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Rice (Oryza sativa) was domesticated around 10,000 years ago and has developed into a staple for half of humanity. The crop evolved and is currently grown in stably wet and intermittently dry agro-ecosystems, but patterns of adaptation to differences in water availability remain poorly understood. While previous field studies have evaluated plant developmental adaptations to water deficit, adaptive variation in functional and hydraulic components, particularly in relation to gene expression, has received less attention. Here, we take an evolutionary systems biology approach to characterize adaptive drought resistance traits across roots and shoots. We find that rice harbors heritable variation in molecular, physiological, and morphological traits that is linked to higher fitness under drought. We identify modules of co-expressed genes that are associated with adaptive drought avoidance and tolerance mechanisms. These expression modules showed evidence of polygenic adaptation in rice subgroups harboring accessions that evolved in drought-prone agro-ecosystems. Fitness-linked expression patterns allowed us to identify the drought-adaptive nature of optimizing photosynthesis and interactions with arbuscular mycorrhizal fungi. Taken together, our study provides an unprecedented, integrative view of rice adaptation to water-limited field conditions.

Development of normal blood cells is often suppressed in juvenile myelomonocytic leukemia (JMML), a myeloproliferative neoplasm (MPN) of childhood, causing complications and impacting therapeutic outcomes. However, the mechanism underlying this phenomenon remains uncharacterized. To address this question, we induced the most common mutation identified in JMML (Ptpn11E76K) specifically in the myeloid lineage with hematopoietic stem cells (HSCs) spared. These mice uniformly developed a JMML-like MPN. Importantly, HSCs in the same bone marrow (BM) microenvironment were aberrantly activated and differentiated at the expense of self-renewal. As a result, HSCs lost quiescence and became exhausted. A similar result was observed in wild-type (WT) donor HSCs when co-transplanted with Ptpn11E76K/+ BM cells into WT mice. Co-culture testing demonstrated that JMML/MPN cells robustly accelerated differentiation in mouse and human normal hematopoietic stem/progenitor cells. Cytokine profiling revealed that Ptpn11E76K/+ MPN cells produced excessive IL-1β, but not IL-6, T NF-α, IFN-γ, IL-1α, or other inflammatory cytokines. Depletion of the IL-1β receptor effectively restored HSC quiescence, normalized their pool size, and rescued them from exhaustion in Ptpn11E76K/+/IL-1R-/- double mutant mice. These findings suggest IL-1β signaling as a potential therapeutic target for preserving normal hematopoietic development in JMML.

Juvenile myelomonocytic leukemia (JMML) is a rare heterogeneous hematological malignancy of early childhood characterized by causative RAS pathway mutations. Classifying patients with JMML using global DNA methylation profiles is useful for risk stratification. We implemented machine learning algorithms (decision tree, support vector machine, and naïve Bayes) to produce a DNA methylation-based classification according to recent international consensus definitions using a well-characterized pooled cohort of patients with JMML (n = 128). DNA methylation was originally categorized into three subgroups: high methylation (HM), intermediate methylation (IM), and low methylation (LM), which is a trichotomized classification. We also dichotomized the subgroups as HM/IM and LM. The decision tree model showed high concordances with 450k-based methylation [82.3% (106/128) for the dichotomized and 83.6% (107/128) for the trichotomized subgroups, respectively]. With an independent cohort (n = 72), we confirmed that these models using both the dichotomized and trichotomized classifications were highly predictive of survival. Our study demonstrates that machine learning algorithms can generate clinical parameter-based models that predict the survival outcomes of patients with JMML and high accuracy. These models enabled us to rapidly and effectively identify candidates for augmented treatment following diagnosis.

Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm that develops during infancy and early childhood. The array-based international consensus definition of DNA methylation has recently classified patients with JMML into the following 3 groups: high (HM), intermediate (IM), and low methylation (LM). To develop a simple and robust methylation clinical test, 137 patients with JMML were analyzed using the Digital Restriction Enzyme Analysis of Methylation (DREAM), which is a next-generation sequencing-based methylation analysis. Unsupervised consensus clustering of the discovery cohort (n = 99) using DREAM data identified HM (HM_DREAM; n = 35) and LM subgroups (LM_DREAM; n = 64). Of the 98 cases that could be compared with the international consensus classification, 90 HM (n = 30) and LM (n = 60) cases had 100% concordance with DREAM clustering results. Of the remaining 8 cases comprising the IM group, 4 were classified as belonging to the HM_DREAM group and 4 to the LM_DREAM group. A machine-learning classifier was successfully constructed using a support vector machine (SVM), which divided the validation cohort (n = 38) into HM (HM_SVM, n = 18) and LM (LM_SVM; n = 20) groups. Patients with the HM_SVM profile had a significantly poorer 5-year overall survival rate than those with the LM_SVM profile. In conclusion, we developed a robust methylation test using DREAM for patients with JMML. This simple and straightforward test can be easily incorporated into diagnosis to generate a methylation classification for patients so they can receive risk-adapted treatment in the context of future clinical trials.

