JAK2V617F promotes replication fork stalling with disease-restricted impairment of the intra-S checkpoint response

Cancers result from the accumulation of genetic lesions, but the cellular consequences of driver mutations remain unclear, especially during the earliest stages of malignancy. The V617F mutation in the JAK2 non-receptor tyrosine kinase (JAK2V617F) is present as an early somatic event in most patients with myeloproliferative neoplasms (MPNs), and the study of these chronic myeloid malignancies provides an experimentally tractable approach to understanding early tumorigenesis. Introduction of exogenous JAK2V617F impairs replication fork progression and is associated with activation of the intra-S checkpoint, with both effects mediated by phosphatidylinositide 3-kinase (PI3K) signaling. Analysis of clonally derived JAK2V617F-positive erythroblasts from MPN patients also demonstrated impaired replication fork progression accompanied by increased levels of replication protein A (RPA)-containing foci. However, the associated intra-S checkpoint response was impaired in erythroblasts from polycythemia vera (PV) patients, but not in those from essential thrombocythemia (ET) patients. Moreover, inhibition of p53 in PV erythroblasts resulted in more gamma-H2Ax (γ-H2Ax)–marked double-stranded breaks compared with in like-treated ET erythroblasts, suggesting the defective intra-S checkpoint function seen in PV increases DNA damage in the context of attenuated p53 signaling. These results demonstrate oncogene-induced impairment of replication fork progression in primary cells from MPN patients, reveal unexpected disease-restricted differences in activation of the intra-S checkpoint, and have potential implications for the clonal evolution of malignancies

STAT1 activation in association with JAK2 exon 12 mutations

La inclusión de la perspectiva de género en la actividad jurisdiccional es una demanda sostenida de los colectivos feministas y de mujeres, dado que las sentencias tienen un poder performativo y envían un mensaje a la sociedad: “[…] tienen un poder individual y colectivo que impactan en la vida de las personas y conforman la identidad del poder judicial como un actor imprescindible en la construcción de un Estado democrático de derecho” (Suprema Corte de Justicia de la Nación, 2013:7). La incorporación de la perspectiva de género viene a garantizar la igualdad de posiciones (Kessler, 2014) entre mujeres y varones como una meta, trascendiendo la mera igualdad de oportunidades que hasta el presente se ha demostrado insuficiente para que las mujeres consigamos una ciudadanía plena. Al momento de incorporar la perspectiva de género en las sentencias, quienes juzgan deben tener presente en primer lugar, el impacto diferenciado de las normas en base al sexo de las personas. En segundo lugar, la interpretación y aplicación de las leyes en relación con (y en base a) estereotipos de género. Si, por ejemplo, quienes imparten justicia no tienen presentes los estereotipos de género vigentes detrás de las violaciones a los derechos humanos de las mujeres, si no los detectan ni cuestionan, entonces los reproducen. Tal como sostiene Scott (1996) el género es una categoría imprescindible para el análisis social. En tercer lugar, al momento del juzgamiento, se deben tener en cuenta las exclusiones legitimadas por la ley por pensar el mundo en términos binarios y androcéntricos; en cuarto lugar, la distribución no equitativa de recursos y poder que opera entre varones y mujeres en el marco de una organización social patriarcal, y, por último, el trato diferenciado por género legitimado por las propias leyes.Eje 3: Tramas violentas y espacios de exclusión.Instituto de Cultura Jurídic

Cystic Fibrosis Foundation and European Cystic Fibrosis Society Survey of cystic fibrosis mental health care delivery

Background: Psychological morbidity in individuals with cystic fibrosis (CF) and their caregivers is common. The Cystic Fibrosis Foundation (CFF) and European Cystic Fibrosis Society (ECFS) Guidelines Committee on Mental Health sought the views of CF health care professionals concerning mental health care delivery. Methods: An online survey which focused on the current provision and barriers to mental health care was distributed to CF health care professionals. Results: Of the 1454 respondents, many did not have a colleague trained in mental health issues and 20% had no one on their team whose primary role was focused on assessing or treating these issues. Insufficient resources and a lack of competency were reported in relation to mental health referrals. Seventy-three percent of respondents had no experience with mental health screening. Of those who did, they utilized 48 different, validated scales. Conclusions: These data have informed the decision-making, dissemination and implementation strategies of the Mental Health Guidelines Committee sponsored by the CFF and ECFS

Study of K0∗(1430)K^*_0(1430) and a0(980)a_0(980) from B→K0∗(1430)πB\to K^*_0(1430)\pi and B→a0(980)KB\to a_0(980)K Decays

We use the decay modes $B \to K^*_0(1430) \pi$ and $B \to a_0(980) K$ to study the scalar mesons $K^*_0(1430)$ and $a_0(980)$ within perturbative QCD framework. For $B \to K^*_0(1430) \pi$, we perform our calculation in two scenarios of the scalar meson spectrum. The results indicate that scenario II is more favored by experimental data than scenario I. The important contribution from annihilation diagrams can enhance the branching ratios about 50% in scenario I, and about 30% in scenario II. The predicted branching ratio of $B \to a_0(980) K$ in scenario I is also less favored by the experiments. The direct CP asymmetries in $B \to K^*_0(1430) \pi$ are small, which are consistent with the present experiments.Comment: More references are added. Published Versio

