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The development of a protective vaccine remains a top priority for the control of the HIV/AIDS pandemic. Here, we show that a messenger RNA (mRNA) vaccine co-expressing membrane-anchored HIV-1 envelope (Env) and simian immunodeficiency virus (SIV) Gag proteins to generate virus-like particles (VLPs) induces antibodies capable of broad neutralization and reduces the risk of infection in rhesus macaques. In mice, immunization with co-formulated env and gag mRNAs was superior to env mRNA alone in inducing neutralizing antibodies. Macaques were primed with a transmitted-founder clade-B env mRNA lacking the N276 glycan, followed by multiple booster immunizations with glycan-repaired autologous and subsequently bivalent heterologous envs (clades A and C). This regimen was highly immunogenic and elicited neutralizing antibodies against the most prevalent (tier-2) HIV-1 strains accompanied by robust anti-Env CD4 + T cell responses. Vaccinated animals had a 79% per-exposure risk reduction upon repeated low-dose mucosal challenges with heterologous tier-2 simian–human immunodeficiency virus (SHIV AD8). Thus, the multiclade env–gag VLP mRNA platform represents a promising approach for the development of an HIV-1 vaccine. An mRNA vaccine platform to prevent HIV-1 infection generated broadly neutralizing antibodies in non-human primates and protected some animals from infection, raising hope that optimization of this approach might lead to an effective HIV vaccine.

After traumatic brain injury (TBI), plasma concentration of glial fibrillary acidic protein (GFAP) correlates with intracranial injury visible on CT scan. Some patients with suspected TBI with normal CT findings show pathology on MRI. We assessed the discriminative ability of GFAP to identify MRI abnormalities in patients with normal CT findings. TRACK-TBI is a prospective cohort study that enrolled patients with TBI who had a clinically indicated head CT scan within 24 h of injury at 18 level 1 trauma centres in the USA. For this analysis, we included patients with normal CT findings (Glasgow Coma Scale score 13–15) who consented to venepuncture within 24 h post injury and who had an MRI scan 7–18 days post injury. We compared MRI findings in these patients with those of orthopaedic trauma controls and healthy controls recruited from the study sites. Plasma GFAP concentrations (pg/mL) were measured using a prototype assay on a point-of-care platform. We used receiver operating characteristic (ROC) analysis to evaluate the discriminative ability of GFAP for positive MRI scans in patients with negative CT scans over 24 h (time between injury and venepuncture). The primary outcome was the area under the ROC curve (AUC) for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings within 24 h of injury. The Dunn Kruskal–Wallis test was used to compare GFAP concentrations between MRI lesion types with Benjamini–Hochberg correction for multiple comparisons. This study is registered with ClinicalTrials.gov, number NCT02119182. Between Feb 26, 2014, and June 15, 2018, we recruited 450 patients with normal head CT scans (of whom 330 had negative MRI scans and 120 had positive MRI scans), 122 orthopaedic trauma controls, and 209 healthy controls. AUC for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings was 0·777 (95% CI 0·726–0·829) over 24 h. Median plasma GFAP concentration was highest in patients with CT-negative and MRI-positive findings (414·4 pg/mL, 25–75th percentile 139·3–813·4), followed by patients with CT-negative and MRI-negative findings (74·0 pg/mL, 17·5–214·4), orthopaedic trauma controls (13·1 pg/mL, 6·9–20·0), and healthy controls (8·0 pg/mL, 3·0–14·0; all comparisons between patients with CT-negative MRI-positive findings and other groups p<0·0001). Analysis of blood GFAP concentrations using prototype assays on a point-of-care platform within 24 h of injury might improve detection of TBI and identify patients who might need subsequent MRI and follow-up. National Institute of Neurological Disorders and Stroke and US Department of Defense.

The power of chemistry to prepare new molecules and materials has driven the quest for new approaches to solve problems having global societal impact, such as in renewable energy, healthcare and information science. In the latter case, the intrinsic quantum nature of the electronic, nuclear and spin degrees of freedom in molecules offers intriguing new possibilities to advance the emerging field of quantum information science. In this Perspective, which resulted from discussions by the co-authors at a US Department of Energy workshop held in November 2018, we discuss how chemical systems and reactions can impact quantum computing, communication and sensing. Hierarchical molecular design and synthesis, from small molecules to supramolecular assemblies, combined with new spectroscopic probes of quantum coherence and theoretical modelling of complex systems, offer a broad range of possibilities to realize practical quantum information science applications. Molecular design and synthesis, from small molecules to supramolecular assemblies, combined with new spectroscopic probes of quantum coherence and theoretical modelling, offer a broad range of possibilities to realize practical quantum information science applications in computing, communications and sensing.

Food production and security will be a major issue for supplying an increasing world population. The problem will almost certainly be exacerbated by climate change. There is a projected need to double food production by 2050. In recent times, the trend has been for incremental modest yield increases for most crops. There is an urgent need to develop integrated and sustainable approaches that will significantly increase both production per unit land area and the resource use efficiency of crops. This review considers some key processes involved in plant growth and development with some examples of ways in which molecular technology, plant breeding and genetics may increase the yield and resource use efficiency of wheat. The successful application of biotechnology to breeding is essential to provide the major increases in production required. However, each crop and each specific agricultural situation presents specific requirements and targets for optimisation. Some increases in production will come about as new varieties are developed which are able to produce satisfactory crops on marginal land presently not considered appropriate for arable crops. Other new varieties will be developed to increase both yield and resource use efficiency on the best land.