Background: The surgical treatment of advanced ovarian cancer is associated with extensive tissue trauma, prolonged operating times and a considerable volume shift. It, therefore, represents a challenge for anaesthesiological management. Aim: The aim of this single-centre, retrospective, observational study was to investigate whether intraoperative extensive volume supply influences postoperative outcomes and long-term survival. Methods: The study included 73 patients with a mean (SD) age of 63 (13) years who underwent extensive tumour-reducing surgery for ovarian cancer between 2012 and 2015. The effect of the intraoperative fluid balance on postoperative complications, such as anastomotic insufficiency or pleural effusions, was investigated using logistic regression. Further, the influence of fluid balance, lactate and creatinine levels on 5-year survival was analysed in a Cox regression model. Associations between anaesthesia time and the intraoperative fluid balance were examined using Spearman’s rank correlation coefficients. Results: The mean (SD) postoperative fluid balance in the considered patient cohort was 9.1 (3.4) litres (l) at a mean (SD) anaesthesia time of 529 (106) minutes. Cox regression did not reveal a statistically significant effect of the fluid balance, but it did reveal a statistically significant association between the lactate level 24 h following surgery and the 5-year survival (HR [95%-CI] fluid balance: 0.97 [0.85, 1.11]; HR [95%-CI] lactate: 1.79 [1.24, 2.58]). According to logistic regression, the intraoperative fluid balance was associated with an increased chance of postoperative complications in the considered patient cohort (OR [95%-CI] 1.28 [1.1, 1.54]). Conclusions: We could not detect a negative impact of an increased fluid balance on 5-year survival, but a negative impact on postoperative complications was found in our patient cohort.

Juvenile myelomonocytic leukemia is an overlapping myeloproliferative and myelodysplastic disorder of early childhood . It is associated with a spectrum of diverse outcomes ranging from spontaneous resolution in rare patients to transformation to acute myeloid leukemia in others that is generally fatal. This unpredictable clinical course, along with initially descriptive diagnostic criteria, led to decades of productive international research. Next-generation sequencing now permits more accurate molecular diagnoses in nearly all patients. However, curative treatment is still reliant on allogeneic hematopoietic cell transplantation for most patients, and additional advances will be required to improve risk stratification algorithms that distinguish those that can be observed expectantly from others who require swift hematopoietic cell transplantation.

Juvenile myelomonocytic leukemia (JMML) is initiated in early childhood by somatic mutations that activate Ras signaling. Although some patients have only a single identifiable oncogenic mutation, others have 1 or more additional alterations. Such secondary mutations, as a group, are associated with an increased risk of relapse after hematopoietic stem cell transplantation or transformation to acute myeloid leukemia. These clinical observations suggest a cooperative effect between initiating and secondary mutations. However, the roles of specific genes in the prognosis or clinical presentation of JMML have not been described. In this study, we investigate the impact of secondary SH2B3 mutations in JMML. We find that patients with SH2B3 mutations have adverse outcomes, as well as higher white blood cell counts and hemoglobin F levels in the peripheral blood. We further demonstrate this interaction in genetically engineered mice. Deletion of Sh2b3 cooperates with conditional Nf1 deletion in a dose-dependent fashion. These studies illustrate that haploinsufficiency for Sh2b3 contributes to the severity of myeloproliferative disease and provide an experimental system for testing treatments for a high-risk cohort of JMML patients.

Abstract Hematologic malignancy is a risk factor for severe coronavirus disease 2019 (COVID‐19) in adults; however, data specific to children with leukemia are limited. High‐quality infectious adverse event data from the ongoing Children's Oncology Group (COG) standard‐risk B acute lymphoblastic leukemia/lymphoma (ALL/LLy) trial, AALL1731, were analyzed to provide a disease‐specific estimate of SARS‐CoV‐2 infection outcomes in pediatric ALL. Of 253 patients with reported infections, the majority (77.1%) were asymptomatic or mildly symptomatic (CTCAE grade 1/2) and there was a single COVID‐19‐related death. These data suggest SARS‐CoV‐2 infection does not confer substantial morbidity among young patients with B‐lymphoblastic leukemia/lymphoma (B‐ALL/LLy).

