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The second generation of the Global navigation satellite system Receiver for Atmospheric Sounding (GRAS-2) is a radio occultation (RO) instrument which is capable of providing 2000 atmospheric profiles per day. The instrument is hosted on all satellites in the MetOp Second Generation (MetOp-SG) series for polar orbit operation. The GRAS-2 instruments provide occultation measurements from the Galileo, GPS, and BeiDou satellites at their common frequencies centred at 1575.42 MHz (L1) and 1176.45 MHz (L5). Using high-gain antennas and an ultra-stable oscillator, neutral bending angles are measured at an unprecedented accuracy of 0.3–0.4 µrad, which is better than the requirement of less than 0.5 µrad. The RO signal will be measured deep into the troposphere using a novel open-loop tracking scheme utilizing multiple correlator outputs for operation with a tailored ground processing algorithm optimized for extracting signals with low amplitudes, approaching the noise floor limitation. Ionosphere measurements to an altitude of 600 km are also acquired.

Background and aim: Many children with an FH mutation also exhibit elevated lipoprotein(a) levels, which is an independent risk factor for atherosclerotic cardiovascular disease. Studies have reported higher levels of lipoprotein(a) in adult and middle-aged women than men. There is limited knowledge on the concentration and change of lipoprotein(a) levels in children with genetic FH, and therefore we investigated sex-differences in lipoprotein(a) level and change in lipoprotein(a) in girls and boys with genetically confirmed FH. Methods: Medical records were reviewed retrospectively in 438 subjects with heterozygous FH that started follow-up below the age of 19 years at the Lipid Clinic, Oslo University Hospital in Norway, and of these we included 386 subjects with at least one Lp(a) measurement. Results: Mean (SD) age at baseline was 13.8 (7.3) years and the age was similar between sexes. Girls had a higher lipoprotein(a) level than boys at baseline: median (25–75 percentile) 223 (108–487) vs. 154 (78–360) mg/L, respectively (p 0.05). Conclusions: We found an increase in Lp(a) levels in children with genetic FH with age, and higher levels in girls than boys, which could impact risk assessment and future ASCVD. Further research is needed to elucidate whether subjects with FH could benefit from lipoprotein(a)-lowering therapies that are under current investigations.

Introduction : Independent Living residences for older adults can be divided into two categories and require better definitions for research purposes; the purpose of this manuscript is to provide those definitions and explore variation in provided services and resident characteristics: (a) Subsidized age-based housing (55+) (Department of Housing and Urban Development (HUD) housing units for low-income adults), and (b) non-subsidized age-based housing. Methods: Residents in the two settings were compared: 37 subsidized locations ( p = 289 residents) and 19 non-subsidized ( p = 208). Aging support services in each housing type were quantified. Results: Subsidized residents are more likely to be female (84.6% vs. 70.2%, p = .0002) and have fair-poor health (36.5% vs. 12.5%, p

Background and aims: Different lipoprotein(a) [Lp(a)] assays may affect risk stratification of individuals and thus clinical decision-making. We aimed to investigate how transitioning between Lp(a) assays at a large central laboratory affected the proportion of individuals with Lp(a) result above clinical thresholds. Methods: We studied nationwide clinical laboratory data including 185,493 unique individuals (47.7 % women) aged 18-50 years with 272,463 Lp(a) measurements using Roche (2000-2009) and Siemens Lp(a) assay (2009-2019). Results: While the majority of individuals (66-75 %) had low levels of Lp(a) (50 mg/dL, 40 % more individuals with Lp(a) >100 mg/dL and 80 % more individuals with Lp(a) > 180 mg/dL than the currently used Siemens assay, likely due to calibration differences. Conclusion: Transitioning from one Lp(a) immunoassay to another had significant impact on Lp(a) results, particularly in individuals approaching clinically relevant Lp(a) thresholds.

Abstract Background Low-grade, chronic inflammation during ageing, (“inflammageing”), is suggested to be involved in the development of frailty in older age. However, studies on the association between frailty, using the frailty index definition, and inflammatory markers are limited. The aim of this study was to investigate the relationship between inflammatory markers and frailty index (FI) in older, home-dwelling adults. Method Home-dwelling men and women aged ≥ 70 years old, living in South-East Norway were recruited and included in a cross-sectional study. The FI used in the current study was developed according to Rockwood’s frailty index and included 38 variables, resulting in an FI score between 0 and 1 for each participant. Circulating inflammatory markers (IL-6, CRP, IGF-1, cystatin C, cathepsin S, and glycoprotein Acetyls) were analyzed from non-fasting blood samples using ELISA. Whole-genome PBMC transcriptomics was used to study the association between FI score and inflammation. Results The study population comprised 403 elderly (52% women), with a median age of 74 years and a mean BMI of 26.2 kg/m2. The mean FI score for the total group was 0.15 (range 0.005–0.56). The group was divided into a frail group (FI score ≥ 0.25) and non-frail group. After adjusting for BMI, age, sex, and smoking in the whole group, IL-6, cathepsin S, cystatin C, and Gp-acetyls remained significant associated to FI score (IL-6: 0.002, 95% CI: 0.001, 0.002, cathepsin S: 6.7e-06, 95% CI 2.44e-06, 0.00001, cystatin C: 0.004, 95% CI: 0.002, 0.006, Gp- Acetyls: 0.09, 95% CI: 0.05, 0.13, p

This study evaluates tropospheric columns of methane, carbon monoxide, and ozone in the Arctic simulated by 11 models. The Arctic is warming at nearly 4 times the global average rate, and with changing emissions in and near the region, it is important to understand Arctic atmospheric composition and how it is changing. Both measurements and modelling of air pollution in the Arctic are difficult, making model validation with local measurements valuable. Evaluations are performed using data from five high-latitude ground-based Fourier transform infrared (FTIR) spectrometers in the Network for the Detection of Atmospheric Composition Change (NDACC). The models were selected as part of the 2021 Arctic Monitoring and Assessment Programme (AMAP) report on short-lived climate forcers. This work augments the model–measurement comparisons presented in that report by including a new data source: column-integrated FTIR measurements, whose spatial and temporal footprint is more representative of the free troposphere than in situ and satellite measurements. Mixing ratios of trace gases are modelled at 3-hourly intervals by CESM, CMAM, DEHM, EMEP MSC-W, GEM-MACH, GEOS-Chem, MATCH, MATCH-SALSA, MRI-ESM2, UKESM1, and WRF-Chem for the years 2008, 2009, 2014, and 2015. The comparisons focus on the troposphere (0–7 km partial columns) at Eureka, Canada; Thule, Greenland; Ny Ålesund, Norway; Kiruna, Sweden; and Harestua, Norway. Overall, the models are biased low in the tropospheric column, on average by −9.7 % for CH4, −21 % for CO, and −18 % for O3. Results for CH4 are relatively consistent across the 4 years, whereas CO has a maximum negative bias in the spring and minimum in the summer and O3 has a maximum difference centered around the summer. The average differences for the models are within the FTIR uncertainties for approximately 15 % of the model–location comparisons.

