TDP-43 and FUS mislocalization in VCP mutant motor neurons is reversed by pharmacological inhibition of the VCP D2 ATPase domain

RNA binding proteins have been shown to play a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Mutations in valosin-containing protein (VCP/p97) cause ALS and exhibit the hallmark nuclear-to-cytoplasmic mislocalization of RNA binding proteins (RBPs). However, the mechanism by which mutations in VCP lead to this mislocalization of RBPs remains incompletely resolved. To address this, we used human-induced pluripotent stem cell-derived motor neurons carrying VCP mutations. We first demonstrate reduced nuclear-to-cytoplasmic ratios of transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS) and splicing factor proline and glutamine rich (SFPQ) in VCP mutant motor neurons. Upon closer analysis, we also find these RBPs are mislocalized to motor neuron neurites themselves. To address the hypothesis that altered function of the D2 ATPase domain of VCP causes RBP mislocalization, we used pharmacological inhibition of this domain in control motor neurons and found this does not recapitulate RBP mislocalization phenotypes. However, D2 domain inhibition in VCP mutant motor neurons was able to robustly reverse mislocalization of both TDP-43 and FUS, in addition to partially relocalizing SFPQ from the neurites. Together these results argue for a gain-of-function of D2 ATPase in VCP mutant human motor neurons driving the mislocalization of TDP-43 and FUS. Our data raise the intriguing possibility of harnessing VCP D2 ATPase inhibitors in the treatment of VCP-related ALS

AXL modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer

The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro, genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer

Quantum generalized constant coupling model for geometrically frustrated antiferromagnets

A generalized constant coupling approximation for quantum geometrically frustrated antiferromagnets is presented. Starting from a frustrated unit, we introduce the interactions with the surrounding units in terms of an internal effective field which is fixed by a self consistency condition. Results for the static magnetic susceptibility and specific heat are compared with previous results in the framework of this same model for the classical limit. The range of applicability of the model is discussed.Comment: 11 pages, 6 figures, 1 Tables, typeset using RevTeX 4, small correction in Table

Quantification of ovarian lesion and fallopian tube vasculature using optical-resolution photoacoustic microscopy

The heterogeneity in the pathological and clinical manifestations of ovarian cancer is a major hurdle impeding early and accurate diagnosis. A host of imaging modalities, including Doppler ultrasound, MRI, and CT, have been investigated to improve the assessment of ovarian lesions. We hypothesized that pathologic conditions might affect the ovarian vasculature and that these changes might be detectable by optical-resolution photoacoustic microscopy (OR-PAM). In our previous work, we developed a benchtop OR-PAM and demonstrated it on a limited set of ovarian and fallopian tube specimens. In this study, we collected data from over 50 patients, supporting a more robust statistical analysis. We then developed an efficient custom analysis pipeline for characterizing the vascular features of the samples, including the mean vessel diameter, vascular density, global vascular directionality, local vascular definition, and local vascular tortuosity/branchedness. Phantom studies using carbon fibers showed that our algorithm was accurate within an acceptable error range. Between normal ovaries and normal fallopian tubes, we observed significant differences in five of six extracted vascular features. Further, we showed that distinct subsets of vascular features could distinguish normal ovaries from cystic, fibrous, and malignant ovarian lesions. In addition, a statistically significant difference was found in the mean vascular tortuosity/branchedness values of normal and abnormal tubes. The findings support the proposition that OR-PAM can help distinguish the severity of tubal and ovarian pathologies

Natural Nuclear Reactor Oklo and Variation of Fundamental Constants Part 1: Computation of Neutronics of Fresh Core

