Sex differences in pharmacological interventions and their effects on lifespan and healthspan outcomes: a systematic review

With an increasing aging population, the burden of age-related diseases magnifies. To alleviate this burden, geroprotection has been an area of intense research focus with the development of pharmacological interventions that target lifespan and/or healthspan. However, there are often sex differences, with compounds mostly tested in male animals. Given the importance of considering both sexes in preclinical research, this neglects potential benefits for the female population, as interventions tested in both sexes often show clear sexual dimorphisms in their biological responses. To further understand the prevalence of sex differences in pharmacological geroprotective intervention studies, we performed a systematic review of the literature according to the PRISMA guidelines. Seventy-two studies met our inclusion criteria and were classified into one of five subclasses: FDA-repurposed drugs, novel small molecules, probiotics, traditional Chinese medicine, and antioxidants, vitamins, or other dietary supplements. Interventions were analyzed for their effects on median and maximal lifespan and healthspan markers, including frailty, muscle function and coordination, cognitive function and learning, metabolism, and cancer. With our systematic review, we found that twenty-two out of sixty-four compounds tested were able to prolong both lifespan and healthspan measures. Focusing on the use of female and male mice, and on comparing their outcomes, we found that 40% of studies only used male mice or did not clarify the sex. Notably, of the 36% of pharmacologic interventions that did use both male and female mice, 73% of these studies showed sex-specific outcomes on healthspan and/or lifespan. These data highlight the importance of studying both sexes in the search for geroprotectors, as the biology of aging is not the same in male and female mice.Systematic Review Registration: [website], identifier [registration number]

Bulge-Disk Decompositions and Structural Bimodality of Ursa Major Cluster Spiral Galaxies

We present bulge and disk (B/D) decompositions of existing K'-band surface brightness profiles for 65 Ursa Major cluster spiral galaxies. This improves upon the disk-only fits of Tully et al. (1996). The 1996 disk fits were used by Tully & Verheijen (1997) for their discovery of the bimodality of structural parameters in the UMa cluster galaxies. It is shown that our new 1D B/D decompositions yield disk structural parameters that differ only slightly from the basic fits of Tully et al. and evidence for structural bimodality of UMa galaxies is maintained. Our B/D software for the decomposition of 1D surface brightness profiles of galaxies uses a non-linear minimization scheme to recover the best fitting Sersic bulge and exponential disk while accounting for the possible presence of a compact nucleus and spiral arms and for the effects of seeing and disk truncations. In agreement with Tully & Verheijen, we find that the distribution of near-infrared disk central surface brightnesses is bimodal with an F-test confidence of 80%. There is also strong evidence for a local minimum in the luminosity function at M_K' ~ -22. A connection between the brightness bimodality and a dynamical bimodality, based on new HI line widths, is identified. The B/D parameters are presented in an Appendix.Comment: Accepted for publication in MNRA

Towards comprehensive understanding of bacterial genetic diversity:large-scale amplifications in Bordetella pertussis and Mycobacterium tuberculosis

Bacterial genetic diversity is often described solely using base-pair changes despite a wide variety of other mutation types likely being major contributors. Tandem duplication/amplifications are thought to be widespread among bacteria but due to their often-intractable size and instability, comprehensive studies of these mutations are rare. We define a methodology to investigate amplifications in bacterial genomes based on read depth of genome sequence data as a proxy for copy number. We demonstrate the approach with Bordetella pertussis , whose insertion sequence element-rich genome provides extensive scope for amplifications to occur. Analysis of data for 2430 B. pertussis isolates identified 272 putative amplifications, of which 94 % were located at 11 hotspot loci. We demonstrate limited phylogenetic connection for the occurrence of amplifications, suggesting unstable and sporadic characteristics. Genome instability was further described in vitro using long-read sequencing via the Nanopore platform, which revealed that clonally derived laboratory cultures produced heterogenous populations rapidly. We extended this research to analyse a population of 1000 isolates of another important pathogen, Mycobacterium tuberculosis . We found 590 amplifications in M. tuberculosis , and like B. pertussis , these occurred primarily at hotspots. Genes amplified in B. pertussis include those involved in motility and respiration, whilst in M. tuberuclosis, functions included intracellular growth and regulation of virulence. Using publicly available short-read data we predicted previously unrecognized, large amplifications in B. pertussis and M. tuberculosis . This reveals the unrecognized and dynamic genetic diversity of B. pertussis and M. tuberculosis , highlighting the need for a more holistic understanding of bacterial genetics

Allelic Expression of Deleterious Protein-Coding Variants across Human Tissues

Personal exome and genome sequencing provides access to loss-of-function and rare deleterious alleles whose interpretation is expected to provide insight into individual disease burden. However, for each allele, accurate interpretation of its effect will depend on both its penetrance and the trait's expressivity. In this regard, an important factor that can modify the effect of a pathogenic coding allele is its level of expression; a factor which itself characteristically changes across tissues. To better inform the degree to which pathogenic alleles can be modified by expression level across multiple tissues, we have conducted exome, RNA and deep, targeted allele-specific expression (ASE) sequencing in ten tissues obtained from a single individual. By combining such data, we report the impact of rare and common loss-of-function variants on allelic expression exposing stronger allelic bias for rare stop-gain variants and informing the extent to which rare deleterious coding alleles are consistently expressed across tissues. This study demonstrates the potential importance of transcriptome data to the interpretation of pathogenic protein-coding variants

Radially Extended Kinematics in the S0 Galaxy NGC 2768 from Planetary Nebulae, Globular Clusters and Starlight

