The loss of HIV-specific CD8+ T cell cytolytic function is a primary factor underlying progressive HIV infection, but whether HIV-specific CD8+ T cells initially possess cytolytic effector capacity, ...and when and why this may be lost during infection, is unclear. Here, we assessed CD8+ T cell functional evolution from primary to chronic HIV infection. We observed a profound expansion of perforin+ CD8+ T cells immediately following HIV infection that quickly waned after acute viremia resolution. Selective expression of the effector-associated transcription factors T-bet and eomesodermin in cytokine-producing HIV-specific CD8+ T cells differentiated HIV-specific from bulk memory CD8+ T cell effector expansion. As infection progressed expression of perforin was maintained in HIV-specific CD8+ T cells with high levels of T-bet, but not necessarily in the population of T-betLo HIV-specific CD8+ T cells that expand as infection progresses. Together, these data demonstrate that while HIV-specific CD8+ T cells in acute HIV infection initially possess cytolytic potential, progressive transcriptional dysregulation leads to the reduced CD8+ T cell perforin expression characteristic of chronic HIV infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The energy yield delivered by different types of photovoltaic device is a key consideration in the selection of appropriate technologies for cheap photovoltaic electricity. The different technologies ...currently on the market, each have certain strengths and weaknesses when it comes to operating in different environments. There is a plethora of comparative tests on-going with sometimes contradictory results. This paper investigates device behaviour of contrasting thin film technologies, specifically a-Si and CIGS derivatives, and places this analysis into context with results reported by others. Specific consideration is given to the accuracy of module inter-comparisons, as most outdoor monitoring at this scale is conducted to compare devices against one another. It is shown that there are five main contributors to differences in energy delivery and the magnitude of these depends on the environments in which the devices are operated. The paper shows that two effects, typically not considered in inter-comparisons, dominate the reported energy delivery. Environmental influences such as light intensity, spectrum and operating temperature introduce performance variations typically in the range of 2–7% in the course of a year. However, most comparative tests are carried out only for short periods of time, in the order of months. Here, the power rating is a key factor and adds uncertainty for new technologies such as thin films often in the range of 10–15%. This dominates inter-comparisons looking at as-new, first-year energy yields, yet considering the life-time energy yield it is found that ageing causes up to 25% variation between different devices. The durability of devices and performance-maintenance is thus the most significant factor affecting energy delivery, a major determinant of electricity cost. The discussion is based on long-term measurements carried out in Loughborough, UK by the Centre for Renewable Energy Systems Technology (CREST) at Loughborough University.
•The paper investigates the energy delivery of thin film photovoltaic devices in a maritime climate for amorphous silicon based modules and Copper -Indium, Gallium -DiSelenide based devices Effects on the energy delivery of thin film photovoltaics are separated and quantified.•Key contributors are measurement accuracy and changes in device behaviour with time rather than environment.•Effects of temperature, irradiance and spectrum are investigated and quantified.•The differences in long term ageing of different devices is quantified.
Objective
We aimed to predict the risk of common maternal postpartum complications requiring an inpatient episode of care.
Design and setting
Maternal data from the beginning of gestation up to and ...including the delivery, and neonatal data recorded at delivery, were used to predict postpartum complications.
Sample
Administrative health data of all inpatient live births (n = 422 509) in the Australian state of Queensland between January 2009 and October 2015.
Method
Gradient boosted trees were used with five‐fold cross‐validation to compare model performance. The best performing models for each outcome were then assessed in the independent validation data using the area under the receiver operating curve (AUC‐ROC).
Main outcome measure
Postpartum complications occurring in the first 12 weeks after delivery requiring hospital admission.
Results
Postpartum hypertensive disorders obtained good discrimination in the independent validation data (AUC = 0.879, 95% CI 0.846–0.912), as did obstetric surgical wound infection (AUC = 0.856, 95% CI 0.838–0.873), whereas postpartum sepsis and haemorrhage obtained poor discrimination.
