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Scholars suggest that culturally responsive instructional supervision (CRIS) is an important component of equitable teaching practices in schools. This fictional case study details the experiences of a fifth-grade team who, along with their principal and their instructional coach, perform a discourse analysis of their own mathematics lessons to diagnose the equity gaps in their teaching and make necessary adjustments. The case narrative highlights the need for equitable teaching practices in the mathematics classroom and the potential needs of school leaders as they work to create more equitable learning environments in their schools through the use of CRIS.

P450 oxidoreductase (POR) selectively activates numerous cytochromes P450 (CYP), crucial for metabolism of drugs, steroids and xenobiotics and natural product biosynthesis. Here, the authors identify ligands that bind POR and bias its specificity towards CYP redox partners, activating distinct metabolic cascades in cells.

Abstract Background Alpha-mannosidosis is a lysosomal storage disorder caused by reduced enzymatic activity of alpha-mannosidase. SPARKLE is an alpha-mannosidosis registry intended to obtain long-term safety and effectiveness data on the use of velmanase alfa during routine clinical care in patients with alpha-mannosidosis. It is a post-approval commitment to European marketing authorization for Velmanase alfa (Lamzede®), the first enzyme replacement therapy for the treatment of non-neurologic manifestations in patients with mild to moderate alpha-mannosidosis. In addition, SPARKLE will expand the current understanding of alpha-mannosidosis by collecting data on the clinical manifestations, progression, and natural history of the disease in treated and untreated patients, respectively. Results The SPARKLE registry is designed as a multicenter, multinational, noninterventional, prospective cohort study of patients with alpha-mannosidosis, starting patient enrollment in 2020. Patients will be followed for up to 15 years. Safety and effectiveness as post-authorization outcomes under routine clinical care in patients with treatment will be evaluated. The primary safety outcomes are the rate of adverse events (anti-velmanase alfa-immunoglobulin G antibody development, infusion-related reactions, and hypersensitivity). Secondary safety outcomes include the evaluation of medical events, change in vital signs, laboratory tests, physical examination, and electrocardiogram results. The primary effectiveness outcome is a global treatment response rate, evaluated as the individual aggregate of single endpoints from pharmacodynamic, functional, and quality-of-life effectiveness outcomes; secondary effectiveness outcomes are to characterize the population of patients with alpha-mannosidosis with regard to clinical manifestation, progression, and natural history of the disease. Any patient in the European Union with a diagnosis of alpha-mannosidosis who is willing to participate will likely be eligible for inclusion in the registry. Publications to disseminate scientific insights from the registry are planned. Conclusion This study will provide real-world data on the long-term safety and effectiveness of velmanase alfa in patients with alpha-mannosidosis during routine clinical care and increase the understanding of the natural course, clinical manifestations, and progression of this ultra-rare disease.

Abstract The objective of this study was to investigate the fat and carbohydrate metabolism in a patient with propionic acidemia (PA) during exercise by means of indirect calorimetry and stable isotope technique. A 34‐year‐old patient with PA performed a 30‐minute submaximal cycle ergometer test. Data were compared to results from six gender‐ and age‐matched healthy controls. Main findings are that the patient with PA had impaired lipolysis, blunted fatty acid oxidation, compensatory increase in carbohydrate utilization, and low work capacity. Our findings indicate that PA should be added to the list of metabolic myopathies.