Introduction: Rate-limiting enzymes (RLEs) are innate slow points in metabolic pathways, and many function in bio-processes related to nutrient sensing. Many RLEs carry causal mutations relevant to inherited metabolic disorders. Because the activity of RLEs in cardiovascular health is poorly characterized, our objective was to assess their involvement in cardiometabolic health and disease and where altered biophysical and biochemical functions can promote disease. Methods: A dataset of 380 human RLEs was compared to protein and gene datasets for factors likely to contribute to cardiometabolic disease, including proteins showing significant age-related altered expression in blood and genetic loci with variants that associate with common cardiometabolic phenotypes. The biochemical reactions catalyzed by RLEs were evaluated for metabolites enriched in RLE subsets associating with various cardiometabolic phenotypes. Most significance tests were based on Z-score enrichment converted to p values with a normal distribution function. Results: Of 380 RLEs analyzed, 112 function in mitochondria, and 53 are assigned to inherited metabolic disorders. There was a depletion of RLE proteins known as aging biomarkers. At the gene level, RLEs were assessed for common genetic variants that associated with important cardiometabolic traits of LDL-cholesterol or any of the five outcomes pertinent to metabolic syndrome. This revealed several RLEs with links to cardiometabolic traits, from a minimum of 26 for HDL-cholesterol to a maximum of 45 for plasma glucose. Analysis of these GWAS-linked RLEs for enrichment of the molecular constituents of the catalyzed reactions disclosed a number of significant phenotype-metabolite links. These included blood pressure with acetate (p = 2.2 × 10−4) and NADP+ (p = 0.0091), plasma HDL-cholesterol and triglyceride with diacylglycerol (p = 2.6 × 10−5, 6.4 × 10−5, respectively) and diolein (p = 2.2 × 10−6, 5.9 × 10−6), and waist circumference with d-glucosamine-6-phosphate (p = 1.8 × 10−4). Conclusion: In the context of cardiometabolic health, aging, and disease, these results highlight key diet-derived metabolites that are central to specific rate-limited processes that are linked to cardiometabolic health. These metabolites include acetate and diacylglycerol, pertinent to blood pressure and triglycerides, respectively, as well as diacylglycerol and HDL-cholesterol.

Abstract Pulmonary vasodilator treatment can improve hemodynamics, right ventricular function, symptoms, and survival in pediatric pulmonary hypertension (PH). However, clinical trial data are lacking due to many constraints. One major limitation is the lack of relevant trial endpoints reflective of hemodynamics or functional status in patients in whom standard exercise testing is impractical, unreliable, or not reproducible. The Kids Mod PAH trial (Mono‐ vs. Duo Therapy for Pediatric Pulmonary Arterial Hypertension) is an ongoing multicenter, Phase III, randomized, open‐label, pragmatic trial to compare the safety and efficacy of first‐line combination therapy (sildenafil and bosentan) to first‐line monotherapy (sildenafil alone) in 100 pediatric patients with PH across North America. Investigators will measure participants’ physical activity with a research‐grade, wrist‐worn actigraphy device at multiple time points as an exploratory secondary outcome. Vector magnitude counts per minute and activity intensity will be compared between the treatment arms. By directly and noninvasively measuring physical activity in the ambulatory setting, we aim to identify a novel, simple, inexpensive, and highly reproducible approach for quantitative assessment of exercise tolerance in pediatric PH. These data will increase the field's understanding of the effect of pulmonary vasodilator treatment on daily activity – a quantitative measure of functional status and wellbeing in pediatric PH and a potential primary outcome for future clinical trials in children with cardiopulmonary disorders.

The back-propagation (BP) method consists of diffractive integrals computed over a trajectory path, projecting a signal to different planes. It unwinds the diffraction and multipath, resulting in minimum disturbance to the BP amplitude when the auxiliary plane coincides with the region causing the diffraction. The method has been previously applied in global navigation satellite system (GNSS) radio occultation (RO) measurements to estimate the location of ionospheric irregularities but without complementary data to validate the estimation. In this study, the BP method is applied to a Communications/Navigation Outage Forecasting System (C/NOFS) occultation event containing scintillation signatures caused by an equatorial plasma bubble (EPB), which was parameterized with the aid of collocated data and reproduced in a wave optics propagator (WOP) simulation. In addition, a few more test cases were designed to assess the BP method with regard to the size, intensity, and placement of single- and multiple-irregularity regions. The results show a location estimate accuracy following the resolution at which the method is implemented (single bubble, reference case), whereas a bias is observed in multiple-bubble scenarios. The minimum detectable disturbance level and the estimation accuracy depend on the receiver noise level and, in the case of several bubbles, on the distance between them. These remarks provide insight into the BP results for two Constellation Observing System for Meteorology Ionosphere and Climate (COSMIC) occultation events.

Abstract Background and methods Inflammation is a hallmark of cancer and its progression. Plasma levels of C‐reactive protein (CRP), interleukin‐6 (IL‐6) and YKL‐40 reflect inflammation, and are elevated in patients with cancer. This study investigated whether plasma CRP, IL‐6 and YKL‐40 had diagnostic value in 753 patients referred with nonspecific signs and symptoms of cancer to a diagnostic outpatient clinic. Results In total, 111 patients were diagnosed with cancer within 3 months and 30 after 3 months. CRP, IL‐6 and YKL‐40 were elevated in 44%, 60% and 45% of the cancer patients, and in 15%, 33% and 25% of the patients without cancer. Elevated levels of all three markers were associated with risk of cancer within 3 months: CRP (odds ratio (OR) 4.41, 95% confidence interval (CI) 2.86–6.81), IL‐6 (OR = 2.89, 1.91–4.37) and YKL‐40 (OR = 2.42, 1.59–3.66). Multivariate explorative analyses showed that increasing values were associated with the risk of getting a cancer diagnosis (continuous scale: CRP (OR = 1.28, 1.12–1.47), carcinoembryonic antigen (CEA) (OR = 1.61, 1.41–1.98), CA19‐9 (OR = 1.15, 1.03–1.29), age (OR = 1.29, 1.02–1.63); dichotomized values: CRP (OR = 2.54, 1.39–4.66), CEA (OR = 4.22, 2.13–8.34), age (OR = 1.42, 1.13–1.80)). CRP had the highest diagnostic value (area under the curve = 0.69). Combined high CRP, IL‐6 and YKL‐40 was associated with short overall survival (HR = 3.8, 95% CI 2.5–5.9, p

Background and aims: The concentration and the duration of exposure to low-density lipoprotein cholesterol (LDL-C) (LDL-C burden) is an important determinant of risk for cardiovascular disease and thresholds has recently been estimated. Individuals with familial hypercholesterolemia (FH) have increased risk of premature cardiovascular disease. The overall aim of the present study was to describe differences in LDL-C level and LDL-C burden in females and males with FH visiting an outpatient lipid clinic from a young age, using multiple LDL-C measurements during a follow-up time of 12 years. First, we aimed to study if the LDL-C concentration and the LDL-C burden is different between females and males at ages 0–10, 10–20, 20–30 and >30 years. Second, we aimed to estimate the subject-specific LDL-C burden at age 19 and 30 years, and the proportion of female and male patients that reach suggested LDL-C thresholds indicating high risk of ASCVD. Methods: Data was retrospectively collected from medical records of 438 subjects (207 girls and 231 boys) with FH, referred to the Lipid Clinic, Oslo University Hospital below the age of 19 years. The LDL-C burden was estimated based on repeated LDL-C measurements over time. Results: Subjects were followed over a period of mean 12.0 (SD 7.0) years, with median 10 years (7–17; 25–75 percentiles, minimum 2), with median 6 (4–9; 25–75 percentiles, minimum 2) available LDL-C measurements, starting at mean age 11 (SD 3.9) years. There was a difference in both LDL-C and LDL-C burden between sexes at different ages. On average, males had lower LDL-C over time, although this difference was less pronounced with age and males also had lower estimated LDL-C burden over time, and this difference was further exacerbated with age. Conclusion: Our study shows that young women with FH have a higher LDL-C burden than their male counterparts, potentially explaining the increased excess CVD risk seen among these. It underscores the importance of careful-follow up and early treatment initiation both prior to and after pregnancies in order to limit statin-free periods.

