p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal

The p53 tumor suppressor limits proliferation in response to cellular stress through several mechanisms. Here, we test whether the recently described ability of p53 to limit stem cell self-renewal suppresses tumorigenesis in acute myeloid leukemia (AML), an aggressive cancer in which p53 mutations are associated with drug resistance and adverse outcome. Our approach combined mosaic mouse models, Cre-lox technology, and in vivo RNAi to disable p53 and simultaneously activate endogenous Kras(G12D)-a common AML lesion that promotes proliferation but not self-renewal. We show that p53 inactivation strongly cooperates with oncogenic Kras(G12D) to induce aggressive AML, while both lesions on their own induce T-cell malignancies with long latency. This synergy is based on a pivotal role of p53 in limiting aberrant self-renewal of myeloid progenitor cells, such that loss of p53 counters the deleterious effects of oncogenic Kras on these cells and enables them to self-renew indefinitely. Consequently, myeloid progenitor cells expressing oncogenic Kras and lacking p53 become leukemia-initiating cells, resembling cancer stem cells capable of maintaining AML in vivo. Our results establish an efficient new strategy for interrogating oncogene cooperation, and provide strong evidence that the ability of p53 to limit aberrant self-renewal contributes to its tumor suppressor activity

Loss of capillary pericytes and the blood–brain barrier in white matter in poststroke and vascular dementias and Alzheimer’s disease

White matter (WM) disease is associated with disruption of the gliovascular unit, which involves breach of the blood‐brain barrier (BBB). We quantified pericytes as components of the gliovascular unit and assessed their status in vascular and other common dementias. Immunohistochemical and immunofluorescent methods were developed to assess the distribution and quantification of pericytes connected to the frontal lobe WM capillaries. Pericytes with a nucleus were identified by collagen 4 (COL4) and platelet derived growth factor receptor‐β (PDGFR‐β) antibodies with further verification using PDGFR‐β specific ELISA. We evaluated a total of 124 post‐mortem brains from subjects with post‐stroke dementia (PSD), vascular dementia (VaD), Alzheimer’s disease (AD), AD‐VaD (Mixed), and post‐stroke non‐demented (PSND) stroke survivors as well as normal ageing controls. COL4 and PDGFR‐β reactive pericytes adopted the characteristic “crescent” or nodule‐like shapes around capillary walls. We estimated densities of pericyte somata to be 225 ±38 and 200 ±13 (SEM) per COL4 mm2 area or 2.0 ±0.1 and 1.7 ±0.1 per mm capillary length in young and older ageing controls. Remarkably, WM pericytes were reduced by ~35‐45 percent in the frontal lobe of PSD, VaD, Mixed and AD subjects compared to PSND and controls subjects (P<0.001). We also found pericyte numbers were correlated with PDGFR‐β reactivity in the WM. Our results first demonstrate a reliable method to quantify COL4‐positive pericytes and then indicate that deep WM pericytes are decreased across different dementias including PSD, VaD, Mixed and AD. Our findings suggest that down regulation of pericytes is associated with the disruption of the BBB in the deep WM in several ageing‐related dementias

Bounding Helly numbers via Betti numbers

We show that very weak topological assumptions are enough to ensure the existence of a Helly-type theorem. More precisely, we show that for any non-negative integers $b$ and $d$ there exists an integer $h(b,d)$ such that the following holds. If $\mathcal F$ is a finite family of subsets of $\mathbb R^d$ such that $\tilde\beta_i\left(\bigcap\mathcal G\right) \le b$ for any $\mathcal G \subsetneq \mathcal F$ and every $0 \le i \le \lceil d/2 \rceil-1$ then $\mathcal F$ has Helly number at most $h(b,d)$. Here $\tilde\beta_i$ denotes the reduced $\mathbb Z_2$-Betti numbers (with singular homology). These topological conditions are sharp: not controlling any of these $\lceil d/2 \rceil$ first Betti numbers allow for families with unbounded Helly number. Our proofs combine homological non-embeddability results with a Ramsey-based approach to build, given an arbitrary simplicial complex $K$, some well-behaved chain map $C_*(K) \to C_*(\mathbb R^d)$.Comment: 29 pages, 8 figure