IntroductionManagement of phenylketonuria (PKU) is mainly achieved through dietary control with limited intake of phenylalanine (Phe) from food, supplemented with low protein (LP) food and a mixture of free synthetic (FS) amino acids (AA) (FSAA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese making by the action of the enzyme chymosin. Because CGMP in its pure form does not contain Phe, it is nutritionally suitable as a supplement in the diet for PKU when enriched with specific AAs. Lacprodan® CGMP-20 (= CGMP) used in this study contained only trace amounts of Phe due to minor presence of other proteins/peptides.ObjectiveThe aims were to address the following questions in a classical PKU mouse model: Study 1, off diet: Can pure CGMP or CGMP supplemented with Large Neutral Amino Acids (LNAA) as a supplement to normal diet significantly lower the content of Phe in the brain compared to a control group on normal diet, and does supplementation of selected LNAA results in significant lower brain Phe level?. Study 2, on diet: Does a combination of CGMP, essential (non-Phe) EAAs and LP diet, provide similar plasma and brain Phe levels, growth and behavioral skills as a formula which alone consist of FSAA, with a similar composition?.Material and methods45 female mice homozygous for the Pahenu2 mutation were treated for 12 weeks in five different groups; G1(N-CGMP), fed on Normal (N) casein diet (75%) in combination with CGMP (25%); G2 (N-CGMP-LNAA), fed on Normal (N) casein diet (75%) in combination with CGMP (19,7%) and selected LNAA (5,3% Leu, Tyr and Trp); G3 (N), fed on normal casein diet (100%); G4 (CGMP-EAA-LP), fed on CGMP (70,4%) in combination with essential AA (19,6%) and LP diet; G5 (FSAA-LP), fed on FSAA (100%) and LP diet. The following parameters were measured during the treatment period: Plasma AA profiles including Phe and Tyr, growth, food and water intake and number of teeth cut. At the end of the treatment period, a body scan (fat and lean body mass) and a behavioral test (Barnes Maze) were performed. Finally, the brains were examined for content of Phe, Tyr, Trp, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindole-acetic acid (5-HIAA), and the bone density and bone mineral content were determined by dual-energy x-ray absorptiometry.ResultsStudy 1: Mice off diet supplemented with CGMP (G1 (N-CGMP)) or supplemented with CGMP in combination with LNAA (G2 (N-CGMP-LNAA)) had significantly lower Phe in plasma and in the brain compared to mice fed only casein (G3 (N)). Extra LNAA (Tyr, Trp and Leu) to CGMP did not have any significant impact on Phe levels in the plasma and brain, but an increase in serotonin was measured in the brain of G2 mice compared to G1. Study 2: PKU mice fed with mixture of CGMP and EAA as supplement to LP diet (G4 (CGMP-EAA-LP)) demonstrated lower plasma-Phe levels but similar brain- Phe levels and growth as mice fed on an almost identical combination of FSAA (G5 (FSAA-LP)).ConclusionCGMP can be a relevant supplement for the treatment of PKU.

Background and aims Alcoholic hepatitis (AH) is characterized by acute liver failure, neurocognitive impairment and renal failure. Severe inflammatory reactions are also known to occur in AH. Inflammation and bacterial translocation in the gut are thought to have major impact on disease development and progression. The mortality rate for AH is close to 50%. We aimed to assess the efficacy of rifaximin in treating AH and its impact on inflammation and metabolism. Methods The trial was approved by relevant authorities (EudraCT no: 2014-02264-33, Scientific Ethics Committee, jr. no: H-1-2014-056). Primary outcomes were changes in metabolic and inflammatory markers. Secondary outcomes were portal hypertension, kidney and neurocognitive function. Results Thirty-two patients were randomized to standard medical therapy (SMT) or SMT plus rifaximin, allocation was concealed. Four patients in the SMT group and five patients in the SMT + rifaximin group died due to AH and liver failure. No adverse events related to the study medication were observed. We found no significant differences in amino acids or inflammation markers (IL-2, IL-6, IL-8, IL-10, TNF-α, interferon-γ) between the groups after 28 and 90 days. Conclusion Rifaximin does not alter inflammation or metabolism in patients with AH.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Here, Alcala and colleagues present a multi-omics analysis of these tumours, revealing distinct molecular and prognostic subgroups.

Abstract Background Scurvy is one of the oldest diseases known to mankind. Although presently rare in the developed world, scurvy was a common potentially fatal disease. In recent times, the most common risk factors for scurvy include alcoholism, low socioeconomic status, and severely poor nutrition or dietary restriction secondary to psychiatric illness or developmental disorders. Our case demonstrates the importance of having a high index of clinical suspicion of an uncommon disease in developed countries and emphasizes the necessity of a dietary screening that could potentially reduce extensive work-up in patients with nonspecific complaints. Case presentation We report a case of a 3-year-old previously healthy female originally seen in the rheumatology clinic for limp. She developed weakness and was admitted to the hospital for further evaluation. She underwent extensive diagnostic testing including blood work, magnetic resonance imaging, lumbar puncture, electromyogram, and nerve conduction studies. Ultimately, her vitamin C level returned undetectable. She had immediate and complete improvement upon starting vitamin C supplementation. Conclusions Despite being developmentally appropriate, our patient’s refusal to eat fruits or vegetables had limited her diet, emphasizing the importance of obtaining a diet history in a child presenting with an unknown diagnosis. In addition, our patient had no other characteristic features of scurvy, which further supports the need to consider this diagnosis in a child presenting with lower extremity weakness or abnormal gait.