Abstract Background Numerous intrauterine factors may affect the offspring’s growth during childhood. We aimed to explore if maternal and paternal prenatal lipid, apolipoprotein (apo)B and apoA1 levels are associated with offspring weight, length, and body mass index from 6 weeks to eight years of age. This has previously been studied to a limited extent. Methods This parental negative control study is based on the Norwegian Mother, Father and Child Cohort Study and uses data from the Medical Birth Registry of Norway. We included 713 mothers and fathers with or without self-reported hypercholesterolemia and their offspring. Seven parental metabolites were measured by nuclear magnetic resonance spectroscopy, and offspring weight and length were measured at 12 time points. Data were analyzed by linear spline mixed models, and the results are presented as the interaction between parental metabolite levels and offspring spline (age). Results Higher maternal total cholesterol (TC) level was associated with a larger increase in offspring body weight up to 8 years of age (0.03 ≤ P interaction ≤ 0.04). Paternal TC level was not associated with change in offspring body weight (0.17 ≤ P interaction ≤ 0.25). Higher maternal high-density lipoprotein cholesterol (HDL-C) and apoA1 levels were associated with a lower increase in offspring body weight up to 8 years of age (0.001 ≤ P interaction ≤ 0.005). Higher paternal HDL-C and apoA1 levels were associated with a lower increase in offspring body weight up to 5 years of age but a larger increase in offspring body weight from 5 to 8 years of age (0.01 ≤ P interaction ≤ 0.03). Parental metabolites were not associated with change in offspring height or body mass index up to 8 years of age (0.07 ≤ P interaction ≤ 0.99). Conclusions Maternal compared to paternal TC, HDL-C, and apoA1 levels were more strongly and consistently associated with offspring body weight during childhood, supporting a direct intrauterine effect.

Abstract Background Little research has examined discontinuation of follow‐up care in patients with head and neck cancer. This exploratory study sought to examine key demographic, disease, and behavioral factors as possible correlates of discontinuation (N = 512). Methods Cross‐sectional study examined correlates of discontinuation of follow‐up care within 1 year. The primary outcome was defined as a disease‐free survivor not returning to cancer clinic for two consecutive follow‐up appointments within the first year of care and not reentering oncologic care at any point thereafter. Demographic, disease, and behavioral factors were examined using multivariable logistic regression. Results One hundred twenty‐six (24.6%) patients discontinued by 12‐month follow‐up. Being unmarried (OR = 1.28, 95% CI = 1.01–1.63, p = 0.041) and having elevated depressive symptomatology (OR = 1.04, 95% CI = 1.01–1.07, p = 0.034) were significantly associated with discontinuation. Receipt of a single (vs. multimodal) treatment approached significance (OR = 1.71, 95% CI = 0.96–3.07, p = 0.071). Conclusion Approximately one quarter of patients disengaged from important follow‐up care within 1 year. Lack of social support, depressive symptomatology, and single treatment modality may be important correlates of discontinuation of care in patients with head and neck cancer. Additional studies of this outcome are needed. Improved understanding of correlates associated with discontinuation could facilitate the identification of at‐risk patients and further development of interventions to keep patients engaged at a crucial time in the survivorship care trajectory.

Abstract Background Patients with end-stage kidney disease (ESKD) may choose to undergo dialysis in-center or at home, but uptake of home dialysis in the US has been minimal despite its benefits over in-center dialysis. Factors that may have led patients to select home dialysis over in-center dialysis are poorly understood in the literature, and interventions to improve selection of home dialysis have focused on patient knowledge and shared decision-making processes between patients and providers. The purpose of this study was to explore micro- and macro-level factors surrounding dialysis modality decision-making among patients undergoing in-center and home dialysis, and explore what leads patients to select home dialysis over in-center dialysis. Methods Semi-structured qualitative interviews were conducted in a dialysis clinic at a large Midwestern research hospital, from September 2019 to December 2020. Participants were 18 years or older, undergoing dialysis for ESKD, and had the cognitive ability to provide consent. Surveys assessing demographic and clinical information were administered to participants following their interviews. Results Forty patients completed interviews and surveys (20 [50%] in-center dialysis, 17 [43%] female, mean [SD] age, 59 [15.99] years). Qualitative findings suggested that healthcare access and engagement before entering nephrology care, after entering nephrology care, and following dialysis initiation influenced patients’ awareness regarding their kidney disease status, progression toward ESKD, and dialysis options. Potential modifiers of these outcomes include race, ethnicity, and language barriers. Most participants adopted a passive-approach during decision-making. Finally, fatigue, concerns regarding one’s dialyzing schedule, and problems with fistula/catheter access sites contributed to overall satisfaction with one’s dialysis modality. Conclusions Findings point to broader factors affecting dialysis selection, including healthcare access and racial/ethnic inequities. Providing dialysis information before entering nephrology and after dialysis initiation may improve patient agency in decision-making. Additional resources should be prioritized for patients of underrepresented backgrounds. Dialysis decision-making may be appropriately modeled under the social-ecological framework to inform future interventions.

While carbon dioxide is the main cause for global warming, modeling short-lived climate forcers (SLCFs) such as methane, ozone, and particles in the Arctic allows us to simulate near-term climate and health impacts for a sensitive, pristine region that is warming at 3 times the global rate. Atmospheric modeling is critical for understanding the long-range transport of pollutants to the Arctic, as well as the abundance and distribution of SLCFs throughout the Arctic atmosphere. Modeling is also used as a tool to determine SLCF impacts on climate and health in the present and in future emissions scenarios. In this study, we evaluate 18 state-of-the-art atmospheric and Earth system models by assessing their representation of Arctic and Northern Hemisphere atmospheric SLCF distributions, considering a wide range of different chemical species (methane, tropospheric ozone and its precursors, black carbon, sulfate, organic aerosol, and particulate matter) and multiple observational datasets. Model simulations over 4 years (2008–2009 and 2014–2015) conducted for the 2022 Arctic Monitoring and Assessment Programme (AMAP) SLCF assessment report are thoroughly evaluated against satellite, ground, ship, and aircraft-based observations. The annual means, seasonal cycles, and 3-D distributions of SLCFs were evaluated using several metrics, such as absolute and percent model biases and correlation coefficients. The results show a large range in model performance, with no one particular model or model type performing well for all regions and all SLCF species. The multi-model mean (mmm) was able to represent the general features of SLCFs in the Arctic and had the best overall performance. For the SLCFs with the greatest radiative impact (CH4, O3, BC, and SO42-), the mmm was within ±25 % of the measurements across the Northern Hemisphere. Therefore, we recommend a multi-model ensemble be used for simulating climate and health impacts of SLCFs. Of the SLCFs in our study, model biases were smallest for CH4 and greatest for OA. For most SLCFs, model biases skewed from positive to negative with increasing latitude. Our analysis suggests that vertical mixing, long-range transport, deposition, and wildfires remain highly uncertain processes. These processes need better representation within atmospheric models to improve their simulation of SLCFs in the Arctic environment. As model development proceeds in these areas, we highly recommend that the vertical and 3-D distribution of SLCFs be evaluated, as that information is critical to improving the uncertain processes in models.

The authors analyze the Allen Institute Brain Observatory Ca2+ imaging data, focusing on mouse visual cortex during locomotive and quiescent states. They find that locomotion increases neural coding fidelity, regardless of whether population activity increases or decreases in response to the population’s preferred stimuli.

Although Trojan asteroids have been known for decades in other Solar System planets, only one Earth Trojan asteroid was detected. Here, the authors show that recently discovered 2020 XL5 is the second transient Earth Trojan asteroid.

We present a numerical demonstration of magnonic crystals hosting unidirectional, topologically protected edge states. The magnonic crystal is formed of dipolarly coupled Permalloy triangles. We show that due to the geometry of the block, the size of the structure can be scaled up. In addition, edge states can be found over a wide frequency range. Experimental detection of edge excitations in the considered system can be done with state-of-the-art techniques. Thus, we demonstrate a proof-of-concept magnonic Chern topological insulator nanostructure with simple geometry feasible for experimental realization. Furthermore, by tuning the strength of the perpendicular magnetic field, we induce a topological phase transition, which results in the change of direction of the topological edge state. Then, we demonstrate the magnonic switch based on this effect.

