Reproductive aging in Caenorhabditis elegans: From molecules to ecology

Aging animals display a broad range of progressive degenerative changes, and one of the most fascinating is the decline of female reproductive function. In the model organis

EFFECTS OF STATIC STRETCHING ON MAXIMAL ISOKINETIC TORQUE

The effects of 20 seconds of agonist (AGO), antagonist (ANT) or no (NO) pre-exercise stretch on concentric (CON) and eccentric (ECC) maximal isokinetic torque produced at the knee were examined. Twelve male semi-pro rugby players performed dominant isokinetic knee extension following the specified stretch protocol. One-way Repeated Measures ANOVA revealed AGO to be significantly less (p < 0.05) than the other protocols for both CON (270 28 Nm) and ECC (309 42 Nm) torque. There was no difference between the ANT or NO for either CON (303 35 Nm and 304 38 Nm, respectively) or ECC (341 40 Nm and 33644 Nm). The results support the theory that pre-exercise agonist stretching may lead to performance decrements in maximal concentric torque production

A dual-center cohort study on the association between early deep sedation and clinical outcomes in mechanically ventilated patients during the COVID-19 pandemic: The COVID-SED study

BACKGROUND: Mechanically ventilated patients have experienced greater periods of prolonged deep sedation during the coronavirus disease (COVID-19) pandemic. Multiple studies from the pre-COVID era demonstrate that early deep sedation is associated with worse outcome. Despite this, there is a lack of data on sedation depth and its impact on outcome for mechanically ventilated patients during the COVID-19 pandemic. We sought to characterize the emergency department (ED) and intensive care unit (ICU) sedation practices during the COVID-19 pandemic, and to determine if early deep sedation was associated with worse clinical outcomes. STUDY DESIGN AND METHODS: Dual-center, retrospective cohort study conducted over 6 months (March-August, 2020), involving consecutive, mechanically ventilated adults. All sedation-related data during the first 48 h were collected. Deep sedation was defined as Richmond Agitation-Sedation Scale of - 3 to - 5 or Riker Sedation-Agitation Scale of 1-3. To examine impact of early sedation depth on hospital mortality (primary outcome), we used a multivariable logistic regression model. Secondary outcomes included ventilator-, ICU-, and hospital-free days. RESULTS: 391 patients were studied, and 283 (72.4%) experienced early deep sedation. Deeply sedated patients received higher cumulative doses of fentanyl, propofol, midazolam, and ketamine when compared to light sedation. Deep sedation patients experienced fewer ventilator-, ICU-, and hospital-free days, and greater mortality (30.4% versus 11.1%) when compared to light sedation (p \u3c 0.01 for all). After adjusting for confounders, early deep sedation remained significantly associated with higher mortality (adjusted OR 3.44; 95% CI 1.65-7.17; p \u3c 0.01). These results were stable in the subgroup of patients with COVID-19. CONCLUSIONS: The management of sedation for mechanically ventilated patients in the ICU has changed during the COVID pandemic. Early deep sedation is common and independently associated with worse clinical outcomes. A protocol-driven approach to sedation, targeting light sedation as early as possible, should continue to remain the default approach

Simple nutrients bypass the requirement for HLH-30 in coupling lysosomal nutrient sensing to survival

Lysosomes are ubiquitous acidified organelles that degrade intracellular and extracellular material trafficked via multiple pathways. Lysosomes also sense cellular nutrient levels to regulate target of rapamycin (TOR) kinase, a signaling enzyme that drives growth and suppresses activity of the MiT/TFE family of transcription factors that control biogenesis of lysosomes. In this study, we subjected worms lacking basic helix–loop–helix transcription factor 30 (hlh-30), the Caenorhabditis elegans MiT/TFE ortholog, to starvation followed by refeeding to understand how this pathway regulates survival with variable nutrient supply. Loss of HLH-30 markedly impaired survival in starved larval worms and recovery upon refeeding bacteria. Remarkably, provision of simple nutrients in a completely defined medium (C. elegans maintenance medium [CeMM]), specifically glucose and linoleic acid, restored lysosomal acidification, TOR activation, and survival with refeeding despite the absence of HLH-30. Worms deficient in lysosomal lipase 2 (lipl-2), a lysosomal enzyme that is transcriptionally up-regulated in starvation in an HLH-30–dependent manner, also demonstrated increased mortality with starvation–refeeding that was partially rescued with glucose, suggesting a critical role for LIPL-2 in lipid metabolism under starvation. CeMM induced transcription of vacuolar proton pump subunits in hlh-30 mutant worms, and knockdown of vacuolar H+-ATPase 12 (vha-12) and its upstream regulator, nuclear hormone receptor 31 (nhr-31), abolished the rescue with CeMM. Loss of Ras-related GTP binding protein C homolog 1 RAGC-1, the ortholog for mammalian RagC/D GTPases, conferred starvation–refeeding lethality, and RAGC-1 overexpression was sufficient to rescue starved hlh-30 mutant worms, demonstrating a critical need for TOR activation with refeeding. These results show that HLH-30 activation is critical for sustaining survival during starvation–refeeding stress via regulating TOR. Glucose and linoleic acid bypass the requirement for HLH-30 in coupling lysosome nutrient sensing to survival.</div

UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction.

Brown adipose tissue (BAT) mitochondria exhibit high oxidative capacity and abundant expression of both electron transport chain components and uncoupling protein 1 (UCP1). UCP1 dissipates the mitochondrial proton motive force (Δp) generated by the respiratory chain and increases thermogenesis. Here we find that in mice genetically lacking UCP1, cold-induced activation of metabolism triggers innate immune signaling and markers of cell death in BAT. Moreover, global proteomic analysis reveals that this cascade induced by UCP1 deletion is associated with a dramatic reduction in electron transport chain abundance. UCP1-deficient BAT mitochondria exhibit reduced mitochondrial calcium buffering capacity and are highly sensitive to mitochondrial permeability transition induced by reactive oxygen species (ROS) and calcium overload. This dysfunction depends on ROS production by reverse electron transport through mitochondrial complex I, and can be rescued by inhibition of electron transfer through complex I or pharmacologic depletion of ROS levels. Our findings indicate that the interscapular BAT of Ucp1 knockout mice exhibits mitochondrial disruptions that extend well beyond the deletion of UCP1 itself. This finding should be carefully considered when using this mouse model to examine the role of UCP1 in physiology

The rocket experiment demonstration of a soft x-ray polarimeter (REDSoX Polarimeter)

The Rocket Experiment Demonstration of a Soft X-ray Polarimeter (REDSoX Polarimeter) is a sounding rocket instrument that can make the first measurement of the linear X-ray p olarization of an extragalactic source in the 0.2-0.8 keV band as low as 10%. We employ multilayer-coated mirrors as Bragg reflectors at the Brewster angle. By matching the dispersion of a spectrometer using replicated optics from MSFC and critical angle transmission gratings from MIT to three laterally graded multilayer mirrors (LGMLs), we achieve polarization modulation factors over 90%. We present a novel arrangement of gratings, designed optimally for the purpose of polarimetry with a converging beam. The entrance aperture is divided into six equal sectors; pairs of blazed gratings from opposite sectors are oriented to disperse to the same LGML. The LGML position angles are 120 degrees to each other. CCD detectors then measure the intensities of the dispersed spectra after reflection and polarizing by the LGMLs, giving the three Stokes parameters needed to determine a source's linear polarization fraction and orientation. A current grant is funding further development to improve the LGMLs. Sample gratings for the project have been fabricated at MIT and the development team continues to improve them under separate funding. Our technological approach is the basis for a possible orbital mission. Keywords: X-ray, polarimeter, astronomy, multilayer, mirror, gratingUnited States. National Aeronautics and Space Administration (Grant NNX17AE11G)United States. National Aeronautics and Space Administration (Grant NNX12AH12G)Kavli Institute for Astrophysics and Space Research (Research Investment Grant)United States. National Aeronautics and Space Administration (Grant NNX17AG43G)United States. National Aeronautics and Space Administration (Grant NNX15AC43G

The Effect Stacking Fault Segregation and Phase Transformations have on Creep Strength in Ni-based Superalloys

