Explore the vast range of titles available.

The cultivation of sterile giant miscanthus (Miscanthus × giganteus, M × g) for bioenergy and bioproducts has expanded into grain‐cropped land in the United States (US) as local markets developed for this high‐yielding perennial grass (10–30 Mg DM ha−1). However, the magnitude of spatial and temporal variability in yield within US Corn Belt fields, along with impacts on economic return and sustainable land management, is poorly understood. This study established a diagnostic model relating remote sensing‐derived vegetation indices to ground truth data from 105 hand‐harvested stem biomass samples, which were strategically selected to represent the full range of vegetation index observations. The high‐resolution satellite‐sensed vegetation indices captured > 90% of the yield variation measured within fields. This model was then used to predict yield variability and assess economic performance across four of the first commercial M × g fields in the Corn Belt state of Iowa, US. Significant spatial variability in biomass dry matter (DM) yields (9.3–18.1 Mg DM ha−1) and net profits ( $83 to $ 1211.5 ha−1) was observed. All fields were profitable in all site‐years. When low profit occurred, it was explained by limited management experience of the crop in Iowa. The breakeven yield at a selling price of$130 Mg−1 varied from 9.0–12.1 Mg ha−1 at 15% moisture content (7.6–10.3 Mg DM ha−1). Breakeven prices ranged from $ 73 to $122.4 Mg−1, matching ranges used in the Department of Energy Billion Ton Report (US Department of Energy, 2023). Notably, M × g yield and profits were commensurate with grain crops particularly with favorable precipitation. This study provides insight on the M × g management “learning curve”, performance on marginal land and in drought conditions, and demonstrates that addressing yield gaps, reducing costs, and implementing precision agriculture strategies can enhance profitability. These findings emphasize the value of remote sensing technologies in guiding sustainable and competitive commercial‐scale M × g production. We developed, tested, and used a satellite remote sensing method to predict the productivity and profitability of sterile Miscanthus × giganteus. Using high‐resolution imagery and ground measurements from Iowa's first commercial miscanthus fields, we made a robust model that accurately estimated yield over 8 site‐years. We found strong profitability and identified where better management could further boost returns. This is the first study with actual yield, costs, and returns of commercial miscanthus in the US. It demonstrates that satellite‐based tools can guide efficient and sustainable biomass production, supporting both farmers and industry.

Models of Alzheimer's disease propose a sequence of amyloid β (Aβ) accumulation, hypometabolism, and structural decline that precedes the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. In this study, we aimed to characterise where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal. Between Jan 1, 2009, and Dec 31, 2015, we analysed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer's Network. We analysed 11C-Pittsburgh Compound B (11C-PiB) PET, 18F-Fluorodeoxyglucose (18F-FDG) PET, and structural MRI data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years to symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers. This study is registered at ClinicalTrials.gov (number NCT00869817) 11C-PiB PET was available for 346 individuals (162 with longitudinal imaging), 18F-FDG PET was available for 352 individuals (175 with longitudinal imaging), and MRI data were available for 377 individuals (201 with longitudinal imaging). We found a sequence to pathological changes, with rates of Aβ deposition in mutation carriers being significantly different from those in non-carriers first (across regions that showed a significant difference, at a mean of 18·9 years [SD 3·3] before expected onset), followed by hypometabolism (14·1 years [5·1] before expected onset), and lastly structural decline (4·7 years [4·2] before expected onset). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region for each method to show divergence between groups (22·2 years before expected onset for Aβ accumulation, 18·8 years before expected onset for hypometabolism, and 13·0 years before expected onset for cortical thinning). Mutation carriers had elevations in Aβ deposition, reduced glucose metabolism, and cortical thinning compared with non-carriers which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Aβ, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials. US National Institutes of Health, the German Center for Neurodegenerative Diseases, and the Medical Research Council Dementias Platform UK.