Rapid advances in the development of sequencing technologies, numbers of commercial providers and diminishing costs have made DNA-based identification and diagnostics increasingly accessible to doctors and laboratories, eliminating the need for local investments in expensive technology and training or hiring of skilled technicians. However, reliable and comparable molecular analyses of bacteria in stool samples are dependent on storage and workflow conditions that do not introduce post-sampling bias, the most important factor being the need to keep the DNA at a stable detectable level. For that reason, there may remain other prohibitively costly requirements for cooling or freezing equipment or special chemical additives. This study investigates the diagnostic detectability of Salmonella and Campylobacter DNA in human, pig and chicken stool samples, stored at different temperatures and with different preservation methods. Stool samples were spiked with 106 CFU/mL of both Salmonella and Campylobacter strains stored at −20 °C, 5 °C and 20 °C (Room temperature, RT) and treated with either RNAlater, EDTA or Silica/ethanol. DNA was extracted at 9 different time points within 30 days and quantified by Qubit (total DNA) and qPCR (Salmonella and Campylobacter DNA). We found no statistically significant differences among the different preservation methods, and DNA from both species was easily detected at all time points and at all temperatures, both with and without preservation. This suggests that infections by these bacteria can be diagnosed and possibly also analysed in further detail simply by taking a stool sample in any suitable sealed container that can be transported to laboratory analysis without special storage or preservation requirements. We briefly discuss how this finding can benefit infection control in both developed and developing countries.

Enzyme reactions at interfaces are common in both Nature and industrial applications but no general kinetic framework exists for interfacial enzymes. Here, the authors kinetically characterize 83 cellulases and identify a scaling relationship between ligand binding strength and maximal turnover, a so-called linear free energy relationship, which may help rationalize cellulolytic mechanisms and guide the selection of technical enzymes.

Abstract Background More than one third of Norwegian women and men between 20 and 40 years of age have elevated cholesterol concentration. Parental metabolic health around conception or during pregnancy may affect the offspring’s cardiovascular disease risk. Lipids are important for fetal development, but the determinants of cord blood lipids have scarcely been studied. We therefore aimed to describe the associations between maternal and paternal peri-pregnancy lipid and metabolic profile and newborn cord blood lipid and metabolic profile. Methods This study is based on 710 mother–father–newborn trios from the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). The sample included in this study consisted of parents with and without self-reported hypercholesterolemia the last 6 months before pregnancy and their partners and newborns. Sixty-four cord blood metabolites detected by nuclear magnetic resonance spectroscopy were analyzed by linear mixed model analyses. The false discovery rate procedure was used to correct for multiple testing. Results Among mothers with hypercholesterolemia, maternal and newborn plasma high-density lipoprotein cholesterol, apolipoprotein A1, linoleic acid, docosahexaenoic acid, alanine, glutamine, isoleucine, leucine, valine, creatinine, and particle concentration of medium high-density lipoprotein were significantly positively associated (0.001 ≤ q ≤ 0.09). Among mothers without hypercholesterolemia, maternal and newborn linoleic acid, valine, tyrosine, citrate, creatinine, high-density lipoprotein size, and particle concentration of small high-density lipoprotein were significantly positively associated (0.02 ≤ q ≤ 0.08). Among fathers with hypercholesterolemia, paternal and newborn ratio of apolipoprotein B to apolipoprotein A1 were significantly positively associated (q = 0.04). Among fathers without hypercholesterolemia, no significant associations were found between paternal and newborn metabolites. Sex differences were found for many cord blood lipids. Conclusions Maternal and paternal metabolites and newborn sex were associated with several cord blood metabolites. This may potentially affect the offspring’s long-term cardiovascular disease risk.

Abstract Ovarian cancer (OC) is the eighth most common type of cancer for women worldwide. The current diagnostic and prognostic routine available for OC management either lack specificity or are very costly. Gene expression profiling has shown to be a very effective tool in exploring new molecular markers for patients with OC, although association of such markers with patient survival and clinical outcome is still elusive. Here, we performed gene expression profiling of different subtypes of OC to evaluate its association with patient overall survival (OS) and aggressive forms of the disease. By global mRNA microarray profiling in a total of 196 epithelial OC patients (161 serous, 15 endometrioid, 11 mucinous, and 9 clear cell carcinomas), we found four candidates—HSPA1A, CD99, RAB3A and POM121L9P, which associated with OS and poor clinicopathological features. The overexpression of all combined was correlated with shorter OS and progression-free survival (PFS). Furthermore, the combination of at least two markers were further associated with advanced grade, chemotherapy resistance, and progressive disease. These results indicate that a panel comprised of a few predictors that associates with a more aggressive form of OC may be clinically relevant, presenting a better performance than one marker alone.

The ALPHA Collaboration, based at the CERN Antiproton Decelerator, has recently implemented a novel beamline for low energy (≲100 eV) positron and antiproton transport between cylindrical Penning traps that have strong axial magnetic fields. Here, we describe how a combination of semianalytical and numerical calculations was used to optimize the layout and design of this beamline. Using experimental measurements taken during the initial commissioning of the instrument, we evaluate its performance and validate the models used for its development. By combining data from a range of sources, we show that the beamline has a high transfer efficiency and estimate that the percentage of particles captured in the experiments from each bunch is (78±3)% for up to 10^{5} antiprotons and (71±5)% for bunches of up to 10^{7} positrons.

Summary: Upon exposure to the prevailing environment, leaves become increasingly colonized by fungi and bacteria located on the surface (epiphytic) or within (endophytic) the leaves. Many cool season grasses, including Achnatherum inebrians, host a seed-borne, intercellular, mutualistic Epichloë fungal endophyte, the growth of which is synchronized with the host grass. A study utilizing illumina sequencing was used to examine the epiphytic and endophytic microbial communities in Epichloë endophyte-infected and endophyte-free A. inebrians plants growing under hot dry field conditions. The presence of Epichloë endophyte increased the Shannon and decreased Simpson diversity of bacterial and fungal communities. Sphingomonas and Hymenobacter bacteria and Filobasidium and Mycosphaerella fungi were growing largely epiphytically, whereas Methylobacterium, Escherichia-Shigella, and the fungus Blumeria were mostly found within leaves with the location of colonization influenced by the Epichloë endophyte. In addition, leaf metabolites in Epichloë-infected and Epichloë-free leaves were examined using LC/MS. Epichloë was significantly correlated with 132 metabolites.

Abstract Background The ever-increasing prevalence of obesity constitutes a major health problem worldwide. A subgroup of obese individuals has been described as “metabolically healthy obese” (MHO). In contrast to metabolically unhealthy obese (MUO), the MHO phenotype has a favorable risk profile. Despite this, the MHO phenotype is still sub-optimally characterized with respect to a comprehensive risk assessment. Our aim was to increase the understanding of metabolic alterations associated with healthy and unhealthy obesity. Methods In this cross-sectional study, men and women (18–70 years) with obesity (body mass index (BMI) ≥ 30 kg/m2) or normal weight (NW) (BMI ≤ 25 kg/m2) were classified with MHO (n = 9), MUO (n = 10) or NW (n = 11) according to weight, lipid profile and glycemic regulation. We characterized individuals by comprehensive metabolic profiling using a commercial available high-throughput proton NMR metabolomics platform. Plasma fatty acid profile, including short chain fatty acids, was measured using gas chromatography. Results The concentrations of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) subclasses were overall significantly higher, and high density lipoprotein (HDL) subclasses lower in MUO compared with MHO. VLDL and IDL subclasses were significantly lower and HDL subclasses were higher in NW compared with MHO. The concentration of isoleucine, leucine and valine was significantly higher in MUO compared with MHO, and the concentration phenylalanine was lower in NW subjects compared with MHO. The fatty acid profile in MHO was overall more favorable compared with MUO. Conclusions Comprehensive metabolic profiling supports that MHO subjects have intermediate-stage cardiovascular disease risk marker profile compared with NW and MUO subjects. Clinical trial registration number NCT01034436 , Fatty acid quality and overweight (FO-study). Graphical abstract

