A short, 14-amino-acid segment called SP1, located in the Gag structural protein
, has a critical role during the formation of the HIV-1 virus particle. During virus assembly, the SP1 peptide and ...seven preceding residues fold into a six-helix bundle, which holds together the Gag hexamer and facilitates the formation of a curved immature hexagonal lattice underneath the viral membrane
. Upon completion of assembly and budding, proteolytic cleavage of Gag leads to virus maturation, in which the immature lattice is broken down; the liberated CA domain of Gag then re-assembles into the mature conical capsid that encloses the viral genome and associated enzymes. Folding and proteolysis of the six-helix bundle are crucial rate-limiting steps of both Gag assembly and disassembly, and the six-helix bundle is an established target of HIV-1 inhibitors
. Here, using a combination of structural and functional analyses, we show that inositol hexakisphosphate (InsP6, also known as IP
) facilitates the formation of the six-helix bundle and assembly of the immature HIV-1 Gag lattice. IP
makes ionic contacts with two rings of lysine residues at the centre of the Gag hexamer. Proteolytic cleavage then unmasks an alternative binding site, where IP
interaction promotes the assembly of the mature capsid lattice. These studies identify IP
as a naturally occurring small molecule that promotes both assembly and maturation of HIV-1.
A pronounced, widespread and persistent regime shift among marine ecosystems is observable on temperate rocky reefs as a result of sea urchin overgrazing. Here, we empirically define regime-shift ...dynamics for this grazing system which transitions between productive macroalgal beds and impoverished urchin barrens. Catastrophic in nature, urchin overgrazing in a well-studied Australian system demonstrates a discontinuous regime shift, which is of particular management concern as recovery of desirable macroalgal beds requires reducing grazers to well below the initial threshold of overgrazing. Generality of this regime-shift dynamic is explored across 13 rocky reef systems (spanning 11 different regions from both hemispheres) by compiling available survey data (totalling 10 901 quadrats surveyed in situ) plus experimental regime-shift responses (observed during a total of 57 in situ manipulations). The emergent and globally coherent pattern shows urchin grazing to cause a discontinuous 'catastrophic' regime shift, with hysteresis effect of approximately one order of magnitude in urchin biomass between critical thresholds of overgrazing and recovery. Different life-history traits appear to create asymmetry in the pace of overgrazing versus recovery. Once shifted, strong feedback mechanisms provide resilience for each alternative state thus defining the catastrophic nature of this regime shift. Importantly, human-derived stressors can act to erode resilience of desirable macroalgal beds while strengthening resilience of urchin barrens, thus exacerbating the risk, spatial extent and irreversibility of an unwanted regime shift for marine ecosystems.
Highlights • Adult rat CNS endothelial cells express functional TLR4. • The opioid receptor-inactive morphine metabolite M3G activates TLR4-dependent inflammatory signaling in endothelial cells. • ...Nalmefene is a mu opioid receptor antagonist without TLR4 activity, whereas CTAP is an antagonist at both receptors. • Stimulation of endothelial cells by M3G induces in vivo responses of decreased mechanical thresholds and vasodilation. • The putative glial inhibitors AV1013 and propentofylline also inhibit the inflammatory response of endothelial cells.
We report on the experimental observation of scaling in the time evolution following a sudden quench into the vicinity of a quantum critical point. The experimental system, a two-component Bose gas ...with coherent exchange between the constituents, allows for the necessary high level of control of parameters as well as the access to time-resolved spatial correlation functions. The theoretical analysis reveals that when quenching the system close to the critical point, the energy introduced by the quench leads to a short-time evolution exhibiting crossover reminiscent of the finite-temperature critical properties in the system's universality class. Observing the time evolution after a quench represents a paradigm shift in accessing and probing experimentally universal properties close to a quantum critical point and allows in a new way benchmarking of quantum many-body theory with experiments.
The geological units on the floor of Jezero crater, Mars, are part of a wider regional stratigraphy of olivine-rich rocks, which extends well beyond the crater. We investigate the petrology of ...olivine and carbonate-bearing rocks of the Séítah formation in the floor of Jezero. Using multispectral images and x-ray fluorescence data, acquired by the Perseverance rover, we performed a petrographic analysis of the Bastide and Brac outcrops within this unit. We find that these outcrops are composed of igneous rock, moderately altered by aqueous fluid. The igneous rocks are mainly made of coarse-grained olivine, similar to some Martian meteorites. We interpret them as an olivine cumulate, formed by settling and enrichment of olivine through multi-stage cooling of a thick magma body.
