Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of d-2-hydroxyglutarate (d-2HG), an oncometabolite that promotes tumorigenesis through ...epigenetic alterations. The cancer cell-intrinsic effects of d-2HG are well understood, but its tumor cell-nonautonomous roles remain poorly explored. We compared the oncometabolite d-2HG with its enantiomer, l-2HG, and found that tumor-derived d-2HG was taken up by CD8
T cells and altered their metabolism and antitumor functions in an acute and reversible fashion. We identified the glycolytic enzyme lactate dehydrogenase (LDH) as a molecular target of d-2HG. d-2HG and inhibition of LDH drive a metabolic program and immune CD8
T cell signature marked by decreased cytotoxicity and impaired interferon-γ signaling that was recapitulated in clinical samples from human patients with
mutant gliomas.
The ChemCam instrument suite on the Mars Science Laboratory (MSL) rover
Curiosity
provides remote compositional information using the first laser-induced breakdown spectrometer (LIBS) on a planetary ...mission, and provides sample texture and morphology data using a remote micro-imager (RMI). Overall, ChemCam supports MSL with five capabilities: remote classification of rock and soil characteristics; quantitative elemental compositions including light elements like hydrogen and some elements to which LIBS is uniquely sensitive (e.g., Li, Be, Rb, Sr, Ba); remote removal of surface dust and depth profiling through surface coatings; context imaging; and passive spectroscopy over the 240–905 nm range. ChemCam is built in two sections: The mast unit, consisting of a laser, telescope, RMI, and associated electronics, resides on the rover’s mast, and is described in a companion paper. ChemCam’s body unit, which is mounted in the body of the rover, comprises an optical demultiplexer, three spectrometers, detectors, their coolers, and associated electronics and data handling logic. Additional instrument components include a 6 m optical fiber which transfers the LIBS light from the telescope to the body unit, and a set of onboard calibration targets. ChemCam was integrated and tested at Los Alamos National Laboratory where it also underwent LIBS calibration with 69 geological standards prior to integration with the rover. Post-integration testing used coordinated mast and instrument commands, including LIBS line scans on rock targets during system-level thermal-vacuum tests. In this paper we describe the body unit, optical fiber, and calibration targets, and the assembly, testing, and verification of the instrument prior to launch.
The coordination of traits from individual organs to whole plants is under strong selection because of environmental constraints on resource acquisition and use. However, the tight coordination of ...traits may provide underlying mechanisms of how locally adapted plant populations can become maladapted because of climate change.
To better understand local adaptation in intraspecific trait coordination, we studied trait variability in the widely distributed foundation tree species, Populus fremontii using a common garden near the mid‐elevational point of this species distribution. We examined 28 traits encompassing four spectra: phenology, leaf economic spectrum (LES), whole‐tree architecture (Corner's Rule) and wood economic spectrum (WES).
Based on adaptive syndrome theory, we hypothesized that trait expression would be coordinated among and within trait spectra, reflecting local adaptation to either exposure to freeze‐thaw conditions in genotypes sourced from high‐elevation populations or exposure to extreme thermal stress in genotypes sourced from low‐elevation populations.
High‐elevation genotypes expressed traits within the phenology and WES that limit frost exposure and tissue damage. Specifically, genotypes sourced from high elevations had later mean budburst, earlier mean budset, higher wood densities, higher bark fractions and smaller xylem vessels than their low‐elevation counterparts. Conversely, genotypes sourced from low elevations expressed traits within the LES that prioritized hydraulic efficiency and canopy thermal regulation to cope with extreme heat exposure, including 40% smaller leaf areas, 67% higher stomatal densities and 34% higher mean theoretical maximum stomatal conductance. Low‐elevation genotypes also expressed a lower stomatal control over leaf water potentials that subsequently dropped to pressures that could induce hydraulic failure.
Synthesis. Our results suggest that Populus fremontii expresses a high degree of coordination across multiple trait spectra to adapt to local climate constraints on photosynthetic gas exchange, growth and survival. These results, therefore, increase our mechanistic understanding of local adaptation and the potential effects of climate change that in turn, improves our capacity to identify genotypes that are best suited for future restoration efforts.
Trait variability among Populus fremontii populations indicates there is a high degree of local adaptation to climate. The coordination of traits may provide underlying mechanisms of how locally adapted plant populations likeP. fremontii along the Bill Williams river (LBWBIL) in western Arizona (pictured) can become maladapted because of climate change. Photo by Hillary Cooper, 2017.
In the framework of MOSFET reliability for RF/AMS applications, a deep investigation of RF parameters degradation is performed. An innovative flow, composed of DC and RF stresses with DC and RF aging ...characterization, is presented. Degradation kinetics of main parameters are physically explained and modeled using PSP compact model to predict the behavior of stressed devices.
Background
In January 2020, the WHO declared the SARS-CoV-2 outbreak a public health emergency; by March 11, a pandemic was declared. To date in Ireland, over 3300 patients have been admitted to ...acute hospitals as a result of infection with COVID-19.
Aims
This article aims to describe the establishment of a COVID Recovery Service, a multidisciplinary service for comprehensive follow-up of patients with a hospital diagnosis of COVID-19 pneumonia.
