Biology subjects

Siddiqi, A.

Publications and source records attributed to Siddiqi, A..

3 recordsLinked to original sources

bioRxiv2025

Fibroblast specialisation across microanatomy in a single-cell atlas of healthy human Achilles tendon

Tendons are transitional tissues linking muscle to bone, enabling locomotion and fine motor control. The cellular biology across the Achilles tendon unit is poorly understood, yet critical for interpreting normal function and pathological changes across its microanatomically-defined functional zones. We generated a spatially-resolved transcriptomic atlas of human Achilles tendon, sampling the tendon-bone junction (enthesis), midbody, myotendinous junction, and adjoining muscle. Six fibroblast subtypes were identified, with distinct transcriptional profiles and spatial distributions, suggesting specialised functional roles across the tendon-muscle unit. Two dominant fibroblast types were specifically positioned in the tendon mid-substance and paratenon (vessel-rich region surrounding the tendon fibrils); other populations included perineural, myotendinous junction-specific, muscle-specific, and lining-layer fibroblasts. These findings demonstrate how cellular diversity across a transitional tissue may underlie microanatomical-specific roles. This atlas provides a foundation for understanding cellular functions across the tendon-muscle unit and will be essential for comparisons with diseased tissue, identifying pathogenic mediators and treatment targets for autoimmune and degenerative pathologies of the Achilles tendon.

genomics↗

bioRxiv2025

Peripheral Neuropathy After Chronic Alcohol Exposure in Mice: Impact of sex, total intake and duration and alcohol metabolism.

Alcohol induced peripheral neuropathy (AIPN) is a neurodegenerative disease caused by chronic alcohol intake and is associated with peripheral nerve damage and somatosensory symptoms, such as allodynia. Current treatments lack efficacy and do not target underlying pathology emphasizing the need for preclinical models of AIPN to elucidate mechanisms and novel targets. Thus, we performed a detailed characterization of a mouse model of AIPN and candidate mechanistic associations including the role of neuroinflammation and acetaldehyde. Our studies showed chronic alcohol induced mechanical and cold hypersensitivity and deficits in spontaneous behaviors in EtOH concentration-, time- and sex-dependent manners. Female mice drank more alcohol and developed more rapid and severe hypersensitivity but less robust deficits of spontaneous behaviors. The grimace test demonstrated chronic alcohol promoted spontaneous pain independent of sex. Duration of intake impacted alcohol-induced deficits in peripheral nerve electrophysiology amplitude and intra-epidermal nerve fiber density. We characterized an extensive time-course of chronic alcohol-induced neuroinflammation in the DRG and spinal cord and found significant time, sex and tissue effects. Polymorphisms of ALDH2 have been associated with alcohol-induced neuroinflammation, alcohol-related pain, and alcohol-induced peripheral neuropathy. We investigated the role of acetaldehyde, via inhibition of ALDH2, in the development of AIPN and showed that ALDH2 inhibition accelerated and exacerbated development of chronic alcohol-induced hypersensitivity in male and female mice. Overall, our studies in a well-controlled model of AIPN strongly point to neuroinflammation and inflammatory modulators such as acetaldehyde as important mechanistic targets for possible intervention in AIPN.

pharmacology and toxicology↗

bioRxiv2020

In Vivo two-photon imaging and parasympathetic neuromodulation of pancreatic microvascular dynamics in rats

The pancreas has long been known to be densely innervated with parasympathetic, sympathetic, and visceral afferent fibers that are believed to exert significant influence on local endocrine activity and vascular function. Yet the extent to which these interactions depend on neurovascular dynamics in the normal and pathological states remain largely unknown. Herein we describe a new method for high resolution functional imaging of the rat pancreas in vivo. The method comprises a number of elements: a stability-optimized preparation in dorsal recumbency immobilizing several square centimeters of intact pancreas for upright fluorescent imaging while leaving access for concurrent manipulation of abdominal nerves, a full-frame two-photon imaging protocol and analysis pipeline supporting high-throughput (100+) monitoring of islet and acinar microvessel diameter dynamics simultaneously, and a first adaptation of random-access linescan imaging to the pancreas capable of tracking internal blood flow speeds up to 5 mm/s at 20 Hz across multiple microvessels. These methods were then deployed in concert to characterize the capacity of parasympathetic fibers to modulate pancreatic microvascular dynamics with compartment specificity. Electrical stimulation was repeatedly applied to the abdominal vagal trunks at various current magnitudes while imaging islet and acinar microvascular populations in the pancreas. Vagal stimulation consistently elicited increases in both islet and acinar capillary population motility in a current-dependent manner, with only acinar responsive vessels trending toward dilation. Further, we found vagal stimulation to profoundly and reversibly disrupt all traces of fast-wave vasomotor oscillation across a lobular arteriole-venule pair, and this was associated with a significant increase in average flow speed. Together, these findings add to mounting evidence that vagal projections exert tangible reversible influence on pancreatic microvascular activity and underscore the potential for new neuromodulation-based strategies to address diabetes, pancreatitis, or other diseases of the pancreas under autonomic nervous influence.

neuroscience↗