Infection by Toxoplasma gondii leads to massive changes to the host cell. Here, we identify a novel host cell effector export pathway that requires the Golgi-resident aspartyl protease 5 (ASP5). We demonstrate that ASP5 cleaves a highly constrained amino acid motif that has similarity to the PEXEL-motif of Plasmodium parasites. We show that ASP5 matures substrates at both the N- and C-terminal ends of proteins and also controls trafficking of effectors without this motif. Furthermore, ASP5 controls establishment of the nanotubular network and is required for the efficient recruitment of host mitochondria to the vacuole. Assessment of host gene expression reveals that the ASP5-dependent pathway influences thousands of the transcriptional changes that Toxoplasma imparts on its host cell. All these changes result in attenuation of virulence of Δasp5 tachyzoites in vivo. This work characterizes the first identified machinery required for export of Toxoplasma effectors into the infected host cell. Toxoplasma gondii is a parasite that is thought to infect over two billion people worldwide. Often these infections cause no noticeable symptoms, but can cause serious illness in people with weakened immune systems. Toxoplasma parasites must enter human cells in order to survive. To dramatically increase their chances of survival, the parasites then deliver specialized proteins into the host cell that disarm the host’s immune defenses. Understanding how these specialized proteins are transported from inside the parasite into the host cell, and how this process can be blocked, may lead to new treatments for these and related parasitic infections. By genetically modifying Toxoplasma parasites to lack a parasite enzyme, Coffey et al. have now discovered that this molecule is required for correctly transporting parasite proteins. This enzyme is called aspartyl protease 5 (ASP5) and is found in the parasite in a structure called the Golgi apparatus, which acts as a main hub for protein transport. ASP5 cuts proteins at a ‘barcode’ that is found in many different types of proteins, priming them for transport out of the parasite and for export into the host cell in some cases. Coffey et al. show that in parasites that lack ASP5, these proteins are no longer cleaved and are not transported correctly, blocking the activities that parasites normally perform to ensure their survival. Therefore, ASP5 plays an important role in transporting a wide range of proteins associated with disease, including transporting certain proteins directly into the host cell. Future studies that compare parasites that lack ASP5 to normal parasites will aim to identify new proteins used by the parasites to defeat the host’s immune defenses.

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans 1 – 7 . Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans 8 , although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined—including variation of around 30-fold in lifespan and around 40,000-fold in body mass—the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing. Whole-genome sequencing is used to analyse the landscape of somatic mutation in intestinal crypts from 16 mammalian species, revealing that rates of somatic mutation inversely scale with the lifespan of the animal across species.

To improve understanding of Alzheimer’s disease, large observational studies are needed to increase power for more nuanced analyses. Combining data across existing observational studies represents one solution. However, the disparity of such datasets makes this a non-trivial task. Here, a machine learning approach was applied to impute longitudinal neuropsychological test scores across two observational studies, namely the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) providing an overall harmonised dataset. MissForest, a machine learning algorithm, capitalises on the underlying structure and relationships of data to impute test scores not measured in one study aligning it to the other study. Results demonstrated that simulated missing values from one dataset could be accurately imputed, and that imputation of actual missing data in one dataset showed comparable discrimination (p < 0.001) for clinical classification to measured data in the other dataset. Further, the increased power of the overall harmonised dataset was demonstrated by observing a significant association between CVLT-II test scores (imputed for ADNI) with PET Amyloid-β in MCI APOE -ε4 homozygotes in the imputed data (N = 65) but not for the original AIBL dataset (N = 11). These results suggest that MissForest can provide a practical solution for data harmonization using imputation across studies to improve power for more nuanced analyses.

Current biofuel feedstock crops such as corn lead to large environmental losses of N through nitrate leaching and N2O emissions; second‐generation cellulosic crops have the potential to reduce these N losses. We measured N losses and cycling in establishing miscanthus (Miscanthus × giganteus), switchgrass (Panicum virgatum L. fertilized with 56 kg N ha−1 yr−1), and mixed prairie, along with a corn (Zea mays L.)–corn–soybean [Glycine max (L.) Merr.] rotation (corn fertilized at 168–202 kg N ha−1). Nitrous oxide emissions, soil N mineralization, mid‐profile nitrate leaching, and tile flow and nitrate concentrations were measured. Perennial crops quickly reduced nitrate leaching at a 50‐cm soil depth as well as concentrations and loads from the tile systems (year 1 tile nitrate concentrations of 10–15 mg N L−1 declined significantly by year 4 in all perennial crops to <0.6 mg N L−1, with losses of <0.8 kg N ha−1 yr−1). Nitrous oxide emissions were 2.2 to 7.7 kg N ha−1 yr−1 in the corn–corn–soybean rotation but were <1.0 kg N ha−1 yr−1 by year 4 in the perennial crops. Overall N balances (atmospheric deposition + fertilization + soybean N2 fixation – harvest, leaching losses, and N2O emissions) were positive for corn and soybean (22 kg N ha−1 yr−1) as well as switchgrass (9.7 kg N ha−1 yr−1) but were −18 and −29 kg N ha−1 yr−1 for prairie and miscanthus, respectively. Our results demonstrate rapid tightening of the N cycle as perennial biofuel crops established on a rich Mollisol soil.

