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

Enhanced Non-linear Response by Manipulating the Dirac Point in the (111) LaTiO3_3/SrTiO3_3 Interface

Tunable spin-orbit interaction (SOI) is an important feature for future spin-based devices. In the presence of a magnetic field, SOI induces an asymmetry in the energy bands, which can produce non-linear transport effects ($V\sim I^2$). Here, we focus on such effects to study the role of SOI in the (111) LaTiO$_3$/SrTiO$_3$ interface. This system is a convenient platform for understanding the role of SOI since it exhibits a single-band Hall-response through the entire gate-voltage range studied. We report a pronounced rise in the non-linear resistance at a critical in-plane field $H_{cr}$. This rise disappears with a small out-of-plane field. We explain these results by considering the location of the Dirac point formed at the crossing of the spin-split energy bands. An in-plane magnetic field pushes this point outside of the Fermi surface, and consequently changes the symmetry of the Fermi contours and intensifies the non-linear transport. An out-of-plane magnetic field opens a gap at the Dirac point, thereby significantly diminishing the non-linear effects. We propose that magnetoresistance effects previously reported in interfaces with SOI could be comprehended within our suggested scenario

The Current State of Sleep Medicine Education in US Neurology Residency Training Programs: Where Do We Go from Here?

To evaluate the current state of sleep medicine educational resources and training offered by US neurology residency programs

The Origins of Time-Delay in Template Biopolymerization Processes

Time-delays are common in many physical and biological systems and they give rise to complex dynamic phenomena. The elementary processes involved in template biopolymerization, such as mRNA and protein synthesis, introduce significant time delays. However, there is not currently a systematic mapping between the individual mechanistic parameters and the time delays in these networks. We present here the development of mathematical, time-delay models for protein translation, based on PDE models, which in turn are derived through systematic approximations of first-principles mechanistic models. Theoretical analysis suggests that the key features that determine the time-delays and the agreement between the time-delay and the mechanistic models are ribosome density and distribution, i.e., the number of ribosomes on the mRNA chain relative to their maximum and their distribution along the mRNA chain. Based on analytical considerations and on computational studies, we show that the steady-state and dynamic responses of the time-delay models are in excellent agreement with the detailed mechanistic models, under physiological conditions that correspond to uniform ribosome distribution and for ribosome density up to 70%. The methodology presented here can be used for the development of reduced time-delay models of mRNA synthesis and large genetic networks. The good agreement between the time-delay and the mechanistic models will allow us to use the reduced model and advanced computational methods from nonlinear dynamics in order to perform studies that are not practical using the large-scale mechanistic models

miR-34a Repression in Proneural Malignant Gliomas Upregulates Expression of Its Target PDGFRA and Promotes Tumorigenesis

Glioblastoma (GBM) and other malignant gliomas are aggressive primary neoplasms of the brain that exhibit notable refractivity to standard treatment regimens. Recent large-scale molecular profiling has revealed distinct disease subclasses within malignant gliomas whose defining genomic features highlight dysregulated molecular networks as potential targets for therapeutic development. The “proneural” designation represents the largest and most heterogeneous of these subclasses, and includes both a large fraction of GBMs along with most of their lower-grade astrocytic and oligodendroglial counterparts. The pathogenesis of proneural gliomas has been repeatedly associated with dysregulated PDGF signaling. Nevertheless, genomic amplification or activating mutations involving the PDGF receptor (PDGFRA) characterize only a subset of proneural GBMs, while the mechanisms driving dysregulated PDGF signaling and downstream oncogenic networks in remaining tumors are unclear. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that regulate gene expression by binding loosely complimentary sequences in target mRNAs. The role of miRNA biology in numerous cancer variants is well established. In an analysis of miRNA involvement in the phenotypic expression and regulation of oncogenic PDGF signaling, we found that miR-34a is downregulated by PDGF pathway activation in vitro. Similarly, analysis of data from the Cancer Genome Atlas (TCGA) revealed that miR-34a expression is significantly lower in proneural gliomas compared to other tumor subtypes. Using primary GBM cells maintained under neurosphere conditions, we then demonstrated that miR-34a specifically affects growth of proneural glioma cells in vitro and in vivo. Further bioinformatic analysis identified PDGFRA as a direct target of miR-34a and this interaction was experimentally validated. Finally, we found that PDGF-driven miR-34a repression is unlikely to operate solely through a p53-dependent mechanism. Taken together, our data support the existence of reciprocal negative feedback regulation involving miR-34 and PDGFRA expression in proneural gliomas and, as such, identify a subtype specific therapeutic potential for miR-34a

Focal plate structure alignment of the Dark Energy Spectroscopic Instrument

The Dark Energy Spectroscopic Instrument (DESI) is under construction to measure the expansion history of the universe using the Baryon Acoustic Oscillation technique. The spectra of 35 million galaxies and quasars spanning over 14,000  deg2 are measured during the life of the experiment. A prime focus corrector for the Kitt Peak National Observatory Mayall telescope delivers light to 5000 robotically positioned optic fibers. The fibers in turn feed 10 broadband spectrographs. Proper alignment of the focal plate structure, mainly consisting of a focal plate ring and 10 focal plate petals, is crucial in ensuring minimal loss of light in the focal plane. A coordinate measurement machine (CMM) metrology-based approach to alignment requires comprehensive characterization of critical dimensions of the petals and the ring, all of which are 100% inspected. The metrology data not only serve for quality assurance but also, with careful modeling of geometric transformations, inform the initial choice of integration accessories, such as gauge blocks, pads, and shims. The integrated focal plate structure is inspected again on a CMM, and each petal is adjusted individually according to the updated focal plate metrology data until all datums are extremely close to nominal positions and optical throughput nearly reached the theoretically best possible value. We present our metrology and alignment methodology and complete results for 12 official DESI petals. The as-aligned, total RMS optical throughput for 6168 positioner holes of 12 production petals is indirectly measured to be 99.88  %    ±  0.12  %  , well above the 99.5% project requirement. The successful alignment fully demonstrated the wealth of data, reproducibility, and micron-level precision made available by our CMM metrology-based approach

Chiral to Nematic Crossover in the Superconducting State of 4Hb-TaS2_2

Most superconductors have an isotropic, single component order parameter, and are well described by the BCS theory for superconductivity. Unconventional, multiple components superconductors are exceptionally rare and are much less understood. Here, we combine scanning tunneling microscopy and angle-resolved macroscopic transport to study the candidate chiral superconductor, 4Hb-TaS$_2$. We reveal quasi-periodic one-dimensional modulations in the tunneling conductance accompanied by two-fold symmetric superconducting critical field. The strong modulation of the in-plane critical field, points to a nematic, unconventional order parameter. However, the imaged vortex core is nearly circular symmetric, suggesting an isotropic order parameter. We reconcile this apparent discrepancy by modeling a competition between a dominating chiral superconducting order parameter and a nematic one, the latter emerges close to the normal phase. Our results strongly support the existence of two-component superconductivity in 4Hb-TaS$_2$ and can provide useful insights to other systems with coexistent charge order and superconductivity