Mastcam-Z is a multispectral, stereoscopic imaging investigation on the Mars 2020 mission’s
Perseverance
rover. Mastcam-Z consists of a pair of focusable, 4:1 zoomable cameras that provide broadband ...red/green/blue and narrowband 400-1000 nm color imaging with fields of view from 25.6° × 19.2° (26 mm focal length at 283 μrad/pixel) to 6.2° × 4.6° (110 mm focal length at 67.4 μrad/pixel). The cameras can resolve (≥ 5 pixels) ∼0.7 mm features at 2 m and ∼3.3 cm features at 100 m distance. Mastcam-Z shares significant heritage with the Mastcam instruments on the Mars Science Laboratory
Curiosity
rover. Each Mastcam-Z camera consists of zoom, focus, and filter wheel mechanisms and a 1648 × 1214 pixel charge-coupled device detector and electronics. The two Mastcam-Z cameras are mounted with a 24.4 cm stereo baseline and 2.3° total toe-in on a camera plate ∼2 m above the surface on the rover’s Remote Sensing Mast, which provides azimuth and elevation actuation. A separate digital electronics assembly inside the rover provides power, data processing and storage, and the interface to the rover computer. Primary and secondary Mastcam-Z calibration targets mounted on the rover top deck enable tactical reflectance calibration. Mastcam-Z multispectral, stereo, and panoramic images will be used to provide detailed morphology, topography, and geologic context along the rover’s traverse; constrain mineralogic, photometric, and physical properties of surface materials; monitor and characterize atmospheric and astronomical phenomena; and document the rover’s sample extraction and caching locations. Mastcam-Z images will also provide key engineering information to support sample selection and other rover driving and tool/instrument operations decisions.
The purpose of this work was to develop an end-to-end patient-specific quality assurance (QA) technique for spot-scanned proton therapy that is more sensitive and efficient than traditional ...approaches. The patient-specific methodology relies on independently verifying the accuracy of the delivered proton fluence and the dose calculation in the heterogeneous patient volume. A Monte Carlo dose calculation engine, which was developed in-house, recalculates a planned dose distribution on the patient CT data set to verify the dose distribution represented by the treatment planning system. The plan is then delivered in a pre-treatment setting and logs of spot position and dose monitors, which are integrated into the treatment nozzle, are recorded. A computational routine compares the delivery log to the DICOM spot map used by the Monte Carlo calculation to ensure that the delivered parameters at the machine match the calculated plan. Measurements of dose planes using independent detector arrays, which historically are the standard approach to patient-specific QA, are not performed for every patient. The nozzle-integrated detectors are rigorously validated using independent detectors in regular QA intervals. The measured data are compared to the expected delivery patterns. The dose monitor reading deviations are reported in a histogram, while the spot position discrepancies are plotted vs. spot number to facilitate independent analysis of both random and systematic deviations. Action thresholds are linked to accuracy of the commissioned delivery system. Even when plan delivery is acceptable, the Monte Carlo second check system has identified dose calculation issues which would not have been illuminated using traditional, phantom-based measurement techniques. The efficiency and sensitivity of our patient-specific QA program has been improved by implementing a procedure which independently verifies patient dose calculation accuracy and plan delivery fidelity. Such an approach to QA requires holistic integration and maintenance of patient-specific and patient-independent QA.