Drainage And Sedimentary Response Of The Northern Andes And The Pebas System To Miocene Strike-slip Tectonics: A Source To Sink Study Of The Magdalena Basin

Miocene strike-slip tectonics was responsible for creating and closing short-lived (ca. 6 Ma) passages and the emergence of isolated topography in the Northern Andes. These geological events likely influenced the migration and/or isolation of biological populations. To better understand the paleogeography of the Miocene hinterland and foreland regions in the Northern Andes, we conducted a source-to-sink approach in the Magdalena Basin. This basin is located between the Central and Eastern Cordilleras of Colombia and contains an ample Miocene record, which includes Lower Miocene fine-grained strata and Middle Miocene to Pliocene coarsening-up strata. Our study presents a new data set that includes detrital U–Pb zircon ages (15 samples), sandstone petrography (45 samples) and low-temperature thermochronology from the Southern Central Cordillera (19 dates); which together with previously published data were used to construct a paleogeographical model of the Miocene hinterland and foreland regions in the Northern Andes. The evolution of the Magdalena Basin during the Miocene was characterized by playa and permanent lake systems at ca. 17.5 Ma, which may be related to a marine incursion into NW South America and western Amazonia. The appearance of Eocene to Miocene volcanic sources in the Honda Group after ca. 16 Ma suggests the development of fluvial passages, which connected the Pacific with the western Amazonia and Caribbean regions. These passages were synchronous with a time of Miocene exhumation and topographic growth (ca. 16 to 10 Ma) in the Central Cordillera and the transition from lacustrine to fluvial deposition in the Magdalena Basin. Middle to Late Miocene strike-slip deformation promoted by oblique plate convergence and the oblique collision of the Panamá-Chocó Block likely explains the synchronous along-strike fragmentation and exhumation in the Central Cordillera

Risk factors and outcome associated with the acquisition of linezolid-resistant Enterococcus faecalis

Objectives: Linezolid is a synthetic oxazolidinone antibiotic frequently used to treat vancomycin-resistant enterococcal infections. Vancomycin-susceptible Enterococcus faecalis can develop resistance to linezolid in environments with excessive linezolid use. The aim of this study was to define risk factors and outcome associated with the acquisition of linezolid-resistant E. faecalis (LREfs). Methods: A retrospective case–control study was designed including patients hospitalised from January 2014 to October 2017 at Hospital Civil de Guadalajara ‘Fray Antonio Alcalde’ in Guadalajara, Mexico. A total of 50 patients culture-positive for LREfs and 100 control patients hospitalised in the same room and time as the cases were included. Clinical and demographic data were collected and analysed. Results: Risk factors for the presence of LREfs included prior linezolid use [odds ratio (OR) = 6.74], prior clindamycin use (OR = 6.72) and previous surgery (OR = 5.79). The mortality rate was 18% for LREfs cases versus 9% for controls. Conclusion: LREfs has emerged and spread in our hospital, an environment in which linezolid use is considerable. Risk factors for LREfs are prior antibiotic use, including linezolid, and previous surgery

The Mass-Metallicity relation explored with CALIFA: I. Is there a dependence on the star formation rate?

We present the results on the study of the global and local M-Z relation based on the first data available from the CALIFA survey (150 galaxies). This survey provides integral field spectroscopy of the complete optical extent of each galaxy (up to 2-3 effective radii), with enough resolution to separate individual HII regions and/or aggregations. Nearly $\sim$3000 individual HII regions have been detected. The spectra cover the wavelength range between [OII]3727 and [SII]6731, with a sufficient signal-to-noise to derive the oxygen abundance and star-formation rate associated with each region. In addition, we have computed the integrated and spatially resolved stellar masses (and surface densities), based on SDSS photometric data. We explore the relations between the stellar mass, oxygen abundance and star-formation rate using this dataset. We derive a tight relation between the integrated stellar mass and the gas-phase abundance, with a dispersion smaller than the one already reported in the literature ($\sigma_{\Delta{\rm log(O/H)}}=$0.07 dex). Indeed, this dispersion is only slightly larger than the typical error derived for our oxygen abundances. However, we do not find any secondary relation with the star-formation rate, other than the one induced due to the primary relation of this quantity with the stellar mass. We confirm the result using the $\sim$3000 individual HII regions, for the corresponding local relations. Our results agree with the scenario in which gas recycling in galaxies, both locally and globally, is much faster than other typical timescales, like that of gas accretion by inflow and/or metal loss due to outflows. In essence, late-type/disk dominated galaxies seem to be in a quasi-steady situation, with a behavior similar to the one expected from an instantaneous recycling/closed-box model.Comment: 19 Pages, 8 figures, Accepted for Publishing in Astronomy and Astrophysics (A&A

