Summary Cryptosporidium spp are well recognised as causes of diarrhoeal disease during waterborne epidemics and in immunocompromised hosts. Studies have also drawn attention to an underestimated ...global burden and suggest major gaps in optimum diagnosis, treatment, and immunisation. Cryptosporidiosis is increasingly identified as an important cause of morbidity and mortality worldwide. Studies in low-resource settings and high-income countries have confirmed the importance of cryptosporidium as a cause of diarrhoea and childhood malnutrition. Diagnostic tests for cryptosporidium infection are suboptimum, necessitating specialised tests that are often insensitive. Antigen-detection and PCR improve sensitivity, and multiplexed antigen detection and molecular assays are underused. Therapy has some effect in healthy hosts and no proven efficacy in patients with AIDS. Use of cryptosporidium genomes has helped to identify promising therapeutic targets, and drugs are in development, but methods to assess the efficacy in vitro and in animals are not well standardised. Partial immunity after exposure suggests the potential for successful vaccines, and several are in development; however, surrogates of protection are not well defined. Improved methods for propagation and genetic manipulation of the organism would be significant advances.
► We reviewed 221 papers that used crop models to assess impacts of climate change. ► Crops most frequently assessed were wheat, maize, soybean and rice. ► Models predominantly used radiation use ...efficiency-based approaches. ► Assumed low baseline CO
2 may exaggerate projected impacts of increased CO
2. ► Coordinated data resources and model intercomparisons may enhance impact studies.
Ecophysiological models are widely used to forecast potential impacts of climate change on future agricultural productivity and to examine options for adaptation by local stakeholders and policy makers. However, protocols followed in such assessments vary to such an extent that they constrain cross-study syntheses and increase the potential for bias in projected impacts. We reviewed 221 peer-reviewed papers that used crop simulation models to examine diverse aspects of how climate change might affect agricultural systems. Six subject areas were examined: target crops and regions; the crop model(s) used and their characteristics; sources and application of data on CO
2 and climate; impact parameters evaluated; assessment of variability or risk; and adaptation strategies. Wheat, maize, soybean and rice were considered in approximately 170 papers. The USA (55 papers) and Europe (64 papers) were the dominant regions studied. The most frequent approach used to simulate response to CO
2 involved adjusting daily radiation use efficiency (RUE) and transpiration, precluding consideration of the interacting effects of CO
2, stomatal conductance and canopy temperature, which are expected to exacerbate effects of global warming. The assumed baseline CO
2 typically corresponded to conditions 10–30 years earlier than the date the paper was accepted, exaggerating the relative impacts of increased CO
2. Due in part to the diverse scenarios for increases in greenhouse gas emissions, assumed future CO
2 also varied greatly, further complicating comparisons among studies. Papers considering adaptation predominantly examined changes in planting dates and cultivars; only 20 papers tested different tillage practices or crop rotations. Risk was quantified in over half the papers, mainly in relation to variability in yield or effects of water deficits, but the limited consideration of other factors affecting risk beside climate change per se suggests that impacts of climate change were overestimated relative to background variability. A coordinated crop, climate and soil data resource would allow researchers to focus on underlying science. More extensive model intercomparison, facilitated by modular software, should strengthen the biological realism of predictions and clarify the limits of our ability to forecast agricultural impacts of climate change on crop production and associated food security as well as to evaluate potential for adaptation.
FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and ...resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.
The prevalence of peripheral artery disease (PAD) continues to increase worldwide. It is important to identify patients with PAD because of the increased risk of myocardial infarction, stroke, and ...cardiovascular death and impaired quality of life because of a profound limitation in exercise performance and the potential to develop critical limb ischemia. Despite effective therapies to lower the cardiovascular risk and prevent progression to critical limb ischemia, patients with PAD continue to be under-recognized and undertreated. The management of PAD patients should include an exercise program, guideline-based medical therapy to lower the cardiovascular risk, and, when revascularization is indicated, an "endovascular first" approach. The indications and strategic choices for endovascular revascularization will vary depending on the clinical severity of the PAD and the anatomic distribution of the disease. In this review, we discuss an evidence-based approach to the management of patients with PAD.
► Identifying genetic markers for yield requires rapid quantification of crop traits. ► Proximal sensing offers promise for field-based phenotyping (FBP). ► Efficient data integration and ...modeling-assisted analysis are key for FBP. ► FBP scaled to thousands of field plots is a feasible, attainable goal. ► FBP systems require new, integrative collaborations that cross disciplines.
