Bioavailable testosterone linearly declines over a wide age spectrum in men and women from the Baltimore longitudinal study of aging

Background: Age-related changes in testosterone levels in older persons and especially in women have not been fully explored. The objective of this study was to describe age-related trajectories of total testosterone (TT), ammonium sulfate precipitation-measured bioavailable testosterone (mBT), and sex hormone-binding glycoprotein (SHBG) in men and women from the Baltimore Longitudinal Study of Aging, with special focus on the oldest adults. Methods: Participants included 788 White men and women aged 30-96 years with excellent representation of old and oldest old, who reported not taking medications known to interfere with testosterone. Longitudinal data were included when available. TT, mBT, and SHBG were assayed. Age-related trajectories of mBT were compared with those obtained using calculated bioavailable testosterone (cBT). Generalized least square models were performed to describe age-related trajectories of TT, mBT, and SHBG in men and women. Results: mBT linearly declines over the life span and even at older ages in both sexes. In men, TT remains quite stable until the age of 70 years and then declines at older ages, whereas in women TT progressively declines in premenopausal years and slightly increases at older ages. Differences in age-related trajectories between total and bioavailable testosterone are only partially explained by age changes in SHBG, whose levels increases at accelerated rates in old persons. Noteworthy, although mBT and cBT highly correlated with one another, mBT is a much stronger correlate of chronological age than cBT. Conclusion: In both men and women, mBT linearly declines over the life span and even at old ages. Its relationship with age-related phenotypes should be further investigated

Comprehension as social and intellectual practice: Rebuilding curriculum in low socioeconomic and cultural minority schools

This article reframes the concept of comprehension as a social and intellectual practice. It reviews current approaches to reading instruction for linguistically and culturally diverse and low socioeconomic students, noting an emphasis on comprehension as autonomous skills. The Four Resources model (Freebody & Luke, 1990) is used to make the case for the integration of comprehension instruction with an emphasis on student cultural and community knowledge, and substantive intellectual and sociocultural content in elementary school curricula. Illustrations are drawn from research underway on the teaching of literacy in primary schools in low SES communities

Limits on the Stochastic Gravitational Wave Background from the North American Nanohertz Observatory for Gravitational Waves

We present an analysis of high-precision pulsar timing data taken as part of the North American Nanohertz Observatory for Gravitational waves (NANOGrav) project. We have observed 17 pulsars for a span of roughly five years using the Green Bank and Arecibo radio telescopes. We analyze these data using standard pulsar timing models, with the addition of time-variable dispersion measure and frequency-variable pulse shape terms. Sub-microsecond timing residuals are obtained in nearly all cases, and the best root-mean-square timing residuals in this set are ~30-50 ns. We present methods for analyzing post-fit timing residuals for the presence of a gravitational wave signal with a specified spectral shape. These optimally take into account the timing fluctuation power removed by the model fit, and can be applied to either data from a single pulsar, or to a set of pulsars to detect a correlated signal. We apply these methods to our dataset to set an upper limit on the strength of the nHz-frequency stochastic supermassive black hole gravitational wave background of h_c (1 yr^-1) < 7x10^-15 (95%). This result is dominated by the timing of the two best pulsars in the set, PSRs J1713+0747 and J1909-3744.Comment: To be submitted to Ap

The international pulsar timing array project: using pulsars as a gravitational wave detector

The International Pulsar Timing Array project combines observations of pulsars from both Northern and Southern hemisphere observatories with the main aim of detecting ultra-low frequency (~10^-9 to 10^-8 Hz) gravitational waves. Here we introduce the project, review the methods used to search for gravitational waves emitted from coalescing supermassive binary black-hole systems in the centres of merging galaxies and discuss the status of the project.Comment: accepted by Classical and Quantum Gravity. Review talk for the Amaldi8 conference serie

Correlations of Calf Muscle Macrophage Content with Muscle Properties and Walking Performance in Peripheral Artery Disease

Background Peripheral artery disease (PAD) is a manifestation of atherosclerosis characterized by reduced blood flow to the lower extremities and mobility loss. Preliminary evidence suggests PAD damages skeletal muscle, resulting in muscle impairments that contribute to functional decline. We sought to determine whether PAD is associated with an altered macrophage profile in gastrocnemius muscles and whether muscle macrophage populations are associated with impaired muscle phenotype and walking performance in patients with PAD. Methods and Results Macrophages, satellite cells, and extracellular matrix in gastrocnemius muscles from 25 patients with PAD and 7 patients without PAD were quantified using immunohistochemistry. Among patients with PAD, both the absolute number and percentage of cluster of differentiation (CD) 11b+CD206+ M2‐like macrophages positively correlated to satellite cell number (r=0.461 [P=0.023] and r=0.416 [P=0.042], respectively) but not capillary density or extracellular matrix. The number of CD11b+CD206− macrophages negatively correlated to 4‐meter walk tests at normal (r=−0.447, P=0.036) and fast pace (r=−0.510, P=0.014). Extracellular matrix occupied more muscle area in PAD compared with non‐PAD (8.72±2.19% versus 5.30±1.03%, P \u3c 0.001) and positively correlated with capillary density (r=0.656, P \u3c 0.001). Conclusions Among people with PAD, higher CD206+ M2‐like macrophage abundance was associated with greater satellite cell numbers and muscle fiber size. Lower CD206− macrophage abundance was associated with better walking performance. Further study is needed to determine whether CD206+ macrophages are associated with ongoing reparative processes enabling skeletal muscle adaptation to damage with PAD. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00693940, NCT01408901, NCT0224660