Background Acute colorectal cancer surgery has been associated with a high postoperative mortality. The primary aim of this study was to examine the association between socioeconomic position and the likelihood of undergoing acute versus elective colorectal cancer surgery. A secondary aim was to determine 1‐year survival among patients treated with acute surgery. Methods All patients who had undergone a surgical procedure according to the Danish Colorectal Cancer Group (DCCG.dk) database, or who were registered with stent or diverting stoma in the National Patient Register from 2007 to 2015, were reviewed. Socioeconomic position was determined by highest attained educational level, income, urbanicity and cohabitation status, obtained from administrative registries. Co‐variables included age, sex, year of surgery, Charlson Co‐morbidity Index score, smoking status, alcohol consumption, BMI, stage and tumour localization. Logistic regression analysis was performed to determine the likelihood of acute colorectal cancer surgery, and Kaplan–Meier and Cox proportional hazards regression methods were used for analysis of 1‐year overall survival. Results In total, 35 661 patients were included; 5310 (14·9 per cent) had acute surgery. Short and medium education in patients younger than 65 years (odds ratio (OR) 1·58, 95 per cent c.i. 1·32 to 1·91, and OR 1·34, 1·15 to 1·55 respectively), low income (OR 1·12, 1·01 to 1·24) and living alone (OR 1·35, 1·26 to 1·46) were associated with acute surgery. Overall, 40·7 per cent of patients died within 1 year of surgery. Short education (hazard ratio (HR) 1·18, 95 per cent c.i. 1·03 to 1·36), low income (HR 1·16, 1·01 to 1·34) and living alone (HR 1·25, 1·13 to 1·38) were associated with reduced 1‐year survival after acute surgery. Conclusion Low socioeconomic position was associated with an increased likelihood of undergoing acute colorectal cancer surgery, and with reduced 1‐year overall survival after acute surgery.

Obesity is associated with many chronic diseases that impair healthy aging and is governed by genetic, epigenetic, and environmental factors and their complex interactions. This study aimed to develop a model that predicts an individual’s risk of obesity by better characterizing these complex relations and interactions focusing on dietary factors. For this purpose, we conducted a combined genome-wide and epigenome-wide scan for body mass index (BMI) and up to three-way interactions among 402,793 single nucleotide polymorphisms (SNPs), 415,202 DNA methylation sites (DMSs), and 397 dietary and lifestyle factors using the generalized multifactor dimensionality reduction (GMDR) method. The training set consisted of 1,573 participants in exam 8 of the Framingham Offspring Study (FOS) cohort. After identifying genetic, epigenetic, and dietary factors that passed statistical significance, we applied machine learning (ML) algorithms to predict participants’ obesity status in the test set, taken as a subset of independent samples (n = 394) from the same cohort. The quality and accuracy of prediction models were evaluated using the area under the receiver operating characteristic curve (ROC-AUC). GMDR identified 213 SNPs, 530 DMSs, and 49 dietary and lifestyle factors as significant predictors of obesity. Comparing several ML algorithms, we found that the stochastic gradient boosting model provided the best prediction accuracy for obesity with an overall accuracy of 70%, with ROC-AUC of 0.72 in test set samples. Top predictors of the best-fit model were 21 SNPs, 230 DMSs in genes such as CPT1A, ABCG1, SLC7A11, RNF145, and SREBF1, and 26 dietary factors, including processed meat, diet soda, French fries, high-fat dairy, artificial sweeteners, alcohol intake, and specific nutrients and food components, such as calcium and flavonols. In conclusion, we developed an integrated approach with ML to predict obesity using omics and dietary data. This extends our knowledge of the drivers of obesity, which can inform precision nutrition strategies for the prevention and treatment of obesity.Clinical Trial Registration: [www.ClinicalTrials.gov], the Framingham Heart Study (FHS), [NCT00005121].

We report a statistically significant detection of nongravitational acceleration on the subkilometer near-Earth asteroid (523599) 2003 RM. Due to its orbit, 2003 RM experiences favorable observing apparitions every 5 yr. Thus, since its discovery, 2003 RM has been extensively tracked with ground-based optical facilities in 2003, 2008, 2013, and 2018. We find that the observed plane-of-sky positions cannot be explained with a purely gravity-driven trajectory. Including a transverse nongravitational acceleration allows us to match all observational data, but its magnitude is inconsistent with perturbations typical of asteroids such as the Yarkovsky effect or solar radiation pressure. After ruling out that the orbital deviations are due to a close approach or collision with another asteroid, we hypothesize that this anomalous acceleration is caused by unseen cometary outgassing. A detailed search for evidence of cometary activity with archival and deep observations from the Panoramic Survey Telescope and Rapid Response System and the Very Large Telescope does not reveal any detectable dust production. However, the best-fitting H _2 O sublimation model allows for brightening due to activity consistent with the scatter of the data. We estimate the production rate required for H _2 O outgassing to power the acceleration and find that, assuming a diameter of 300 m, 2003 RM would require Q(H _2 O) ∼ 10 ^23 molec s ^−1 at perihelion. We investigate the recent dynamical history of 2003 RM and find that the object most likely originated in the mid-to-outer main belt (∼86% probability) as opposed to from the Jupiter-family comet region (∼11% probability). Further observations, especially in the infrared, could shed light on the nature of this anomalous acceleration.

Remdesivir dry powder for inhalation was previously developed using thin film freezing (TFF). A single-dose 24-h pharmacokinetic study in hamsters demonstrated that pulmonary delivery of TFF remdesivir can achieve plasma remdesivir and GS-441524 levels higher than the reported EC50s of both remdesivir and GS-441524 (in human epithelial cells) over 20 h. The half-life of GS-4412524 following dry powder insufflation was about 7 h, suggesting the dosing regimen would be twice-daily administration. Although the remdesivir-Captisol® (80/20 w/w) formulation showed faster and greater absorption of remdesivir and GS-4412524 in the lung, remdesivir-leucine (80/20 w/w) exhibited a greater Cmax with shorter Tmax and lower AUC of GS-441524, indicating lower total drug exposure is required to achieve a high effective concentration against SAR-CoV-2. In conclusion, remdesivir dry powder for inhalation would be a promising alternative dosage form for the treatment of COVID-19 disease.

Food protein or food-derived peptides may regulate blood glucose levels; however, studies have shown inconsistent results. The aim of the present study was to characterize subgroups of individuals with increased risk of type 2 diabetes (T2D) and to investigate the cardiometabolic effects of fish protein in the same subgroups. We first divided participants into high insuliniAUC and low insuliniAUC subjects based on their insulin incremental area under the curve (iAUC) levels after a 2 h oral glucose tolerance test (OGTT), and secondly based on whether they had received 5.2 g salmon fish protein or placebo for 8 weeks, in a previously conducted randomized controlled trial (RCT). We then profiled these groups by analyzing plasma metabolomics and peripheral blood mononuclear cell (PBMC) gene expression. Compared to the low insuliniAUC group, the high insuliniAUC group had higher plasma concentrations of monounsaturated fatty acids (MUFAs) and glycated proteins (GlycA) and lower concentrations of glycine and acetate. After intervention with fish protein compared to placebo, however, only acetate was significantly increased in the low insuliniAUC group. In conclusion, we identified metabolic biomarkers known to be associated with T2D; also, intervention with fish protein did not affect cardiometabolic risk markers in subgroups with increased risk of T2D.

