Targeted Deletion of Ptp4a3 Inhibits Colon Carcinogenesis and Angiogenesis

Protein tyrosine phosphatase 4a3 (Ptp4a3) is an enigmatic member of the Ptp4a family of prenylated protein tyrosine phosphatases, which are highly expressed in many human cancers. Despite strong correlations with tumor metastasis and poor patient prognosis, there is very limited understanding of this gene family’s role in malignancy. A gene targeted mouse knockout model for Ptp4a3, the most widely studied Ptp4a family member, was created. Mice deficient for PTP4A3 were grossly normal. However, fewer homozygous-null males were observed at weaning and they maintained a decreased body mass into adulthood. Although PTP4A3 is normally associated with late-stage cancer and metastasis, increased Ptp4a3 mRNA was observed in the colon of C57BL/6J mice immediately following treatment with the carcinogen azoxymethane. A well characterized murine colitis-associated colon cancer model was used to investigate the role of PTP4A3 in malignancy. Wildtype mice treated with azoxymethane and dextran sodium sulfate (AOM/DSS) developed approximately 7-10 tumors per mouse in the distal colon. The resulting tumor tissue had 4-fold more Ptp4a3 mRNA relative to normal colon epithelium and increased PTP4A3 protein. Ptp4a3-null mice developed 50% fewer colon tumors than wildtype mice after exposure to AOM/DSS. Tumors from the Ptp4a3-null mice had elevated levels of both IGF1Rβ and c-MYC compared to tumors replete with PTP4A3, suggesting an enhanced cell signaling pathway engagement in the absence of the phosphatase. Furthermore, c-MYC activity was able to increase Ptp4a3 gene expression in a fibroblast cell culture model. These results provide the first definitive evidence implicating PTP4A3 in colon carcinogenesis and highlight the potential value of the phosphatase as a therapeutic target for early stage malignant disease. Interestingly, PTP4A3 is also expressed in the tumor vasculature and has been proposed to be a direct target of vascular endothelial growth factor (VEGF) signaling in endothelial cells. Compared to wildtype controls, colon tumor tissue isolated from Ptp4a3-null mice revealed reduced microvessel density demonstrated by CD31 staining. Vascular cells derived from Ptp4a3-null tissue explants exhibited decreased invasiveness ex vivo compared to wildtype tissues. When primary endothelial cells were isolated and cultured in vitro, Ptp4a3-null cells displayed less migration compared to wildtype cells and loss of VEGF-induced phosphorylation of SRC protein. Reduced migration and SRC activation were also observed when human endothelial cells were treated with a small molecule inhibitor of PTP4A3. These findings strongly support a role for PTP4A3 as an important contributor to cancer progression as well as endothelial cell function in vivo

Pressure buildup during CO2 injection in brine aquifers using the Forchheimer equation

If geo-sequestration of CO2 is to be employed as a key emissions reduction method in the global effort to mitigate climate change, simple yet robust screening of the risks of disposal in brine aquifers will be needed. There has been significant development of simple analytical and semi-analytical techniques to support screening analysis and performance assessment for potential carbon sequestration sites. These techniques have generally been used to estimate the size of CO2 plumes for the purpose of leakage rate estimation. A common assumption has been that both the fluids and the geological formation are incompressible. Consequently, calculation of pressure distribution requires the specification of an arbitrary radius of influence. In this talk, a new similarity solution is derived using the method of matched asymptotic expansions. By allowing for slight compressibility in the fluids and formation, the solution improves on previous work by not requiring the specification of an arbitrary radius of influence. A large-time approximation of the solution is then extended to account for non-Darcy inertial effects using the Forchheimer equation. Both solutions are verified by comparison with finite difference solutions. The results show that inertial losses will often be comparable, and sometimes greater than, the viscous Darcy-like losses associated with the brine displacement, although this is strongly dependent on formation porosity and permeability