There are only a few tracers available to probe the kinematics of individual early-type galaxies beyond one effective radius. Here we directly compare a sample of planetary nebulae (PNe), globular clusters (GCs) and galaxy starlight velocities out to ~4 effective radii, in the S0 galaxy NGC 2768. Using a bulge-to-disk decomposition of a K-band image we assign PNe and starlight to either the disk or the bulge. We show that the bulge PNe and bulge starlight follow the same radial density distribution as the red subpopulation of GCs, whereas the disk PNe and disk starlight are distinct components. We find good kinematic agreement between the three tracers to several effective radii (and with stellar data in the inner regions). Further support for the distinct nature of the two galaxy components come from our kinematic analysis. After separating the tracers into bulge and disk components we find the bulge to be a slowly rotating pressure-supported system, whereas the disk reveals a rapidly rising rotation curve with a declining velocity dispersion profile. The resulting V/sigma ratio for the disk resembles that of a spiral galaxy and hints at an origin for NGC 2768 as a transformed late-type galaxy. A two-component kinematic analysis for a sample of S0s will help to elucidate the nature of this class of galaxy.Comment: 10 pages, 5 figures, accepted for publication in MRA

The stellar kinematics and populations of boxy bulges: cylindrical rotation and vertical gradients

Boxy and peanut-shaped bulges are seen in about half of edge-on disc galaxies. Comparisons of the photometry and major-axis gas and stellar kinematics of these bulges to simulations of bar formation and evolution indicate that they are bars viewed in projection. If the properties of boxy bulges can be entirely explained by assuming they are bars, then this may imply that their hosts are pure disc galaxies with no classical bulge. A handful of these bulges, including that of the Milky Way, have been observed to rotate cylindrically, i.e. with a mean stellar velocity independent of height above the disc. In order to assess whether such behaviour is ubiquitous in boxy bulges, and whether a pure disc interpretation is consistent with their stellar populations, we have analysed the stellar kinematics and populations of the boxy or peanut-shaped bulges in a sample of five edge-on galaxies. We placed slits along the major axis of each galaxy and at three offset but parallel positions to build up spatial coverage. The boxy bulge of NGC3390 rotates perfectly cylindrically within the spatial extent and uncertainties of the data. This is consistent with the metallicity and alpha-element enhancement of the bulge, which are the same as in the disk. This galaxy is thus a pure disc galaxy. The boxy bulge of ESO311-G012 also rotates very close to cylindrically. The boxy bulge of NGC1381 is neither clearly cylindrically nor non-cylindrically rotating, but it has a negative vertical metallicity gradient and is alpha-enhanced with respect to its disc, suggesting a composite bulge comprised of a classical bulge and bar (and possibly a discy pseudobulge) [abridged] Even this relatively small sample is sufficient to demonstrate that boxy bulges display a range of rotational and population properties, indicating that they do not form a homogeneous class of object.Comment: MNRAS accepted. 10 page

The Next Generation Virgo Cluster Survey - Infrared (NGVS-IR): I. A new Near-UV/Optical/Near-IR Globular Cluster selection tool

The NGVS-IR project (Next Generation Virgo Survey - Infrared) is a contiguous near-infrared imaging survey of the Virgo cluster of galaxies. It complements the optical wide-field survey of Virgo (NGVS). The current state of NGVS-IR consists of Ks-band imaging of 4 deg^2 centered on M87, and J and Ks-band imaging of 16 deg^2 covering the region between M49 and M87. In this paper, we present the observations of the central 4 deg^2 centered on Virgo's core region. The data were acquired with WIRCam on the Canada-France-Hawaii Telescope and the total integration time was 41 hours distributed in 34 contiguous tiles. A survey-specific strategy was designed to account for extended galaxies while still measuring accurate sky brightness within the survey area. The average 5\sigma limiting magnitude is Ks=24.4 AB mag and the 50% completeness limit is Ks=23.75 AB mag for point source detections, when using only images with better than 0.7" seeing (median seeing 0.54"). Star clusters are marginally resolved in these image stacks, and Virgo galaxies with \mu_Ks=24.4 AB mag arcsec^-2 are detected. Combining the Ks data with optical and ultraviolet data, we build the uiK color-color diagram which allows a very clean color-based selection of globular clusters in Virgo. This diagnostic plot will provide reliable globular cluster candidates for spectroscopic follow-up campaigns needed to continue the exploration of Virgo's photometric and kinematic sub-structures, and will help the design of future searches for globular clusters in extragalactic systems. Equipped with this powerful new tool, future NGVS-IR investigations based on the uiK diagram will address the mapping and analysis of extended structures and compact stellar systems in and around Virgo galaxies.Comment: 23 pages, 18 figures. Accepted for publication in ApJ

Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans

More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein α-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associ

Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production

Angiogenesis, the formation of new blood vessels by endothelial cells (ECs), is an adaptive response to oxygen/nutrient deprivation orchestrated by vascular endothelial growth factor (VEGF) upon ischemia or exercise. Hypoxia is the best-understood trigger of VEGF expression via the transcription factor HIF1 alpha. Nutrient deprivation is inseparable from hypoxia during ischemia, yet its role in angiogenesis is poorly characterized. Here, we identified sulfur amino acid restriction as a proangiogenic trigger, promoting increased VEGF expression, migration and sprouting in ECs in vitro, and increased capillary density in mouse skeletal muscle in vivo via the GCN2/ATF4 amino acid starvation response pathway independent of hypoxia or HIF1 alpha. We also identified a requirement for cystathionine-gamma-lyase in VEGF-dependent angiogenesis via increased hydrogen sulfide (H2S) production. H2S mediated its proangiogenic effects in part by inhibiting mitochondrial electron transport and oxidative phosphorylation, resulting in increased glucose uptake and glycolytic ATP production.11Ysciescopu