Niclosamide is an FDA-approved anthelmintic that is being studied in clinical trials as a chemotherapeutic and broad-spectrum antiviral. Additionally, several other applications are currently in the preclinical stage. Unfortunately, niclosamide is a poorly water soluble molecule, with reduced oral bioavailability, which hinders its use for new indications. Moreover, niclosamide is a poor glass former; in other words, the molecule has a high tendency to recrystallize, and it is virtually impossible to generate a stable amorphous solid employing the neat molecule. Previously, our group reported the development of an amorphous solid dispersion (ASD) of niclosamide (niclosamide ASD) that generates nanoparticles during its dissolution, not only increasing niclosamide’s apparent solubility from 6.6 ± 0.4 to 481.7 ± 22.2 µg/mL in fasted state simulated intestinal fluid (FaSSIF) but also its oral bioavailability 2.6-fold in Sprague–Dawley rats after being administered as a suspension. Nevertheless, niclosamide ASD undergoes recrystallization in acidic media, and an enteric oral dosage form is needed for its translation into the clinic. In this work, we further characterized the nanoparticles that generated during the dissolution of the niclosamide ASD. Cryogenic transmission electron microscopy (Cryo-TEM) and wide-angle X-ray scattering (WAXS) revealed that the nanoparticles were amorphous and had a particle size of ~150 nm. The oral dosage forms of niclosamide ASD were formulated using commercial enteric capsules (Capsuline® and EudracapTM) and as enteric-coated tablets. The enteric dosage forms were tested using pH-shift dissolution and acid-uptake tests, using the USP type II dissolution apparatus and the disintegration apparatus, respectively. The capsules exhibited a higher percentage of weight gain, and visual rupture of the Capsuline capsules was observed. Eudracap capsules protected the formulation from the acidic media, but polymer gelling and the formation of a nondispersible plug were noted during dissolution testing. In contrast, enteric-coated tablets protected the formulation from acid ingress and maintained the performance of niclosamide ASD granules during dissolution in FaSSIF media. These enteric-coated tablets were administered to beagle dogs at a niclosamide dose of 75 mg/kg, resulting in plasma concentrations of niclosamide higher than those reported in the literature using solubilized niclosamide at a higher dose (i.e., 100 mg/kg). In summary, an enteric oral dosage form of niclosamide ASD was formulated without hindering the generation of nanoparticles while maintaining the increase in the niclosamide’s apparent solubility. The enteric-coated tablets successfully increased the niclosamide plasma levels in dogs when compared to a niclosamide solution prepared using organic solvents.

Photosynthesis is essential for the growth of all green plants, and the presence of an Epichloë endophyte enhances the photosynthesis of Achnatherum inebrians (drunken horse grass, DHG), including when it is under attack by fungal pathogens. However, few studies have examined the mechanism of the increased photosynthetic activity at the molecular level of A. inebrians when it is under pathogen stress. The present study investigated the effects of the presence of the Epichloë endophyte on the net photosynthetic rate, intercellular CO2 concentration, stomatal conductance, and transpiration rate of DHG plants under a Blumeria graminis infection condition, and we compared the transcriptomes using RNA sequencing. The results showed that the photosynthetic rate of Epichloë endophyte-infected (E+) plants was higher under the B. graminis infection condition, and also without this pathogen, when it was compared with Epichloë endophyte-free (E-) plants. The E+ plants uninfected with B. graminis had 15 up-regulated unigenes that are involved in photosynthesis which were compared to the E- plants that were uninfected with this pathogen. This suggests that the presence of an Epichloë endophyte up-regulates the genes that are involved in the process of photosynthesis.

Abstract The clinical threshold in wheat-dependent, exercise-induced anaphylaxis seems to be lowered in patients on wheat free diet, whereas the opposite is seen in patients on regular wheat intake. Therefore, a recommendation of wheat consumption, if considered safe to the patient based on case-history and challenge results, could be advised.

Vicinity of small bodies might be dangerous to the spacecrafts and to their instrumentation. Here the authors show the operational environment of asteroid Bennu, validate its photometric phase function and demonstrate the accelerating rotational rate due to YORP effect using the data acquired during the approach phase of OSIRIS-REx mission.

Motivated by the need to predict how the Arctic atmosphere will change in a warming world, this article summarizes recent advances made by the research consortium NETCARE (Network on Climate and Aerosols: Addressing Key Uncertainties in Remote Canadian Environments) that contribute to our fundamental understanding of Arctic aerosol particles as they relate to climate forcing. The overall goal of NETCARE research has been to use an interdisciplinary approach encompassing extensive field observations and a range of chemical transport, earth system, and biogeochemical models. Several major findings and advances have emerged from NETCARE since its formation in 2013. (1) Unexpectedly high summertime dimethyl sulfide (DMS) levels were identified in ocean water (up to 75 nM) and the overlying atmosphere (up to 1 ppbv) in the Canadian Arctic Archipelago (CAA). Furthermore, melt ponds, which are widely prevalent, were identified as an important DMS source (with DMS concentrations of up to 6 nM and a potential contribution to atmospheric DMS of 20 % in the study area). (2) Evidence of widespread particle nucleation and growth in the marine boundary layer was found in the CAA in the summertime, with these events observed on 41 % of days in a 2016 cruise. As well, at Alert, Nunavut, particles that are newly formed and grown under conditions of minimal anthropogenic influence during the months of July and August are estimated to contribute 20 % to 80 % of the 30–50 nm particle number density. DMS-oxidation-driven nucleation is facilitated by the presence of atmospheric ammonia arising from seabird-colony emissions, and potentially also from coastal regions, tundra, and biomass burning. Via accumulation of secondary organic aerosol (SOA), a significant fraction of the new particles grow to sizes that are active in cloud droplet formation. Although the gaseous precursors to Arctic marine SOA remain poorly defined, the measured levels of common continental SOA precursors (isoprene and monoterpenes) were low, whereas elevated mixing ratios of oxygenated volatile organic compounds (OVOCs) were inferred to arise via processes involving the sea surface microlayer. (3) The variability in the vertical distribution of black carbon (BC) under both springtime Arctic haze and more pristine summertime aerosol conditions was observed. Measured particle size distributions and mixing states were used to constrain, for the first time, calculations of aerosol–climate interactions under Arctic conditions. Aircraft- and ground-based measurements were used to better establish the BC source regions that supply the Arctic via long-range transport mechanisms, with evidence for a dominant springtime contribution from eastern and southern Asia to the middle troposphere, and a major contribution from northern Asia to the surface. (4) Measurements of ice nucleating particles (INPs) in the Arctic indicate that a major source of these particles is mineral dust, likely derived from local sources in the summer and long-range transport in the spring. In addition, INPs are abundant in the sea surface microlayer in the Arctic, and possibly play a role in ice nucleation in the atmosphere when mineral dust concentrations are low. (5) Amongst multiple aerosol components, BC was observed to have the smallest effective deposition velocities to high Arctic snow (0.03 cm s−1).

Cuticular wax plays a critical role as a plant protectant against various environmental stresses. We predicted that the presence of the mutualistic fungal endophyte Epichloë gansuensis in Achnatherum inebrians would change both the composition of leaf cuticular wax as plants aged during the growing season and the gene expression levels associated with the wax biosynthesis pathway. Endophyte-infected (EI) and endophyte-free (EF) A. inebrians plants were established for a four-month pot experiment. In agreement with our prediction, the presence of E. gansuensis can change the composition of leaf cuticular wax at different growing periods, particularly the proportion of esters, fatty acids and hydrocarbons. The proportion of fatty acids in EI plants was lower than that in EF plants. The proportion of hydrocarbons increased and esters decreased as plants grew. Furthermore, we found 11 DEGs coding for proteins involved in cuticular wax biosynthesis, including FabF, FAB2, ECR, FAR, CER1, ABCB1 and SEC61A. The present study highlights the significant contribution of E. gansuensis to leaf cuticular wax composition and biosynthesis in A. inebrians plants.