Gamow-Teller β decay is forbidden if the number of nodes in the radial wave functions of the initial and final states is different. This Δn=0 requirement plays a major role in the β decay of heavy neutron-rich nuclei, affecting the nucleosynthesis through the increased half-lives of nuclei on the astrophysical r-process pathway below both Z=50 (for N>82) and Z=82 (for N>126). The level of forbiddenness of the Δn=1ν1g9/2→π0g7/2 transition has been investigated from the β− decay of the ground state of 207Hg into the single-proton-hole nucleus 207Tl in an experiment at the ISOLDE Decay Station. From statistical observational limits on possible γ-ray transitions depopulating the π0g7/2−1 state in 207Tl, an upper limit of 3.9×10−3% was obtained for the probability of this decay, corresponding to log⁡ft>8.8 within a 95% confidence limit. This is the most stringent test of the Δn=0 selection rule to date.

There is a significant knowledge gap in the current state of the terrestrial carbon (C) budget. Recent studies have highlighted a poor understanding particularly of C pool transit times and of whether productivity or biomass dominate these biases. The Arctic, accounting for approximately 50 % of the global soil organic C stocks, has an important role in the global C cycle. Here, we use the CARbon DAta MOdel (CARDAMOM) data-assimilation system to produce pan-Arctic terrestrial C cycle analyses for 2000–2015. This approach avoids using traditional plant functional type or steady-state assumptions. We integrate a range of data (soil organic C, leaf area index, biomass, and climate) to determine the most likely state of the high-latitude C cycle at a 1∘ × 1∘ resolution and also to provide general guidance about the controlling biases in transit times. On average, CARDAMOM estimates regional mean rates of photosynthesis of 565 g C m−2 yr−1 (90 % confidence interval between the 5th and 95th percentiles: 428, 741), autotrophic respiration of 270 g C m−2 yr−1 (182, 397) and heterotrophic respiration of 219 g C m−2 yr−1 (31, 1458), suggesting a pan-Arctic sink of −67 (−287, 1160) g Cm−2 yr−1, weaker in tundra and stronger in taiga. However, our confidence intervals remain large (and so the region could be a source of C), reflecting uncertainty assigned to the regional data products. We show a clear spatial and temporal agreement between CARDAMOM analyses and different sources of assimilated and independent data at both pan-Arctic and local scales but also identify consistent biases between CARDAMOM and validation data. The assimilation process requires clearer error quantification for leaf area index (LAI) and biomass products to resolve these biases. Mapping of vegetation C stocks and change over time and soil C ages linked to soil C stocks is required for better analytical constraint. Comparing CARDAMOM analyses to global vegetation models (GVMs) for the same period, we conclude that transit times of vegetation C are inconsistently simulated in GVMs due to a combination of uncertainties from productivity and biomass calculations. Our findings highlight that GVMs need to focus on constraining both current vegetation C stocks and net primary production to improve a process-based understanding of C cycle dynamics in the Arctic.

Background There is an association between overweight status and life span in kenneled dogs, but a similar association has not been reported for pet dogs. Objectives To examine the effects of being overweight in middle age on the life span of neutered client‐owned dogs. Animals Fifty‐thousand seven‐hundred eighty seven middle‐aged neutered client‐owned dogs attending a network of approximately 900 veterinary hospitals across North America. Methods Retrospective case‐control study. For each of 12 breeds, groups of dogs aged between 6.5 and 8.5 years were identified as being in “overweight” or “normal” body condition. Within each breed and sex, differences in life span between dogs in normal body condition and overweight body condition in the 2 groups were then analyzed by Cox proportional hazards models. Results For all breeds, instantaneous risk of death for dogs in overweight body condition was greater than those in normal body condition throughout the age range studied, with hazard ratios ranging from 1.35 (99.79% confidence interval [CI] 1.05‐1.73) for German Shepherd dog to 2.86 (99.79% CI 2.14‐3.83) for Yorkshire Terrier. In all breeds, median life span was shorter in overweight compared with normal weight dogs, with the difference being greatest in Yorkshire Terriers (overweight: 13.7 years, 99.79% CI 13.3‐14.2; normal: 16.2 years, 99.79% CI 15.7‐16.5) and least in German Shepherd dogs (overweight: 12.1 years, 99.79% CI 11.8‐12.4; normal: 12.5 years, 99.79% CI 12.2‐12.9). Conclusions and Clinical Importance Veterinary professionals should consider promoting healthy body condition for dogs, particularly from midlife onward.

