Using Overlapping Communities and Network Structure for Identifying Reduced Groups of Stress Responsive Genes

This paper proposes a workflow to identify genes responding to a specific treatment in an organism, such as abiotic stresses, a main cause of extensive agricultural production losses worldwide. On input RNA sequencing read counts (measured for genotypes under control and treatment conditions) and biological replicates, it outputs a collection of characterized genes, potentially relevant to treatment. Technically, the proposed approach is both a generalization and an extension of WGCNA; its main goal is to identify specific modules in a network of genes after a sequence of normalization and filtering steps. In this work, module detection is achieved by using Hierarchical Link Clustering, which can recognize overlapping communities and thus have more biological meaning given the overlapping regulatory domains of systems that generate co-expression. Additional steps and information are also added to the workflow, where some networks in the intermediate steps are forced to be scale-free and LASSO regression is employed to select the most significant modules of phenotypical responses to stress. Finally, the workflow is showcased with a systematic study on rice (Oryza sativa), a major food source that is known to be highly sensitive to salt stress: a total of 6 modules are detected as relevant in the response to salt stress in rice; these genes may act as potential targets for the improvement of salinity tolerance in rice cultivars. The proposed workflow has the potential to ultimately reduce the search-space for candidate genes responding to a specific treatment, which can considerably optimize the effort, time, and money invested by researchers in the experimental validation of stress responsive genes

Optimal Distribution of Heterogeneous Agents under Delays

Abstract-An analytical framework for the study of a generic distribution problem is introduced in which a group of agents with different capabilities intend to maximize total utility by dividing themselves into various subgroups without any form of global information-sharing or centralized decision-making. The marginal utility of belonging to a particular subgroup rests on the well-known concept in economic theory of the law of diminishing returns. For a class of discrete event systems, we identify a set of conditions that define local information and cooperation requirements, and prove that if the proposed conditions are satisfied a stable agent distribution representing a Pareto optimum is achieved even under random but bounded decision and transition delays

Methylation in the CHH context allows to predict recombination in rice

DNA methylation is the most studied epigenetic trait. It is considered a key factor in regulating plant development and physiology, and has been associated with the regulation of several genomic features, including transposon silencing, regulation of gene expression, and recombination rates. Nonetheless, understanding the relation between DNA methylation and recombination rates remains a challenge. This work explores the association between recombination rates and DNA methylation for two commercial rice varieties. The results show negative correlations between recombination rates and methylated cytosine counts for all contexts tested at the same time, and for CG and CHG contexts independently. In contrast, a positive correlation between recombination rates and methylated cytosine count is reported in CHH contexts. Similar behavior is observed when considering only methylated cytosines within genes, transposons, and retrotransposons. Moreover, it is shown that the centromere region strongly affects the relationship between recombination rates and methylation. Finally, machine learning regression models are applied to predict recombination using the count of methylated cytosines in the CHH context as the entrance feature. These findings shed light on the understanding of the recombination landscape of rice and represent a reference framework for future studies in rice breeding, genetics, and epigenetics

Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT - A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party

Elevated serum ferritin levels occur due to iron overload or during inflammation and macrophage activation. A correlation of high serum ferritin levels with increased mortality after alloSCT has been suggested by several retrospective analyses as well as by two smaller prospective studies. This prospective multicentric study aimed to study the association of ferritin serum levels before start of conditioning with alloSCT outcome. Patients with acute leukemia, lymphoma or MDS receiving a matched sibling alloSCT for the first time were considered for inclusion, regardless of conditioning. A comparison of outcomes between patients with high and low ferritin level was performed using univariate analysis and multivariate analysis using cause-specific Cox model. Twenty centers reported data on 298 alloSCT recipients. The ferritin cut off point was determined at 1500 mu g/l (median of measured ferritin levels). In alloSCT recipients with ferritin levels above cut off measured before the start of conditioning, overall survival (HR = 2.5, CI = 1.5-4.1, p = 0.0005) and progression-free survival (HR = 2.4, CI = 1.6-3.8, p <0.0001) were inferior. Excess mortality in the high ferritin group was due to both higher relapse incidence (HR = 2.2, CI = 1.2-3.8, p = 0.007) and increased non-relapse mortality (NRM) (HR = 3.1, CI = 1.5-6.4, p = 0.002). NRM was driven by significantly higher infection-related mortality in the high ferritin group (HR = 3.9, CI = 1.6-9.7, p = 0.003). Acute and chronic GVHD incidence or severity were not associated to serum ferritin levels. We conclude that ferritin levels can serve as routine laboratory biomarker for mortality risk assessment before alloSCT.Peer reviewe

Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission : final results of quality of life and long-term outcome analysis of a phase 3 randomised study

Background We previously showed that human anti-T-lymphocyte globulin (ATLG) plus ciclosporin and methotrexate given to patients with acute leukaemia in remission, having allogeneic haemopoietic stem-cell transplantation with peripheral blood stem cells from an HLA-identical sibling donor after myeloablative conditioning, significantly reduced 2-year chronic graft-versus-host disease (cGVHD) incidence and severity, without increasing disease relapse and infections, and improves cGVHD-free and relapse-free survival (cGRFS). The aim of an extended follow-up study was the assessment of long-term outcomes, which are, in this context, scarcely reported in the literature. We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension. Methods In the original open-label study, patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, having sibling HLA-identical allogeneic peripheral blood stem-cell transplantation, were randomly assigned (1:1) to receive ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG group) or standard GVHD prophylaxis without ATLG (non-ATLG group). Conditioning regimens were cyclophosphamide 120 mg/kg with either total body irradiation (12 Gy) or busulfan (12 . 8 mg/kg intravenously or 16 mg/kg orally), with or without etoposide (30-60 mg/kg). Randomisation was stratified according to centre and disease risk. The primary endpoint was cumulative incidence of cGVHD at 2 years. The primary and secondary endpoints, excluding QoL, have been published. QoL, assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-HDC29 questionnaires, was an unpublished secondary endpoint, which we now report here. A follow-up extension was then done, with the primary endpoint cumulative incidence of cGVHD. Enrolment has been completed for both studies. Findings In the original study, from Dec 14, 2006, to Feb 2, 2012, 161 patients were enrolled and 155 were randomly assigned to either the ATLG group (n=83) or to the non-ATLG group (n=72). In the follow-up study, which started on Feb 7, 2017, and was completed on June 30, 2017, 61 patients were included in the ATLG group and 53 were included in the non-ATLG group. Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group (p=0 . 02; treatment by visit interaction). ATLG was descriptively superior to non-ATLG at 24 months for physical function (points estimate -14.8 [95% CI -26.4 to-3.1]; p= 0.014) and social function (-19.1 [-38.0 to -0.2]; p=0.047), gastrointestinal side-effects (8 . 8 [2.5-15.1]; p=0 . 008) and effect on family (13.5 [1.2-25.8]; p=0.032). Extended follow-up (median 5 . 9 years [IQR 1.7-7.9]) confirmed a lower 5-year cGVHD incidence (30.0% [95% CI 21.4-41.9] vs 69.1% [59.1-80.1]; analysis for entire follow-up, p Interpretation The addition of ATLG to standard GVHD prophylaxis improves the probability of surviving without disease relapse and cGVHD after myeloablative peripheral blood stem-cell transplantation from an HLA-identical sibling donor for patients with acute leukaemia in remission. Further additional benefits are better QoL and shorter immunosuppressive treatment compared with standard GVHD prophylaxis without ATLG. Therefore, in this setting, ATLG plus standard GVHD prophylaxis should be preferred over the standard GVHD prophylaxis alone. Copyright (C) 2019 Elsevier Ltd. All rights reserved.Peer reviewe

Validation of the revised IPSS at transplant in patients with myelodysplastic syndrome/transformed acute myelogenous leukemia receiving allogeneic stem cell transplantation

The International Prognostic Scoring System has been revised (IPSS-R) to predict prognosis of patients with myelodysplastic syndromes at diagnosis. To validate the use of the IPSS-R assesse