Abstract Propionic acid (PPA) is used to study the role of mitochondrial dysfunction in neurodevelopmental conditions like autism spectrum disorders. PPA is known to disrupt mitochondrial biogenesis, metabolism, and turnover. However, the effect of PPA on mitochondrial dynamics, fission, and fusion remains challenging to study due to the complex temporal nature of these mechanisms. Here, we use complementary quantitative visualization techniques to examine how PPA influences mitochondrial ultrastructure, morphology, and dynamics in neuronal-like SH-SY5Y cells. PPA (5 mM) induced a significant decrease in mitochondrial area (p

Background: Classical toxin-mediated respiratory diphtheria has become less common because of widespread effective vaccination globally but invasive disease as a result of non-toxigenic strains of Corynebacterium diphtheriae is not prevented by vaccination and may result in severe disease, including infective endocarditis (IE). Objectives: To describe the outbreak and subsequent investigation of a cluster of five cases of non-toxigenic C. diphtheriae endocarditis. Method: A retrospective observational case series of five cases of non-toxigenic C. diphtheriae endocarditis identified in the rural West Coast district of the Western Cape province of South Africa between May 2021 and June 2021. Results: Non-toxigenic C. diphtheriae IE had an aggressive clinical course with high mortality in this cohort. Only one of five patients survived to hospital discharge. The surviving patient received a prompt diagnosis with early surgical intervention but still had a complicated clinical course. Notably, only one case had a pre-existing risk factor for IE, namely a prosthetic valve. Whole genome sequencing of clinical isolates confirmed that all isolates were of the same novel sequence type of non-toxigenic C. diphtheriae but despite a thorough investigation no epidemiological link was ever found between the cases. Conclusion: Non-toxigenic strains of C. diphtheriae are less well known but may be highly virulent and cause severe invasive disease. Contribution: This is the largest cluster of non-toxigenic C. diphtheriae IE ever described in South Africa and expands the body of literature on this unusual but possibly emerging infection.

The two-planet transiting system LHS 1140 has been extensively observed since its discovery in 2017, notably with Spitzer, HST, TESS, and ESPRESSO, placing strong constraints on the parameters of the M4.5 host star and its small temperate exoplanets, LHS 1140 b and c. Here, we reanalyze the ESPRESSO observations of LHS 1140 with the novel line-by-line framework designed to fully exploit the radial velocity content of a stellar spectrum while being resilient to outlier measurements. The improved radial velocities, combined with updated stellar parameters, consolidate our knowledge of the mass of LHS 1140 b (5.60 ± 0.19 M _⊕ ) and LHS 1140 c (1.91 ± 0.06 M _⊕ ) with an unprecedented precision of 3%. Transits from Spitzer, HST, and TESS are jointly analyzed for the first time, allowing us to refine the planetary radii of b (1.730 ± 0.025 R _⊕ ) and c (1.272 ± 0.026 R _⊕ ). Stellar abundance measurements of refractory elements (Fe, Mg, and Si) obtained with NIRPS are used to constrain the internal structure of LHS 1140 b. This planet is unlikely to be a rocky super-Earth, as previously reported, but rather a mini-Neptune with a ∼0.1% H/He envelope by mass or a water world with a water-mass fraction between 9% and 19%, depending on the atmospheric composition and relative abundance of Fe and Mg. While the mini-Neptune case would not be habitable, a water-abundant LHS 1140 b potentially has habitable surface conditions according to 3D global climate models, suggesting liquid water at the substellar point for atmospheres with relatively low CO _2 concentration, from Earth-like to a few bars.

Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss of function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells (HPCs) also demonstrated sensitivity of SH2B3- mutated HPCs to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.