Using modern methods of reactor physics we have performed full-scale calculations of the natural reactor Oklo. For reliability we have used recent version of two Monte Carlo codes: Russian code MCU REA and world wide known code MCNP (USA). Both codes produce similar results. We have constructed a computer model of the reactor Oklo zone RZ2 which takes into account all details of design and composition. The calculations were performed for three fresh cores with different uranium contents. Multiplication factors, reactivities and neutron fluxes were calculated. We have estimated also the temperature and void effects for the fresh core. As would be expected, we have found for the fresh core a significant difference between reactor and Maxwell spectra, which was used before for averaging cross sections in the Oklo reactor. The averaged cross section of Sm-149 and its dependence on the shift of resonance position (due to variation of fundamental constants) are significantly different from previous results. Contrary to results of some previous papers we find no evidence for the change of the fine structure constant in the past and obtain new, most accurate limits on its variation with time: -4 10^{-17}year^{-1} < d alpha/dt/alpha < 3 10^{-17} year^{-1} A further improvement in the accuracy of the limits can be achieved by taking account of the core burnup. These calculations are in progress.Comment: 25 pages, 14 figures, 12 tables, minor corrections, typos correcte

A CCR4 antagonist reverses the tumor-promoting microenvironment of renal cancer

CRUK programme grant C587/A16354 and a research grant from Affitech AS.The study was supported by Cancer Research UK (CRUK) programme grant C587/A16354 and a research grant from Affitech AS

Frustration driven lattice distortion; an NMR investigation of Y2Mo2O7

We have investigated the 89Y NMR spectrum and spin lattice relaxation, T1, in the magnetically frustrated pyrochlore Y2Mo2O7. We find that upon cooling the spectrum shifts, and broadens asymmetrically. A detailed examination of the low T spectrum reveals that it is constructed from multiple peaks, each shifted by a different amount. We argue that this spectrum is due to discrete lattice distortions, and speculate that these distortions relieve the frustration and reduce the system's energy.Comment: To be published in Phys. Rev. Let

Assessing the transferability of the regional climate model REMO to different COordinated Regional Climate Downscaling EXperiment (CORDEX) Regions

The transferability of the regional climate model REMO with a standard setup over different regions of the world has been evaluated. The study is based on the idea that the modeling parameters and parameterizations in a regional climate model should be robust to adequately simulate the major climatic characteristic of different regions around the globe. If a model is not able to do that, there might be a chance of an “overtuning” to the “home-region”, which means that the model physics are tuned in a way that it might cover some more fundamental errors, e.g., in the dynamics. All simulations carried out in this study contribute to the joint effort by the international regional downscaling community called COordinated Regional climate Downscaling EXperiment (CORDEX). REMO has been integrated over six CORDEX domains forced with the so-called perfect boundary conditions obtained from the global reanalysis dataset ERA-Interim for the period 1989 to 2008. These six domains include Africa, Europe, North America, South America, West Asia and the Mediterranean region. Each of the six simulations was conducted with the identical model setup which allows investigating the transferability of a single model to regions with substantially different climate characteristics. For the consistent evaluation over the different domains, a new evaluation framework is presented by combining the Köppen-Trewartha climate classification with temperature-precipitation relationship plots and a probability density function (PDF) skill score method. The evaluation of the spatial and temporal characteristics of simulated precipitation and temperature, in comparison to observational datasets, shows that REMO is able to simulate the mean annual climatic features over all the domains quite reasonably, but still some biases remain. The regions over the Amazon and near the coast of major upwelling regions have a significant warm bias. Wet and dry biases appear over the mountainous regions and East Africa, respectively. The temperature over South America and precipitation over the tundra and highland climate of West Asia are misrepresented. The probable causes leading to these biases are discussed and ideas for improvements are suggested. The annual cycle of precipitation and temperature of major catchments in each domain are also well represented by REMO. The model has performed well in simulating the inter- and intra-seasonal characteristics of different climate types in different regions. Moreover, the model has a high ability in representing the general characteristics of different climate types as measured by the probability density function (PDF) skill score method. Although REMO seems to perform best over its home domain in Europe (domain of development and testing), the model has simulated quite well the climate characteristics of other regions with the same set of parameterization options. Therefore, these results lead us to the conclusion that REMO is well suited for long-term climate change simulations to examine projected future changes in all these regions