose alignment across all joints (root mean square error range: 3.7-7.8 degrees; manual: 8.3-24.2 degrees; neutral: 15.5-35.5 degrees). These results indicate that IMU-derived kinematic accuracy is context-dependent, varying with joint and movement type, suggesting that accuracy should be established for the specific movements and joints relevant to each clinical application.

bioengineering↗

bioRxiv2024

Low effective population size but high heterozygosity revealed by SNP analyses in adult and juvenile Thuja plicata in UK Woodlands

Thuja plicata is a conifer tree that is appreciated for its cultural, ecological and wood quality features in its natural range in western North America. It is also used in Europe and the UK for timber production. Some T. Plicata plantations in the UK are converted to Continuous Cover Forestry (CCF) management which uses natural regeneration and concerns have been raised about the genetic diversity in both the adult trees and the offspring. We studied species diversity, stand structure, and genetic diversity in four UK woodlands planted with T. plicata which contained both adults and naturally regenerated individuals. We discovered 61,104 Single Nucleotide Polymorphisms (SNPs) using Genotyping-by-Sequencing (GBS) and retained 504 SNPs for analysis. We selected 67 SNPs for PCR-based genotyping of 163 adults and 176 juveniles. We found a large number of monomorphic sites (40.3%) most of which were restricted to adults in a single woodland, indicative of a high genetic differentiation among woodlands. The effective population size (Ne) was very low across all sites (Ne < 100), varied between adults and juveniles, and was lowest in the most diverse woodland in terms of species and structure. In contrast, heterozygosity was high overall (Ho = 0.38), except in the divergent woodland (Ho = 0.26), and did not vary between adults and juveniles. Our findings and genotyping methods provide insights into the ability of CCF-managed woodlands, including instances of low genetic diversity in T. plicata, to face environmental shifts and disease threats.

genomics↗

bioRxiv2023

Enhanced spine stability and survival lead to increases in dendritic spine density as an early response to local alpha-synuclein overexpression in mouse prefrontal cortex

Lewy Body Dementias (LBD), including Parkinsons disease dementia and Dementia with Lewy Bodies, are characterized by widespread accumulation of intracellular alpha-Synuclein protein deposits in regions beyond the brainstem, including in the cortex. Patients with LBDs develop cognitive changes, including abnormalities in executive function, attention, hallucinations, slowed processing, and cognitive fluctuations. The causes of these non-motor symptoms remain unclear; however, accumulation of alpha-Synuclein aggregates in the cortex and subsequent interference of synaptic and cellular function could contribute to psychiatric and cognitive symptoms. It is unknown how the cortex responds to local pathology in the absence of significant secondary effects of alpha-Synuclein pathology in the brainstem. To investigate this, we employed viral overexpression of human alpha-Synuclein protein targeting the mouse prefrontal cortex (PFC). We then used in vivo 2-photon microscopy to image awake head-fixed mice via an implanted chronic cranial window to assess the early consequences of alpha-Synuclein overexpression in the weeks following overexpression. We imaged apical tufts of Layer V pyramidal neurons in the PFC of Thy1-YFP transgenic mice at 1-week intervals from 1-2 weeks before and 9 weeks following viral overexpression, allowing analysis of dynamic changes in dendritic spines. We found an increase in the relative dendritic spine density following local overexpression of alpha-Synuclein, beginning at 5 weeks post-injection, and persisting for the remainder of the study. We found that alpha-Synuclein overexpression led to an increased percentage and longevity of newly-persistent spines, without significant changes in the total density of newly formed or eliminated spines. A follow up study utilizing confocal microscopy revealed that the increased spine density is found in cortical cells within the alpha-Synuclein injection site, but negative for alpha-Synuclein phosphorylation at Serine-129, highlighting the potential for effects of dose and local circuits on spine survival. These findings have important implications for the physiological role and early pathological stages of alpha-Synuclein in the cortex.

