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"Smith, T"
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High-coverage plasma lipidomics reveals novel sex-specific lipidomic fingerprints of age and BMI: Evidence from two large population cohort studies
Obesity and related metabolic diseases show clear sex-related differences. The growing burden of these diseases calls for better understanding of the age- and sex-related metabolic consequences. High-throughput lipidomic analyses of population-based cohorts offer an opportunity to identify disease-risk-associated biomarkers and to improve our understanding of lipid metabolism and biology at a population level. Here, we comprehensively examined the relationship between lipid classes/subclasses and molecular species with age, sex, and body mass index (BMI). Furthermore, we evaluated sex specificity in the association of the plasma lipidome with age and BMI. Some 747 targeted lipid measures, representing 706 molecular lipid species across 36 classes/subclasses, were measured using a high-performance liquid chromatography coupled mass spectrometer on a total of 10,339 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), with 563 lipid species being validated externally on 4,207 participants of the Busselton Health Study (BHS). Heat maps were constructed to visualise the relative differences in lipidomic profile between men and women. Multivariable linear regression analyses, including sex-interaction terms, were performed to assess the associations of lipid species with cardiometabolic phenotypes. Associations with age and sex were found for 472 (66.9%) and 583 (82.6%) lipid species, respectively. We further demonstrated that age-associated lipidomic fingerprints differed by sex. Specific classes of ether-phospholipids and lysophospholipids (calculated as the sum composition of the species within the class) were inversely associated with age in men only. In analyses with women alone, higher triacylglycerol and lower lysoalkylphosphatidylcholine species were observed among postmenopausal women compared with premenopausal women. We also identified sex-specific associations of lipid species with obesity. Lysophospholipids were negatively associated with BMI in both sexes (with a larger effect size in men), whilst acylcarnitine species showed opposing associations based on sex (positive association in women and negative association in men). Finally, by utilising specific lipid ratios as a proxy for enzymatic activity, we identified stearoyl CoA desaturase (SCD-1), fatty acid desaturase 3 (FADS3), and plasmanylethanolamine Δ1-desaturase activities, as well as the sphingolipid metabolic pathway, as constituent perturbations of cardiometabolic phenotypes. Our analyses elucidate the effect of age and sex on lipid metabolism by offering a comprehensive view of the lipidomic profiles associated with common cardiometabolic risk factors. These findings have implications for age- and sex-dependent lipid metabolism in health and disease and suggest the need for sex stratification during lipid biomarker discovery, establishing biological reference intervals for assessment of disease risk.
Journal Article
Wide field-of-view, multi-region, two-photon imaging of neuronal activity in the mammalian brain
Simultaneous imaging of neural activity in large regions of the mouse brain at subcellular resolution is made possible with a wide field-of-view two-photon microscope.
Two-photon calcium imaging provides an optical readout of neuronal activity in populations of neurons with subcellular resolution. However, conventional two-photon imaging systems are limited in their field of view to ∼1 mm
2
, precluding the visualization of multiple cortical areas simultaneously. Here, we demonstrate a two-photon microscope with an expanded field of view (>9.5 mm
2
) for rapidly reconfigurable simultaneous scanning of widely separated populations of neurons. We custom designed and assembled an optimized scan engine, objective, and two independently positionable, temporally multiplexed excitation pathways. We used this new microscope to measure activity correlations between two cortical visual areas in mice during visual processing.
Journal Article
Sex differences in measures of central sensitization and pain sensitivity to experimental sleep disruption: implications for sex differences in chronic pain
Females demonstrate heightened central sensitization (CS), a risk factor for chronic pain characterized by enhanced responsivity of central nervous system nociceptors to normal or subthreshold input. Sleep disruption increases pain sensitivity, but sex has rarely been evaluated as a moderator and few experiments have measured CS. We evaluated whether two nights of sleep disruption alter CS measures of secondary hyperalgesia and mechanical temporal summation in a sex-dependent manner. We also evaluated differences in measures of pain sensitivity.