Abstract Permafrost soils and arctic wetlands methane emissions represent an important challenge for modeling the future climate. Here we present a process‐based model designed to correctly represent the main thermal, hydrological, and biogeochemical processes related to these emissions for general land surface modeling. We propose a new multilayer soil carbon and gas module within the Interaction Soil‐Biosphere‐Atmosphere (ISBA) land‐surface model (LSM). This module represents carbon pools, vertical carbon dynamics, and both oxic and anoxic organic matter decomposition. It also represents the soil gas processes for CH4, CO2, and O2 through the soil column. We base CH4 production and oxydation on an O2 control instead of the classical water table level strata approach used in state‐of‐the‐art soil CH4 models. We propose a new parametrization of CH4 oxydation using recent field experiments and use an explicit O2 limitation for soil carbon decomposition. Soil gas transport is computed explicitly, using a revisited formulation of plant‐mediated transport, a new representation of gas bulk diffusivity in porous media closer to experimental observations, and an innovative advection term for ebullition. We evaluate this advanced model on three climatically distinct sites : two in Greenland (Nuuk and Zackenberg) and one in Siberia (Chokurdakh). The model realistically reproduces methane and carbon dioxide emissions from both permafrosted and nonpermafrosted sites. The evolution and vertical characteristics of the underground processes leading to these fluxes are consistent with current knowledge. Results also show that physics is the main driver of methane fluxes, and the main source of variability appears to be the water table depth.

Purpose: To identify the mutation for Volkmann cataract (CTRCT8) at 1p36.33. Methods: The genes in the candidate region 1p36.33 were Sanger and parallel deep sequenced, and informative single nucleotide polymorphisms (SNPs) were identified for linkage analysis. Expression analysis with reverse transcription polymerase chain reaction (RT-PCR) of the candidate gene was performed using RNA from different human tissues. Quantitative transcription polymerase chain reaction (qRT-PCR) analysis of the GNB1 gene was performed in affected and healthy individuals. Bioinformatic analysis of the linkage regions including the candidate gene was performed. Results: Linkage analysis of the 1p36.33 CCV locus applying new marker systems obtained with Sanger and deep sequencing reduced the candidate locus from 2.1 Mb to 0.389 Mb flanked by the markers STS-22AC and rs549772338 and resulted in an logarithm of the odds (LOD) score of Z = 21.67. The identified mutation, rs763295804, affects the donor splice site in the long non-coding RNA gene RP1–140A9.1 (ENSG00000231050). The gene including splice-site junctions is conserved in primates but not in other mammalian genomes, and two alternative transcripts were shown with RT–PCR. One of these transcripts represented a lens cell–specific transcript. Meta-analysis of the Cross-Linking-Immuno-Precipitation sequencing (CLIP-Seq) data suggested the RNA binding protein (RBP) eIF4AIII is an active counterpart for RP1–140A9.1, and several miRNA and transcription factors binding sites were predicted in the proximity of the mutation. ENCODE DNase I hypersensitivity and histone methylation and acetylation data suggest the genomic region may have regulatory functions. Conclusions: The mutation in RP1–140A9.1 suggests the long non-coding RNA as the candidate cataract gene associated with the autosomal dominant inherited congenital cataract from CCV. The mutation has the potential to destroy exon/intron splicing of both transcripts of RP1–140A9.1. Sanger and massive deep resequencing of the linkage region failed to identify alternative candidates suggesting the mutation in RP1–140A9.1 is causative for the CCV phenotype.

Objectives: Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder resulting from deficient lysosomal alpha-mannosidase activity. Clinical manifestations include progressive balance disorders, immune deficiency, skeletal abnormalities and cognitive deficits beginning in early childhood. Enzyme replacement therapy with recombinant human alpha-mannosidase (velmanase alfa) is scheduled for clinical development in the US beginning in 2020 and has been approved in the EU for treatment of non-neurological manifestations in cases of mild to moderate disease. This study assessed effects of velmanase alfa on fine and gross motor proficiency in children and adults. Methods: Integrated Bruininks-Oseretsky (BOT-2) test of Motor Proficiency data from velmanase alfa clinical trials was stratified by age for 14 adults and 19 children treated for up to 4 years. Results: Patients showed global developmental delays at baseline. For the combined adult and pediatric group there was a statistically significant increase (improvement) in BOT-2 total point score of 13% (p = .035, 95% CI 1.0, 25.0) from baseline to last observation. When stratified by pediatric versus adult patients, there was improvement in BOT-2 total point score in patients