A major challenge for crop research in the 21st century is how to predict crop performance as a function of genetic architecture. Advances in “next generation” DNA sequencing have greatly improved genotyping efficiency and reduced genotyping costs. Methods for characterizing plant traits (phenotypes), however, have much progressed more slowly over the past 30 years, and constraints in phenotyping capability limit our ability to dissect the genetics of quantitative traits, especially those related to harvestable yield and stress tolerance. As a case in point, mapping populations for major crops may consist of 20 or more families, each represented by as many as 200 lines, necessitating field trials with over 20,000 plots at a single location. Investing in the resources and labor needed to quantify even a few agronomic traits for linkage with genetic markers in such massive populations is currently impractical for most breeding programs. Herein, we define key criteria, experimental approaches, equipment and data analysis tools required for robust, high-throughput field-based phenotyping (FBP). The focus is on simultaneous proximal sensing for spectral reflectance, canopy temperature, and plant architecture where a vehicle carrying replicated sets of sensors records data on multiple plots, with the potential to record data throughout the crop life cycle. The potential to assess traits, such as adaptations to water deficits or acute heat stress, several times during a single diurnal cycle is especially valuable for quantifying stress recovery. Simulation modeling and related tools can help estimate physiological traits such as canopy conductance and rooting capacity. Many of the underlying techniques and requisite instruments are available and in use for precision crop management. Further innovations are required to better integrate the functions of multiple instruments and to ensure efficient, robust analysis of the large volumes of data that are anticipated. A complement to the core proximal sensing is high-throughput phenotyping of specific traits such as nutrient status, seed composition, and other biochemical characteristics, as well as underground root architecture. The ability to “ground truth” results with conventional measurements is also necessary. The development of new sensors and imaging systems undoubtedly will continue to improve our ability to phenotype very large experiments or breeding nurseries, with the core FBP abilities achievable through strong interdisciplinary efforts that assemble and adapt existing technologies in novel ways.
The introduction of two new non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the past 5 years and the identification of novel NNRTI-associated mutations have made it necessary to reassess ...the extent of phenotypic NNRTI cross-resistance.
We analysed a dataset containing 1975, 1967, 519 and 187 genotype-phenotype correlations for nevirapine, efavirenz, etravirine and rilpivirine, respectively. We used linear regression to estimate the effects of RT mutations on susceptibility to each of these NNRTIs.
Sixteen mutations at 10 positions were significantly associated with the greatest contribution to reduced phenotypic susceptibility (≥10-fold) to one or more NNRTIs, including: 14 mutations at six positions for nevirapine (K101P, K103N/S, V106A/M, Y181C/I/V, Y188C/L and G190A/E/Q/S); 10 mutations at six positions for efavirenz (L100I, K101P, K103N, V106M, Y188C/L and G190A/E/Q/S); 5 mutations at four positions for etravirine (K101P, Y181I/V, G190E and F227C); and 6 mutations at five positions for rilpivirine (L100I, K101P, Y181I/V, G190E and F227C). G190E, a mutation that causes high-level nevirapine and efavirenz resistance, also markedly reduced susceptibility to etravirine and rilpivirine. K101H, E138G, V179F and M230L mutations, associated with reduced susceptibility to etravirine and rilpivirine, were also associated with reduced susceptibility to nevirapine and/or efavirenz.
The identification of novel cross-resistance patterns among approved NNRTIs illustrates the need for a systematic approach for testing novel NNRTIs against clinical virus isolates with major NNRTI-resistance mutations and for testing older NNRTIs against virus isolates with mutations identified during the evaluation of a novel NNRTI.
High-throughput phenotyping platforms (HTPPs) provide novel opportunities to more effectively dissect the genetic basis of drought-adaptive traits. This genome-wide association study (GWAS) compares ...the results obtained with two Unmanned Aerial Vehicles (UAVs) and a ground-based platform used to measure Normalized Difference Vegetation Index (NDVI) in a panel of 248 elite durum wheat (
L. ssp
Desf.) accessions at different growth stages and water regimes. Our results suggest increased ability of aerial over ground-based platforms to detect quantitative trait loci (QTL) for NDVI, particularly under terminal drought stress, with 22 and 16 single QTLs detected, respectively, and accounting for 89.6 vs. 64.7% phenotypic variance based on multiple QTL models. Additionally, the durum panel was investigated for leaf chlorophyll content (SPAD), leaf rolling and dry biomass under terminal drought stress. In total, 46 significant QTLs affected NDVI across platforms, 22 of which showed concomitant effects on leaf greenness, 2 on leaf rolling and 10 on biomass. Among 9 QTL hotspots on chromosomes 1A, 1B, 2B, 4B, 5B, 6B, and 7B that influenced NDVI and other drought-adaptive traits, 8 showed
effects unrelated to phenology.
The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of ...pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.
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