The CP-conserving two-Higgs-doublet model: the approach to the decoupling limit

A CP-even neutral Higgs boson with Standard-Model-like couplings may be the lightest scalar of a two-Higgs-doublet model. We study the decoupling limit of the most general CP-conserving two-Higgs-doublet model, where the mass of the lightest Higgs scalar is significantly smaller than the masses of the other Higgs bosons of the model. In this case, the properties of the lightest Higgs boson are nearly indistinguishable from those of the Standard Model Higgs boson. The first non-trivial corrections to Higgs couplings in the approach to the decoupling limit are also evaluated. The importance of detecting such deviations in precision Higgs measurements at future colliders is emphasized. We also clarify the case in which a neutral Higgs boson can possess Standard-Model-like couplings in a regime where the decoupling limit does not apply. The two-Higgs-doublet sector of the minimal supersymmetric model illustrates many of the above features.Comment: 54 pages, 2 tables, revtex4 format, some new material added (including elegant forms for the three-Higgs and four-Higgs couplings) and typographical errors fixe

Inhibiting ERK Activation with CI-1040 Leads to Compensatory Upregulation of Alternate MAPKs and Plasminogen Activator Inhibitor-1 following Subtotal Nephrectomy with No Impact on Kidney Fibrosis

Extracellular-signal regulated kinase (ERK) activation by MEK plays a key role in many of the cellular processes that underlie progressive kidney fibrosis including cell proliferation, apoptosis and transforming growth factor β1-mediated epithelial to mesenchymal transition. We therefore assessed the therapeutic impact of ERK1/2 inhibition using a MEK inhibitor in the rat 5/6 subtotal nephrectomy (SNx) model of kidney fibrosis. There was a twentyfold upregulation in phospho-ERK1/2 expression in the kidney after SNx in Male Wistar rats. Rats undergoing SNx became hypertensive, proteinuric and developed progressive kidney failure with reduced creatinine clearance. Treatment with the MEK inhibitor, CI-1040 abolished phospho- ERK1/2 expression in kidney tissue and prevented phospho-ERK1/2 expression in peripheral lymphocytes during the entire course of therapy. CI-1040 had no impact on creatinine clearance, proteinuria, glomerular and tubular fibrosis, and α-smooth muscle actin expression. However, inhibition of ERK1/2 activation led to significant compensatory upregulation of the MAP kinases, p38 and JNK in kidney tissue. CI-1040 also increased the expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasmin-dependent matrix metalloproteinases. Thus inhibition of ERK1/2 activation has no therapeutic effect on kidney fibrosis in SNx possibly due to increased compensatory activation of the p38 and JNK signalling pathways with subsequent upregulation of PAI-1

Span Morphing Using the Compliant Spar

This paper develops and models the Compliant Spar concept that allows the wing span to be varied to provide roll control and enhance the operational performance for a medium altitude long endurance (MALE) UAV. The wing semi-span is split into morphing partitions and the concept maybe incorporated in each partition; however only the tip partition is considered here. The Compliant Spar is made of compliant joints arrange in series to allow the partition to be flexible under axial (spanwise) loads but at the same time stiff enough to resist bending loads. Each compliant joint consists of two concentric overlapping AL 2024-T3 tubes joined together using elastomeric material. Under axial (spanwise) loading, the elastomeric material deforms in shear allowing the overlapping distance between the tubes to vary and hence the length (in the spanwise direction) of the joint/spar to vary. High fidelity modelling of the concept is performed. Then, structural optimisation studies are performed to minimise the axial stiffness and the structural mass of the concept for various design constraints. The flexible skin and actuation system to be used are also addressed