Seventy-nine healthy adults (female n = 46) participated in a randomized crossover experiment comparing two consecutive nights of eight pseudorandomly distributed forced awakenings (FA [-200 min sleep time]) against two nights of undisturbed sleep (US). We conducted sensory testing the mornings following Night 2; the heat-capsaicin pain model was used to induce secondary hyperalgesia.
FA reduced total sleep time (REM and NREM Stage 3) more profoundly in males. We observed divergent, sex-dependent effects of FA on secondary hyperalgesia and temporal summation. FA significantly increased secondary hyperalgesia in males and significantly increased temporal summation in females. Sex differences were not attributable to differential sleep loss in males. FA also significantly reduced heat-pain threshold and cold pressor pain tolerance, independently of sex.
Sleep disruption enhances different pain facilitatory measures of CS in males and females suggesting that sleep disturbance may increase risk for chronic pain in males and females via distinct pathways. Findings have implications for understanding sex differences in chronic pain and investigating sleep in chronic pain prevention efforts.
Journal Article
Assessing multiple score functions in Rosetta for drug discovery
Rosetta is a computational software suite containing algorithms for a wide variety of macromolecular structure prediction and design tasks including small molecule protocols commonly used in drug discovery or enzyme design. Here, we benchmark RosettaLigand score functions and protocols in comparison to results of other software recently published in the Comparative Assessment of Score Functions (CASF-2016). The CASF-2016 benchmark covers a wide variety of tests including scoring and ranking multiple compounds against a target, ligand docking of a small molecule to a target, and virtual screening to extract binders from a compound library. Direct comparison to the score functions provided by CASF-2016 results shows that the original RosettaLigand score function ranks among the top software for scoring, ranking, docking and screening tests. Most notably, the RosettaLigand score function ranked 2/34 among other report score functions in CASF-2016. We additionally perform a ligand docking test with full sampling to mimic typical use cases. Despite improved performance of newer score functions in canonical protein structure prediction and design, we demonstrate here that more recent Rosetta score functions have reduced performance across all small molecule benchmarks. The tests described here have also been uploaded to the Rosetta scientific benchmarking server and will be run weekly to track performance as the code is continually being developed.
Journal Article
Mr. Penguin and the lost treasure
Aspiring Professional Adventurer Mr. Penguin and his colleague, Colin the spider, try to find a treasure rumored to be buried in The Museum of Extraordinary Objects before bandits do.
Book
Star Formation and Molecular Gas Diagnostics with Mid- and Far-infrared Emission
With the start of JWST observations, mid-infrared (MIR) emission features from polycyclic aromatic hydrocarbons (PAHs), H2 rotational lines, fine structure lines from ions, and dust continuum will be widely available tracers of gas and star formation rate (SFR) in galaxies at various redshifts. Many of these tracers originate from dust and gas illuminated by UV photons from massive stars, so they generally trace both SFR and gas to varying degrees. We investigate how MIR spectral features from 5–35 μm and photometry from 3.4–250 μm correlate with SFR and molecular gas. In general, we find MIR emission features (i.e., PAHs and H2 rotational lines) trace both CO and SFR better than CO and SFR trace one another. H2 lines and PAH features correlate best with CO. Fine structure lines from ions correlate best with SFR. The [S iii] lines at 18.7 and 33.5 μm, in particular, have a very tight correlation with SFR, and we use them to calibrate new single-parameter MIR tracers of SFR that have negligible metallicity dependence in our sample. The 17 μm/7.7 μm PAH feature ratio increases as a function of CO emission which may be evidence of PAH growth or neutralization in molecular gas. The degree to which dust continuum emission traces SFR or CO varies as a function of wavelength, with continuum between 20 and 70 μm better tracing SFR, while longer wavelengths better trace CO.
Journal Article