L'épigénétique est communément définie comme l’étude de l'ensemble des mécanismes moléculaires impliqués dans la régulation de l’expression des gènes qui sont réversibles et transmissibles au cours du développement et parfois entre générations, sans altérer la séquence de l'ADN. Plusieurs mécanismes épigénétiques sont maintenant bien connus, comme la méthylation de l'ADN, les variants et modifications post-traductionnelles des histones, ainsi que certains ARN non codants. Grâce au développement technologique du séquençage tout-génome, ces « marques » épigénétiques peuvent être étudiées à l'échelle du génome entier. Il est aujourd’hui clairement établi que l’épigénome, c'est-à-dire l'ensemble des marques épigénétiques d'un tissu, est sensible aux fluctuations de l’environnement, notamment la température ou l’alimentation. Des stratégies de programmation précoce des phénotypes reposant sur ces mécanismes épigénétiques sont ainsi envisagées comme levier pour adapter le phénotype ultérieur des individus à leurs conditions de vie. Par ailleurs, au cours des dernières décennies, la sélection génétique a contribué à l’amélioration considérable des performances des animaux. Bien que la composante génétique puisse être estimée avec précision, une grande partie de la variabilité phénotypique n'est pas directement accessible par les approches actuelles. Dans un contexte de diversification des environnements de production (changement climatique, modes de production plus respectueux du bien-être et de l'environnement), il est nécessaire de comprendre l'impact de l'environnement sur la variabilité phénotypique via les marques épigénétiques, pour optimiser les systèmes d'élevage et mieux prédire le phénotype d'un animal. Comme la sélection génomique il y a quelques années, l'apport de la recherche en épigénétique pourrait contribuer à rendre les systèmes de production avicole plus efficaces et plus durables.

Zirconium nitride (ZrN) is widely used in many industrial sectors for its outstanding performances including its mechanical properties, high chemical and thermal stability. Associated with its plasmonic behavior, these properties make ZrN a suitable candidate for optical applications at high temperature or in extreme environments. The authors present an innovative, easy-to-use and rapid process for producing ZrN thin films from a photo-structurable ZrO2 sol-gel using a rapid thermal nitridation (RTN) process. In this process, a ZrO2 sol-gel layer is converted into a ZrN thin film in a few minutes by rapid thermal annealing (RTA) under ammonia gas. Compared to physical or chemical vapor deposition, usually used to produce ZrN thin films, the advantages of the sol-gel method include suitability for non-planar and large substrates and the possibility of nanotexturing of crystallized ZrN surfaces in considerably less time, at a larger scale and at a lower cost. The ZrO2 and ZrN thin films were characterized by Raman spectroscopy, X-ray diffraction and Transmission Electron Microscopy, to confirm complete nitridation. The optical, electrical and tribological properties were also investigated. Finally, the nitridation method was also used on structured ZrO2 layers and showed the versatility of the process e.g. enabling the production of micro-nanostructured ZrN films without using any etching techniques.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.See related commentary by Bornhauser and Bourquin, p. 1322.This article is highlighted in the In This Issue feature, p. 1307.

Despite high vaccine coverage with either the whole-cell or acellular vaccine in many countries, the incidence of pertussis has increased globally during the past 20 years (1-4). Disease increase has [...]

Abstract Low grade serous ovarian carcinoma (LGSOC) demonstrates unique clinical and molecular features compared to other ovarian cancer types. The relationship between common histological features of LGSOC and molecular events, such as hormone receptor expression patterns and MAPK gene mutation status, remains poorly understood. Recent data suggest some of these molecular features may be biomarkers of response to recently introduced biologically-targeted therapies, namely endocrine therapy and MEK inhibitors. We utilize a cohort of 63 pathologically-confirmed LGSOC cases with whole exome sequencing and hormone receptor expression data to investigate these relationships. LGSOC cases demonstrated uniformly high oestrogen receptor (ER) expression, but variable progesterone receptor (PR) expression intensity. 60% and 37% of cases demonstrated micropapillary and macropapillary patterns of stromal invasion, respectively. 63% of cases demonstrated desmoplasia, which was significantly associated with advanced disease stage and visible residual disease after cytoreductive surgery. MAPK-mutant cases (KRAS, BRAF, NRAS) more frequently demonstrated macropapillary stromal invasion, while Chr1p loss was associated with desmoplasia and low PR expression. Presence of micropapillary stromal invasion and low PR expression were associated with significantly poorer survival after accounting for stage and residual disease status. Together, these data identify novel relationships between histopathological features and molecularly-defined subgroups in LGSOC.