This study was conducted to explore effects of the systemic fungal endophyte Epichloë gansuensis on root and rhizosphere soil bacterial diversity of Achnatherum inebrians host plants growing under different moisture conditions. Soil properties of different treatments were compared using standard techniques. A total of 4371379 16S rRNA gene sequences were obtained and assigned to 5025 operational taxonomic units (OTUs). These OTUs in roots and rhizosphere soil were divided into 13 and 17 phyla, respectively, and the Actinobacteria and Proteobacteria were the most abundant phyla both in roots and rhizosphere soil. Shannon diversity and Chao1 richness index of bacteria in rhizosphere soil was significantly higher than in roots. E. gansuensis decreased the Shannon diversity of the root-associated bacterial community, and increased Shannon diversity and Chao1 richness index of the rhizosphere soil bacterial community of A. inebrians. Meanwhile, Chao1 richness of the rhizosphere soil bacterial community of A. inebrians significantly increased with the increase of the soil moisture level. Structural equation modeling also emphasized that E. gansuensis decreased the diversity of the root-associated bacterial community and increased the diversity of the rhizosphere soil bacterial community through decreasing soil available N. Additionally, soil moisture increased the diversity of the rhizosphere soil bacterial community through increased soil pH, C/N, and NN, and decreased soil AP. The E. gansuensis endophyte and soil moisture effects on root and rhizosphere soil bacterial diversity were likely to be from responses to modifications of the rhizosphere soil properties.

Notch pathway haploinsufficiency can cause severe developmental syndromes with highly variable penetrance. Currently, we have a limited mechanistic understanding of phenotype variability due to gene dosage. Here, we unexpectedly found that inserting an enhancer containing pioneer transcription factor sites coupled to Notch dimer sites can induce a subset of Notch haploinsufficiency phenotypes in Drosophila with wild type Notch gene dose. Using Drosophila genetics, we show that this enhancer induces Notch phenotypes in a Cdk8-dependent, transcription-independent manner. We further combined mathematical modeling with quantitative trait and expression analysis to build a model that describes how changes in Notch signal production versus degradation differentially impact cellular outcomes that require long versus short signal duration. Altogether, these findings support a ‘bind and discard’ mechanism in which enhancers with specific binding sites promote rapid Cdk8-dependent Notch turnover, and thereby reduce Notch-dependent transcription at other loci and sensitize tissues to gene dose based upon signal duration.

Abstract Thermal springs are excellent locations for discovery of thermostable microorganisms and enzymes. In this study, we identify a novel thermotolerant bacterial strain related to Paenibacillus dendritiformis, denoted Paenibacillus sp. 3179, which was isolated from a thermal spring in East Greenland. A functional expression library of the strain was constructed, and the library screened for β‐d‐galactosidase and α‐l‐fucosidase activities on chromogenic substrates. This identified two genes encoding a β‐d‐galactosidase and an α‐l‐fucosidase, respectively. The enzymes were recombinantly expressed, purified, and characterized using oNPG (2‐nitrophenyl‐β‐d‐galactopyranoside) and pNP‐fucose (4‐nitrophenyl‐α‐l‐fucopyranoside), respectively. The enzymes were shown to have optimal activity at 50°C and pH 7–8, and they were able to hydrolyze as well as transglycosylate natural carbohydrates. The transglycosylation activities were investigated using TLC and HPLC, and the β‐d‐galactosidase was shown to produce the galactooligosaccharides (GOS) 6'‐O‐galactosyllactose and 3'‐O‐galactosyllactose using lactose as substrate, whereas the α‐l‐fucosidase was able to transfer the fucose moiety from pNP‐fuc to lactose, thereby forming 2'‐O‐fucosyllactose. Since enzymes that are able to transglycosylate carbohydrates at elevated temperature are desirable in many industrial processes, including food and dairy production, we foresee the potential use of enzymes from Paenibacillus sp. 3179 in the production of, for example, instant formula.

Powdery mildew caused by Erysiphe pisi is a major factor that affects the growth of standing milkvetch (Astragalus adsurgens). As arbuscular mycorrhizal fungi (AMF) have shown to be enhancing the resistance of plants to biotrophic pathogens such as powdery mildew, a study was carried out to look at the effects of three AMF, either singularly or in combination, on the growth of standing milkvetch and susceptibility to E. pisi. The results showed that the presence of AMF enhanced the growth of standing milkvetch even though their presence in the roots increased susceptibility to this foliage pathogen compared with plants having no AMF. This increase in growth of plants with severe infection of powdery mildew was especially surprising as leaves contained lower levels of chlorophyll than plants without AMF and had a greater concentration of malondialdehyde, an indicator of the damage of cell membrane. The effects on the extent of growth and powdery mildew enhancement differed inconsistently with the type of AMF in roots. The effects on growth and powdery mildew were not related to intensity of AMF colonisation. The peroxidase (POD) was consistently higher activity (15% to 72%) in plants with AMF than plants without them.

Objectives: Bacteria with common microbiological and clinical characteristics are often recognized as a particular group. The acronym HACEK stands for five fastidious genera associated with infective endocarditis (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella). Data on the epidemiology of HACEK are sparse. This article reports a 6-year nationwide study of HACEK bacteraemia in Denmark. Methods: Cases of HACEK bacteraemia occurring during the years 2010–2015 were retrieved from the national Danish microbiology database, covering an average surveillance population of 5.6 million per year. Results: A total of 147 cases of HACEK bacteraemia were identified, corresponding to an annual incidence of 0.44 per 100 000 population. The annual incidence for males was 0.56 per 100 000 and for females was 0.31 per 100 000. The median age was 56 years (range 0–97 years), with variation among the genera. One hundred and forty-three isolates were identified to the species level and six to the genus level: Haemophilus spp, n = 55; Aggregatibacter spp, n = 37; Cardiobacterium spp, n = 9; Eikenella corrodens n = 21; and Kingella spp, n = 27. Conclusions: This is the first study on the incidence of HACEK bacteraemia in a large surveillance population and may inspire further studies on the HACEK group. Haemophilus spp other than Haemophilus influenzae accounted for most cases of HACEK bacteraemia in Denmark, with Aggregatibacter spp in second place. Keywords: Epidemiology, Incidence, Age, Sex, Haemophilus, Aggregatibacter

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Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and a key contributor to the large health care burden associated with prematurity, longer hospital stays, higher hospital costs, and frequent re-hospitalizations of affected patients through the first year of life and increased resource utilization throughout childhood. This disease is associated with abnormal pulmonary function that may lead to BPD-associated pulmonary hypertension (PH), a major contributor to neonatal mortality and morbidity. In the absence of any definitive treatment options, this life-threatening disease is associated with high resource utilization during and after neonatal intensive care unit (NICU) stay. The goal of this study was to test the safety and efficacy of a small molecule derivative of chitin, AVR-48, as prophylactic therapy for preventing experimental BPD in a mouse model. Two doses of AVR-48 were delivered either intranasally (0.11 mg/kg), intraperitoneally (10 mg/kg), or intravenously (IV) (10 mg/kg) to newborn mouse pups on postnatal day (P)2 and P4. The outcomes were assessed by measuring total inflammatory cells in the broncho-alveolar lavage fluid (BALF), chord length, septal thickness, and radial alveolar counts of the alveoli, Fulton’s Index (for PH), cell proliferation and cell death by immunostaining, and markers of inflammation by Western blotting and ELISA. The bioavailability and safety of the drug were assessed by pharmacokinetic and toxicity studies in both neonatal mice and rat pups (P3-P5). Following AVR-48 treatment, alveolar simplification was improved, as evident from chord length, septal thickness, and radial alveolar counts; total inflammatory cells were decreased in the BALF; Fulton’s Index was decreased and lung inflammation and cell death were decreased, while angiogenesis and cell proliferation were increased. AVR-48 was found to be safe and the no-observed-adverse-effect level (NOAEL) in rat pups was determined to be 100 mg/kg when delivered via IV dosing with a 20-fold safety margin. With no reported toxicity and with a shorter half-life, AVR-48 is able to reverse the worsening cardiopulmonary phenotype of experimental BPD and BPD-PH, compared to controls, thus positioning it as a future drug candidate.