Methods
A hybrid model of virtual and in-person clinics was established, supported by a multidisciplinary team consisting of respiratory, critical care, infectious diseases, psychiatry, and psychology services. This model identifies patients who need enhanced follow-up following COVID-19 pneumonia and aims to support patients with complications of COVID-19 and those who require integrated community care.
Results
We describe a post-COVID-19 service structure together with detailed protocols for multidisciplinary follow-up. One hundred seventy-four patients were discharged from Beaumont Hospital after COVID-19 pneumonia. Sixty-seven percent were male with a median age (IQR) of 66.5 (51–97). Twenty-two percent were admitted to the ICU for mechanical ventilation, 11% had non-invasive ventilation or high flow oxygen, and 67% did not have specialist respiratory support. Early data suggests that 48% of these patients will require medium to long-term specialist follow-up.
Conclusions
We demonstrate the implementation of an integrated multidisciplinary approach to patients with COVID-19, identifying those with increased physical and mental healthcare needs. Our initial experience suggests that significant physical, psychological, and cognitive impairments may persist despite clinical resolution of the infection.
This randomized, noninferiority trial compared ketamine with electroconvulsive therapy in treatment-resistant depression. Ketamine was noninferior to ECT for treatment-resistant depression without ...psychosis.
Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 ...pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.
This study investigated the saltwater upconing mechanism in fractured coastal aquifers. Head-induced saline intrusion was initiated into three narrow sandbox aquifers containing individual horizontal ...discontinuities placed on different positions. Subsequently, using a peristaltic pump, freshwater was abstracted from the aquifers’ center, triggering saltwater upconing. Progressively larger pumping rates were applied until critical conditions, resulting in the wells’ salinization, were achieved. Advanced image analysis algorithms were utilized to recreate the saltwater concentration fields and quantify the extent of the saline wedges with a high accuracy. A numerical model was successfully employed to simulate the laboratory results and conduct a comprehensive sensitivity analysis, further expanding the findings of this investigation. The impact of the fractures’ length, permeability and position on the upconing mechanism was identified. It was established that the presence of high permeability discontinuities significantly affected aquifer hydrodynamics. The conclusions of this study could constitute a contribution towards the successful management of real-world fractured coastal aquifers.
IntroductionThere is a paucity of data that can be used to guide the management of critically ill patients with COVID-19. In response, a research and data-sharing collaborative—The COVID-19 Critical ...Care Consortium—has been assembled to harness the cumulative experience of intensive care units (ICUs) worldwide. The resulting observational study provides a platform to rapidly disseminate detailed data and insights crucial to improving outcomes.Methods and analysisThis is an international, multicentre, observational study of patients with confirmed or suspected SARS-CoV-2 infection admitted to ICUs. This is an evolving, open-ended study that commenced on 1 January 2020 and currently includes >350 sites in over 48 countries. The study enrols patients at the time of ICU admission and follows them to the time of death, hospital discharge or 28 days post-ICU admission, whichever occurs last. Key data, collected via an electronic case report form devised in collaboration with the International Severe Acute Respiratory and Emerging Infection Consortium/Short Period Incidence Study of Severe Acute Respiratory Illness networks, include: patient demographic data and risk factors, clinical features, severity of illness and respiratory failure, need for non-invasive and/or mechanical ventilation and/or extracorporeal membrane oxygenation and associated complications, as well as data on adjunctive therapies.Ethics and disseminationLocal principal investigators will ensure that the study adheres to all relevant national regulations, and that the necessary approvals are in place before a site may contribute data. In jurisdictions where a waiver of consent is deemed insufficient, prospective, representative or retrospective consent will be obtained, as appropriate. A web-based dashboard has been developed to provide relevant data and descriptive statistics to international collaborators in real-time. It is anticipated that, following study completion, all de-identified data will be made open access.Trial registration numberACTRN12620000421932 (http://anzctr.org.au/ACTRN12620000421932.aspx).
We report the Transiting Exoplanet Survey Satellite (TESS) discovery of three terrestrial-size planets transiting L 98-59 (TOI-175, TIC 307210830)-a bright M dwarf at a distance of 10.6 pc. Using the ...Gaia-measured distance and broadband photometry, we find that the host star is an M3 dwarf. Combined with the TESS transits from three sectors, the corresponding stellar parameters yield planet radii ranging from 0.8 R⊕ to 1.6 R⊕. All three planets have short orbital periods, ranging from 2.25 to 7.45 days with the outer pair just wide of a 2:1 period resonance. Diagnostic tests produced by the TESS Data Validation Report and the vetting package DAVE rule out common false-positive sources. These analyses, along with dedicated follow-up and the multiplicity of the system, lend confidence that the observed signals are caused by planets transiting L 98-59 and are not associated with other sources in the field. The L 98-59 system is interesting for a number of reasons: the host star is bright (V = 11.7 mag, K = 7.1 mag) and the planets are prime targets for further follow-up observations including precision radial-velocity mass measurements and future transit spectroscopy with the James Webb Space Telescope; the near-resonant configuration makes the system a laboratory to study planetary system dynamical evolution; and three planets of relatively similar size in the same system present an opportunity to study terrestrial planets where other variables (age, metallicity, etc.) can be held constant. L 98-59 will be observed in four more TESS sectors, which will provide a wealth of information on the three currently known planets and have the potential to reveal additional planets in the system.
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