Biology subjects

McIntyre, S.

Publications and source records attributed to McIntyre, S..

6 recordsLinked to original sources

bioRxiv2026

Allosteric modulation of β1 integrin through the hybrid domain reverses articular cartilage injury and functional impairment in a murine model of inflammatory arthritis

Rheumatoid arthritis is a chronic inflammatory joint disease in which progressive destruction of cartilage and bone drives long-term disability. Current disease-modifying therapies target the immune and cytokine networks that sustain synovial inflammation, but none is directed at the chondrocyte, the resident cell responsible for maintaining cartilage matrix. Chondrocyte survival and matrix homeostasis depend on {beta}1-integrin-mediated adhesion to the extracellular matrix, and dysregulated integrin signalling has been implicated in cartilage injury. Here we test the hypothesis that allosteric modulation of {beta}1 integrin, rather than simple adhesion blockade, is chondroprotective. Using the monoclonal antibody JB1a, which binds an epitope in the hybrid domain of {beta}1 integrin and stabilises the receptor in a low-affinity conformation, we show that intra-articular administration produces both functional and structural amelioration of Freunds complete adjuvant (FCA)-induced arthritis in mice. JB1a abolished the FCA-induced increase in joint diameter and hyperalgesia and markedly reduced synovial inflammation, pannus formation and cartilage erosion, with no effect on the contralateral joint and no observed adverse effects. These changes were accompanied by a reduction in chondrocyte apoptosis in vivo. In primary human articular chondrocytes, JB1a abolished interleukin-1{beta} (IL-1{beta})-induced caspase 3/7 activation, reduced IL-8 secretion, and restored the sinusoidal oscillation of intracellular ATP that was otherwise abrogated by IL-1{beta}. In contrast, the adhesion-blocking, integrin-clustering antibody 6S6 activated caspase 3/7 and amplified IL-1{beta}-induced IL-8 secretion, indicating that the therapeutic effect is a property of the specific mode of receptor engagement rather than of adhesion blockade per se. These findings identify {beta}1-integrin conformational state as a determinant of chondrocyte energy homeostasis and survival, and nominate allosteric {beta}1-integrin modulation as a mechanistically distinct, chondrocyte-directed therapeutic strategy in inflammatory arthritis.

pharmacology and toxicology↗

bioRxiv2026

Challenges and Solutions in Quantifying Brain β-Hydroxybutyrate (BHB) with 1H-MRS Following Oral Keto-Ester Consumption

Purpose{beta}-hydroxybutyrate (BHB), a ketone body and alternative cerebral energy substrate, can be measured in vivo using J-difference edited proton magnetic resonance spectroscopy (1H-MRS). Oral ketone supplementation with substrates such as the ketone monoester (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate (KME) and 1,3-butanediol (BD) have gained attention as a mechanism to elevate circulating BHB and induce ketosis without dietary restrictions. Elevated brain ketone availability is of growing therapeutic interest as a strategy to support neuronal energetics in conditions such as epilepsy, neurodegenerative disease, and alcohol use disorder (AUD). However, both pathways introduce BD into the bloodstream, which crosses the blood-brain barrier. Critically, BD exhibits a spectral signature that closely resembles the prominent BHB peak in JDE-MR spectroscopic imaging (MRSI), identified in a pilot AUD study. MethodsTwo separate JDE-MRSI acquisitions tailored for BHB and BD editing were implemented, exploiting frequency separation between the BHB (4.14ppm) and BD (3.95ppm) coupling partners of the observed 1.2ppm resonance to independently quantify each metabolite. ResultsBrain BD concentrations (0.25-0.58mM) were comparable to or exceeded corresponding BHB concentrations (0.20-0.27mM) in all volunteers after consumption of a single dose of the KME, indicating that BD constitutes a major fraction of the signal conventionally attributed to BHB. Combined BHB+BD concentrations ([~]0.45-0.85mM) were consistent with brain BHB values reported in prior studies employing similar doses of the KME, indicating that those measurements likely reflect a combined BHB+BD signal. ConclusionsSeparate quantification of the two metabolites is important for interpreting brain ketone studies and for understanding the full pharmacology of KME supplementation.

neuroscience↗

bioRxiv2025

Tactile Illusion Reveals Central Neural Basis for Touch Pleasantness

C-low threshold mechanoreceptors (C-LTMRs) have been highlighted in mediating the pleasantness of slow, caressing touch. This has given rise to the "Affective Touch Hypothesis," which posits that velocity tuning of C-LTMRs underpins pleasantness perception. The known activation preferences of C-LTMRs have been used as a proxy for pleasant touch, yet recent findings have raised questions about the necessity of this peripheral mechanism. This project explored the peripheral and central mechanisms in affective touch through comparing two motion-conditions: gentle brushing-like motion and apparent motion, an illusory perception of movement produced by successive touches along the skin. We used this illusion to examine whether previously established velocity tuning of true lateral motion is observed in apparent motion, when local information provided to individual peripheral afferents is held constant. The sole dependence on peripheral modulation predicts that the characteristic inverted-U-shaped relationship between velocity and pleasantness, regularly associated with C-LTMRs, would only be observed for brushing-like motion. Central modulation would instead predict a more similar relationship between the motion-conditions. To investigate this, pleasantness-ratings and velocity-ratings were collected across different velocities (0.1-30cm/s, N=23) for both conditions. Linear and quadratic regression analyses were performed and for both conditions adding a quadratic term improved the overall model fit, reaching significance (p<0.001). The quadratic term coefficients were negative for both conditions, displaying an inverted-U-shape. Further analyses revealed that motion-condition did not significantly alter the relationship between stimulus-velocity and pleasantness. These findings suggest that the velocity tuning of pleasantness cannot solely be attributed to velocity tuning of individual C-LTMRs. Key pointsO_LIC-low threshold mechanoreceptors (C-LTMRs) have been shown to display a unique inverted-U-shaped relationship between firing frequencies and stroking velocity, which is not seen with any other cutaneous afferents C_LIO_LIAn inverted-U-shaped relationship is also observed between perceived touch pleasantness and stroking velocity, giving rise to a hypothesis which posits that the velocity tuning of C-LTMRs underpins the perception of pleasant touch C_LIO_LIWe compared traditional stroking (brushing-like motion) to an illusory perception of movement produced by successive touches along the skin (apparent motion) to examine if similar velocity-dependent pleasantness patterns would be observed when information provided to individual peripheral afferents is held constant C_LIO_LIIn our experiment, the type of motion did not significantly alter the relationship between perceived pleasantness and stimulus-velocity C_LIO_LIThese findings suggest that the velocity tuning of pleasantness cannot solely be attributed to velocity tuning of individual C-LTMRs C_LI

