Summary
The interiors of plants are colonized by diverse microorganisms that are referred to as endophytes. Endophytes have received much attention over the past few decades, yet many questions ...remain unanswered regarding patterns in their biodiversity at local to global scales. To characterize research effort to date, we synthesized results from ~600 published studies. Our survey revealed a global research interest and highlighted several gaps in knowledge. For instance, of the 17 biomes encompassed by our survey, 7 were understudied and together composed only 7% of the studies that we considered. We found that fungal endophyte diversity has been characterized in at least one host from 30% of embryophyte families, while bacterial endophytes have been surveyed in hosts from only 10.5% of families. We complimented our survey with a vote counting procedure to determine endophyte richness patterns among plant tissue types. We found that variation in endophyte assemblages in above‐ground tissues varied with host growth habit. Stems were the richest tissue in woody plants, whereas roots were the richest tissue in graminoids. For forbs, we found no consistent differences in relative tissue richness among studies. We propose future directions to fill the gaps in knowledge we uncovered and inspire further research.
Nirsevimab, a monoclonal antibody with an extended half-life, is designed to protect infants from respiratory syncytial virus disease after a single intramuscular dose. This placebo-controlled trial ...involving 1447 preterm infants at 164 sites in 23 countries assessed the effectiveness of nirsevimab over 150 days after the dose was administered.
Nirsevimab is a monoclonal antibody targeting respiratory syncytial virus. In this trial, the safety of nirsevimab was assessed in infants eligible to receive palivizumab, including those born ...preterm (at 35 weeks of gestation or less) and those with congenital heart disease or chronic lung disease of prematurity. No safety concerns were identified.
We present a meta-analysis of plant responses to fertilization experiments conducted in lowland, species-rich, tropical forests. We also update a key result and present the first species-level ...analyses of tree growth rates for a 15-yr factorial nitrogen (N), phosphorus (P), and potassium (K) experiment conducted in central Panama. The update concerns community-level tree growth rates, which responded significantly to the addition of N and K together after 10 yr of fertilization but not after 15 yr. Our experimental soils are infertile for the region, and species whose regional distributions are strongly associated with low soil P availability dominate the local tree flora. Under these circumstances, we expect muted responses to fertilization, and we predicted species associated with low-P soils would respond most slowly. The data did not support this prediction, species-level tree growth responses to P addition were unrelated to species-level soil P associations. The meta-analysis demonstrated that nutrient limitation is widespread in lowland tropical forests and evaluated two directional hypotheses concerning plant responses to N addition and to P addition. The meta-analysis supported the hypothesis that tree (or biomass) growth rate responses to fertilization are weaker in old growth forests and stronger in secondary forests, where rapid biomass accumulation provides a nutrient sink. The meta-analysis found no support for the long-standing hypothesis that plant responses are stronger for P addition and weaker for N addition. We do not advocate discarding the latter hypothesis. There are only 14 fertilization experiments from lowland, species-rich, tropical forests, 13 of the 14 experiments added nutrients for five or fewer years, and responses vary widely among experiments. Potential fertilization responses should be muted when the species present are well adapted to nutrient-poor soils, as is the case in our experiment, and when pest pressure increases with fertilization, as it does in our experiment. The statistical power and especially the duration of fertilization experiments conducted in old growth, tropical forests might be insufficient to detect the slow, modest growth responses that are to be expected.
Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential ...(CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown.
We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease.
The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (
<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 95% 1.10-1.68;
=0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 95% CI, 1.10-1.79;
=0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 95% CI, 1.23-2.44;
=0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 95% CI, 1.30-2.80;
<0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only
CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 95% CI, 1.07-1.73;
=0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 95% CI, 1.13-1.94;
=0.005).
Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.
