The Small GTPase RhoA Localizes to the Nucleus and Is Activated by Net1 and DNA Damage Signals

Rho GTPases control many cellular processes, including cell survival, gene expression and migration. Rho proteins reside mainly in the cytosol and are targeted to the plasma membrane (PM) upon specific activation by guanine nucleotide exchange factors (GEFs). Accordingly, most GEFs are also cytosolic or associated with the PM. However, Net1, a RhoA-specific GEF predominantly localizes to the cell nucleus at steady-state. Nuclear localization for Net1 has been seen as a mechanism for sequestering the GEF away from RhoA, effectively rendering the protein inactive. However, considering the prominence of nuclear Net1 and the fact that a biological stimulus that promotes Net1 translocation out the nucleus to the cytosol has yet to be discovered, we hypothesized that Net1 might have a previously unidentified function in the nucleus of cells.Using an affinity precipitation method to pulldown the active form of Rho GEFs from different cellular fractions, we show here that nuclear Net1 does in fact exist in an active form, contrary to previous expectations. We further demonstrate that a fraction of RhoA resides in the nucleus, and can also be found in a GTP-bound active form and that Net1 plays a role in the activation of nuclear RhoA. In addition, we show that ionizing radiation (IR) specifically promotes the activation of the nuclear pool of RhoA in a Net1-dependent manner, while the cytoplasmic activity remains unchanged. Surprisingly, irradiating isolated nuclei alone also increases nuclear RhoA activity via Net1, suggesting that all the signals required for IR-induced nuclear RhoA signaling are contained within the nucleus.These results demonstrate the existence of a functional Net1/RhoA signaling pathway within the nucleus of the cell and implicate them in the DNA damage response

The long lives of primates and the ‘invariant rate of ageing’ hypothesis

This work was supported by NIA P01AG031719 to J.W.V. and S.C.A., with additional support provided by the Max Planck Institute of Demographic Research and the Duke University Population Research Institute.Is it possible to slow the rate of ageing, or do biological constraints limit its plasticity? We test the ‘invariant rate of ageing’ hypothesis, which posits that the rate of ageing is relatively fixed within species, with a collection of 39 human and nonhuman primate datasets across seven genera. We first recapitulate, in nonhuman primates, the highly regular relationship between life expectancy and lifespan equality seen in humans. We next demonstrate that variation in the rate of ageing within genera is orders of magnitude smaller than variation in pre-adult and age-independent mortality. Finally, we demonstrate that changes in the rate of ageing, but not other mortality parameters, produce striking, species-atypical changes in mortality patterns. Our results support the invariant rate of ageing hypothesis, implying biological constraints on how much the human rate of ageing can be slowed.Publisher PDFPeer reviewe

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Triboelectric Charging and Dissipation Characteristics of the Maquet Quadrox-D Membrane Oxygenator

Triboelectric charging is commonly detected during cardiopulmonary bypass in circuits using roller pumps and PVC tubing. Dissipation of this charging is needed to prevent a spontaneous discharge from occurring. We evaluated the ability of the Quadrox-D (Maquet) to effectively remove the electrostatic charge accumulation, with and without a heater/cooler connection (H/C). A Quadrox-D oxygenator was evaluated using a Stockert SIII pump head, Cincinnati subzero H/E, and a custom adult extracorporeal membrane oxygenation tubing pack with 1/2′ PVC raceway. The circuit was primed and evaluated for triboelectric accumulation with and without H/C use. The results showed a linear relationship between increasing pump flow and static charge build-up when an H/C was not applied. The calculated r2 value was .95. Incorporation of the H/C effectively eliminated charge accumulation. Increasing pump speed increases the amount of static charge created without the use of an H/C. Incorporation of an H/C effectively eliminates charge build-up in the Quadrox-D and is recommended while priming the circuit

The Pandemic Allocation of Ventilators Model Penalizes Infants with Bronchopulmonary Dysplasia

During the COVID-19 pandemic, institutions developed ventilator allocation models. In one proposed model, neonates compete with adults for ventilators using a scoring system. Points are given for conditions that increase one- and five-year (y) mortality. For example, comparable points were added for adult conditions with mortality of 71.3% and for neonates with moderate or severe bronchopulmonary dysplasia (mod/sBPD). We hypothesized that this model overestimates mortality in neonates with BPD and would penalize these infants unfairly. There was little information available on 1 y and 5 y mortality risk for mod/sBPD. To evaluate this allocation protocol, a retrospective chart review was performed on infants born ≥22 weeks and weighing <1500 g admitted to Rainbow Babies and Children’s Hospital in 2015 to identify babies with BPD. The main outcomes were 1 and 5 y mortality. In 2015, 28 infants were diagnosed with mod/s BPD based on NIH 2001 definition; 4 infants had modBPD and 24 had sBPD. All infants (100%) with modBPD survived to 5 y; 2 infants with sBPD died by 1 y (8%) and 22 survived (92%) to 1 y; 3 died (12.5%) by 5 y; and at least 13 survived (54%) to 5 y. Infants with mod/s BPD had lower-than-predicted 1 and 5 y mortality, suggesting the points assigned in the model are too high for these conditions. We believe this model would unfairly penalize these babies

In vitro evaluation of the Fresenius Kabi CATSmart Autotransfusion System.