neuroscience↗

bioRxiv2022

Helicobacter pylori vacuolating cytotoxin A exploits human endosomes for intracellular activation

Helicobacter pylori infection is the main cause of gastric cancer. Vacuolating cytotoxin A (VacA) is a H. pylori pore-forming toxin and a key determinant of gastric cancer risk. VacA is secreted as an 88-kDa polypeptide (p88) that upon interaction with host cells induces cytotoxic effects, including cell vacuolation and mitochondrial dysfunction. These effects are currently believed to be due to VacA p88 accumulating inside host cells and forming oligomeric anion-specific channels in membranes of intracellular compartments. However, the molecular nature of intracellular VacA channels in host cells remains undefined. Here we show that VacA p88 does not accumulate inside human epithelial cells, but instead is rapidly processed in endosomes into smaller p31/p28 and p37 products in a manner that precedes VacA-induced vacuolation. VacA processing requires endosomal acidification and concerted cleavage by multiple endo-lysosomal proteases including cathepsins. In situ structural mapping reveals that upon processing, the toxins central hydrophilic linker and globular C-terminus are excised, whereas oligomerization determinants are retained. Congruently, the processed products are constituents of a high-molecular-weight complex inside the host cell [boxh] which we propose is the intracellular, mature and active VacA pore. These findings suggest that VacA exploits human endosomes for proteolytic processing and intracellular activation. Significance StatementHelicobacter pylori is a cancer-causing bacterium that infects the stomach of billions of people worldwide. Vacuolating cytotoxin A (VacA) is an important H. pylori virulence factor and its activity directly correlates with gastric carcinogenesis. Yet despite decades of intense research, the mechanisms underlying VacA activity in human cells remain incompletely understood. Here, we present evidence suggesting that VacA is activated inside human cells by multi-step proteolytic processing involving endo-lysosomal proteases including cathepsins. We also track and identify the functional processed VacA isoforms in host cells. These results revolutionize our understanding of the mechanism of VacA activation in human cells, whilst expanding our knowledge of the diversity of microbial virulence factors that exploit human endo-lysosomes for pathogenesis.

molecular biology↗

bioRxiv2022

Aspirin synergizes with regorafenib to reduce growth of colorectal cancer

PurposeRegorafenib is a multi-kinase inhibitor approved for refractory metastatic colorectal cancer. Previous studies have suggested that combining kinase inhibitors with aspirin may improve patient outcomes. We aimed to determine the effects of aspirin and regorafenib combination treatment in preclinical models of colorectal cancer. Experimental DesignSW480, RKO and LIM1215 colorectal cancer cell lines were treated with aspirin and regorafenib to determine effects on proliferation and cytotoxicity. RNA sequencing and Western blotting were performed to explore underlying molecular effects. Aspirin and regorafenib combination treatment was also tested using organoids derived from three human colorectal cancer tissue specimens. For the in vivo study, SW480-derived tumors were established in athymic mice. Tumor volume was measured during treatment with aspirin and regorafenib, followed by immunohistochemical staining for markers of proliferation and apoptosis. ResultsAspirin and regorafenib synergistically inhibited proliferation of colorectal cancer cell lines and patient-derived organoids, irrespective of KRAS or BRAF mutation status. This was associated with inhibition of the PI3K-Akt-mTOR pathway and activation of the AMPK pathway. Aspirin and regorafenib effectively inhibited growth of microsatellite stable KRAS-mutant SW480-derived tumors in vivo. Immunohistochemical staining for Ki67 and cleaved caspase 3 showed that combination treatment elicited a synergistic anti-proliferative effect, in addition to a pro-apoptotic effect that was driven by regorafenib. ConclusionsAspirin and regorafenib demonstrate synergistic anti-proliferative effects in preclinical models of colorectal cancer. This suggests that combining regorafenib with aspirin may be an improved treatment strategy for patients with refractory metastatic colorectal cancer.

