IFN-γ-producing CD4+ T cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the brain.

It is well established that IFN-γ is required for the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the temporal and tissue-specific cellular sources of IFN-γ during P. berghei ANKA infection have not been investigated, and it is not known whether IFN-γ production by a single cell type in isolation can induce cerebral pathology. In this study, using IFN-γ reporter mice, we show that NK cells dominate the IFN-γ response during the early stages of infection in the brain, but not in the spleen, before being replaced by CD4(+) and CD8(+) T cells. Importantly, we demonstrate that IFN-γ-producing CD4(+) T cells, but not innate or CD8(+) T cells, can promote the development of ECM in normally resistant IFN-γ(-/-) mice infected with P. berghei ANKA. Adoptively transferred wild-type CD4(+) T cells accumulate within the spleen, lung, and brain of IFN-γ(-/-) mice and induce ECM through active IFN-γ secretion, which increases the accumulation of endogenous IFN-γ(-/-) CD8(+) T cells within the brain. Depletion of endogenous IFN-γ(-/-) CD8(+) T cells abrogates the ability of wild-type CD4(+) T cells to promote ECM. Finally, we show that IFN-γ production, specifically by CD4(+) T cells, is sufficient to induce expression of CXCL9 and CXCL10 within the brain, providing a mechanistic basis for the enhanced CD8(+) T cell accumulation. To our knowledge, these observations demonstrate, for the first time, the importance of and pathways by which IFN-γ-producing CD4(+) T cells promote the development of ECM during P. berghei ANKA infection

Impact of a Reduced Nicotine Standard on Young Adult Appeal for Menthol and Non-Menthol Cigarettes

Introduction The Food and Drug Administration (FDA) announced its intention to reduce the nicotine content in cigarettes as a strategy to promote cessation and reduce smoking-related harm. A low nicotine product standard will apply to all cigarettes on the market, including menthol cigarettes. In December 2021, the FDA approved a modified risk tobacco product application for menthol and non-menthol flavoured very low nicotine cigarettes (VLNC) from the 22nd Century Group. Notably, experimentation with menthol cigarettes is linked to smoking progression, as well as greater nicotine dependence relative to non-menthol cigarette use. If menthol VLNCs are perceived as more appealing than non-menthol VLNCs, this would indicate that some aspect of menthol may maintain smoking even in the absence of nicotine and FDA’s regulatory authority to ban or restrict the sale of menthol cigarettes should apply to reduced nicotine content of cigarettes. In April 2022, the FDA announced proposed rulemaking to prohibit menthol cigarettes, however it is unclear if a menthol prohibition would apply to VLNCs. Methods and analysis This study will recruit 172 young adult menthol smokers (with a specific subsample of n=40 sexual and gender minority young adults) and measure appeal for smoking experimental menthol and non-menthol VLNCs, and the impact of proposed product standards on tobacco product purchasing behaviour using an Experimental Tobacco Marketplace. Appeal across product standards will be assessed in a controlled laboratory and using ecological momentary assessment. Ethics and dissemination The protocol was approved by the University of Oklahoma Health Sciences Center Institutional Review Board (#11865). Findings will examine the effects of a reduced nicotine standard and a menthol ban on young adult smoking and will be disseminated through peer-reviewed journal articles and presentations at scientific conferences. Trial registration number NCT04340947

Ionizable lipid nanoparticles for in utero mRNA delivery.

Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)-mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing

Skeletal adaptations in young male mice after 4 weeks aboard the International Space Station

Gravity has an important role in both the development and maintenance of bone mass. This is most evident in the rapid and intense bone loss observed in both humans and animals exposed to extended periods of microgravity in spaceflight. Here, cohabitating 9-week-old male C57BL/6 mice resided in spaceflight for ~4 weeks. A skeletal survey of these mice was compared to both habitat matched ground controls to determine the effects of microgravity and baseline samples in order to determine the effects of skeletal maturation on the resulting phenotype. We hypothesized that weight-bearing bones would experience an accelerated loss of bone mass compared to non-weight-bearing bones, and that spaceflight would also inhibit skeletal maturation in male mice. As expected, spaceflight had major negative effects on trabecular bone mass of the following weight-bearing bones: femur, tibia, and vertebrae. Interestingly, as opposed to the bone loss traditionally characterized for most weight-bearing skeletal compartments, the effects of spaceflight on the ribs and sternum resembled a failure to accumulate bone mass. Our study further adds to the insight that gravity has site-specific influences on the skeleton