Use of autotransfusion systems to collect, wash, and concentrate shed blood during surgical procedures is a widely used method for reducing postoperative anemia and the need for blood transfusions. The aim of this study was to evaluate the CATSmart Continuous Autotransfusion System wash program performance with small (200 or 700 mL) and large volumes (1,000 mL) of shed blood and to determine non-inferiority of the CATSmart to the C.A.T.

In Vitro Evaluation of the Fresenius Kabi CATSmart Autotransfusion System

Use of autotransfusion systems to collect, wash, and concentrate shed blood during surgical procedures is a widely used method for reducing postoperative anemia and the need for blood transfusions. The aim of this study was to evaluate the CATSmart Continuous Autotransfusion System wash program performance with small (200 or 700 mL) and large volumes (1,000 mL) of shed blood and to determine non-inferiority of the CATSmart to the C.A.T.Splus system. Human whole blood was collected in citrate phosphate dextrose, diluted, and divided into two aliquots to be processed as a pair using the C.A.T.Splus and CATSmart systems with their corresponding wash programs: low-volume, high quality/smart, or emergency wash. Final packed red cell product was analyzed for red blood cell (RBC), white blood cell, and platelet counts; hemoglobin; hemolysis; RBC recovery rates; and elimination of albumin, total protein, and potassium. The mean hematocrit (HCT) after processing with CATSmart and C.A.T.Splus systems were 59.63% and 57.71%, respectively. The calculated overall RBC recovery rates on the CATSmart and C.A.T.Splus systems were 85.41% and 84.99%, respectively. Elimination of albumin (97.5%, 98.0%), total proteins (97.1%, 97.5%), and potassium (92.1%, 91.9%) were also calculated for the CATSmart and C.A.T.Splus systems. The CATSmart and C.A.T.Splus systems both provided a high-quality product in terms of HCT, protein elimination, and hemolysis rates across the range of tested shed blood volumes and all wash programs. The study was able to confirm the CATSmart is non-inferior to the C.A.T.Splus system

Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: a prospective, community-based study

Objective To assess medium-term organ impairment in symptomatic individuals following recovery from acute SARS-CoV-2 infection.Design Baseline findings from a prospective, observational cohort study.Setting Community-based individuals from two UK centres between 1 April and 14 September 2020.Participants Individuals ≥18 years with persistent symptoms following recovery from acute SARS-CoV-2 infection and age-matched healthy controls.Intervention Assessment of symptoms by standardised questionnaires (EQ-5D-5L, Dyspnoea-12) and organ-specific metrics by biochemical assessment and quantitative MRI.Main outcome measures Severe post-COVID-19 syndrome defined as ongoing respiratory symptoms and/or moderate functional impairment in activities of daily living; single-organ and multiorgan impairment (heart, lungs, kidneys, liver, pancreas, spleen) by consensus definitions at baseline investigation.Results 201 individuals (mean age 45, range 21–71 years, 71% female, 88% white, 32% healthcare workers) completed the baseline assessment (median of 141 days following SARS-CoV-2 infection, IQR 110–162). The study population was at low risk of COVID-19 mortality (obesity 20%, hypertension 7%, type 2 diabetes 2%, heart disease 5%), with only 19% hospitalised with COVID-19. 42% of individuals had 10 or more symptoms and 60% had severe post-COVID-19 syndrome. Fatigue (98%), muscle aches (87%), breathlessness (88%) and headaches (83%) were most frequently reported. Mild organ impairment was present in the heart (26%), lungs (11%), kidneys (4%), liver (28%), pancreas (40%) and spleen (4%), with single-organ and multiorgan impairment in 70% and 29%, respectively. Hospitalisation was associated with older age (p=0.001), non-white ethnicity (p=0.016), increased liver volume (p&lt;0.0001), pancreatic inflammation (p&lt;0.01), and fat accumulation in the liver (p&lt;0.05) and pancreas (p&lt;0.01). Severe post-COVID-19 syndrome was associated with radiological evidence of cardiac damage (myocarditis) (p&lt;0.05).Conclusions In individuals at low risk of COVID-19 mortality with ongoing symptoms, 70% have impairment in one or more organs 4 months after initial COVID-19 symptoms, with implications for healthcare and public health, which have assumed low risk in young people with no comorbidities.Trial registration number NCT04369807; Pre-results