Conclusions
Our study suggests that routinely collected health data have the potential to play an important role in helping determine women's risk of common postpartum complications leading to hospital admission. This information can be presented to clinical staff after delivery to help guide immediate postpartum care, delayed discharge, and post‐discharge patient follow up. For such a system to be effective and valued, it must produce accurate predictions, and our findings suggest areas where routine data collection could be strengthened to this end.
Tweetable
Improved prediction of maternal postnatal hypertensive disorders and wound infection via machine learning.
Tweetable
Improved prediction of maternal postnatal hypertensive disorders and wound infection via machine learning.
Alpha-1 antitrypsin (AAT) deficiency is well-suited as a target for human gene transfer. We performed a phase 1, open-label, dose-escalation clinical trial of a recombinant adeno-associated virus ...(rAAV) vector expressing normal (M) AAT packaged into serotype 1 AAV capsids delivered by i.m. injection. Nine AAT-deficient subjects were enrolled sequentially in cohorts of 3 each at doses of 6.9 x 10¹², 2.2 x 10¹³, and 6.0 x 10¹³ vector genome particles per patient. Four subjects receiving AAT protein augmentation discontinued therapy 28 or 56 days before vector administration. Vector administration was well tolerated, with only mild local reactions and 1 unrelated serious adverse event (bacterial epididymitis). There were no changes in hematology or clinical chemistry parameters. M-specific AAT was expressed above background in all subjects in cohorts 2 and 3 and was sustained at levels 0.1% of normal for at least 1 year in the highest dosage level cohort, despite development of neutralizing antibody and IFN-γ enzyme-linked immunospot responses to AAV1 capsid at day 14 in all subjects. These findings suggest that immune responses to AAV capsid that develop after i.m. injection of a serotype 1 rAAV vector expressing AAT do not completely eliminate transduced cells in this context.
Despite recent research identifying a clear anthropogenic impact on glacier recession, the effect of recent climate change on glacier-related hazards is at present unclear. Here we present the first ...global spatio-temporal assessment of glacial lake outburst floods (GLOFs) focusing explicitly on lake drainage following moraine dam failure. These floods occur as mountain glaciers recede and downwaste. GLOFs can have an enormous impact on downstream communities and infrastructure. Our assessment of GLOFs associated with the rapid drainage of moraine-dammed lakes provides insights into the historical trends of GLOFs and their distributions under current and future global climate change. We observe a clear global increase in GLOF frequency and their regularity around 1930, which likely represents a lagged response to post-Little Ice Age warming. Notably, we also show that GLOF frequency and regularity – rather unexpectedly – have declined in recent decades even during a time of rapid glacier recession. Although previous studies have suggested that GLOFs will increase in response to climate warming and glacier recession, our global results demonstrate that this has not yet clearly happened. From an assessment of the timing of climate forcing, lag times in glacier recession, lake formation and moraine-dam failure, we predict increased GLOF frequencies during the next decades and into the 22nd century.
B cell subsets expressing the transcription factor T-bet are associated with humoral immune responses and autoimmunity. Here, we examined the anatomic distribution, clonal relationships, and ...functional properties of T-bet+ and T-bet− memory B cells (MBCs) in the context of the influenza-specific immune response. In mice, both T-bet− and T-bet+ hemagglutinin (HA)-specific B cells arose in germinal centers, acquired memory B cell markers, and persisted indefinitely. Lineage tracing and IgH repertoire analyses revealed minimal interconversion between T-bet− and T-bet+ MBCs, and parabionts showed differential tissue residency and recirculation properties. T-bet+ MBCs could be subdivided into recirculating T-betlo MBCs and spleen-resident T-bethi MBCs. Human MBCs displayed similar features. Conditional gene deletion studies revealed that T-bet expression in B cells was required for nearly all HA stalk-specific IgG2c antibodies and for durable neutralizing titers to influenza. Thus, T-bet expression distinguishes MBC subsets that have profoundly different homing, residency, and functional properties, and mediate distinct aspects of humoral immune memory.