It is increasingly recognized that the location of excess adiposity, particularly increased deposition of visceral adipose tissue (VAT), is important when determining the adverse health effects of ...overweight and obesity. Exercise therapy is an integral component of obesity management, but the most potent exercise prescription for VAT benefit is unclear. We aimed to evaluate the independent and synergistic effects of aerobic exercise (AEx) and progressive resistance training (PRT) and to directly compare the efficacy of AEx and PRT for beneficial VAT modulation. A systematic review and meta‐analysis was performed to assess the efficacy of exercise interventions on VAT content/volume in overweight and obese adults. Relevant databases were searched to November 2010. Included studies were randomized controlled designs in which AEx or PRT in isolation or combination were employed for 4 weeks or more in adult humans, where computed tomography (CT) or magnetic resonance imaging (MRI) was used for quantification of VAT pre‐ and post‐intervention. Of the 12196 studies from the initial search, 35 were included. After removal of outliers, there was a significant pooled effect size (ES) for the comparison between AEx therapy and control (−0.33, 95% CI: −0.52 to −0.14; P < 0.01) but not for the comparison between PRT therapy and control (0.09, 95% CI: −0.17 to −0.36; P = 0.49). Of the available nine studies which directly compared AEx with PRT, the pooled ES did not reach statistical significance (ES = 0.23, 95% CI: −0.02 to 0.50; P = 0.07 favouring AEx). The pooled ES did not reach statistical significance for interventions that combined AEx and PRT therapy vs. control (−0.28, 95% CI: −0.69 to 0.14; P = 0.19), for which only seven studies were available. These data suggest that aerobic exercise is central for exercise programmes aimed at reducing VAT, and that aerobic exercise below current recommendations for overweight/obesity management may be sufficient for beneficial VAT modification. Further investigation is needed regarding the efficacy and feasibility of multi‐modal training as a means of reducing VAT.
This phase III randomized study compared concurrent cisplatin–radiotherapy (CRT) versus radiotherapy (RT) alone in patients with locoregionally advanced nasopharyngeal carcinoma. A total of 350 ...patients were randomly assigned to receive external RT alone or concurrently with cisplatin at a dosage of 40 mg/m2 weekly. The primary endpoint was overall survival, and the median follow-up was 5.5 years. The 5-year overall survival was 58.6% (95% confidence interval CI = 50.9% to 66.2%) for the RT arm and 70.3% (95% CI = 63.4% to 77.3%) for the CRT arm. In Cox regression analysis adjusted for T stage, age, and overall stage, the difference in overall survival was statistically significantly in favor of concurrent CRT (P = .049, hazard ratio HR = 0.71 95% CI = 0.5 to 1.0). Subgroup analysis demonstrated that there was no difference between overall survival in the arms for T1/T2 stage (P = .74, HR = 0.93 95% CI = 0.59 to 1.4), whereas there was a difference between the arms for T3/T4 stage (P = .013, HR = 0.51 95% CI = 0.3 to 0.88), favoring the CRT arm. The regimen of weekly concurrent CRT is a promising standard treatment strategy for locoregionally advanced nasopharyngeal carcinoma patients.
The COVID-19 pandemic constitutes a social crisis that will have long-term health consequences for much of the global population, especially for adolescents. Adolescents are triply affected as they: ...1) are experiencing its immediate, direct effects, 2) will carry forward health habits they develop now into adulthood, and 3) as future parents, will shape the early life health of the next generation. It is therefore imperative to assess how the pandemic is influencing adolescent wellbeing, identify sources of resilience, and outline strategies for attenuating its negative impacts.
We report the results of longitudinal analyses of qualitative data from 28 focus group discussions (FGDs) with 39 Canadian adolescents and of cross-sectional analyses of survey data from 482 Canadian adolescents gathered between September 2020 and August 2021. FGD participants and survey respondents reported on their: socio-demographic characteristics; mental health and wellbeing before and during the pandemic; pre- and during-pandemic health behaviours; experiences living through a crisis; current perceptions of their school, work, social, media, and governmental environments; and ideas about pandemic coping and mutual aid. We plotted themes emerging from FGDs along a pandemic timeline, noting socio-demographic variations. Following assessment for internal reliability and dimension reduction, quantitative health/wellbeing indicators were analyzed as functions of composite socio-demographic, health-behavioural, and health-environmental indicators.
Our mixed methods analyses indicate that adolescents faced considerable mental and physical health challenges due to the pandemic, and were generally in poorer health than expected in non-crisis times. Nevertheless, some participants showed significantly better outcomes than others, specifically those who: got more exercise; slept better; were food secure; had clearer routines; spent more time in nature, deep in-person social relationships, and leisure; and spent less time on social media.
Support for youth during times of crisis is essential to future population health because adolescence is a period in the life course which shapes the health behaviours, socio-economic capacities, and neurophysiology of these future parents/carers and leaders. Efforts to promote resilience in adolescents should leverage the factors identified above: helping them find structure and senses of purpose through strong social connections, well-supported work and leisure environments, and opportunities to engage with nature.
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