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At least 10 Dm genes conferring resistance to the oomycete downy mildew fungus Bremia lactucae map to the major resistance cluster in lettuce. We investigated the structure of this cluster in the lettuce cultivar Diana, which contains Dm3. A deletion breakpoint map of the chromosomal region flanking Dm3 was saturated with a variety of molecular markers. Several of these markers are components of a family of resistance gene candidates (RGC2) that encode a nucleotide binding site and a leucine-rich repeat region. These motifs are characteristic of plant disease resistance genes. Bacterial artificial chromosome clones were identified by using duplicated restriction fragment length polymorphism markers from the region, including the nucleotide binding site-encoding region of RGC2. Twenty-two distinct members of the RGC2 family were characterized from the bacterial artificial chromosomes; at least two additional family members exist. The RGC2 family is highly divergent; the nucleotide identity was as low as 53% between the most distantly related copies. These RGC2 genes span at least 3.5 Mb. Eighteen members were mapped on the deletion breakpoint map. A comparison between the phylogenetic and physical relationships of these sequences demonstrated that closely related copies are physically separated from one another and indicated that complex rearrangements have shaped this region. Analysis of low-copy genomic sequences detected no genes, including RGC2, in the Dm3 region, other than sequences related to retrotransposons and transposable elements. The related but divergent family of RGC2 genes may act as a resource for the generation of new resistance phenotypes through infrequent recombination or unequal crossing over

In the present article, the rheological responses and dispersion stability of magnetorheological (MR) fluids were investigated experimentally. Suspensions of magnetite and carbonyl iron particles were prepared as model MR fluids. Under an external magnetic field (H0) and a steady shear flow, the yield stress depends upon H03/2. The Yield stress depended on the volume fraction of the particle (φ) linearly only at low concentration and increased faster at high fraction. Rheological behavior of MR fluids subjected to a small-strain oscillatory shear flow was investigated as a function of the strain amplitude, frequency, and the external magnetic field. In order to improve the stability of MR fluid, ferromagnetic Co-γ-Fe2O3 and CrO2 particles were added as the stabilizing and thickening agent in the carbonyl iron suspension. Such needle-like particles seem to play a role in the steric repulsion between the relatively large carbonyl iron particles, resulting in improved stability against rapid sedimentation of dense iron particles. Furthermore, the additive-containing MR suspensions exhibited larger yield stress, especially at higher magnetic field strength.

Electro-rheological suspensions (ERS) are known to undergo liquid-to-solid transition under the application of an electric field. Long-range interaction between neighboring particles results in sample-spanning particulate structures which behave as soft solids. Here, we studied the rheological expression of this field-induced transition which has many similarities with chemical gelation. This similarity shows in mechanical spectroscopy on a suspension of monodisperse silica in PDMS as model ERS. Upon application of the electric field, dynamic moduli G′, G′′ grow by orders of magnitude and evolve in a pattern which is otherwise typical for gelation of network polymers (random chemical or physical gelation). At the gel point, the slow dynamics is governed by power-law relaxation behavior (frequency-independent tan δ). A low field strength is sufficient to reach the gel point and, correspondingly, the percolating particle structure at the gel point is still very fragile. It can be broken by the imposition of low stress. For inducing a finite yield stress, the field strength needs to be increased further until the long-range electrostatic interaction generates string-like particle alignments which become clearly visible under the optical microscope. The onset of fragile connectivity was defined experimentally by the tan δ method. The ERS was probed dynamically at low frequencies where the transition is most pronounced, and also in steady shear where the rate of structure formation equals the rate of internal breaking.

One of the most pressing challenges facing food systems in Africa is ensuring availability of a healthy and sustainable diet to 2.4 billion people by 2050. The continent has struggled with development challenges, particularly chronic food insecurity and pervasive poverty. In Africa’s food systems, fish and other aquatic foods play a multifaceted role in generating income, and providing a critical source of essential micronutrients. To date, there are no estimates of investment and potential returns for domestic fish production in Africa. To contribute to policy debates about the future of fish in Africa, we applied the International Model for Policy Analysis of Agriculture Commodities and Trade (IMPACT) to explore two Pan-African scenarios for fish sector growth: a business-as-usual ( BAU ) scenario and a high-growth scenario for capture fisheries and aquaculture with accompanying strong gross domestic product growth ( HIGH ). Post-model analysis was used to estimate employment and aquaculture investment requirements for the sector in Africa. Africa’s fish sector is estimated to support 20.7 million jobs in 2030, and 21.6 million by 2050 under the BAU . Approximately 2.6 people will be employed indirectly along fisheries and aquaculture value chains for every person directly employed in the fish production stage. Under the HIGH scenario, total employment in Africa’s fish food system will reach 58.0 million jobs, representing 2.4% of total projected population in Africa by 2050. Aquaculture production value is estimated to achieve US $ 3.3 billion and US$20.4 billion per year under the BAU and HIGH scenarios by 2050, respectively. Farm-gate investment costs for the three key inputs (fish feeds, farm labor, and fish seed) to achieve the aquaculture volumes projected by 2050 are estimated at US $ 1.8 billion per year under the BAU and US$11.6 billion per year under the HIGH scenario. Sustained investments are critical to sustain capture fisheries and support aquaculture growth for food system transformation towards healthier diets.

Author guidelines for journals could help to promote transparency, openness, and reproducibility Transparency, openness, and reproducibility are readily recognized as vital features of science ( 1 , 2 ). When asked, most scientists embrace these features as disciplinary norms and values ( 3 ). Therefore, one might expect that these valued features would be routine in daily practice. Yet, a growing body of evidence suggests that this is not the case ( 4 – 6 ).

Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma. We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0–1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m2 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m2 for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT02569242, and follow-up for long-term outcomes is ongoing. Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10·5 months (IQR 4·5–19·0) in the nivolumab group and 8·0 months (4·6–15·2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17·6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10·9 months, 95% CI 9·2–13·3 vs 8·4 months, 7·2–9·9; hazard ratio for death 0·77, 95% CI 0·62–0·96; p=0·019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease). Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients. ONO Pharmaceutical Company and Bristol-Myers Squibb.

An increasing volume of prostate biopsies and a worldwide shortage of urological pathologists puts a strain on pathology departments. Additionally, the high intra-observer and inter-observer variability in grading can result in overtreatment and undertreatment of prostate cancer. To alleviate these problems, we aimed to develop an artificial intelligence (AI) system with clinically acceptable accuracy for prostate cancer detection, localisation, and Gleason grading. We digitised 6682 slides from needle core biopsies from 976 randomly selected participants aged 50–69 in the Swedish prospective and population-based STHLM3 diagnostic study done between May 28, 2012, and Dec 30, 2014 (ISRCTN84445406), and another 271 from 93 men from outside the study. The resulting images were used to train deep neural networks for assessment of prostate biopsies. The networks were evaluated by predicting the presence, extent, and Gleason grade of malignant tissue for an independent test dataset comprising 1631 biopsies from 246 men from STHLM3 and an external validation dataset of 330 biopsies from 73 men. We also evaluated grading performance on 87 biopsies individually graded by 23 experienced urological pathologists from the International Society of Urological Pathology. We assessed discriminatory performance by receiver operating characteristics and tumour extent predictions by correlating predicted cancer length against measurements by the reporting pathologist. We quantified the concordance between grades assigned by the AI system and the expert urological pathologists using Cohen's kappa. The AI achieved an area under the receiver operating characteristics curve of 0·997 (95% CI 0·994–0·999) for distinguishing between benign (n=910) and malignant (n=721) biopsy cores on the independent test dataset and 0·986 (0·972–0·996) on the external validation dataset (benign n=108, malignant n=222). The correlation between cancer length predicted by the AI and assigned by the reporting pathologist was 0·96 (95% CI 0·95–0·97) for the independent test dataset and 0·87 (0·84–0·90) for the external validation dataset. For assigning Gleason grades, the AI achieved a mean pairwise kappa of 0·62, which was within the range of the corresponding values for the expert pathologists (0·60–0·73). An AI system can be trained to detect and grade cancer in prostate needle biopsy samples at a ranking comparable to that of international experts in prostate pathology. Clinical application could reduce pathology workload by reducing the assessment of benign biopsies and by automating the task of measuring cancer length in positive biopsy cores. An AI system with expert-level grading performance might contribute a second opinion, aid in standardising grading, and provide pathology expertise in parts of the world where it does not exist. Swedish Research Council, Swedish Cancer Society, Swedish eScience Research Center, EIT Health.

A randomized trial evaluating spinal as compared with general anesthesia for hip-fracture surgery in adults 50 years of age or older did not show superiority of spinal anesthesia with respect to a composite of death or an inability to walk unassisted at 60 days. Postoperative delirium occurred in similar percentages of patients in the two groups.

Neuropsychiatric disorders are increasingly conceptualized as overlapping spectra sharing multi-level neurobiological alterations. However, whether transdiagnostic cortical alterations covary in a biologically meaningful way is currently unknown. Here, we studied co-alteration networks across six neurodevelopmental and psychiatric disorders, reflecting pathological structural covariance. In 12,024 patients and 18,969 controls from the ENIGMA consortium, we observed that co-alteration patterns followed normative connectome organization and were anchored to prefrontal and temporal disease epicenters. Manifold learning revealed frontal-to-temporal and sensory/limbic-to-occipitoparietal transdiagnostic gradients, differentiating shared illness effects on cortical thickness along these axes. The principal gradient aligned with a normative cortical thickness covariance gradient and established a transcriptomic link to cortico-cerebello-thalamic circuits. Moreover, transdiagnostic gradients segregated functional networks involved in basic sensory, attentional/perceptual, and domain-general cognitive processes, and distinguished between regional cytoarchitectonic profiles. Together, our findings indicate that shared illness effects occur in a synchronized fashion and along multiple levels of hierarchical cortical organization. Neuropsychiatric disorders may have shared features. Here the authors identified hubs of transdiagnostic co-alteration networks using meta-analytical maps of ENIGMA neuroimaging data for six neurodevelopmental and psychiatric disorders.

Background Recent evidence suggests that biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of chronic rhinosinusitis with nasal polyposis (CRSwNP). There remains a population in CRSwNP that despite medical therapy and endoscopic sinus surgery have persistent signs and symptoms of disease. Therefore, biologics, monoclonal antibody agents, could be beneficial therapeutic treatments for these patients. There have been eight randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL-5R, IL-33, and immunoglobulin (Ig)E. However, there are no formal recommendations for the optimal use of biologics in managing Chronic Rhinosinusitis (CRS) within the Canadian health care environment. Methods A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. 17 fellowship trained rhinologists across Canada evaluated the 28 original statements on a scale of 1–10 and provided comments. A rating within 1–3 indicated disagreement, 8–10 demonstrated agreement and 4–7 represented being neutral towards a statement. All ratings were quantitively reviewed by mean, median, mode, range and standard deviation. Consensus was defined by removing the highest and lowest of the scores and using the “3 point relaxed system”. Results After three rounds, a total of 11 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with CRS. Conclusion This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of patients with CRS, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years. Graphical abstract