This paper describes dog owner and veterinarian perceptions around the use of a validated canine quality of life (QOL) survey to facilitate wellness conversations in two clinical settings: a veterinary teaching hospital (pilot, Phase 1) and five corporate general practice hospitals (Phase 2). Phase 1 results showed that dog owners felt the survey was valuable for understanding their dog's QOL, with 81% of owners expressing interest in learning more about canine QOL. Phase 2 reinforced owner perceptions about the survey conveyed during the pilot phase, and veterinarians reported that the survey facilitated client communication related to preventive care without increasing consultation time. These results demonstrate that beyond using QOL assessments to track patient health, the use of a QOL survey during veterinary visits could improve owner-veterinarian discussions around QOL, wellness, services and preventive care. To fully realize these benefits in clinical settings, veterinary staff preparation may be needed to communicate the purpose of QOL assessments to clients and thus facilitate deeper conversations about client needs and concerns. Key tools for achieving these could therefore include (1) sufficient veterinary team training to understand the QOL assessment and its purpose (2) training in how to communicate QOL to clients, and (3) reflexive use of QOL assessment results to engage clients in preventive care discussions. The veterinarian and client can then discuss the pros and cons of the various aspects of QOL and preventive care to arrive at a cooperative decision.

Surface–atmosphere energy exchange is strongly ecosystem-specific. At the same time, as the energy balance constitutes responses of an ecosystem to environmental stressors including precipitation, humidity and solar radiation, it results in feedbacks of potential importance for the regional climate. Northern peatlands represent a diverse class of ecosystems that cover nearly 6 × 106 km2 in the Boreal region, which makes the inter-comparison of their energy balances an important objective. With this in mind we studied energy exchange across a broad spectrum of peatlands from pristine fens and bogs to forested and agriculturally managed peatlands, which represent a large fraction of the landscape in Finland and Sweden. The effects of management activities on the energy balance were extensively examined from the micrometeorological point of view, using eddy covariance data from eight sites in these two countries (56º 12'–62º 11' N, 13º 03'–30º 05' E). It appears that the surface energy balance varies widely amongst the different peatland types. Generally, energy exchange features including the Bowen ratio, surface conductance, coupling to the atmosphere, responses to water table fluctuations and vapour pressure deficit could be associated directly with the peatland type. The relative constancy of the Bowen ratio in natural open mires contrasted with its variation in tree-covered and agricultural peatlands. We conclude that the impacts of management and the consequences of land-use change in peatlands for the local and regional climate might be substantial.

This study quantifies future changes in tropospheric ozone (O3) using a simple parameterisation of source–receptor relationships based on simulations from a range of models participating in the Task Force on Hemispheric Transport of Air Pollutants (TF-HTAP) experiments. Surface and tropospheric O3 changes are calculated globally and across 16 regions from perturbations in precursor emissions (NOx, CO, volatile organic compounds – VOCs) and methane (CH4) abundance only, neglecting any impact from climate change. A source attribution is provided for each source region along with an estimate of uncertainty based on the spread of the results from the models. Tests against model simulations using the Hadley Centre Global Environment Model version 2 – Earth system configuration (HadGEM2-ES) confirm that the approaches used within the parameterisation perform well for most regions. The O3 response to changes in CH4 abundance is slightly larger in the TF-HTAP Phase 2 than in the TF-HTAP Phase 1 assessment (2010) and provides further evidence that controlling CH4 is important for limiting future O3 concentrations. Different treatments of chemistry and meteorology in models remain one of the largest uncertainties in calculating the O3 response to perturbations in CH4 abundance and precursor emissions, particularly over the Middle East and south Asia regions. Emission changes for the future Evaluating the CLimate and Air Quality ImPacts of Short-livEd Pollutants (ECLIPSE) scenarios and a subset of preliminary Shared Socioeconomic Pathways (SSPs) indicate that surface O3 concentrations will increase regionally by 1 to 8 ppbv in 2050. Source attribution analysis highlights the growing importance of CH4 in the future under current legislation. A change in the global tropospheric O3 radiative forcing of +0.07 W m−2 from 2010 to 2050 is predicted using the ECLIPSE scenarios and SSPs, based solely on changes in CH4 abundance and tropospheric O3 precursor emissions and neglecting any influence of climate change. Current legislation is shown to be inadequate in limiting the future degradation of surface ozone air quality and enhancement of near-term climate warming. More stringent future emission controls provide a large reduction in both surface O3 concentrations and O3 radiative forcing. The parameterisation provides a simple tool to highlight the different impacts and associated uncertainties of local and hemispheric emission control strategies on both surface air quality and the near-term climate forcing by tropospheric O3.