neuroscience↗

bioRxiv2023

Human foot outperforms the hand in mechanical pain discrimination

Tactile discrimination has been extensively studied, but mechanical pain discrimination remains poorly characterised. Here, we measured the capacity for mechanical pain discrimination using a twoalternative forced choice paradigm, with force-calibrated indentation stimuli (Semmes-Weinstein monofilaments) applied to the hand and foot dorsa of healthy human volunteers. In order to characterise the relationship between peripheral neural and perceptual processes, we recorded singleunit activity from myelinated (A) and unmyelinated (C) mechanosensitive nociceptors in the skin using microneurography. At the perceptual level, we found that the foot was better at discriminating noxious forces than the hand, which stands in contrast to that for innocuous force discrimination, where the hand performed better than the foot. This observation of superior mechanical pain discrimination on the foot compared to the hand could not be explained by the responsiveness of single primary afferents. We found no significant difference in the discrimination performance of either the myelinated or unmyelinated class of nociceptors between skin regions. This suggests the possibility that other factors such as skin biophysics, receptor density or central mechanisms may underlie these regional differences. Significance StatementStandard clinical practice for diagnosing neuropathies and pain disorders often involves assessing thresholds for pain or light touch. The ability to discriminate between different stimulus intensities is a separate but equally important sensory function, however this is not typically assessed in the clinic, and so studying this may provide insights into pain signalling mechanisms. Here, we investigated the ability of healthy individuals to discriminate between different forces of painful indentation. We found that the foot was better at this than the hand. This difference could not be explained by the firing activity of peripheral nociceptors (pain-signalling neurons) between the two regions, suggesting that mechanisms other than nociceptor sensitivity are involved.

neuroscience↗

bioRxiv2023

Mechanoreceptive Aβ primary afferents discriminate naturalistic social touch inputs at a functionally relevant time scale

Interpersonal touch is an important part of our social and emotional interactions. How these physical, skin-to-skin touch expressions are processed in the peripheral nervous system is not well understood. From single-unit microneurography recordings in humans, we evaluated the capacity of six subtypes of cutaneous afferents to differentiate perceptually distinct social touch expressions. By leveraging conventional statistical analyses and classification analyses using convolutional neural networks and support vector machines, we found that single units of multiple A{beta} subtypes, especially slowly adapting type II (SA-II) and fast adapting hair follicle afferents (HFA), can reliably differentiate the skin contact of those expressions at accuracies similar to those perceptually. Rapidly adapting field (Field) afferents exhibit lower accuracies, whereas C-tactile (CT), fast adapting Pacinian corpuscles (FA-II), and muscle spindle (MS) afferents can barely differentiate the expressions, despite responding to the stimuli. We then identified the most informative firing patterns of SA-II and HFA afferents spike trains, which indicate that an average duration of 3-4 s of firing provides sufficient discriminative information. Those two subtypes also exhibit robust tolerance to shifts in spike-timing of up to 10 ms. A greater shift in spike-timing, however, drastically compromises an afferents discrimination capacity, and can change a firing patterns envelope to resemble that of another expression. Altogether, the findings indicate that SA-II and HFA afferents differentiate the skin contact of social touch at time scales relevant for such interactions, which is 1-2 orders of magnitude longer than those relevant for discriminating non-social touch inputs.

neuroscience↗

bioRxiv2019

Tactile sensory channels over-ruled by frequency decoding system that utilizes spike pattern regardless of receptor type

The established view is that vibrotactile stimuli evoke two qualitatively distinctive cutaneous sensations, flutter (frequencies < 60 Hz) and vibratory hum (frequencies > 60 Hz), subserved by two distinct receptor types (Meissners and Pacinian corpuscle, respectively) which may engage different neural processing pathways or channels and fulfill quite different biological roles. In psychological and physiological literature those two systems have been labelled as Pacinian and non-Pacinian channels. However, we present evidence that low-frequency spike trains in Pacinian afferents can readily induce a vibratory percept with the same low frequency attributes as sinusoidal stimuli of the same frequency thus demonstrating a universal frequency decoding system. We achieved this using brief low-amplitude pulsatile mechanical stimuli to selectively activate Pacinian afferents. This indicates that spiking pattern, regardless of receptor type, determines vibrotactile frequency perception. This mechanism may underlie the constancy of vibrotactile frequency perception across different skin regions innervated by distinct afferent types.

neuroscience↗