Biology subjects

Watt, M. J.

Publications and source records attributed to Watt, M. J..

10 recordsLinked to original sources

bioRxiv2026

Spectral characterisation of short-wave infrared (SWIR) tissue chromophores and tissue-mimicking phantom optical properties

Significance Short-wave infrared (SWIR) sensors promise to expand the capabilities of optical sensing technologies, but the lack of robust data characterising tissue-constituent optical properties in the SWIR makes instrument design challenging. Aim We characterise and evaluate the optical properties of the dominant chromophores in tissue and tissue- mimicking phantoms, from visible to SWIR wavelengths. Approach Using single-integrating sphere systems, we measured the optical properties of single-component chromophores (H2O, haemoglobin, corn oil, synthetic melanin) and multi-component tissues (whole blood, lard), to decouple contributions from optical scattering, H2O absorption and other contributing chromophores; we also characterised commonly-used phantom materials and investigated their potential to mimic soft tissues in the SWIR range using simulations. Results We provide a consistent dataset of absorption and reduced scattering coefficients ({micro}a and {micro}'s) that characterise the dominant tissue chromophores from 450 nm out to 1600 nm. These results were shown to be consistent with literature data, where available. We integrate these data into an open-source Python toolkit, SIMPA, for optical modelling and demonstrate soft tissue simulations that can be probed continuously from visible to SWIR wavelengths. Our findings are compared with tissue-mimicking phantoms, highlighting a need for additives for polymer-based phantoms that mimic SWIR water absorption. Conclusions By providing this open-source dataset, we aim to enable future studies exploring SWIR light-tissue interactions that facilitate rapid assessment and prototyping of next-generation spectroscopy and imaging techniques.

bioengineering↗

bioRxiv2025

Spatial Transcriptomic Signature of Progressive Fibrosis in Human MASLD: Role of Senescence and Metabolic Reprogramming.

Granular detail about the location and nature of liver cell interactions and the metabolic, inflammatory and fibrogenic pathways driving progressive fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) is needed to deliver novel therapeutic targets. Here we used spatial transcriptomic data from human MASLD liver biopsies to identify the major cell types and their potential interconnected activities within specific tissue regions across the spectrum of MASLD. Gene expression data were generated using 10X Genomics Visium technology from 33 formalin-fixed paraffin-embedded liver biopsy samples and overlaid with annotated anatomical regions. Differential gene expression (DEG) and pathway analyses, cellular deconvolution and ligand-receptor interactions were conducted for each annotated anatomical category, with specific protein expression validated using CODEX spatial proteomics and immunohistochemistry staining. Unsupervised gene expression data grouped the annotated spots into 2 main clusters enriched for early/intermediate vs late fibrosis and transcriptome-based cellular deconvolution was well aligned with annotated histopathological features. In addition to extracellular matrix/receptor interactions and immune cell recruitment and trafficking, several genes encoding immunoglobulins were highly upregulated in late-stage fibrosis and were spatially associated with a senescence signature. Upregulated DEGs for early/intermediate-stage fibrosis were significantly enriched for metabolic pathways, oxidative phosphorylation and fatty acid metabolism. In contrast glycolysis genes were strongly co-expressed with late stage fibrosis. MASLD progression is accompanied by a decline in normal liver metabolic function and significant reprogramming of metabolic fuel utilisation. The spatial association of a senescence signature with expression of genes encoding immunoglobulins and complement has been linked to aging and is associated with progressive fibrosis. This work provides a valuable discovery dataset spanning different stages of human liver fibrosis and highlights the complex crosstalk between metabolic perturbations and inflammation underpinning fibrosis progression.

genomics↗

bioRxiv2025

Omics-based insights into human liver reveal GTPase-driven mechanisms of MASLD progression in obesity

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often asymptomatic early on but can progress to irreversible conditions like cirrhosis. Due to limited access to human liver biopsies, systematic and integrative molecular resources remain scarce. In this study, we performed transcriptomic analyses on liver and metabolomic analyses on liver and plasma samples from morbidly obese individuals without liver pathology or at early-stage MASLD. While, the plasma metabolomic profile did not fully mirror liver histological features, dual-omics integration of liver samples revealed significantly remodeled lipid and amino acid metabolism pathways. Integrative network analysis uncoupled metabolic remodeling and gene expression as independent features of hepatic steatosis and fibrosis progression, respectively. Notably, GTPases and their regulators emerged as a novel class of genes linked to early liver fibrosis. This study offers a detailed molecular landscape of early MASLD in obesity and highlights potential targets of obesity-linked liver fibrosis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/632747v3_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1188eborg.highwire.dtl.DTLVardef@1340070org.highwire.dtl.DTLVardef@108d560org.highwire.dtl.DTLVardef@f0adda_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in Amyotrophic Lateral Sclerosis