Display omitted
•T-bet+ B cells are a separate and durable memory subset in mice and humans•T-bethi memory B cells are absent from the lymphatic circulation•Influenza-specific T-bethi memory B cells are spleen-resident in mice•B cell-intrinsic T-bet is required for >90% of flu- and HA stalk-specific antibodies
Johnson, Rosenthal, Knox, Myles, et al. find that differential T-bet expression marks subsets of memory B cells (MBCs) with distinct homing and tissue residency patterns and functional properties. Distinguishing features of T-bet−, T-bethi, and T-betlo MBCs are seen also in humans.
A new generation of an Earth system model now includes a number of land-surface processes directly relevant to analyzing potential impacts of climate change. This model, HadGEM2-ES, allows us to ...assess the impacts of climate change, multiple interactions, and feedbacks as the model is run. This paper discusses the results of century-scale HadGEM2-ES simulations from an impacts perspective – specifically, terrestrial ecosystems and water resources – for four different scenarios following the representative concentration pathways (RCPs), used in the Fifth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC, 2013, 2014). Over the 21st century, simulated changes in global and continental-scale terrestrial ecosystems due to climate change appear to be very similar in all 4 RCPs, even though the level of global warming by the end of the 21st century ranges from 2 °C in the lowest scenario to 5.5° in the highest. A warming climate generally favours broadleaf trees over needleleaf, needleleaf trees over shrubs, and shrubs over herbaceous vegetation, resulting in a poleward shift of temperate and boreal forests and woody tundra in all scenarios. Although climate related changes are slightly larger in scenarios of greater warming, the largest differences between scenarios arise at regional scales as a consequence of different patterns of anthropogenic land cover change. In the model, the scenario with the lowest global warming results in the most extensive decline in tropical forest cover due to a large expansion of agriculture. Under all four RCPs, fire potential could increase across extensive land areas, particularly tropical and sub-tropical latitudes. River outflows are simulated to increase with higher levels of CO2 and global warming in all projections, with outflow increasing with mean temperature at the end of the 21st century at the global scale and in North America, Asia, and Africa. In South America, Europe, and Australia, the relationship with climate warming and CO2 rise is less clear, probably as a result of land cover change exerting a dominant effect in those regions.
The objective of this article is to provide evidence-based recommendations for the management of patients with herpes zoster (HZ) that take into account clinical efficacy, adverse effects, impact on ...quality of life, and costs of treatment. Systematic literature reviews, published randomized clinical trials, existing guidelines, and the authors' clinical and research experience relevant to the management of patients with HZ were reviewed at a consensus meeting. The results of controlled trials and the clinical experience of the authors support the use of acyclovir, brivudin (where available), famciclovir, and valacyclovir as first-line antiviral therapy for the treatment of patients with HZ. Specific recommendations for the use of these medications are provided. In addition, suggestions are made for treatments that, when used in combination with antiviral therapy, may further reduce pain and other complications of HZ.
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.
Weyl fermions are a recently discovered ingredient for correlated states of electronic matter. A key difficulty has been that real materials also contain non-Weyl quasiparticles, and disentangling ...the experimental signatures has proven challenging. Here we use magnetic fields up to 95 T to drive the Weyl semimetal TaAs far into its quantum limit, where only the purely chiral 0th Landau levels of the Weyl fermions are occupied. We find the electrical resistivity to be nearly independent of magnetic field up to 50 T: unusual for conventional metals but consistent with the chiral anomaly for Weyl fermions. Above 50 T we observe a two-order-of-magnitude increase in resistivity, indicating that a gap opens in the chiral Landau levels. Above 80 T we observe strong ultrasonic attenuation below 2 K, suggesting a mesoscopically textured state of matter. These results point the way to inducing new correlated states of matter in the quantum limit of Weyl semimetals.
PDF