In this study, two commercially similar polycrystalline Ni-based disk superalloys (LSHR and ME3) were creep tested at 760C and 552MPa to approximately 0.3% plastic strain. LSHR consistently displayed superior creep properties at this stress/temperature regime even though the microstructural characteristics between the two alloys were comparable. High resolution structural and chemical analysis, however, revealed significant differences between the two alloys among active gamma prime shearing modes involving superlattice intrinsic and extrinsic stacking faults. In ME3, Co and Cr segregation and Ni and Al depletion were observed along the intrinsic faults - revealing a gamma prime -to- gamma phase transformation. Conversely in LSHR, an alloy with a higher W content, Co and W segregation was observed along the intrinsic faults. This observation combined with scanning transmission electron microscopy (STEM) simulations confirm a gamma prime-to-D019 phase transformation along the intrinsic faults in LSHR. Using experimental observations and density functional theory calculations, a novel local phase transformation strengthening mechanism is proposed that could be further utilized to improve the high temperature creep capabilities of Ni-base disk alloys

Colorado Ultraviolet Transit Experiment: a dedicated CubeSat mission to study exoplanetary mass loss and magnetic fields

The Colorado Ultraviolet Transit Experiment (CUTE) is a near-UV (2550 to 3300  Å) 6U CubeSat mission designed to monitor transiting hot Jupiters to quantify their atmospheric mass loss and magnetic fields. CUTE will probe both atomic (Mg and Fe) and molecular (OH) lines for evidence of enhanced transit absorption, and to search for evidence of early ingress due to bow shocks ahead of the planet’s orbital motion. As a dedicated mission, CUTE will observe ≳100 spectroscopic transits of hot Jupiters over a nominal 7-month mission. This represents the equivalent of <700 orbits of the only other instrument capable of these measurements, the Hubble Space Telescope. CUTE efficiently utilizes the available CubeSat volume by means of an innovative optical design to achieve a projected effective area of ∼28  cm^2, low instrumental background, and a spectral resolving power of R∼3000 over the primary science bandpass. These performance characteristics enable CUTE to discern transit depths between 0.1% and 1% in individual spectral absorption lines. We present the CUTE optical and mechanical design, a summary of the science motivation and expected results, and an overview of the projected fabrication, calibration, and launch timeline

The metabolic enzyme hexokinase 2 localizes to the nucleus in AML and normal haematopoietic stem and progenitor cells to maintain stemness

Thomas, Egan et al. report that hexokinase 2 localizes to the nucleus of leukaemic and normal haematopoietic cells to maintain stemness by interacting with nuclear proteins and modulating chromatin accessibility independently of its kinase activity. Mitochondrial metabolites regulate leukaemic and normal stem cells by affecting epigenetic marks. How mitochondrial enzymes localize to the nucleus to control stem cell function is less understood. We discovered that the mitochondrial metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus in leukaemic and normal haematopoietic stem cells. Overexpression of nuclear HK2 increases leukaemic stem cell properties and decreases differentiation, whereas selective nuclear HK2 knockdown promotes differentiation and decreases stem cell function. Nuclear HK2 localization is phosphorylation-dependent, requires active import and export, and regulates differentiation independently of its enzymatic activity. HK2 interacts with nuclear proteins regulating chromatin openness, increasing chromatin accessibilities at leukaemic stem cell-positive signature and DNA-repair sites. Nuclear HK2 overexpression decreases double-strand breaks and confers chemoresistance, which may contribute to the mechanism by which leukaemic stem cells resist DNA-damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes influence stem cell function independently of their metabolic function

Design of a broadband soft x-ray polarimeter

We describe an optical design and possible implementation of a broadband soft x-ray polarimeter. Our arrangement of gratings is designed optimally for the purpose of polarimetry with broadband focusing optics by matching the dispersion of the spectrometer channels to laterally graded multilayers (LGMLs). The system can achieve polarization modulation factors over 90%. We implement this design using a single optical system by dividing the entrance aperture into six sectors; high efficiency, blazed gratings from opposite sectors are oriented to disperse to a common LGML forming three channels covering the wavelength range from 35 to 75 Å (165 to 350 eV). The grating dispersions and LGML position angles for each channel are 120 deg to each other. CCD detectors then measure the intensities of the dispersed spectra after reflection and polarizing by the LGMLs, giving the three Stokes parameters needed to determine a source's linear polarization fraction and orientation. The design can be extended to higher energies as LGMLs are developed further. We describe examples of the potential scientific return from instruments based on this design