Arginine methylation is a protein post-translational modification important for the development of skeletal muscle mass and function. Despite this, our understanding of the regulation of arginine methylation under settings of health and disease remains largely undefined. Here, we investigated the regulation of arginine methylation in skeletal muscles in response to exercise and hypertrophic growth, and in diseases involving metabolic dysfunction and atrophy. We report a limited regulation of arginine methylation under physiological settings that promote muscle health, such as during growth and acute exercise, nor in disease models of insulin resistance. In contrast, we saw a significant remodeling of asymmetric dimethylation in models of atrophy characterized by the loss of innervation, including in muscle biopsies from patients with amyotrophic lateral sclerosis (ALS). Mass spectrometry-based quantification of the proteome and asymmetric arginine dimethylome of skeletal muscle from individuals with ALS revealed the largest compendium of protein changes with the identification of 793 regulated proteins, and novel site-specific changes in asymmetric dimethyl arginine (aDMA) of key sarcomeric and cytoskeletal proteins. Finally, we show that in vivo overexpression of PRMT1 and aDMA resulted in increased fatigue resistance and functional recovery in mice. Our study provides evidence for asymmetric dimethylation as a regulator of muscle pathophysiology and presents a valuable proteomics resource and rationale for numerous methylated and non-methylated proteins, including PRMT1, to be pursued for therapeutic development in ALS.

physiology↗

bioRxiv2023

Sex differences in the effects of mild traumatic brain injury and progesterone treatment on anxiety-like behavior and fear conditioning in rats

Mild traumatic brain injuries (mild TBIs) commonly occur in young adults of both sexes, oftentimes in high-stress environments. In humans, sex differences have been observed in the development of post-concussive anxiety and PTSD-like behaviors. Progesterone, a sex steroid that has neuroprotective properties, restores cognitive function in animal models following more severe TBI, but its effectiveness in preventing the psychological symptoms associated with mild TBI has not been evaluated. Using a model of mild TBI that pairs a social stressor (social defeat) with weight drop, male and naturally estrous-cycling female rats were treated with 4 mg/kg progesterone or vehicle once daily for 5 days after injury. Behavioral measures, including elevated plus maze (EPM), contextual fear conditioning, and novel object recognition (NOR) were assessed following progesterone treatment. Anxiety-like behavior was increased by mild TBI in male rats, with a smaller effect seen in female rats in the diestrus phase at the time of EPM testing. In contrast, mild TBI impaired fear learning in female rats in estrus at the time of fear acquisition. Progesterone treatment failed to attenuate post-mild TBI anxiety-like behavior in either sex. Furthermore, progesterone increased fear conditioning and impaired NOR discrimination in male rats, independent of TBI status. Overall, both sex and estrous cycle contributed to psychological outcomes following mild TBI, which were not ameliorated by post-TBI progesterone. This suggests sex steroids play an important role as a moderator of the expression of mild TBI-induced psychological symptoms, rather than as a potential treatment for their underlying etiology.

neuroscience↗

bioRxiv2022

ACSM1 and ACSM3 regulate prostate cancer fatty acid metabolism to promote tumour growth and constrain ferroptosis

Prostate tumours are highly reliant on lipids for energy, growth and survival. Activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes in prostate cancer, although the molecular underpinnings of this relationship remain to be fully elucidated. Here, we identified Acyl-CoA Synthetase Medium Chain Family Members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 are upregulated in prostate tumours compared to non-malignant tissues and other cancer types. Both enzymes enhanced proliferation and protected PCa cells from death in vitro, while silencing ACSM3 led to reduced tumour growth in an orthotopic xenograft model. We show that ACSM1 and ACSM3 are major regulators of the PCa lipidome and enhance energy production via fatty acid oxidation. Metabolic dysregulation caused by loss of ACSM1/3 led to mitochondrial oxidative stress, lipid peroxidation and cell death by ferroptosis. Conversely, over-expression of ACSM1/3 enabled PCa cells to survive toxic doses of medium chain fatty acids and promoted resistance to ferroptosis-inducing drugs and AR antagonists. Collectively, these studies uncover a new link between AR and lipid metabolism and position ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance.

cancer biology↗

bioRxiv2022

Mechanisms underlying the efficacy of a rodent model of vertical sleeve gastrectomy - a focus on energy expenditure

Background and aimsBariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study is to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. MethodsDiet-induced obese male Sprague-Dawley rats were either sham-operated, underwent VSG surgery or were pairfed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of lean rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 2 deoxy-D-glucose (2DG)-14C, administered intraperitoneally. Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. ResultsFollowing VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in lean animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlight a patent neural link between the gut and BAT that include groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. ConclusionCollectively, these data support a role for BAT in mediating the metabolic sequelae, particularly the improvement in glucose regulation following VSG surgery and highlight the need to better understand the contribution from this tissue in human patients.

physiology↗

bioRxiv2021

Intergenerational effects of a paternal Western diet during adolescence on offspring gut microbiota, stress reactivity and social behavior

