Histone H3.3 regulates mitotic progression in mouse embryonic fibroblasts

H3.3 is a histone variant that marks transcription start sites as well as telomeres and heterochromatic sites on the genome. The presence of H3.3 is thought to positively correlate with the transcriptional status of its target genes. Using a conditional genetic strategy against H3.3B, combined with short hairpin RNAs against H3.3A, we essentially depleted all H3.3 gene expression in mouse embryonic fibroblasts. Following nearly complete loss of H3.3 in the cells, our transcriptomic analyses show very little impact on global gene expression or on the localization of histone variant H2A.Z. Instead, fibroblasts displayed slower cell growth and an increase in cell death, coincident with large-scale chromosome misalignment in mitosis and large polylobed or micronuclei in interphase cells. Thus, we conclude that H3.3 may have an important under-explored additional role in chromosome segregation, nuclear structure, and the maintenance of genome integrity. © 2017 Published by NRC Research Press

State of the art biology, progression, and clinical management of monoclonal B-cell lymphocytosis (MBL):consensus report from the Intercepting Blood Cancers Workshop Committee

In March 2023 and 2024, a panel of international experts convened at the first and second Intercepting Blood Cancers (IBC) Workshops, with the aim of better appreciating the diagnostic challenges, pathophysiology, and potential therapeutic interventions for precursor malignant hematology conditions. Here, we report a summary of the proceedings from the sessions focused on monoclonal B-cell lymphocytosis (MBL)/chronic lymphocytic leukemia (CLL). We highlight four main content areas: biology of MBL, clinical implications of MBL, progression of MBL and transformation from indolent CLL to aggressive disease, and opportunities for therapeutic intervention in early CLL. We additionally outline key consensus management recommendations and research goals.</p

Nanosecond electron pulses in the analytical electron microscopy of a fast irreversible chemical reaction

We show how the kinetics of a fast and irreversible chemical reaction in a nanocrystalline material at high temperature can be studied using nanosecond electron pulses in an electron microscope. Infrared laser pulses first heat a nanocrystalline oxide layer on a carbon film, then single nanosecond electron pulses allow imaging, electron diffraction and electron energy-loss spectroscopy. This enables us to study the evolution of the morphology, crystallography, and elemental composition of the system with nanosecond resolution. Here, NiO nanocrystals are reduced to elemental nickel within 5 mu s after the laser pulse. At high temperatures induced by laser heating, reduction results first in a liquid nickel phase that crystallizes on microsecond timescales. We show that the reaction kinetics in the reduction of nanocrystalline NiO differ from those in bulk materials. The observation of liquid nickel as a transition phase explains why the reaction is first order and occurs at high rates

Atomic Resolution Cryo-EM Structure Of A Nativelike CENP-A Nucleosome Aided By An Antibody Fragment

Genomic DNA in eukaryotes is organized into chromatin through association with core histones to form nucleosomes, each distinguished by their DNA sequences and histone variants. Here, we used a single-chain antibody fragment (scFv) derived from the anti-nucleosome antibody mAb PL2-6 to stabilize human CENP-A nucleosome containing a native α-satellite DNA and solved its structure by the cryo-electron microscopy (cryo-EM) to 2.6 Å resolution. In comparison, the corresponding cryo-EM structure of the free CENP-A nucleosome could only reach 3.4 Å resolution. We find that scFv binds to a conserved acidic patch on the histone H2A-H2B dimer without perturbing the nucleosome structure. Our results provide an atomic resolution cryo-EM structure of a nucleosome and insight into the structure and function of the CENP-A nucleosome. The scFv approach is applicable to the structural determination of other native-like nucleosomes with distinct DNA sequences

Pesticide exposure and lymphohaematopoietic cancers: a case-control study in an agricultural region (Larissa, Thessaly, Greece)

<p>Abstract</p> <p>Background</p> <p>The causality of lymphohaematopoietic cancers (LHC) is multifactorial and studies investigating the association between chemical exposure and LHC have produced variable results. The aim of this study was to investigate the relationships between exposure to pesticides and LHC in an agricultural region of Greece.</p> <p>Methods</p> <p>A structured questionnaire was employed in a hospital-based case control study to gather information on demographics, occupation, exposure to pesticides, agricultural practices, family and medical history and smoking. To control for confounders, backward conditional and multinomial logistic regression analyses were used. To assess the dose-response relationship between exposure and disease, the chi-square test for trend was used.</p> <p>Results</p> <p>Three hundred and fifty-four (354) histologically confirmed LHC cases diagnosed from 2004 to 2006 and 455 sex- and age-matched controls were included in the study. Pesticide exposure was associated with total LHC cases (OR 1.46, 95% CI 1.05-2.04), myelodysplastic syndrome (MDS) (OR 1.87, 95% CI 1.00-3.51) and leukaemia (OR 2.14, 95% CI 1.09-4.20). A dose-response pattern was observed for total LHC cases (P = 0.004), MDS (P = 0.024) and leukaemia (P = 0.002). Pesticide exposure was independently associated with total LHC cases (OR 1.41, 95% CI 1.00 - 2.00) and leukaemia (OR 2.05, 95% CI 1.02-4.12) after controlling for age, smoking and family history (cancers, LHC and immunological disorders). Smoking during application of pesticides was strongly associated with total LHC cases (OR 3.29, 95% CI 1.81-5.98), MDS (OR 3.67, 95% CI 1.18-12.11), leukaemia (OR 10.15, 95% CI 2.15-65.69) and lymphoma (OR 2.72, 95% CI 1.02-8.00). This association was even stronger for total LHC cases (OR 18.18, 95% CI 2.38-381.17) when eating simultaneously with pesticide application.</p> <p>Conclusions</p> <p>Lymphohaematopoietic cancers were associated with pesticide exposure after controlling for confounders. Smoking and eating during pesticide application were identified as modifying factors increasing the risk for LHC. The poor pesticide work practices identified during this study underline the need for educational campaigns for farmers.</p

