Sirolimus, also known as rapamycin, and its closely related rapamycin analog (rapalog) Everolimus inhibit “mammalian target of rapamycin complex 1” (mTORC1), whose activity is required for ...spermatogenesis. Everolimus is Food and Drug Administration approved for treating human patients to slow growth of aggressive cancers and preventing organ transplant rejection. Here, we test the hypothesis that rapalog inhibition of mTORC1 activity has a negative, but reversible, impact upon spermatogenesis. Juvenile (P20) or adult (P>60) mice received daily injections of sirolimus or Everolimus for 30 days, and tissues were examined at completion of treatment or following a recovery period. Rapalog treatments reduced body and testis weights, testis weight/body weight ratios, cauda epididymal sperm counts, and seminal vesicle weights in animals of both ages. Following rapalog treatment, numbers of differentiating spermatogonia were reduced, with concomitant increases in the ratio of undifferentiated spermatogonia to total number of remaining germ cells. To determine if even low doses of Everolimus can inhibit spermatogenesis, an additional group of adult mice received a dose of Everolimus ∼6-fold lower than a human clinical dose used to treat cancer. In these animals, only testis weights, testis weight/body weight ratios, and tubule diameters were reduced. Return to control values following a recovery period was variable for each of the measured parameters and was duration and dose dependent. Together, these data indicate rapalogs exerted a dose-dependent restriction on overall growth of juvenile and adult mice and negative impact upon spermatogenesis that were largely reversed; following treatment cessation, males from all treatment groups were able to sire offspring. Summary Sentence Treatments of juvenile and adult mice with rapamycin and its analog (rapalog) Everolimus cause reproductive deficits, but males are able to sire offspring following cessation of treatment.
ABSTRACT
The Planck All-Sky Survey to Analyze Gravitationally-lensed Extreme Starbursts project aims to identify a population of extremely luminous galaxies using the Planck all-sky survey and to ...explore the nature of their gas fuelling, induced starburst, and the resulting feedback that shape their evolution. Here, we report the identification of 22 high-redshift luminous dusty star-forming galaxies (DSFGs) at z = 1.1–3.3 drawn from a candidate list constructed using the Planck Catalogue of Compact Sources and Wide-field Infrared Survey Explorer all-sky survey. They are confirmed through follow-up dust continuum imaging and CO spectroscopy using AzTEC and the Redshift Search Receiver on the Large Millimeter Telescope Alfonso Serrano. Their apparent infrared luminosities span (0.1–3.1) × 1014 L⊙ (median of 1.2 × 1014 L⊙), making them some of the most luminous galaxies found so far. They are also some of the rarest objects in the sky with a source density of ≲0.01 deg−2. Our Atacama Large Millimeter/submillimeter Array 1.1 mm continuum observations with θ ≈ 0.4 arcsec resolution show clear ring or arc morphologies characteristic of strong lensing. Their lensing-corrected luminosity of LIR ≳ 1013 L⊙ (star-formation rate ≳ 103 M⊙ yr−1) indicates that they are the magnified versions of the most intrinsically luminous DSFGs found at these redshifts. Our spectral energy distribution analysis finds little detectable active galactic nucleus (AGN) activity despite their enormous luminosity, and any AGN activity present must be extremely heavily obscured.
Abstract Hosseini SM, Oyster ML, Kirby RL, Harrington AL, Boninger ML. Manual wheelchair skills capacity predicts quality of life and community integration in persons with spinal cord injury. ...Objectives To determine wheelchair (WC) skills success rates for manual WC users with spinal cord injury (SCI), to determine subject characteristics associated with the lowest success rates of WC skills, and to characterize the relationship between WC skills and measures of community integration and quality of life (QOL). Design Cross-sectional multisite study. Setting Six Spinal Cord Injury Model Systems (SCIMS) centers. Participants Individuals with SCI (N=214) who were at least 11 months postinjury, treated at an SCIMS center, and who used a manual WC as their primary means of mobility. Intervention Not applicable. Main Outcome Measures Wheelchair Skills Test (WST) and questionnaires of demographics and characteristics, QOL, and community participation. Results Of the 31 skills in the WST assessed, success rates ranged from 19.6% to 100%. Eight skills had success rates of ≤75%: folding/unfolding the WC (71.5%), ascending (19.6%) and descending (47.2%) a 15-cm curb, ascending (23.2%) and descending (26.5%) stairs, transferring from ground to WC (40.6%), turning 180° in wheelie position (55.2%), and holding a 30-second stationary wheelie (59.9%). Male sex, paraplegia, employed status, lower education, younger age at injury, and white race were among the participant characteristics bivariately associated with higher success rates of several WC skills. After controlling for covariates, higher success rates of several WC skills and a higher total WST score predicted better self-perceived health, higher life satisfaction, and more community participation. Conclusions For people with SCI who use a manual WC as their primary means of mobility, their ability to perform manual WC skills is associated with higher community participation and life satisfaction. Factors contributing to low success rates need to be investigated, and interventions to improve these rates are needed.