Mechanical ventilation (MV) elicits complex and clinically relevant cellular responses in the lungs. The current study was designed to define the role of the transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2), a major regulator of the cellular antioxidant defense system, in the pulmonary response to MV. Nrf2 activity was quantified in ventilated isolated perfused mouse lungs (IPL). Regulation of amphiregulin (AREG) was investigated in BEAS-2B cells with inactivated Nrf2 or Keap1, the inhibitor of Nrf2, using a luciferase vector with AREG promoter. AREG-dependent Nrf2 activity was examined in BEAS-2B cells, murine precision-cut lung slices (PCLS), and IPL. Finally, Nrf2 knockout and wild-type mice were ventilated to investigate the interplay between Nrf2 and AREG during MV in vivo. Lung functions and inflammatory parameters were measured. Nrf2 was activated in a ventilation-dependent manner. The knockdown of Nrf2 and Keap1 via short hairpin RNA in BEAS-2B cells and an EMSA with lung tissue revealed that AREG is regulated by Nrf2. Conversely, AREG application induced a significant Nrf2 activation in BEAS-2B cells, PCLS, and IPL. The signal transduction of ventilation-induced Nrf2 activation was shown to be p38 MAP kinase–dependent. In vivo ventilation experiments indicated that AREG is regulated by Nrf2 during MV. We conclude that Areg expression is regulated by Nrf2. During high-pressure ventilation, Nrf2 becomes activated and induces AREG, leading to a positive feedback loop between Nrf2 and AREG, which involves the p38 MAPK and results in the expression of cytoprotective genes.

ObjectivesUpRi is a first-in-class NaPi2b ADC with a novel scaffold-linker-payload that enables high drug-to-antibody ratio and controlled bystander effect. NaPi2b is a sodium-dependent phosphate transporter protein broadly expressed in high-grade serous ovarian cancer (HGSOC), with limited expression in healthy tissues. Interim data from the Phase 1b expansion cohort of heavily pretreated patients with recurrent HGSOC has been reported. These data demonstrated clinically meaningful activity, notably in patients with NaPi2b-high tumors (TPS≥75). Effective and well-tolerated treatments for PROC remains an unmet medical need. The standard of care, single-agent chemotherapy, has limited efficacy, significant toxicities, and short duration of response. UPLIFT was designed as a single-arm Ph2 registrational trial for UpRi monotherapy in PROC.MethodsUPLIFT is enrolling patients with PROC with up to 4 prior LoT. Prior bevacizumab is required for patients with 1–2 prior LoT only; it’s not required for patients with 3–4 prior LoT. Patients may enroll regardless of NaPi2b expression; ≤ Grade 2 peripheral neuropathy is permitted. Primary platinum refractory patients are excluded. UPLIFT will enroll ~180 patients globally, including ~100 patients with high NaPi2b expression. UpRi is dosed IV at 36 mg/m2 up to ~80 mg dose maximum Q4W. Baseline tumor samples (fresh or archived) will be collected for central analysis of NaPi2b expression. The primary endpoint is ORR in NaPi2b-high expressing patients. The cut-off for high NaPi2b expression is TPS≥75. Secondary endpoints include ORR in the overall population, duration of response, and safety. UPLIFT is conducted in collaboration with ENGOT (ENGOT-ov67) and GOG (GOG-3048). NCT03319628Results trialinprogressConclusions trialinprogress

Amanda, 24, lives mostly isolated and has never had any friends, even if it's the thing she wants the most. Amanda chooses as her new mission to convince her childhood friend that they are still best friends.

We reconstructed air temperature for two periods in the growth season from cell dimension and cell number variability in cross-dated tree rings of Larix cajanderi Mayr. from northeastern Siberia. Thirteen tree-ring chronologies based on cell size, cell wall thickness, and cell number were developed for AD 1642-1993. No clear evidence was found of an age-related trend in cell dimensions in the sampled materials, but cell numbers were correlated with cambial age. The chronologies contain strong temperature signals associated with the timing of xylem growth. We obtained reliable reconstructions of mean June temperature from the total cell number and July-September temperature from the cell wall thickness of latewood. June temperature and July-September temperature covaried for most of the period from AD 1642 to AD 1978. After that time, June temperature became cooler relative to July-September temperature. This difference caused disproportional changes in earlywood tracheids because of the late start of growth and cool conditions in June followed by warming during the rest of the season. The identification of this unusual recent change has shown that intraseasonal resolution may be achieved by cell dimension and cell number chronologies.

The spatial organization and time dependence of Jupiter's stratospheric temperatures have been measured by observing thermal emission from the 7.8-micrometer CH$_4$ band. These temperatures, observed through the greater part of a Jovian year, exhibit the influence of seasonal radiative forcing. Distinct bands of high temperature are located at the poles and mid-latitudes, while the equator alternates between warm and cold with a period of approximately 4 years. Substantial longitudinal variability is often observed within the warm mid-latitude bands, and occasionally elsewhere on the planet. This variability includes small, localized structures, as well as large-scale waves with wavelengths longer than ∼30,000 kilometers. The amplitudes of the waves vary on a time scale of ∼1 month; structures on a smaller scale may have lifetimes of only days. Waves observed in 1985, 1987, and 1988 propagated with group velocities less than ±30 meters per second.

The spatial organization and time dependence of Jupiter's temperatures near 250-millibar pressure were measured through a jovian year by imaging thermal emission at 18 micrometers. The temperature field is influenced by seasonal radiative forcing, and its banded organization is closely correlated with the visible cloud field. Evidence was found for a quasi-periodic oscillation of temperatures in the Equatorial Zone, a correlation between tropospheric and stratospheric waves in the North Equatorial Belt, and slowly moving thermal features in the North and South Equatorial Belts. There appears to be no common relation between temporal changes of temperature and changes in the visual albedo of the various axisymmetric bands.