Peatlands store substantial amounts of carbon and are vulnerable to climate change. We present a modified version of the Organising Carbon and Hydrology In Dynamic Ecosystems (ORCHIDEE) land surface model for simulating the hydrology, surface energy, and CO2 fluxes of peatlands on daily to annual timescales. The model includes a separate soil tile in each 0.5° grid cell, defined from a global peatland map and identified with peat-specific soil hydraulic properties. Runoff from non-peat vegetation within a grid cell containing a fraction of peat is routed to this peat soil tile, which maintains shallow water tables. The water table position separates oxic from anoxic decomposition. The model was evaluated against eddy-covariance (EC) observations from 30 northern peatland sites, with the maximum rate of carboxylation (Vcmax) being optimized at each site. Regarding short-term day-to-day variations, the model performance was good for gross primary production (GPP) (r2 = 0.76; Nash–Sutcliffe modeling efficiency, MEF = 0.76) and ecosystem respiration (ER, r2 = 0.78, MEF = 0.75), with lesser accuracy for latent heat fluxes (LE, r2 = 0.42, MEF = 0.14) and and net ecosystem CO2 exchange (NEE, r2 = 0.38, MEF = 0.26). Seasonal variations in GPP, ER, NEE, and energy fluxes on monthly scales showed moderate to high r2 values (0.57–0.86). For spatial across-site gradients of annual mean GPP, ER, NEE, and LE, r2 values of 0.93, 0.89, 0.27, and 0.71 were achieved, respectively. Water table (WT) variation was not well predicted (r2 Vcmax and latitude (temperature), which better reflects the spatial gradients of annual NEE than using an average Vcmax value.

It is important that climate models can accurately simulate the terrestrial carbon cycle in the Arctic due to the large and potentially labile carbon stocks found in permafrost-affected environments, which can lead to a positive climate feedback, along with the possibility of future carbon sinks from northward expansion of vegetation under climate warming. Here we evaluate the simulation of tundra carbon stocks and fluxes in three land surface schemes that each form part of major Earth system models (JSBACH, Germany; JULES, UK; ORCHIDEE, France). We use a site-level approach in which comprehensive, high-frequency datasets allow us to disentangle the importance of different processes. The models have improved physical permafrost processes and there is a reasonable correspondence between the simulated and measured physical variables, including soil temperature, soil moisture and snow. We show that if the models simulate the correct leaf area index (LAI), the standard C3 photosynthesis schemes produce the correct order of magnitude of carbon fluxes. Therefore, simulating the correct LAI is one of the first priorities. LAI depends quite strongly on climatic variables alone, as we see by the fact that the dynamic vegetation model can simulate most of the differences in LAI between sites, based almost entirely on climate inputs. However, we also identify an influence from nutrient limitation as the LAI becomes too large at some of the more nutrient-limited sites. We conclude that including moss as well as vascular plants is of primary importance to the carbon budget, as moss contributes a large fraction to the seasonal CO2 flux in nutrient-limited conditions. Moss photosynthetic activity can be strongly influenced by the moisture content of moss, and the carbon uptake can be significantly different from vascular plants with a similar LAI. The soil carbon stocks depend strongly on the rate of input of carbon from the vegetation to the soil, and our analysis suggests that an improved simulation of photosynthesis would also lead to an improved simulation of soil carbon stocks. However, the stocks are also influenced by soil carbon burial (e.g. through cryoturbation) and the rate of heterotrophic respiration, which depends on the soil physical state. More detailed below-ground measurements are needed to fully evaluate biological and physical soil processes. Furthermore, even if these processes are well modelled, the soil carbon profiles cannot resemble peat layers as peat accumulation processes are not represented in the models. Thus, we identify three priority areas for model development: (1) dynamic vegetation including (a) climate and (b) nutrient limitation effects; (2) adding moss as a plant functional type; and an (3) improved vertical profile of soil carbon including peat processes.

The Collaborative Cross (CC) is a panel of reproducible recombinant inbred mouse strains with high levels of standing genetic variation, affording an unprecedented opportunity to perform experiments in a small animal model containing controlled genetic diversity while allowing for genetic replicates. Here, we advance the utility of this unique mouse resource for immunology research because it allows for both examination and genetic dissection of mechanisms behind adaptive immune states in mice with distinct and defined genetic makeups. This approach is based on quantitative trait locus mapping: identifying genetically variant genome regions associated with phenotypic variance in traits of interest. Furthermore, the CC can be utilized for mouse model development; distinct strains have unique immunophenotypes and immune properties, making them suitable for research on particular diseases and infections. Here, we describe variations in cellular immune phenotypes across F1 crosses of CC strains and reveal quantitative trait loci responsible for several immune phenotypes.