cancer biology↗

bioRxiv2020

Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva

Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues due to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2/ACVR1. From a screen of known biologically active compounds, we identified saracatinib as a potent ALK2 kinase inhibitor. In enzymatic and cell-based assays, saracatinib preferentially inhibited ALK2 compared with other receptors of the BMP/TGF{beta} signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1Q207D transgenic mouse line, which provides a model of heterotopic ossification, as well as an inducible ACVR1R206H knock-in, which serves as a genetically and physiologically faithful model of FOP. In both models, saracatinib was well tolerated and potently inhibited the development of heterotopic ossification even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in the treatment of FOP, offering an accelerated path to clinical proof of efficacy studies and potentially significant benefits to individuals with this devastating condition.

molecular biology↗

bioRxiv2020

Therapeutic assessment of targeting ASNS combined with L-Asparaginase treatment in solid tumors and investigation of resistance mechanisms

Asparagine deprivation by L-Asparaginase (L-ASNase) is an effective therapeutic strategy in Acute Lymphoblastic Leukemia, with resistance occurring due to upregulation of ASNS, the only human enzyme synthetizing Asparagine1. L-Asparaginase efficacy in solid tumors is limited by dose-related toxicities 2. Large-scale loss of function genetic in vitro screens identified ASNS as a cancer dependency in several solid malignancies 3,4. Here we evaluate the therapeutic potential of targeting ASNS in melanoma cells. While we confirm in-vitro dependency on ASNS silencing, this is largely dispensable for in vivo tumor growth, even in face of asparagine deprivation, prompting us characterize such resistance mechanism to devise novel therapeutic strategies. Using ex vivo quantitative proteome and transcriptome profiling, we characterize the compensatory mechanism elicited by ASNS knockout melanoma cells allowing their survival. Mechanistically, a genome-wide CRISPR screen revealed that such resistance mechanism is elicited by a dual axis: GCN2-ATF4 aimed at restoring amino acids levels and MAPK-BCLXL to promote survival. Importantly, pharmacological inhibition of such nodes synergizes with L-Asparaginase-mediated Asparagine deprivation in ASNS deficient cells suggesting novel potential therapeutic combinations in melanoma.

cancer biology↗

bioRxiv2019

NOD1 mediates non-canonical inflammasome processing of interleukin-18 in epithelial cells to Helicobacter pylori infection.

The interleukin-1 family members, IL-1{beta} and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1{beta} processing in myeloid cells have been extensively studied, those involved in IL-18 processing, particularly in non-myeloid cells, are still poorly understood. Here, we have identified the cytosolic sensor NOD1 as a key regulator of IL-18 processing in epithelial cells responding to Helicobacter pylori infection. Importantly, NOD1 processing of IL-18 occurs independently of the canonical inflammasome proteins, NLRP3 and ASC. Instead, NOD1 interacts directly with caspase-1 via homotypic binding of caspase-activation recruitment domains. We show that IL-18 is important in maintaining tissue homeostasis and protecting against pre-neoplastic changes due to gastric H. pylori infection. These findings reveal an unanticipated role for NOD1 in a new type of inflammasome that regulates epithelial cell production of bioactive IL-18 with tissue protective functions.

immunology↗

bioRxiv2018

Assessment of abduction movement in older people with painful shoulder: an analysis based on inertial sensors

