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Herein, we studied the impact of empty LNP (eLNP), component of mRNA-based vaccine, on anti-viral pathways and immune function of cells from young and aged individuals. eLNP induced maturation of monocyte derived dendritic cells (MDDCs). We further show that eLNP upregulated CD40 and induced cytokine production in multiple DC subsets and monocytes. This coincided with phosphorylation of TANK binding kinase 1 (pTBK1) and interferon response factor 7 (pIRF7). In response to eLNP, healthy older adults (>65 yrs) have decreased CD40 expression, and IFN-γ output compared to young adults (<65 yrs). Additionally, cells from older adults have a dysregulated anti-viral signaling response to eLNP stimulation, measured by the defect in type I IFN production, and phagocytosis. Overall, our data show function of eLNP in eliciting DC maturation and innate immune signaling pathways that is impaired in older adults resulting in lower immune responses to SARS-CoV-2 mRNA-based vaccines. The role of empty lipid nanoparticles in eliciting dendritic cell maturation and innate immune signaling is shown to be impaired in older adults, potentially contributing to lower immune responses to SARS-CoV-2 mRNA-based vaccines.

The detailed chemical information contained in the vibrational spectrum of a cryogenically cooled analyte ion would, in principle, make infrared (IR) ion spectroscopy a gold standard technique for molecular identification in mass spectrometry. Despite this immense potential, there are considerable challenges in both instrumentation and methodology to overcome before the technique is analytically useful. Here, we discuss the promise of IR ion spectroscopy for small molecule analysis in the context of metabolite identification. Experimental strategies to address sensitivity constraints, poor overall duty cycle, and speed of the experiment are intimately tied to the development of a mass-selective cryogenic trap. Therefore, the most likely avenues for success, in the authors’ opinion, are presented here, alongside alternative approaches and some thoughts on data interpretation. Graphical Abstract ᅟ

We report on the performance of a cryogenic 2D linear ion trap (cryoLIT) that is shown to be mass-selective in the temperature range of 17–295 K. As the cryoLIT is cooled, the ejection voltages during the mass instability scan decrease, which results in an effective mass shift to lower m/z relative to room temperature. This is attributed to a decrease in trap radius caused by thermal contraction. Additionally, the cryoLIT generates reproducible mass spectra from day-to-day, and is capable of performing stored waveform inverse Fourier transform (SWIFT) mass isolation of fragile N 2 -tagged ions for the purpose of background-free infrared dissociation spectroscopy. Graphical Abstract ᅟ

The progressive impairment of immunity to pathogens and vaccines with aging is a significant public health problem as the world population shifts to an increased percentage of older adults (> 65). We have previously demonstrated that cells obtained from older volunteers have delayed and defective induction of type I interferons and T cell and B cell helper cytokines in response to TLR ligands when compared to those from adult subjects. However, the underlying intracellular mechanisms are not well described. Herein, we studied two critical pathways important in the production of type I interferon (IFN), the interferon response factor 7 (pIRF7), and TANK-binding kinase (pTBK-1). We show a decrease in pIRF7 and pTBK-1 in cross-priming dendritic cells (cDC1s), CD4 + T cell priming DCs (cDC2s), and CD14 dim CD16 + vascular patrolling monocytes from older adults ( n  = 11) following stimulation with pathway-specific agonists in comparison with young individuals ( n  = 11). The decrease in these key antiviral pathway proteins correlates with decreased phagocytosis, suggesting impaired function in Overall, our findings describe molecular mechanisms which explain the innate functional impairment in older adults and thus could inform us of novel approaches to restore these defects. Graphical abstract

The idea of the “flipped classroom” is a relatively new concept in education that has become increasingly popular. Instructors who flip their classrooms reverse the roles of school work and homework by recording video lectures for students to watch before coming to class. Students then work on their homework in the classroom while the instructor is present to help them. Very little research has been done on the effectiveness of the flipped classroom to determine if students can perform better on exams by learning in a flipped classroom environment, especially for high school demographics. The purpose of this research is to add to the body of knowledge and help provide data to investigate how well students learn physics content by using the flipped classroom in a high school physics class and identify students' attitudes towards the flipped classroom. Seven periods of Physics with Technology at Lone Peak High School in Highland, UT were used in this study. Three of the classes were randomly assigned to be “flipped” while the other four were taught using what is considered a “traditional” method of instruction of physics, which is based on a guided inquiry method. The pacing and content was matched each day and all classes participated in the same labs, homework, quizzes and tests. The defining difference is the method which the content is covered. The flipped classes watched video lectures at home to learn the majority of the content, then did what is traditionally known as “homework” in class with the teacher present to help. In this study, it was found that there was no statistically or practically significant difference in mean test scores for the first three units in a high school Physics with Technology class. Student responses on a survey also showed very little statistically different in the students' attitudes towards the classroom environment in either instructional method.