Fatty acid-binding proteins (FABPs) are a widely expressed group of calycins that play a well established role in solubilizing cellular fatty acids. Recent studies, however, have recast FABPs as ...active participants in vital lipid-signaling pathways. FABP5, like its family members, displays a promiscuous ligand binding profile, capable of interacting with numerous long chain fatty acids of varying degrees of saturation. Certain “activating” fatty acids induce the protein's cytoplasmic to nuclear translocation, stimulating PPARβ/δ transactivation; however, the rules that govern this process remain unknown. Using a range of structural and biochemical techniques, we show that both linoleic and arachidonic acid elicit FABP5's translocation by permitting allosteric communication between the ligand-sensing β2 loop and a tertiary nuclear localization signal within the α-helical cap of the protein. Furthermore, we show that more saturated, nonactivating fatty acids inhibit nuclear localization signal formation by destabilizing this activation loop, thus implicating FABP5 specifically in cis-bonded, polyunsaturated fatty acid signaling.
Intracellular lipid-binding proteins stimulate lipid-induced gene expression.
Fatty acid-binding protein 5 (FABP5) uses a molecular switch that controls nuclear import when complexed with activating fatty acids.
FABP5 is tuned to selectively stimulate peroxisome proliferation-activated receptor β/δ transactivation in response to specific fatty acids based on their structural features.
FABPs provide a second level of regulatory control of nuclear receptor-mediated lipid signaling.
Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related ...acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.
In a phase 2b trial and the phase 3 MELODY trial, nirsevimab, an extended half-life, monoclonal antibody against respiratory syncytial virus (RSV), protected healthy infants born preterm or at full ...term against medically attended RSV lower respiratory tract infection (LRTI). In the MEDLEY phase 2-3 trial in infants at higher risk for severe RSV infection, nirsevimab showed a similar safety profile to that of palivizumab. The aim of the current analysis was to assess the efficacy of nirsevimab using a weight-banded dosing regimen in infants born between 29 weeks gestational age and full term.
Infants enrolled in the phase 2b and MELODY trials were randomised (2:1) to receive a single intramuscular injection of nirsevimab (infants weighing <5 kg received 50 mg; those weighing ≥5 kg received 100 mg) or placebo before the RSV season. Infants in MEDLEY were randomised (2:1) to receive one dose of nirsevimab (infants weighing <5 kg received 50 mg; those weighing ≥5 kg received 100 mg) followed by four monthly placebo doses, or five once-a-month intramuscular doses of palivizumab. We report a prespecified pooled efficacy analysis assessing the weight-banded dosing regimen proposed on the basis of the phase 2b and MELODY trials, in addition to extrapolated efficacy in infants with chronic lung disease, congenital heart disease, or extreme preterm birth (<29 weeks' gestational age) based on pharmacokinetic data from the phase 2-3 MEDLEY safety trial. For the pooled efficacy analysis, the primary endpoint was incidence of medically attended RSV LRTI through 150 days post-dose. The secondary efficacy endpoint was number of admissions to hospital for medically attended RSV LRTI. The incidence of very severe RSV LRTI was an exploratory endpoint, defined as cases of hospital admission for medically attended RSV LRTI that required supplemental oxygen or intravenous fluids. We also did a prespecified exploratory analysis of medically attended LRTI of any cause (in the investigator's judgement) and hospital admission for respiratory illness of any cause (defined as any upper respiratory tract infection or LRTI leading to hospital admission). Post hoc exploratory analyses of outpatient visits and antibiotic use were also done. Nirsevimab serum concentrations in MEDLEY were assessed using population pharmacokinetic methods and the pooled data from the phase 2b and MELODY trials. An exposure target was defined on the basis of an exposure-response analysis. To successfully demonstrate extrapolation, more than 80% of infants in MEDLEY had to achieve serum nirsevimab exposures at or above the predicted efficacious target.