The global consumption of highly processed, calorie-dense foods has contributed to an epidemic of overweight and obesity, along with negative consequences for metabolic dysfunction and disease susceptibility. As it becomes apparent that overweight and obesity have ripple effects through generations, understanding of the processes involved is required, in both maternal and paternal epigenetic inheritance. We focused on the patrilineal effects of a Western-style high-fat (21%) and high-sugar (34%) diet (WD) compared to control diet (CD) during adolescence and investigated F0 and F1 mice for physiological and behavioral changes. F0 males (fathers) showed increased body weight, impaired glycemic control, and decreased attractiveness to females. Paternal WD caused significant phenotypic changes in F1 offspring, including higher body weights of pups, increased Actinobacteria abundance in the gut microbiota (ascertained using 16S microbiome profiling), a food preference for WD pellets, increased male dominance and attractiveness to females, as well as decreased behavioral despair. These results collectively demonstrate the long-term intergenerational effects of a Western-style diet during paternal adolescence. The behavioral and physiological alterations in F1 offspring provide evidence of adaptive paternal programming via epigenetic inheritance. These findings have important implications for understanding paternally mediated intergenerational inheritance, and its relevance to offspring health and disease susceptibility.

neuroscience↗

bioRxiv2020

Proteome analysis of human visceral and subcutaneous adipocytes identifies depot-specific heterogeneity at metabolic control points

Adipose tissue is a primary regulator of energy balance and metabolism. The distribution of adipose tissue depots is of clinical interest because the accumulation of upper-body subcutaneous (ASAT) and visceral adipose tissue (VAT) is associated with cardiometabolic diseases, whereas lower-body gluteal-femoral adipose tissue (GFAT) appears to be protective. There is heterogeneity in morphology and metabolism of adipocytes obtained from different regions of the body, but detailed knowledge of the constituent proteins in each depot is lacking. Here, we determined the human adipocyte proteome from ASAT, VAT and GFAT using high-resolution SWATH mass spectrometry proteomics. We quantified 4220 proteins in adipocytes, and 2329 proteins were expressed in all three adipose depots. Comparative analysis revealed significant differences between adipocytes from different regions (6 and 8% when comparing VAT vs. ASAT and GFAT, 3% when comparing ASAT vs. GFAT), with marked differences in proteins that regulate metabolic functions. The VAT adipocyte proteome was overrepresented with proteins of glycolysis, lipogenesis, oxidative stress and mitochondrial dysfunction. The GFAT adipocyte proteome predicted activation of PPAR, fatty acid and BCAA oxidation, enhanced TCA cycle flux and oxidative phosphorylation, which was supported by metabolomic data obtained from adipocytes from the same patient donors. Together, this proteomic analysis provides an important resource and novel insights that enhance the understanding of metabolic heterogeneity in the regional adipocytes of humans.

physiology↗

bioRxiv2018

Sex Differences in Aggression: Differential Roles of 5-HT2, Neuropeptide F and Tachykinin

Despite the conserved function of aggression across taxa in obtaining critical resources such as food and mates, serotonins (5-HT) modulatory role on aggressive behavior appears to be largely inhibitory for vertebrates but stimulatory for invertebrates. However, critical gaps exist in our knowledge of invertebrates that need to be addressed before definitively stating opposing roles for 5-HT and aggression. Specifically, the role of 5-HT receptor subtypes are largely unknown, as is the potential interactive role of 5-HT with other neurochemical systems known to play a critical role in aggression. Similarly, the influence of these systems in driving sex differences in aggressive behavior of invertebrates is not well understood. Here, we investigated these questions by employing complementary approaches in a novel invertebrate model of aggression, the stalk-eyed fly. A combination of altered social conditions, pharmacological manipulation and 5-HT2 receptor knockdown by siRNA revealed an inhibitory role of this receptor subtype on aggression. Additionally, we provide evidence for 5-HT2s involvement in regulating neuropeptide F activity, a suspected inhibitor of aggression. However, this function appears to be stage-specific, altering only the initiation stage of aggressive conflicts. Alternatively, pharmacologically increasing systemic concentrations of 5-HT significantly elevated the expression of the neuropeptide tachykinin, which did not affect contest initiation but instead promoted escalation via production of high intensity aggressive behaviors. Notably, these effects were limited solely to males, with female aggression and neuropeptide expression remaining unaltered by any manipulation that affected 5-HT. Together, these results demonstrate a more nuanced role for 5-HT in modulating aggression in invertebrates, revealing an important interactive role with neuropeptides that is more reminiscent of vertebrates. The sex-differences described here also provide valuable insight into the evolutionary contexts of this complex behavior.\n\nSignificance StatementSerotonins (5-HT) modulatory role in aggression is generally reported as inhibitory in vertebrates but stimulatory in invertebrates. Using a novel invertebrate model system, we provide evidence of common pathways of aggression at the 5-HT receptor subtype level as well as 5-HTs interactive role with other neurochemical systems namely neuropeptide F and tachykinin. Additionally, we found that these effects were sex-dependent as well as stage-dependent affecting either the initiation or escalation stage of an aggressive contest. Our results reveal the impressive level of conservation with respect to neurochemical mechanisms among species as diverse as vertebrates and invertebrates, and highlights the need to consider multiple factors when determining potential taxonomic differences in how 5-HT mediates aggression.

neuroscience↗