We present new light curves of the massive hot Jupiter system WASP-18 obtained with the Spitzer spacecraft covering the entire orbit at 3.6 and 4.5 μm. These light curves are used to measure the ...amplitude, shape and phase of the thermal phase effect for WASP-18 b. We find that our results for the thermal phase effect are limited to an accuracy of about 0.01 per cent by systematic noise sources of unknown origin. At this level of accuracy we find that the thermal phase effect has a peak-to-peak amplitude approximately equal to the secondary eclipse depth, has a sinusoidal shape and that the maximum brightness occurs at the same phase as mid-occultation to within about 5 ° at 3.6 μm and to within about 10 ° at 4.5 μm. The shape and amplitude of the thermal phase curve imply very low levels of heat redistribution within the atmosphere of the planet. We also perform a separate analysis to determine the system geometry by fitting a light curve model to the data covering the occultation and the transit. The secondary eclipse depths we measure at 3.6 and 4.5 μm are in good agreement with previous measurements and imply a very low albedo for WASP-18 b. The parameters of the system (masses, radii, etc.) derived from our analysis are also in good agreement with those from previous studies, but with improved precision. We use new high-resolution imaging and published limits on the rate of change of the mean radial velocity to check for the presence of any faint companion stars that may affect our results. We find that there is unlikely to be any significant contribution to the flux at Spitzer wavelengths from a stellar companion to WASP-18. We find that there is no evidence for variations in the times of eclipse from a linear ephemeris greater than about 100 s over 3 years.
The classical model of tissue renewal posits that small numbers of quiescent stem cells (SCs) give rise to proliferating transit-amplifying cells before terminal differentiation. However, many organs ...house pools of SCs with proliferative and differentiation potentials that diverge from this template. Resolving SC identity and organization is therefore central to understanding tissue renewal. Here, using a combination of single-cell RNA sequencing (scRNA-seq), mouse genetics and tissue injury approaches, we uncover cellular hierarchies and mechanisms that underlie the maintenance and repair of the continuously growing mouse incisor. Our results reveal that, during homeostasis, a group of actively cycling epithelial progenitors generates enamel-producing ameloblasts and adjacent layers of non-ameloblast cells. After injury, tissue repair was achieved through transient increases in progenitor-cell proliferation and through direct conversion of Notch1-expressing cells to ameloblasts. We elucidate epithelial SC identity, position and function, providing a mechanistic basis for the homeostasis and repair of a fast-turnover ectodermal appendage.
Aggregation of the tau protein into fibrillar cross-β aggregates is a hallmark of Alzheimer's diseases (AD) and many other neurodegenerative tauopathies. Recently, several core structures of ...patient-derived tau paired helical filaments (PHFs) have been solved revealing a structural variability that often correlates with a specific tauopathy. To further characterize the dynamics of these fibril cores, to screen for strain-specific small molecules as potential biomarkers and therapeutics, and to develop strain-specific antibodies, recombinant in-vitro models of tau filaments are needed. We recently showed that a 95-residue fragment of tau (from residue 297 to 391), termed dGAE, forms filaments
in the absence of polyanionic co-factors often used for
aggregation of full-length tau. Tau(297-391) was identified as the proteolytic resistant core of tau PHFs and overlaps with the structures characterized by cryo-electron microscopy in
PHFs, making it a promising model for the study of AD tau filaments
. In the present study, we used solid-state NMR to characterize tau(297-391) filaments and show that such filaments assembled under non-reducing conditions are more dynamic and less ordered than those made in the presence of the reducing agent DTT. We further report the resonance assignment of tau(297-391)+DTT filaments and compare it to existing core structures of tau.
Micro-Abstract Aberrant expression of immunomodulatory proteins B7-H1 and B7-H3 by malignant cells may contribute to tumoral immune evasion. Immunohistochemistry for B7-H1 and B7-H3 was performed on ...214 resected pulmonary squamous cell carcinoma specimens: 42 of 214 (19.6%) were positive for B7-H1, and 189 of 214 (88.3%) were positive for B7-H3. These markers do not have independent prognostic value but are commonly expressed by tumor cells in pulmonary squamous carcinomas.
Two PEMFC failure modes (dehydration and flooding) were investigated using in situ electrochemical impedance spectroscopy (EIS) on a four-cell stack under load. The EIS measurements were made at ...different temperatures (70 and 80
°C), covering the current density range 0.1–1.0
A
cm
−2, and the frequency range 0.1–2
×
10
5
Hz. Dehydration and flooding effects were observed in the frequency ranges 0.5–10
5 and 0.5–10
2
Hz, respectively.
We propose that impedance measurements at separate frequency ranges (or narrow bands thereof) can be used to distinguish between flooding and dehydration events. Similar approaches may be used to diagnose other important PEMFC failures.
Objective:
Depression has been shown to be a risk factor for Alzheimer’s disease (AD), and in older adults may provide a marker for the beginning of the prodromal phase of AD. The purpose of this ...systematic review is to examine the relationship between amyloid-β (Aβ), a key biomarker of AD, and depression in older adults.
Method:
The literature search was limited to studies conducted from 2006 to 2014 that were published in English in peer-reviewed journals. Studies were selected if they included a group of older adults who either met established criteria for Major Depressive Disorder or Dysthymia; or were assessed for depressive symptoms on a standardised measure. Studies were also required to include an outcome variable that was a direct measure of Aβ levels in either blood or cerebrospinal fluid (CSF) samples, or via neuroimaging techniques such as positron emission tomography (PET).
Results:
Nineteen studies were identified, 15 of which found significant differences in Aβ levels between depressed and non-depressed older adults. However, studies were limited by their cross-sectional design, reliance on blood-based measures of Aβ, and potential sample bias.
Conclusions:
Future investigations should consider prospective longitudinal design using neuroimaging and CSF measures of Aβ.
Biological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed ...as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood-DNA-methylation measure that is sensitive to variation in pace of biological aging among individuals born the same year. We first modeled change-over-time in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in n = 954 members of the Dunedin Study born in 1972-1973. Rates of change in each biomarker over ages 26-38 years were composited to form a measure of aging-related decline, termed Pace-of-Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace-of-Aging, called DunedinPoAm for Dunedin(P)ace(o)f(A)ging(m)ethylation. Validation analysis in cohort studies and the CALERIE trial provide proof-of-principle for DunedinPoAm as a single-time-point measure of a person's pace of biological aging.
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