Physical Activity Associated Proteomics of Skeletal Muscle: Being Physically Active in Daily Life May Protect Skeletal Muscle From Aging

Muscle strength declines with aging and increasing physical activity is the only intervention known to attenuate this decline. In order to adequately investigate both preventive and therapeutic interventions against sarcopenia, a better understanding of the biological changes that are induced by physical activity in skeletal muscle is required. To determine the effect of physical activity on the skeletal muscle proteome, we utilized liquid-chromatography mass spectrometry to obtain quantitative proteomics data on human skeletal muscle biopsies from 60 well-characterized healthy individuals (20–87 years) who reported heterogeneous levels of physical activity (not active, active, moderately active, and highly active). Over 4,000 proteins were quantified, and higher self-reported physical activity was associated with substantial overrepresentation of proteins associated with mitochondria, TCA cycle, structural and contractile muscle, and genome maintenance. Conversely, proteins related to the spliceosome, transcription regulation, immune function, and apoptosis, DNA damage, and senescence were underrepresented with higher self-reported activity. These differences in observed protein expression were related to different levels of physical activity in daily life and not intense competitive exercise. In most instances, differences in protein levels were directly opposite to those reported in the literature observed with aging. These data suggest that being physically active in daily life has strong and biologically detectable beneficial effects on muscle

Conserved and species-specific molecular denominators in mammalian skeletal muscle aging

Aging is a complex phenomenon involving functional decline in multiple physiological systems. We undertook a comparative analysis of skeletal muscle from four different species, i.e. mice, rats, rhesus monkeys, and humans, at three different representative stages during their lifespan (young, middle, and old) to identify pathways that modulate function and healthspan. Gene expression profiling and computational analysis revealed that pathway complexity increases from mice to humans, and as mammals age, there is predominantly an upregulation of pathways in all species. Two downregulated pathways, the electron transport chain and oxidative phosphorylation, were common among all four species in response to aging. Quantitative PCR, biochemical analysis, mitochondrial DNA measurements, and electron microscopy revealed a conserved age-dependent decrease in mitochondrial content, and a reduction in oxidative phosphorylation complexes in monkeys and humans. Western blot analysis of key proteins in mitochondrial biogenesis discovered that (i) an imbalance toward mitochondrial fusion occurs in aged skeletal muscle and (ii) mitophagy is not overtly affected, presumably leading to the observed accumulation of abnormally large, damaged mitochondria with age. Select transcript expression analysis uncovered that the skeletal inflammatory profile differentially increases with age, but is most pronounced in humans, while increased oxidative stress (as assessed by protein carbonyl adducts and 4-hydroxynonenal) is common among all species. Expression studies also found that there is unique dysregulation of the nutrient sensing pathways among the different species with age. The identification of conserved pathways indicates common molecular mechanisms intrinsic to health and lifespan, whereas the recognition of species-specific pathways emphasizes the importance of human studies for devising optimal therapeutic modalities to slow the aging process

Molecular cloning and AlphaFold modeling of Thyrotropin (ag-TSH) from the amazonian fish pirarucu (Arapaima gigas).

Arapaima gigas, known as Pirarucu in Brazil, is one of the largest freshwater fish in the world. Some individuals could reach 3m in length and weight up to 200kg. Due to extinction risks and its economic value, the species has been a focus for preservation and reproduction studies. Thyrotropin (TSH) is a glycoprotein hormone formed by 2 subunits a and b whose main activity is related to the synthesis of thyroid hormones (THs)?T3 and T4. In this work, we present a combination of bioinformatics tools to identify Arapaima gigas bTSH (ag-bTSH), modeling its molecular structure and express the recombinant heterodimer form in mammalian cells. Using the combination of computational biology, based on genome-related information, in silico molecular cloning and modeling led to confirm results of the ag-bTSH sequence by reverse transcriptase-polymerase chain reaction (RT-PCR) and transient expression in human embryonic kidney (HEK293F) cells. Molecular cloning of ag-bTSH retrieved 146 amino acids with a signal peptide of 21 amino acid residues and 6 disulfide bonds. The sequence has a similarity to 39 fish species, ranging between 43.1% and 81.6%, whose domains are extremely conserved, such as cystine knot motif and N-glycosylation site. The Arapaima gigas thyrotropin (ag-TSH) model, solved by AlphaFold, was used in molecular dynamics simulations with Scleropages formosus receptor, providing similar values of free energy AGbind and AGPMF in comparison with Homo sapiens model. The recombinant expression in HEK293F cells reached a yield of 25mg/L, characterized via chromatographic and physical-chemical techniques. This work shows that other Arapaima gigas proteins could be studied in a similar way, using the combination of these techniques, recovering more information from its genome and improving the reproduction and preservation of this prehistoric fish