Reduced range of motion in the shoulder can be a source of functional limitation. Current quantitative evaluation systems are limited to assessing the functionality or the maximum articular amplitudes in each of the planes of movement, both in isolation. These separate clinical evaluation systems may not allow the identification of the underlying impairments contributing to the functional limitation. The use of inertial sensors to quantify movement in addition to more common clinical assessments of the shoulder may allow clinicians to understand that are potentially unnoticed by the human eye. The main objective of this cross-sectional study was to generate an explanatory model for shoulder abduction based on data from inertial sensors. Shoulder abduction of thirteen older adults suffering from shoulder dysfunction was evaluated using two inertial sensors placed on the humerus and scapula. Movement variables (maximum angular mobility, angular peak of velocity, peak of acceleration) were used to explain the functionality of the upper limb (assessed using the Upper Limb Functional Index). Abduction movement of the shoulder was explained by six variables related to the mobility of the shoulder joint complex. A manova analysis was used to explain the results obtained on the functionality of the upper limb. The MANOVA model based on angular mobility explained 69% of the variance of the ULFI value (r-squared=0.69). The most relevant variables were the abduction-adduction of the humerus and the medial and lateral rotation of the scapula. However, given the limited sample size, none of these individual variables were statistically significant in the decomposition model on their own. The method used in the present study reveals the potential importance of the analysis of the scapular and humeral movements for comprehensive evaluation of the upper limb. Further research should include a wider sample and may seek to use this assessment technique in a range of potential clinical applications.

bioengineering↗

bioRxiv2017

Intrinsically photosensitive retinal ganglion cell mediated pupil function is impaired in Parkinson’s disease

Parkinsons disease is characterised by non-motor symptoms including sleep and circadian disruption, but the underlying aetiology is not well understood. Melanopsin-expressing intrinsically photosensitive Retinal Ganglion Cells (ipRGC) transmit light signals from the eye to brain areas controlling circadian rhythms and the pupil light reflex. Here we evaluate the hypothesis that these non-motor symptoms in people with Parkinsons disease may be linked to ipRGC dysfunction. Using chromatic pupillometry, we measured intrinsic (melanopsin-mediated) ipRGC and extrinsic (rod/cone photoreceptor-mediated) inputs to the pupil control pathway in a group of optimally medicated participants with a diagnosis of Parkinsons disease (PD, n = 17) compared to controls (n = 12). Autonomic tone was evaluated by measuring pupillary unrest in darkness. The PD participants underwent additional clinical assessments using the Unified Parkinsons disease Rating Scale (UPDRS) and the Hoehn and Yahr scale (H&Y).\n\nCompared to controls, the PD group demonstrated an attenuated pupil constriction amplitude in response to long wavelength pulsed stimulation, and reduced post-illumination pupil response (PIPR) amplitude in response to both short wavelength pulsed and sinusoidal stimulation. In the PD group, PIPR amplitude did not correlate with measures of sleep quality, retinal nerve fibre layer thickness, UPDRS or H&Y score, or medication dosage. Both groups exhibited similar pupillary unrest in darkness.\n\nWe show that melanopsin and the rod/cone-photoreceptor contributions to the pupil control pathway are impaired in people with early-stage Parkinsons disease. Given that the deficits are independent of clinical assessment severity and are observed despite optimal medication, the melanopsin-mediated PIPR may be a biomarker for the detection of Parkinsons disease and its continued monitoring in both medicated and unmedicated individuals.

neuroscience↗

bioRxiv2017

Sorting & Sequencing Flies By Size: Identification Of Novel TOR Regulators And Parameters For Successful Sorting

As DNA sequencing throughput increases, novel strategies for discovering genes that affect traits of interest become available. One strategy starts with a population of animals and selects individuals over multiple generations for a particular trait. Subsequent whole genome sequencing should identify loci affecting this trait. We apply this strategy by sorting flies for wing length over 18 generations, obtaining two populations that differ in wing length by 20%. Flies with longer wings had increased overall body sizes and elevated TOR activity, suggesting that genetic variation targets TOR signaling to influence body size. High-throughput sequencing of big and small flies identified thousands of single nucleotide polymorphisms that differed between the two populations, leading us to identify five novel regulators of TOR signaling. Surprisingly, stochastic simulations of the process show that large fractions of the genetic differences between the big and small flies are probably biological false positives, selected by chance by random drift. We employ these computer simulations to identify experimental setup parameters to improve the signal-to-noise ratio for successfully running sort-and-sequence experiments - a resource which will hopefully be useful for the community.

genetics↗