A SINE-based dichotomous key for primate identification

For DNA samples or \u27divorced\u27 tissues, identifying the organism from which they were taken generally requires some type of analytical method. The ideal approach would be robust even in the hands of a novice, requiring minimal equipment, time, and effort. Genotyping SINEs (Short INterspersed Elements) is such an approach as it requires only PCR-related equipment, and the analysis consists solely of interpreting fragment sizes in agarose gels. Modern primate genomes are known to contain lineage-specific insertions of Alu elements (a primate-specific SINE); thus, to demonstrate the utility of this approach, we used members of the Alu family to identify DNA samples from evolutionarily divergent primate species. For each node of a combined phylogenetic tree (56 species; n = 8 [Hominids]; 11 [New World monkeys]; 21 [Old World monkeys]; 2 [Tarsiformes]; and, 14 [Strepsirrhines]), we tested loci (\u3e 400 in total) from prior phylogenetic studies as well as newly identified elements for their ability to amplify in all 56 species. Ultimately, 195 loci were selected for inclusion in this Alu-based key for primate identification. This dichotomous SINE-based key is best used through hierarchical amplification, with the starting point determined by the level of initial uncertainty regarding sample origin. With newly emerging genome databases, finding informative retrotransposon insertions is becoming much more rapid; thus, the general principle of using SINEs to identify organisms is broadly applicable. © 2006 Elsevier B.V. All rights reserved

Frame-Dragging Vortexes and Tidal Tendexes Attached to Colliding Black Holes: Visualizing the Curvature of Spacetime

When one splits spacetime into space plus time, the spacetime curvature (Weyl tensor) gets split into an "electric" part E_{jk} that describes tidal gravity and a "magnetic" part B_{jk} that describes differential dragging of inertial frames. We introduce tools for visualizing B_{jk} (frame-drag vortex lines, their vorticity, and vortexes) and E_{jk} (tidal tendex lines, their tendicity, and tendexes), and also visualizations of a black-hole horizon's (scalar) vorticity and tendicity. We use these tools to elucidate the nonlinear dynamics of curved spacetime in merging black-hole binaries.Comment: 4 pages, 5 figure

Visualizing Spacetime Curvature via Frame-Drag Vortexes and Tidal Tendexes I. General Theory and Weak-Gravity Applications

When one splits spacetime into space plus time, the Weyl curvature tensor (vacuum Riemann tensor) gets split into two spatial, symmetric, and trace-free (STF) tensors: (i) the Weyl tensor's so-called "electric" part or tidal field, and (ii) the Weyl tensor's so-called "magnetic" part or frame-drag field. Being STF, the tidal field and frame-drag field each have three orthogonal eigenvector fields which can be depicted by their integral curves. We call the integral curves of the tidal field's eigenvectors tendex lines, we call each tendex line's eigenvalue its tendicity, and we give the name tendex to a collection of tendex lines with large tendicity. The analogous quantities for the frame-drag field are vortex lines, their vorticities, and vortexes. We build up physical intuition into these concepts by applying them to a variety of weak-gravity phenomena: a spinning, gravitating point particle, two such particles side by side, a plane gravitational wave, a point particle with a dynamical current-quadrupole moment or dynamical mass-quadrupole moment, and a slow-motion binary system made of nonspinning point particles. [Abstract is abbreviated; full abstract also mentions additional results.]Comment: 25 pages, 20 figures, matches the published versio

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL

The cellular and synaptic architecture of the mechanosensory dorsal horn

The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties. Remarkably, LTMRs form synapses on between four and 11 LTMR-RZ interneuron subtypes, while each LTMR-RZ interneuron subtype samples inputs from at least one to three LTMR classes, as well as spinal cord interneurons and corticospinal neurons. Thus, the LTMR-RZ is a somatosensory processing region endowed with a neuronal complexity that rivals the retina and functions to pattern the activity of ascending touch pathways that underlie tactile perception

Murine Typhus and Febrile Illness, Nepal

Murine typhus was diagnosed by PCR in 50 (7%) of 756 adults with febrile illness seeking treatment at Patan Hospital in Kathmandu, Nepal. Of patients with murine typhus, 64% were women, 86% were residents of Kathmandu, and 90% were unwell during the winter. No characteristics clearly distinguished typhus patients from those with blood culture–positive enteric fever