Mosses are a highly diverse lineage of land plants, whose diversification, spanning at least 400 million years, remains phylogenetically ambiguous due to the lack of fossils, massive early extinctions, late radiations, limited morphological variation, and conflicting signal among previously used markers. Here, we present phylogenetic reconstructions based on complete organellar exomes and a comparable set of nuclear genes for this major lineage of land plants. Our analysis of 142 species representing 29 of the 30 moss orders reveals that relative average rates of non-synonymous substitutions in nuclear versus plastid genes are much higher in mosses than in seed plants, consistent with the emerging concept of evolutionary dynamism in mosses. Our results highlight the evolutionary significance of taxa with reduced morphologies, shed light on the relative tempo and mechanisms underlying major cladogenic events, and suggest hypotheses for the relationships and delineation of moss orders. Mosses are a highly diverse lineage of land plants. Here, the authors provide a detailed phylogeny of 29 orders of moss, using nuclear and organelle data to provide robust hypotheses for most of the ordinal moss relationships.

Among hospitals in the NICHD Neonatal Research Network, rates of active treatment of infants born at 22 to 24 weeks of gestation varied substantially and accounted for a substantial proportion of between-hospital variation in overall survival and survival without impairment. The decision to initiate or forgo potentially lifesaving treatment in infants who are born near the limit of viability is extremely difficult. 1 , 2 Clinicians recognize that in some cases, the infant is too immature for treatment to be effective, whereas in other cases, treatment is clearly indicated. Yet, in many cases, it is unclear whether treatment is in the infant’s best interest. 3 , 4 Although factors such as the infant’s birth weight and sex, plurality of birth (singleton vs. multiple), and exposure to antenatal glucocorticoids affect the prognosis of extremely preterm infants, 5 , 6 many groups still make recommendations about active treatment . . .

Transient receptor potential (TRP) proteins form a superfamily Ca 2+ -permeable cation channels regulated by a range of chemical and physical stimuli. Structural analysis of a ‘minimal’ TRP vanilloid subtype 1 (TRPV1) elucidated a mechanism of channel activation by agonists through changes in its outer pore region. Though homologous to TRPV1, other TRPV channels (TRPV2–6) are insensitive to TRPV1 activators including heat and vanilloids. To further understand the structural basis of TRPV channel function, we determined the structure of full-length TRPV2 at ∼5 Å resolution by cryo-electron microscopy. Like TRPV1, TRPV2 contains two constrictions, one each in the pore-forming upper and lower gates. The agonist-free full-length TRPV2 has wider upper and lower gates compared with closed and agonist-activated TRPV1. We propose these newly revealed TRPV2 structural features contribute to diversity of TRPV channels. Transient receptor potential (TRP) proteins are Ca 2+ -permeable cation channels activated by a range of chemical and physical stimuli. Here the authors describe a cryo-EM structure of the full-length TRPV2 channel that provides insight into the regulation of the TRPV subfamily of channels.

Lopinavir–ritonavir has been proposed as a treatment for COVID-19 on the basis of in vitro activity, preclinical studies, and observational studies. Here, we report the results of a randomised trial to assess whether lopinavir–ritonavir improves outcomes in patients admitted to hospital with COVID-19. In this randomised, controlled, open-label, platform trial, a range of possible treatments was compared with usual care in patients admitted to hospital with COVID-19. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus lopinavir–ritonavir (400 mg and 100 mg, respectively) by mouth for 10 days or until discharge (or one of the other RECOVERY treatment groups: hydroxychloroquine, dexamethasone, or azithromycin) using web-based simple (unstratified) randomisation with allocation concealment. Randomisation to usual care was twice that of any of the active treatment groups (eg, 2:1 in favour of usual care if the patient was eligible for only one active group, 2:1:1 if the patient was eligible for two active groups). The primary outcome was 28-day all-cause mortality. Analyses were done on an intention-to-treat basis in all randomly assigned participants. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Between March 19, 2020, and June 29, 2020, 1616 patients were randomly allocated to receive lopinavir–ritonavir and 3424 patients to receive usual care. Overall, 374 (23%) patients allocated to lopinavir–ritonavir and 767 (22%) patients allocated to usual care died within 28 days (rate ratio 1·03, 95% CI 0·91–1·17; p=0·60). Results were consistent across all prespecified subgroups of patients. We observed no significant difference in time until discharge alive from hospital (median 11 days [IQR 5 to >28] in both groups) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 0·98, 95% CI 0·91–1·05; p=0·53). Among patients not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion who met the composite endpoint of invasive mechanical ventilation or death (risk ratio 1·09, 95% CI 0·99–1·20; p=0·092). In patients admitted to hospital with COVID-19, lopinavir–ritonavir was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death. These findings do not support the use of lopinavir–ritonavir for treatment of patients admitted to hospital with COVID-19. Medical Research Council and National Institute for Health Research.