An improvement in our process-based understanding of carbon (C) exchange in the Arctic and its climate sensitivity is critically needed for understanding the response of tundra ecosystems to a changing climate. In this context, we analysed the net ecosystem exchange (NEE) of CO2 in West Greenland tundra (64° N) across eight snow-free periods in 8 consecutive years, and characterized the key processes of net ecosystem exchange and its two main modulating components: gross primary production (GPP) and ecosystem respiration (Reco). Overall, the ecosystem acted as a consistent sink of CO2, accumulating −30 g C m−2 on average (range of −17 to −41 g C m−2) during the years 2008–2015, except 2011 (source of 41 g C m−2), which was associated with a major pest outbreak. The results do not reveal a marked meteorological effect on the net CO2 uptake despite the high interannual variability in the timing of snowmelt and the start and duration of the growing season. The ranges in annual GPP (−182 to −316 g C m−2) and Reco (144 to 279 g C m−2) were > 5 fold larger than the range in NEE. Gross fluxes were also more variable (coefficients of variation are 3.6 and 4.1 % respectively) than for NEE (0.7 %). GPP and Reco were sensitive to insolation and temperature, and there was a tendency towards larger GPP and Reco during warmer and wetter years. The relative lack of sensitivity of NEE to meteorology was a result of the correlated response of GPP and Reco. During the snow-free season of the anomalous year of 2011, a biological disturbance related to a larvae outbreak reduced GPP more strongly than Reco. With continued warming temperatures and longer growing seasons, tundra systems will increase rates of C cycling. However, shifts in sink strength will likely be triggered by factors such as biological disturbances, events that will challenge our forecasting of C states.

Abstract Background Better surgical techniques, chemotherapy and biological therapy have improved survival in patients with colorectal cancer (CRC), most markedly in younger patients. About half of patients over 70 years receive dose reductions or early treatment discontinuation of the planned adjuvant or first-line treatment due to side effects. The Comprehensive Geriatric Assessment (CGA) is a multidisciplinary evaluation of an elderly individual’s health status. This assessment in older patients with cancer can predict survival, chemotherapy toxicity and morbidity. Methods This randomized phase II trial (GERICO) is designed to investigate whether comprehensive geriatric assessment and intervention before and during treatment with chemotherapy in frail elderly patients with stages II–IV CRC will increase the number of patients completing chemotherapy. All patients ≥70 years in whom chemotherapy for CRC is planned to start at Herlev and Gentofte Hospital are screened for frailty using the G8 questionnaire at the first visit to the outpatient clinic. The G8 questionnaire is a multi-domain screening tool to identify frail or vulnerable patients at risk of increased toxicity and morbidity. Frail patients are offered inclusion and are then randomized to two groups (the intervention group and the control group). Patients in the intervention group receive a full geriatric assessment of comorbidity, medication, psycho-cognitive function, physical, functional and nutrition status, and interventions are undertaken on identified health issues. Simultaneously, they are treated for their cancer according to international guidelines. Patients in the control group receive the same chemotherapy regimens and standard of care. Primary outcome is number of patients completing scheduled chemotherapy at starting dose. Secondary outcomes are dose reductions, treatment delays, toxicity, time to recurrence, survival, cancer-related mortality and quality of life. Discussion This ongoing trial is one of the first to evaluate the effect of geriatric intervention in frail elderly patients with CRC. The trial will provide new and valuable knowledge about whether it is beneficial for the elderly patient undergoing chemotherapy to be treated simultaneously by a geriatrician. Trial registration ClinicalTrials.gov ID: NCT02748811 . The trial was registered retrospectively; registration date 04/28/2016.

Summary: Arenaviruses can cause severe hemorrhagic disease in humans, which can progress to organ failure and death. The underlying mechanisms causing lethality and person-to-person variation in outcome remain incompletely explained. Herein, we characterize a mouse model that recapitulates many features of pathogenesis observed in humans with arenavirus-induced hemorrhagic disease, including thrombocytopenia, severe vascular leakage, lung edema, and lethality. The susceptibility of congenic B6.PL mice to lymphocytic choriomeningitis virus (LCMV) infection is associated with increased antiviral T cell responses in B6.PL mice compared with C57BL/6 mice and is T cell dependent. Pathogenesis imparted by the causative locus is inherited in a semi-dominant manner in F1 crosses. The locus includes PL-derived sequence variants in both poorly annotated genes and genes known to contribute to immune responses. This model can be used to further interrogate how limited genetic differences in the host can remarkably alter the disease course of viral infection. : Arenaviruses can cause devastating illness, including severe systemic hemorrhaging and death in humans. Misumi et al. characterize a mouse model that recapitulates many features of pathogenesis observed in humans and identify a genetic locus that regulates T cell responses, platelet frequencies, and pathogenesis during arenavirus infection. Keywords: viral hemorrhagic disease, viral pathogenesis, arenavirus, LCMV, mouse genetics, forward genetic mapping, CD8+ T cells, thrombocytopenia