Optimal care for the management of older people non-weight bearing after lower limb fracture: a consensus study

Background: Older people who are non-weight-bearing after a lower limb fracture are at risk of poor outcomes but there are no clinical guidelines for this group of patients. Given the paucity of the research evidence base, we conducted a consensus exercise to ascertain expert opinion about the management of this group. Methods: A three-round e-Delphi technique was planned to use the online JISC survey tool with a multidisciplinary panel of health professionals. Panellists were invited by email via professional organisations and UK NHS Trusts. The initial statements for this study were prepared by the authors based upon the findings of their scoping review. Consensus required >/= 70% agreement with statements. Results: Only 2 survey rounds were required. Ninety panellists, representing seven clinical disciplines, reached consensus for 24 statements about general issues (osteoporosis detection and management, falls risk reduction and nutrition) and specific non-weight bearing issues (such as the need for activity to be promoted during this period). Conclusions: These findings can be used in the generation of a clinical guideline for this group of patients

Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2V617F-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10−10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10−9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2 P=7.3 × 10−7). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype

Study of the Process e+ e- --> omega pi0 --> pi0 pi0 gamma in c.m. Energy Range 920--1380 MeV at CMD-2

The cross section of the process e+ e- --> omega pi0 --> pi0 pi0 gamma has been measured in the c.m. energy range 920-1380 MeV with the CMD-2 detector. Its energy dependence is well described by the interference of the rho(770) and rho'(1450) mesons decaying to omega pi0. Upper limits for the cross sections of the direct processes e+ e- --> pi0 pi0 gamma, eta pi0 gamma have been set.Comment: Accepted for publication in PL

Heavy quarkonium: progress, puzzles, and opportunities

A golden age for heavy quarkonium physics dawned a decade ago, initiated by the confluence of exciting advances in quantum chromodynamics (QCD) and an explosion of related experimental activity. The early years of this period were chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in 2004, which presented a comprehensive review of the status of the field at that time and provided specific recommendations for further progress. However, the broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles could only be partially anticipated. Since the release of the YR, the BESII program concluded only to give birth to BESIII; the $B$-factories and CLEO-c flourished; quarkonium production and polarization measurements at HERA and the Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the deconfinement regime. All these experiments leave legacies of quality, precision, and unsolved mysteries for quarkonium physics, and therefore beg for continuing investigations. The plethora of newly-found quarkonium-like states unleashed a flood of theoretical investigations into new forms of matter such as quark-gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the spectroscopy, decays, production, and in-medium behavior of c\bar{c}, b\bar{b}, and b\bar{c} bound states have been shown to validate some theoretical approaches to QCD and highlight lack of quantitative success for others. The intriguing details of quarkonium suppression in heavy-ion collisions that have emerged from RHIC have elevated the importance of separating hot- and cold-nuclear-matter effects in quark-gluon plasma studies. This review systematically addresses all these matters and concludes by prioritizing directions for ongoing and future efforts.Comment: 182 pages, 112 figures. Editors: N. Brambilla, S. Eidelman, B. K. Heltsley, R. Vogt. Section Coordinators: G. T. Bodwin, E. Eichten, A. D. Frawley, A. B. Meyer, R. E. Mitchell, V. Papadimitriou, P. Petreczky, A. A. Petrov, P. Robbe, A. Vair

Genetic basis of maize resistance to multiple insect pests: integrated genome-wide comparative mapping and candidate gene prioritization

Several species of herbivores feed on maize in field and storage setups, making the development of multiple insect resistance a critical breeding target. In this study, an association mapping panel of 341 tropical maize lines was evaluated in three field environments for resistance to fall armyworm (FAW), whilst bulked grains were subjected to a maize weevil (MW) bioassay and genotyped with Diversity Array Technology’s single nucleotide polymorphisms (SNPs) markers. A multi-locus genome-wide association study (GWAS) revealed 62 quantitative trait nucleotides (QTNs) associated with FAW and MW resistance traits on all 10 maize chromosomes, of which, 47 and 31 were discovered at stringent Bonferroni genome-wide significance levels of 0.05 and 0.01, respectively, and located within or close to multiple insect resistance genomic regions (MIRGRs) concerning FAW, SB, and MW. Sixteen QTNs influenced multiple traits, of which, six were associated with resistance to both FAWandMW, suggesting a pleiotropic genetic control. Functional prioritization of candidate genes (CGs) located within 10–30 kb of the QTNs revealed 64 putative GWAS-based CGs (GbCGs) showing evidence of involvement in plant defense mechanisms. Only one GbCG was associated with each of the five of the six combined resistance QTNs, thus reinforcing the pleiotropy hypothesis. In addition, through in silico co-functional network inferences, an additional 107 network-based CGs (NbCGs), biologically connected to the 64 GbCGs, and di erentially expressed under biotic or abiotic stress, were revealed within MIRGRs. The provided multiple insect resistance physical map should contribute to the development of combined insect resistance in maize