The study of the contribution of the plant defence hormones, salicylic acid (SA) and jasmonic acid (JA), in the resistance against pathogens of plants associated with Epichloë fungal endophytes has been scanty. We hypothesised that Epichloë spp., capable of inducing host plant SA-dependent defences, would increase the levels of plant resistance against biotrophic pathogens. Plants of Achnatherum inebrians, with and without the fungal endophyte Epichloë gansuensis, were inoculated with the biotrophic fungal pathogen Blumeria graminis. We measured the status of plant defences (associated with SA and JA signalling pathways) and the levels of resistance to the pathogen. Plants associated with the endophyte showed less disease symptoms caused by the biotrophic pathogen than plants without the endophyte. In agreement with our hypothesis, the Epichloë endophyte increased the plant production of SA and enhanced the expression levels of plant genes of synthesis and response to the SA hormone. The elevated expression of SA-related genes coding for putative plant enzymes with anti-fungal activities promoted by the endophyte may explain the enhanced resistance to the pathogen. The present study highlights that interaction between the plant immune system and Epichloë fungal endophytes can contribute significantly to the resistance of endophyte-symbiotic plants against pathogens.

The present study was designed to explore the effects of the endophyte Epichloë gansuensis on gene expression related to plant hormone biosynthesis and response pathways and the content of salicylic acid (SA) and jasmonic acid (JA) hormones of Achnatherum inebrians, under different moisture conditions. Through a pot experiment and transcriptome analysis, we found a total of 51 differentially expressed genes (DEGs) related to hormone biosynthesis and response pathways, including 12 auxin related genes, 8 cytokinin (CTK) related genes, 3 gibberellin (GA) related genes, 7 abscisic acid (ABA) related genes, 7 ethylene (ET) related genes, 12 JA related genes and 4 SA related genes. Furthermore, key genes of JA and SA biosynthesis and response pathways, such as LOX2S, AOS, OPR, ACX, JMT, JAZ, PAL, NPR1, TGA and PR-1, showed different degrees of upregulation or downregulation. Under 60% soil moisture content, the JA content of endophyte-free (EF) A. inebrians was significantly (p < 0.05) higher than that of endophyte-infected (EI) A. inebrians. Under 30% and 60% soil moisture content, the SA content of EF A. inebrians was significantly (p < 0.05) higher than that of EI A. inebrians. SA content of EI A. inebrians under 30% and 60% soil moisture content was significantly (p < 0.05) higher than that under 15% soil moisture content. With both EI and EF plants, the SA and JA levels, respectively, are very similar at 15% soil moisture content. This study has revealed that E. gansuensis differentially activated plant hormone synthesis and signal transduction pathways of A. inebrians plants under different soil moisture availability.

The sol–gel transition of conductive nanocomposites consisting of poly(3-hexylthiophene) (P3HT) and ZnO nanowires in o-dichlorobenzene (o-DCB) has been investigated rheologically. The physical gelation of P3HT in o-DCB spontaneously occurs upon adding the small amount of ZnO nanowires. The rheological properties of the P3HT/ZnO nanocomposite gels have been systematically studied by varying factors such as polymer concentration, nanowire loading, and temperature. The nanocomposite gel exhibits shear-thinning in the low shear rate range and shear-thickening in the high shear rate range. The elastic storage modulus of the nanocomposite gel gradually increases with gelation time and is consistently independent of frequency at all investigated ranges. The isothermal gelation kinetics has been analyzed by monitoring the storage modulus with gelation time, and the data are well fitted with a first-order rate law. The structural analysis data reveal that the polymer forms the crystalline layer coated on ZnO nanowires. A fringed micelle model is proposed to explain the possible gelation mechanism.

Solid state Pt(II)-pincer complexes exhibiting vapochromic responses show promise for chemical sensing applications, but their slow responses typically limit their utility. Here, Raithby and colleagues design a Pt(II)-pincer complex with a subsecond, highly-selective vapochromic response to water and methanol.

Abstract Background Obesity, a major cause of death and disability, is increasing worldwide. Obesity is characterized by a chronic, low-grade inflammatory state which is suggested to play a critical role in the development of obesity-related diseases like cardiovascular diseases and type 2 diabetes. In fact, in the hours following consumption of a meal, a transient increase in inflammatory markers occurs, a response that is exaggerated in obese subjects. Dietary composition, including content of dietary fatty acids, may affect this inflammatory response both acutely and chronically, and thereby be predictive of progression of disease. The aim of the review was to summarize the literature from 2010 to 2016 regarding the effects of dietary fat intake on levels of inflammatory markers in overweight and obesity in human randomized controlled trials. Methods and results We performed a literature search in MEDLINE, EMBASE, and PubMed databases. The literature search included human randomized controlled trials, both postprandial and long-term interventions, from January 2010 to September 2016. In total, 37 articles were included. Interventions with dairy products, vegetable oils, or nuts showed minor effects on inflammatory markers. The most consistent inflammatory-mediating effects were found in intervention with whole diets, which suggests that many components of the diet reduce inflammation synergistically. Furthermore, interventions with weight reduction and different fatty acids did not clearly show beneficial effects on inflammatory markers. Conclusion Most interventions showed either no or minor effects of dietary fat intake on inflammatory markers in overweight and obese subjects. To progress our understanding on how diet and dietary components affect our health, mechanistic studies are required. Hence, future studies should include whole diets and characterization of obese phenotypes at a molecular level, including omics data and gut microbiota.

Abstract Background The aim was to improve upon an existing blood-based colorectal cancer (CRC) test directed to high-risk symptomatic patients, by developing a new CRC classifier to be used with a new test embodiment. The new test uses a robust assay format—electrochemiluminescence immunoassays—to quantify protein concentrations. The aim was achieved by building and validating a CRC classifier using concentration measures from a large sample set representing a true intent-to-test (ITT) symptomatic population. Methods 4435 patient samples were drawn from the Endoscopy II sample set. Samples were collected at seven hospitals across Denmark between 2010 and 2012 from subjects with symptoms of colorectal neoplasia. Colonoscopies revealed the presence or absence of CRC. 27 blood plasma proteins were selected as candidate biomarkers based on previous studies. Multiplexed electrochemiluminescence assays were used to measure the concentrations of these 27 proteins in all 4435 samples. 3066 patients were randomly assigned to the Discovery set, in which machine learning was used to build candidate classifiers. Some classifiers were refined by allowing up to a 25% indeterminate score range. The classifier with the best Discovery set performance was successfully validated in the separate Validation set, consisting of 1336 samples. Results The final classifier was a logistic regression using ten predictors: eight proteins (A1AG, CEA, CO9, DPPIV, MIF, PKM2, SAA, TFRC), age, and gender. In validation, the indeterminate rate of the new panel was 23.2%, sensitivity/specificity was 0.80/0.83, PPV was 36.5%, and NPV was 97.1%. Conclusions The validated classifier serves as the basis of a new blood-based CRC test for symptomatic patients. The improved performance, resulting from robust concentration measures across a large sample set mirroring the ITT population, renders the new test the best available for this population. Results from a test using this classifier can help assess symptomatic patients’ CRC risk, increase their colonoscopy compliance, and manage next steps in their care.

The data in this relies on a previous publication: “Altered leukocyte distribution under hypercholesterolemia: a cross-sectional study in children with familial hypercholesterolemia” (Christensen et al. 2016) [1]. In the present paper, whole blood leukocyte distribution and plasma inflammatory proteins were measured for association with cholesterol concentration and CRP in children with familial hypercholesterolemia (FH) and healthy children.