Background: Understanding the pathogenic role of extracellular vesicles (EVs) in disease and their potential diagnostic and therapeutic utility is extremely reliant on in-depth quantification, measurement and identification of EV sub-populations. Quantification of EVs has presented several challenges, predominantly due to the small size of vesicles such as exosomes and the availability of various technologies to measure nanosized particles, each technology having its own limitations. Materials and Methods: A standardized methodology to measure the concentration of extracellular vesicles (EVs) has been developed and tested. The method is based on measuring the EV concentration as a function of a defined size range. Blood plasma EVs are isolated and purified using size exclusion columns (qEV) and consecutively measured with tunable resistive pulse sensing (TRPS). Six independent research groups measured liposome and EV samples with the aim to evaluate the developed methodology. Each group measured identical samples using up to 5 nanopores with 3 repeat measurements per pore. Descriptive statistics and unsupervised multivariate data analysis with principal component analysis (PCA) were used to evaluate reproducibility across the groups and to explore and visualise possible patterns and outliers in EV and liposome data sets. Results: PCA revealed good reproducibility within and between laboratories, with few minor outlying samples. Measured mean liposome (not filtered with qEV) and EV (filtered with qEV) concentrations had coefficients of variance of 23.9% and 52.5%, respectively. The increased variance of the EV concentration measurements could be attributed to the use of qEVs and the polydisperse nature of EVs. Conclusion: The results of this study demonstrate the feasibility of this standardized methodology to facilitate comparable and reproducible EV concentration measurements.

Snow cover is one of the key factors controlling Arctic ecosystem functioning and productivity. In this study we assess the impact of strong variability in snow accumulation during 2 subsequent years (2013–2014) on the land–atmosphere interactions and surface energy exchange in two high-Arctic tundra ecosystems (wet fen and dry heath) in Zackenberg, Northeast Greenland. We observed that record-low snow cover during the winter 2012/2013 resulted in a strong response of the heath ecosystem towards low evaporative capacity and substantial surface heat loss by sensible heat fluxes (H) during the subsequent snowmelt period and growing season. Above-average snow accumulation during the winter 2013/2014 promoted summertime ground heat fluxes (G) and latent heat fluxes (LE) at the cost of H. At the fen ecosystem a more muted response of LE, H and G was observed in response to the variability in snow accumulation. Overall, the differences in flux partitioning and in the length of the snowmelt periods and growing seasons during the 2 years had a strong impact on the total accumulation of the surface energy balance components. We suggest that in a changing climate with higher temperature and more precipitation the surface energy balance of this high-Arctic tundra ecosystem may experience a further increase in the variability of energy accumulation, partitioning and redistribution.

The closed chamber technique is widely used to measure the exchange of methane (CH4) and carbon dioxide (CO2) from terrestrial ecosystems. There is, however, large uncertainty about which model should be used to calculate the gas flux from the measured gas concentrations. Due to experimental uncertainties the simple linear regression model (first-order polynomial) is often applied, even though theoretical considerations of the technique suggest the application of other, curvilinear models. High-resolution automatic chamber systems which sample gas concentrations several hundred times per flux measurement make it possible to resolve the curvilinear behavior and study the information imposed by the natural variability of the temporal concentration changes. We used more than 50 000 such flux measurements of CH4 and CO2 from five field sites located in peat-forming wetlands ranging from 56 to 78° N to quantify the typical differences between flux estimates of different models. In addition, we aimed to assess the curvilinearity of the concentration time series and test the general applicability of curvilinear models. Despite significant episodic differences between the calculated flux estimates, the overall differences are generally found to be smaller than the local flux variability on the plot scale. The curvilinear behavior of the gas concentrations within the chamber is strongly influenced by wind-driven chamber leakage, and less so by changing gas concentration gradients in the soil during chamber closure. Such physical processes affect both gas species equally, which makes it possible to isolate biochemical processes affecting the gases differently, such as photosynthesis limitation by chamber headspace CO2 concentrations under high levels of incoming solar radiation. We assess the possibility to exploit this effect for a partitioning of the net CO2 flux into photosynthesis and ecosystem respiration as an example of how high-resolution automatic chamber measurements could be used for purposes beyond the estimation of the net gas flux. This shows that while linear and curvilinear calculation schemes can provide similar net fluxes, only curvilinear models open additional possibilities for high-resolution automatic chamber measurements.