Comparison of germinal center markers CD10, BCL6 and human germinal center-associated lymphoma (HGAL) in follicular lymphomas

<p>Abstract</p> <p>Background</p> <p>Recently, human germinal center-associated lymphoma (HGAL) gene protein has been proposed as an adjunctive follicular marker to CD10 and BCL6.</p> <p>Methods</p> <p>Our aim was to evaluate immunoreactivity for HGAL in 82 cases of follicular lymphomas (FLs) - 67 nodal, 5 cutaneous and 10 transformed - which were all analysed histologically, by immunohistochemistry and PCR.</p> <p>Results</p> <p>Immunostaining for HGAL was more frequently positive (97.6%) than that for BCL6 (92.7%) and CD10 (90.2%) in FLs; the cases negative for bcl6 and/or for CD10 were all positive for HGAL, whereas the two cases negative for HGAL were positive with BCL6; no difference in HGAL immunostaining was found among different malignant subtypes or grades.</p> <p>Conclusions</p> <p>Therefore, HGAL can be used in the immunostaining of FLs as the most sensitive germinal center (GC)-marker; when applied alone, it would half the immunostaining costs, reserving the use of the other two markers only to HGAL-negative cases.</p

Reduced leakage currents and possible charge carriers tuning in Mg-doped Ga0.6Fe1.4O3 thin films

Ga0.6Fe1.4O3 is predicted to be magnetoelectric with non zero magnetization at room temperature. However, in thin films, electric properties are overshadowed by strong leakage currents. In this Letter, we show that Mg doping in Ga0.6Fe1.4O3 thin films grown by pulsed laser deposition allows decreasing the leakage current density by four orders of magnitude and might simultaneously allow tuning the carriers' nature. These results suggest the possibility to develop a new class of material exhibiting room temperature magnetization, tunable transport properties, and magnetoelectric properties. (C) 2012 American Institute of Physics.This work was supported by the CNRS PICS program #5733 and the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST) (2011-00267)

Optical transitions in magnetoelectric Ga0.6Fe1.4O3 from 0.73 to 6.45 eV

The optical properties of polycrystalline Ga0.6Fe1.4O3 bulk are determined by spectroscopic ellipsometry from 0.73 to 6.45 eV. Complex dielectric function epsilon = epsilon(1) + i epsilon(2) spectra are obtained from the multilayer analysis. The ellipsometric data exhibit numerous optical structures, and the transition energies are accurately obtained by analyzing the second-energy derivatives of the data. The origins of the optical structures are explained in terms of Fe3+ ligand field transitions and ligand-to-metal charge transfer transitions. (C) 2012 American Vacuum Society. [http://dx.doi.org/10.1116/1.4721649

Specific core-shell approaches and related properties in nanostructured ferroelectric ceramics

Interfaces are a major issue when designing ferroelectric nanostructured materials with tailored properties. In a context of integration and multifunctionality in the field of electronics, several strategies have been developed to control the microstructure and defect chemistry of interfaces that strongly impact the macroscopic properties. The suitability of the core-shell approaches that allow a subtle tuning of interface phenomena at different scales has been widely demonstrated. We focus here on the flexibility of the core-shell approach devoted to the processing of nanostructured ferroelectric composites. Our strategy relies on the use of advanced synthesis processes to design ferroelectric grains coated with shells of different nature, morphology and crystallinity. Typical examples will be reviewed with a specific attention on their impact on both microstructure and dielectric properties. Our approach, based also on the use of fast sintering technique, provides a guidance to design 3D bulk nanostructured ferroelectrics while controlling and/or exploiting size, interface and defects chemistry. The contribution of specific spectroscopies to probe interfacial chemistry and defects is underlined. The high density of interfaces in core-shell materials is obviously an advantage to target additional functionality such as magneto-electric coupling. This is illustrated in 3D composites and one dimensional nanostructures that coaxially combine electric and magnetic materials. The core-shell approach described here could be transferred to a much broader range of materials covering many functionalities provided a deeper understanding of the interfaces at the atomic scale is achieved and a further development of low temperature processing is reached

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like [ABC], germinal-center B-cell-like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. METHODS: We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. RESULTS: We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on "chronic active" B-cell receptor signaling that is amenable to therapeutic inhibition. CONCLUSIONS: We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.).This research was supported by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute and by a National Cancer Institute Strategic Partnering to Evaluate Cancer Signatures (SPECS II) grant (5U01CA157581-05). R.S. was supported by the Dr Mildred Scheel Stiftung für Krebsforschung (Deutsche Krebshilfe). D.J.H. was a Kay Kendall Leukaemia Fund Intermediate research fellow. M.K. was supported by the National Institutes of Health Oxford-Cambridge Scholars Program and the Washington University in St. Louis Medical Scientist Training Progra