Overall, 2350 infants (1564 in the nirsevimab group and 786 in the placebo group) in the phase 2b and MELODY trials were included in the pooled analysis. Nirsevimab showed efficacy versus placebo with respect to the primary endpoint of medically attended RSV LRTI (19 1% nirsevimab recipients vs 51 6% placebo recipients; relative risk reduction RRR 79·5% 95% CI 65·9-87·7). Consistent efficacy was shown for additional endpoints of RSV LRTI hospital admission (nine 1% nirsevimab recipients vs 21 3% placebo recipients; 77·3% 50·3-89·7) and very severe RSV (five <1% vs 18 2%; 86·0% 62·5-94·8). Nirsevimab recipients had fewer hospital admissions for any-cause respiratory illness (RRR 43·8% 18·8-61·1), any-cause medically attended LRTI (35·4% 21·5-46·9), LRTI outpatient visits (41·9% 25·7-54·6), and antibiotic prescriptions (23·6% 3·8-39·3). Among infants with chronic lung disease, congenital heart disease, or extreme preterm birth in MEDLEY, nirsevimab serum exposures were similar to those found in the pooled data; exposures were above the target in more than 80% of the overall MEDLEY trial population (94%), including infants with chronic lung disease (94%) or congenital heart disease (80%) and those born extremely preterm (94%).
A single dose of nirsevimab protected healthy infants born at term or preterm from medically attended RSV LRTI, associated hospital admission, and severe RSV. Pharmacokinetic data support efficacy extrapolation to infants with chronic lung disease, congenital heart disease, or extreme prematurity. Together, these data suggest that nirsevimab has the potential to change the landscape of infant RSV disease by reducing a major cause of infant morbidity and the consequent burden on caregivers, clinicians, and health-care providers.
AstraZeneca and Sanofi.
We report a magic angle spinning (MAS) NMR structure of the drug-resistant S31N mutation of M218–60 from Influenza A. The protein was dispersed in diphytanoyl-sn-glycero-3-phosphocholine lipid ...bilayers, and the spectra and an extensive set of constraints indicate that M218–60 consists of a dimer of dimers. In particular, ∼280 structural constraints were obtained using dipole recoupling experiments that yielded well-resolved 13C–15N, 13C–13C, and 1H–15N 2D, 3D, and 4D MAS spectra, all of which show cross-peak doubling. Interhelical distances were measured using mixed 15N/13C labeling and with deuterated protein, MAS at ωr/2π = 60 kHz, ω0H/2π = 1000 MHz, and 1H detection of methyl–methyl contacts. The experiments reveal a compact structure consisting of a tetramer composed of four transmembrane helices, in which two opposing helices are displaced and rotated in the direction of the membrane normal relative to a four-fold symmetric arrangement, yielding a two-fold symmetric structure. Side chain conformations of the important gating and pH-sensing residues W41 and H37 are found to differ markedly from four-fold symmetry. The rmsd of the structure is 0.7 Å for backbone heavy atoms and 1.1 Å for all heavy atoms. This two-fold symmetric structure is different from all of the previous structures of M2, many of which were determined in detergent and/or with shorter constructs that are not fully active. The structure has implications for the mechanism of H+ transport since the distance between His and Trp residues on different helices is found to be short. The structure also exhibits two-fold symmetry in the vicinity of the binding site of adamantyl inhibitors, and steric constraints may explain the mechanism of the drug-resistant S31N mutation.
Producing and retaining leaves underlie the performance and survivorship of seedlings in deeply shaded tropical forests. These habitats are characterized by conditions ideal for foliar bacteria, ...which can be potent plant pathogens. Leaf production, retention and susceptibility to enemies may ultimately depend upon interactions among soil nutrients and foliar microbes, yet this has never been tested.
We experimentally evaluated the degree that foliar bacteria and soil resource supply mediate leaf dynamics for five common tree species (five different families) in a Panamanian forest. We reduced foliar bacteria with antibiotics for 29 months and measured leaf production, retention and damage for seedlings nested within a replicated 15-yr factorial nutrient enrichment experiment (nitrogen, N; phosphorus, P; potassium, K).
Our results demonstrate that when we applied antibiotics, soil nutrients – particularly N – always regulated seedling leaf production (and to a lesser extent herbivore damage) for all five tree species. In addition, it was common for two macronutrients together to negate or completely reverse the impact of applying either one alone.
Our findings of frequent plant–microbe–nutrient interactions are novel and suggest that these interactions may reinforce plant species–environment associations, thereby creating a fairly cryptic and fine-scale dimension of niche differentiation for coexisting tree species.
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