Abstract Background The NSD2 p.E1099K (EK) mutation is shown to be enriched in patients with relapsed acute lymphoblastic leukemia (ALL), indicating a role in clonal evolution and drug resistance. Results To uncover 3D chromatin architecture-related mechanisms underlying drug resistance, we perform Hi-C on three B-ALL cell lines heterozygous for NSD2 EK. The NSD2 mutation leads to widespread remodeling of the 3D genome, most dramatically in terms of compartment changes with a strong bias towards A compartment shifts. Systematic integration of the Hi-C data with previously published ATAC-seq, RNA-seq, and ChIP-seq data show an expansion in H3K36me2 and a shrinkage in H3K27me3 within A compartments as well as increased gene expression and chromatin accessibility. These results suggest that NSD2 EK plays a prominent role in chromatin decompaction through enrichment of H3K36me2. In contrast, we identify few changes in intra-topologically associating domain activity. While compartment changes vary across cell lines, a common core of decompacting loci are shared, driving the expression of genes/pathways previously implicated in drug resistance. We further perform RNA sequencing on a cohort of matched diagnosis/relapse ALL patients harboring the relapse-specific NSD2 EK mutation. Changes in patient gene expression upon relapse significantly correlate with core compartment changes, further implicating the role of NSD2 EK in genome decompaction. Conclusions In spite of cell-context-dependent changes mediated by EK, there appears to be a shared transcriptional program dependent on compartment shifts which could explain phenotypic differences across EK cell lines. This core program is an attractive target for therapeutic intervention.

Oncogenic gene fusions are frequent in childhood cancers but remain poorly understood and untargeted. Here, the authors identify 272 oncogenic fusions in transcriptomics data from 5190 childhood cancer patients, revealing their possible etiologies, their links with tumor progression and evolution, and their potential as therapeutic targets.

Objective: The aim of this study is to investigate the difference in impact between distal transradial access (dTRA) and classical transradial access (TRA) on vascular function using flow-mediated vasodilation (FMD) following coronary diagnostic and therapeutic catheterizations.

Abstract Background Harvest index is an important component of grain yield and is typically reduced by reproductive stage drought stress in rice. Multiple drought response mechanisms can affect harvest index including plant water status and the degree of stem carbohydrate mobilization during grain filling. In this study, we aimed to dissect the contributions of plant water status and stem carbohydrate mobilization to harvest index. Pairs of genotypes selected for contrasting harvest index but similar biomass and days to flowering were characterized at ICAR-RCER, Patna, India and at IRRI, Philippines. Results Multiple traits were related with harvest index across experiments, including mobilization efficiency at both sites as indicated by groupings in principal component analysis, and plant water status as indicated by direct correlations. Biomass-related traits were positively correlated with harvest index at IRRI but biomass was negatively correlated with harvest index at ICER-RCER, Patna. We observed that some pairs of genotypes showed differences in harvest index across environments, whereas other showed differences in harvest index only under drought. Of all time points measured when all genotypes were considered together, the stem carbohydrate levels at maturity were most consistently (negatively) correlated with harvest index under drought, but not under well-watered conditions. However, in the pairs of genotypes grouped as those whose differences in harvest index were stable across environments, improved plant water status resulted in a greater ability to both accumulate and remobilize stored carbohydrate, i.e. starch. Conclusion By distinguishing between genotypes whose harvest index was improved across conditions as opposed to specifically under drought, we can attribute the mechanisms behind the stable high-harvest index genotypes to be more related to stem carbohydrate remobilization than to plant water status. The stable high-harvest index lines in this study (Aus 257 and Wanni Dahanala) may confer mechanisms to improve harvest index that are independent of drought response and therefore may be useful for breeding improved rice varieties.

PurposeKnown clinical and genetic markers have limitations in predicting disease course and outcome in juvenile myelomonocytic leukemia (JMML). DNA methylation patterns in JMML have correlated with outcome across multiple studies, suggesting it as a biomarker to improve patient stratification. However, standardized approaches to classify JMML on the basis of DNA methylation patterns are lacking. We, therefore, sought to define an international consensus for DNA methylation subgroups in JMML and develop classification methods for clinical implementation.Experimental designPublished DNA methylation data from 255 patients with JMML were used to develop and internally validate a classifier model. Accuracy across platforms (EPIC-arrays and MethylSeq) was tested using a technical validation cohort (32 patients). The suitability of both methods for single-patient classification was demonstrated using an independent cohort (47 patients).ResultsAnalysis of pooled, published data established three DNA methylation subgroups as a de facto standard. Unfavorable prognostic parameters (PTPN11 mutation, elevated fetal hemoglobin, and older age) were significantly enriched in the high methylation (HM) subgroup. A classifier was then developed that predicted subgroups with 98% accuracy across different technological platforms. Applying the classifier to an independent validation cohort confirmed an association of HM with secondary mutations, high relapse incidence, and inferior overall survival (OS), while the low methylation subgroup was associated with a favorable disease course. Multivariable analysis established DNA methylation subgroups as the only significant factor predicting OS.ConclusionsThis study provides an international consensus definition for DNA methylation subgroups in JMML. We developed and validated methods which will facilitate the design of risk-stratified clinical trials in JMML.