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM

Planetary Candidates Observed by Kepler VI: Planet Sample from Q1-Q16 (47 Months)

\We present the sixth catalog of Kepler candidate planets based on nearly 4 years of high precision photometry. This catalog builds on the legacy of previous catalogs released by the Kepler project and includes 1493 new Kepler Objects of Interest (KOIs) of which 554 are planet candidates, and 131 of these candidates have best fit radii <1.5 R_earth. This brings the total number of KOIs and planet candidates to 7305 and 4173 respectively. We suspect that many of these new candidates at the low signal-to-noise limit may be false alarms created by instrumental noise, and discuss our efforts to identify such objects. We re-evaluate all previously published KOIs with orbital periods of >50 days to provide a consistently vetted sample that can be used to improve planet occurrence rate calculations. We discuss the performance of our planet detection algorithms, and the consistency of our vetting products. The full catalog is publicly available at the NASA Exoplanet Archive.Comment: 18 pages, to be published in the Astrophysical Journal Supplement Serie

Forecasting the ambient solar wind with numerical models. II. An adaptive prediction system for specifying solar wind speed near the Sun

The ambient solar wind flows and fields influence the complex propagation dynamics of coronal mass ejections in the interplanetary medium and play an essential role in shaping Earth's space weather environment. A critical scientific goal in the space weather research and prediction community is to develop, implement, and optimize numerical models for specifying the large-scale properties of solar wind conditions at the inner boundary of the heliospheric model domain. Here we present an adaptive prediction system that fuses information from in situ measurements of the solar wind into numerical models to better match the global solar wind model solutions near the Sun with prevailing physical conditions in the vicinity of Earth. In this way, we attempt to advance the predictive capabilities of well-established solar wind models for specifying solar wind speed, including the Wang–Sheeley–Arge model. In particular, we use the Heliospheric Upwind eXtrapolation (HUX) model for mapping the solar wind solutions from the near-Sun environment to the vicinity of Earth. In addition, we present the newly developed Tunable HUX (THUX) model, which solves the viscous form of the underlying Burgers equation. We perform a statistical analysis of the resulting solar wind predictions for the period 2006–2015. The proposed prediction scheme improves all the investigated coronal/heliospheric model combinations and produces better estimates of the solar wind state at Earth than our reference baseline model. We discuss why this is the case and conclude that our findings have important implications for future practice in applied space weather research and prediction

A multi-scale comparison of modeled and observed seasonal methane emissions in northern wetlands

Wetlands are the largest global natural methane (CH4) source, and emissions between 50 and 70° N latitude contribute 10–30% to this source. Predictive capability of land models for northern wetland CH4 emissions is still low due to limited site measurements, strong spatial and temporal variability in emissions, and complex hydrological and biogeochemical dynamics. To explore this issue, we compare wetland CH4 emission predictions from the Community Land Model 4.5 (CLM4.5-BGC) with siteto regional-scale observations. A comparison of the CH4 fluxes with eddy flux data highlighted needed changes to the model’s estimate of aerenchyma area, which we implemented and tested. The model modification substantially reduced biases in CH4 emissions when compared with CarbonTracker CH4 predictions. CLM4.5 CH4 emission predictions agree well with growing season (May–September) CarbonTracker Alaskan regional-level CH4 predictions and sitelevel observations. However, CLM4.5 underestimated CH4 emissions in the cold season (October–April). The monthly atmospheric CH4 mole fraction enhancements due to wetland emissions are also assessed using the Weather Research and Forecasting-Stochastic Time-Inverted Lagrangian Transport (WRF-STILT) model coupled with daily emissions from CLM4.5 and compared with aircraft CH4 mole fraction measurements from the Carbon in Arctic Reservoirs Vulnerability Experiment (CARVE) campaign. Both the tower and aircraft analyses confirm the underestimate of cold-season CH4 emissions by CLM4.5. The greatest uncertainties in predicting the seasonal CH4 cycle are from the wetland extent, coldseason CH4 production and CH4 transport processes. We recommend more cold-season experimental studies in highlatitude systems, which could improve the understanding and parameterization of ecosystem structure and function during this period. Predicted CH4 emissions remain uncertain, but we show here that benchmarking against observations across spatial scales can inform model structural and parameter improvements