1,029 research outputs found
A Premium on Good Judgment
This is an institution with a great tradition, and I am honored to have been asked to address you on this day—an honor made all the greater given the distinguished individuals who preceded me in years past. I will be characteristically blunt: you are departing the War College at a time of considerable international turmoil. Ours is a time of war, or to be more precise, wars—a global war on terrorism, a war in Afghanistan, and a war in Iraq, not to mention a conflict in Colombia and conflicts in several countries in Africa. Those who predicted that the world after the end of the Cold War would be tranquil were wrong, or at least premature. One result is that military force, par- ticularly American military force, remains relevant, and then some
Switching the sphingolipid rheostat in the treatment of diabetes and cancer comorbidity from a problem to an advantage
© 2015 Nikolas K. Haass et al. Cancer and diabetes are among the most common diseases in western societies. Epidemiological studies have shown that diabetic patients have a significantly higher risk of developing a number of different types of cancers and that individuals with comorbidity (cancer and diabetes/prediabetes) have a poorer prognosis relative to nondiabetic cancer patients. The increasing frequency of comorbidity of cancer and diabetes mellitus, mainly type 2 diabetes, has driven the development of therapeutic interventions that target both disease states. There is strong evidence to suggest that balancing the sphingolipid rheostat, ceramide - sphingosine - sphingosine-1-phosphate (S1P) is crucial in the prevention of diabetes and cancer and sphingosine kinase/S1P modulators are currently under development for the treatment of cancer and diabetes. This paper will highlight some of the complexities inherent in the use of the emerging sphingosine kinase/S1P modulators in the treatment of comorbidity of diabetes and cancer
Pantophysin is a ubiquitously expressed synaptophysin homologue and defines constitutive transport vesicles
FGFR2-activating mutations disrupt cell polarity to potentiate migration and invasion in endometrial cancer cell models
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that control a diverse range of biological processes during development and in adult tissues. We recently reported that somatic FGFR2 mutations are associated with shorter survival in endometrial cancer. However, little is known about how these FGFR2 mutations contribute to endometrial cancer metastasis. Here, we report that expression of the activating mutations FGFR2N550K and FGFR2Y376C in an endometrial cancer cell model induce Golgi fragmentation, and loss of polarity and directional migration. In mutant FGFR2-expressing cells, this was associated with an inability to polarise intracellular pools of FGFR2 towards the front of migrating cells. Such polarization defects were exacerbated in three-dimensional culture, where FGFR2 mutant cells were unable to form well-organised acini, instead undergoing exogenous ligand-independent invasion. Our findings uncover collective cell polarity and invasion as common targets of disease-associated FGFR2 mutations that lead to poor outcome in endometrial cancer patients
Decoupling of optoelectronic properties from morphological changes in sodium treated kesterite thin film solar cells
Sodium is typically used during the synthesis of kesterite thin films to enhance the performance of solar cells. As sodium tends to affect grain growth and morphology, it is difficult to analyse solely the electronic effects of sodium as dopant. To decouple the structural and electronic effects from each other, two processes were designed in this work to successfully incorporate sodium into a vacuum-processed Cu2ZnSnSe4absorber without changing the morphology. A thin layer of NaF is deposited before precursor deposition (Pre-NaF) or after absorber synthesis to undergo a post deposition treatment (NaF-PDT). While composition and distribution of matrix elements remain unchanged, the sodium concentration is increased upon sodium treatment up to 140 ppm as measured by inductively coupled plasma mass spectrometry. X-ray photoelectron spectroscopy showed that the surface composition was not altered. Within its detection limit, sodium was not present at the absorber surface. For a Pre-NaF sample measured with atom probe tomography a sodium concentration of 30 ppm was measured in a grain, suggesting that sodium might segregate at grain boundaries. The additional sodium content in the film leads to an increased acceptor concentration, which results in improved open-circuit voltage and fill factor.Financial support from the Swiss National Science Foundation (SNF)
in the network of the Indo-Swiss Joint Research Programme (ISJRP)
[IZLIZ2_157140/1] is gratefully acknowledged. T. Schwarz is grateful for the support of the
German Research Foundation (DFG) [Contract GA 2450/1-1]. R.
Caballero acknowledges financial support from Spanish MINECO
within the Ramón y Cajal program [RYC-2011-08521], MINECO project
WINCOST [ENE2016-80788-C5-2-R] and from Spanish Ministry of
Education, Culture and Sport within the José Castillejo program [CAS
15/00070
Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration
BACKGROUND: The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration. METHODS: We included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer's disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years). RESULTS: Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen's f2 = 0.137) and memory decline (p = 0.006, Cohen's f2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen's f2 = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ1-42, p-tau181). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group. CONCLUSION: Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD
Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric aggregates
The presence of oligomeric aggregates, which is often observed during the
process of amyloid formation, has recently attracted much attention since it
has been associated with neurodegenerative conditions such as Alzheimer's and
Parkinson's diseases. We provide a description of a sequence-indepedent
mechanism by which polypeptide chains aggregate by forming metastable
oligomeric intermediate states prior to converting into fibrillar structures.
Our results illustrate how the formation of ordered arrays of hydrogen bonds
drives the formation of beta-sheets within the disordered oligomeric aggregates
that form early under the effect of hydrophobic forces. Initially individual
beta-sheets form with random orientations, which subsequently tend to align
into protofilaments as their lengths increases. Our results suggest that
amyloid aggregation represents an example of the Ostwald step rule of first
order phase transitions by showing that ordered cross-beta structures emerge
preferentially from disordered compact dynamical intermediate assemblies.Comment: 14 pages, 4 figure
BACE1 Processing of NRG1 Type III Produces a Myelin-Inducing Signal but Is Not Essential for the Stimulation of Myelination
Myelin sheath thickness is precisely adjusted to axon caliber, and in the peripheral nervous system, neuregulin 1 (NRG1) type III is a key regulator of this process. It has been proposed that the protease BACE1 activates NRG1 dependent myelination. Here, we characterize the predicted product of BACE1-mediated NRG1 type III processing in transgenic mice. Neuronal overexpression of a NRG1 type III-variant, designed to mimic prior cleavage in the juxtamembrane stalk region, induces hypermyelination in vivo and is sufficient to restore myelination of NRG1 type III-deficient neurons. This observation implies that the NRG1 cytoplasmic domain is dispensable and that processed NRG1 type III is sufficient for all steps of myelination. Surprisingly, transgenic neuronal overexpression of full-length NRG1 type III promotes hypermyelination also in BACE1 null mutant mice. Moreover, NRG1 processing is impaired but not abolished in BACE1 null mutants. Thus, BACE1 is not essential for the activation of NRG1 type III to promote myelination. Taken together, these findings suggest that multiple neuronal proteases collectively regulate NRG1 processing. © 2011 Wiley Periodicals, Inc
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