Enhanced Recovery After Surgery (ERAS) protocols for cesarean deliveries (CDs) utilize multimodal pain management strategies that often include gabapentin. While gabapentin is excreted in breast milk, its pharmacokinetics in immediately postpartum lactating women are not known. This observational pharmacokinetic study (NCT05099484) enrolled 21 healthy singleton pregnant individuals, ≥ 18 years old, undergoing CD and planning to breastfeed. Participants received 300 mg oral gabapentin before CD and every 6 h for 48 h per hospital protocol. Serial maternal plasma and breast milk samples were collected over a single dosing interval. Gabapentin pharmacokinetics were assessed using two structurally distinct population pharmacokinetic (POPPK) models to describe transfer of drug into breast milk utilizing (A) milk‐to‐plasma ratio and (B) inter‐compartmental rate constants. These models were then used to estimate exposure to breastfed infants. Postpartum gabapentin plasma concentrations fit a 1‐compartment model that was adapted to include breast milk concentrations. The two POPPK models both estimated relative infant doses (RID0–48h) of gabapentin < 0.15% of maternal dose within the first 48 h postpartum. Infant daily dose (IDD) from 24 to 48 h was estimated to be 0.0137 (0.0058–0.0316) mg/kg/day and 0.0139 (0.00041–0.0469) mg/kg/day by models A and B, respectively. These findings indicate limited neonatal exposure to gabapentin administered as part of a postpartum enhanced recovery after surgery protocol.

Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging aimed to recruit 1000 individuals aged over 60 to assist with prospective research into Alzheimer's disease (AD). This paper describes the recruitment of the cohort and gives information about the study methodology, baseline demography, diagnoses, medical comorbidities, medication use, and cognitive function of the participants. Methods: Volunteers underwent a screening interview, had comprehensive cognitive testing, gave 80 ml of blood, and completed health and lifestyle questionnaires. One quarter of the sample also underwent amyloid PET brain imaging with Pittsburgh compound B (PiB PET) and MRI brain imaging, and a subgroup of 10% had ActiGraph activity monitoring and body composition scanning. Results: A total of 1166 volunteers were recruited, 54 of whom were excluded from further study due to comorbid disorders which could affect cognition or because of withdrawal of consent. Participants with AD (211) had neuropsychological profiles which were consistent with AD, and were more impaired than participants with mild cognitive impairment (133) or healthy controls (768), who performed within expected norms for age on neuropsychological testing. PiB PET scans were performed on 287 participants, 100 had DEXA scans and 91 participated in ActiGraph monitoring. Conclusion: The participants comprising the AIBL cohort represent a group of highly motivated and well-characterized individuals who represent a unique resource for the study of AD. They will be reassessed at 18-month intervals in order to determine the predictive utility of various biomarkers, cognitive parameters and lifestyle factors as indicators of AD, and as predictors of future cognitive decline.

The IMPROVE study (NCT02408315) compared the efficacy and safety of vaginal and buccal administration of misoprostol for full‐term, uncomplicated labor induction. This report compares the pharmacokinetics of misoprostol between vaginal and buccal routes. Women greater than or equal to 14 years of age undergoing induction of labor greater than or equal to 37 weeks gestation without significant complications were randomized to vaginal or buccal misoprostol 25 μg followed by 50 μg doses every 4 h. Misoprostol acid concentrations were determined using liquid chromatography‐tandem mass spectrometry for the first 8 h in a subgroup of participants. A population pharmacokinetic model was developed using NONMEM. Plasma concentrations (n = 469) from 47 women were fit to a one‐compartment nonlinear clearance model. The absorption rate constant (ka) was dependent on both route and dose of administration: buccal 25 μg 0.724 (95% confidence interval, 0.54–0.92) h−1; 50 μg 0.531 (0.37–0.63) h−1; vaginal 25 μg 0.507 (0. 2–1. 4) h−1; and 50 μg 0.246 (0.103–0.453) h−1. Relative bioavailability for vaginal compared to buccal route was 2.4 (1.63–4.77). There was no effect of body mass index or age on apparent clearance 705 (431–1099) L/h or apparent volume of distribution 632 (343–1008) L. The area under the concentration–time curve to 4 h following the first 25 μg dose of misoprostol was 16.5 (15.4–17.5) pg h/ml for buccal and 34.3 (32.5–36.1) pg h/ml for vaginal administration. The rate of buccal absorption was two times faster than that of vaginal, whereas bioavailability of vaginal administration was 2.4 times higher than that of buccal. Decreased time to delivery observed with vaginal dosing may be due to higher exposure to misoprostol acid compared to buccal.