The αvβ6 Integrin in cancer

The epithelial restricted αvβ6 integrin is known to have minimal expression in healthy tissue and to be upregulated in cancer and healing wounds. This thesis explores the role of αvβ6 in cancer and tests the hypothesis that αvβ6 has a prognostic and therapeutic utility in cancer. Using immunohistochemistry, increased αvβ6 expression was found in nonmelanoma skin cancers (NMSC), particularly in morphoeic type basal cell carcinoma. In cell culture experiments, αvβ6 was found to activate TGF-β and promote myofibroblast differentiation, producing a tumour stroma rich in smooth muscle actin (SMA). These findings prompted a study of αvβ6 and SMA as prognostic indicators in oral squamous cell carcinoma (OSCC). A study of 282 cases of OSCC found that although αvβ6 was not a prognostic marker, patients with high SMA levels had a highly significant increased risk of disease specific mortality (HR 3.06 [CI 1.65-5.66], p<0.001). Next, the utility of αvβ6 as a target was explored through the development of a single chain antibody fragment (scFv) specific for αvβ6. The scFv was tested for the delivery of targeted magnetic fluid hyperthermia (MFH), an experimental cancer treatment based on the generation of heat by magnetic nanoparticles when placed within an alternating magnetic field. The αvβ6-specific scFv (B6.3) was manufactured and high ligand specificity confirmed on ELISA and FACS analysis. B6.3 was successfully conjugated to two alternative iron nanoparticles. In-vitro studies demonstrated increased cellular uptake of scFv-nanoparticle complexes and greater cellular toxicity on exposure to MFH compared to nanoparticles alone. In conclusion, αvβ6 is a potential target for therapy in NMSC and OSCC. SMA is found to be an independent prognostic marker in OSCC and αvβ6 identified as a proinvasive factor in morphoeic BCC. Finally, the production αvβ6 specific scFvs and use for in-vitro MFH potentiates the development of αvβ6 targeted MFH cancer therapy

The Emission of Electromagnetic Radiation from Charges Accelerated by Gravitational Waves and its Astrophysical Implications

We provide calculations and theoretical arguments supporting the emission of electromagnetic radiation from charged particles accelerated by gravitational waves (GWs). These waves have significant indirect evidence to support their existence, yet they interact weakly with ordinary matter. We show that the induced oscillations of charged particles interacting with a GW, which lead to the emission of electromagnetic radiation, will also result in wave attenuation. These ideas are supported by a small body of literature, as well as additional arguments for particle acceleration based on GW memory effects. We derive order of magnitude power calculations for various initial charge distributions accelerated by GWs. The resulting power emission is extremely small for all but very strong GWs interacting with large quantities of charge. If the results here are confirmed and supplemented, significant consequences such as attenuation of early universe GWs could result. Additionally, this effect could extend GW detection techniques into the electromagnetic regime. These explorations are worthy of study to determine the presence of such radiation, as it is extremely important to refine our theoretical framework in an era of active GW astrophysics.Comment: Appears in Gravitational Wave Astrophysics, Editor C.F. Sopuerta, Astrophysics and Space Science Proceedings, Volume 40. ISBN 978-3-319-10487-4. Springer International Publishing Switzerland, 2015, p. 30

Heterozygous mutations in HSD17B4 cause juvenile peroxisomal D-bifunctional protein deficiency

Objective: To determine the genetic cause of slowly progressive cerebellar ataxia, sensorineural deafness, and hypergonadotropic hypogonadism in 5 patients from 3 different families. Methods: The patients comprised 2 sib pairs and 1 sporadic patient. Clinical assessment included history, physical examination, and brain MRI. Linkage analysis was performed separately on the 2 sets of sib pairs using single nucleotide polymorphism microarrays, followed by analysis of the intersection of the regions. Exome sequencing was performed on 1 affected patient with variant filtering and prioritization undertaken using these intersected regions. Results: Using a combination of sequencing technologies, we identified compound heterozygous mutations in HSD17B4 in all 5 affected patients. In all 3 families, peroxisomal D-bifunctional protein (DBP) deficiency was caused by compound heterozygosity for 1 nonsense/deletion mutation and 1 missense mutation. Conclusions: We describe 5 patients with juvenile DBP deficiency from 3 different families, bringing the total number of reported patients to 14, from 8 families. This report broadens and consolidates the phenotype associated with juvenile DBP deficiency

Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss

Objective: To determine the molecular basis of a severe neurologic disorder in a large consanguineous family with complete agenesis of the corpus callosum (ACC), pontocerebellar hypoplasia (PCH), and peripheral axonal neuropathy. Methods: Assessment included clinical evaluation, neuroimaging, and nerve conduction studies (NCSs). Linkage analysis used genotypes from 7 family members, and the exome of 3 affected siblings was sequenced. Molecular analyses used Sanger sequencing to perform segregation studies and cohort analysis and Western blot of patient-derived cells. Results: Affected family members presented with postnatal microcephaly and profound developmental delay, with early death in 3. Neuroimaging, including a fetal MRI at 30 weeks, showed complete ACC and PCH. Clinical evaluation showed areflexia, and NCSs revealed a severe axonal neuropathy in the 2 individuals available for electrophysiologic study. A novel homozygous stopgain mutation in adenosine monophosphate deaminase 2 (AMPD2) was identified within the linkage region on chromosome 1. Molecular analyses confirmed that the mutation segregated with disease and resulted in the loss of AMPD2. Subsequent screening of a cohort of 42 unrelated individuals with related imaging phenotypes did not reveal additional AMPD2 mutations. Conclusions: We describe a family with a novel stopgain mutation in AMPD2. We expand the phenotype recently described as PCH type 9 to include progressive postnatal microcephaly, complete ACC, and peripheral axonal neuropathy. Screening of additional individuals with related imaging phenotypes failed to identify mutations in AMPD2, suggesting that AMPD2 mutations are not a common cause of combined callosal and pontocerebellar defects

Larval dispersion along an axially symmetric mid-ocean ridge

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Deep Sea Research Part I: Oceanographic Research Papers 57 (2010): 880-892, doi:10.1016/j.dsr.2010.04.003.We investigated planktonic larval transport processes along an axially symmetric mid-ocean ridge with characteristics similar to that of the East Pacific Rise (EPR) segment at 9-10°N. The hydrodynamic basis for this study is a primitive equation model implemented in two dimensions (depth and across-ridge), forced at the open boundaries to provide suitably realistic simulation of currents observed on the EPR ridge crest from May to November 1999. Three-dimensional trajectories of numerical larvae are computed assuming homogeneity in currents in the along-ridge direction. Larval dispersal fluctuates significantly in time. Transport distance decreases systematically with height above the bottom where numerical larvae are less subject to strong currents along the flanks of the ridge. The probability that the simulated larvae will be located near the ridge crest at settlement depends strongly on their behavioral characteristics (vertical position in the water column during the larval stage) and the length of their precompetency period.We gratefully acknowledge the support of NSF grant OCE-0424953, which funded the Larval Dispersion along the Deep East Pacific Rise (LADDER) project. JWL was supported by the National Oceanic and Atmospheric Administration's (NOAA) Vents Program and by NOAA’s Pacific Marine Environmental Laboratory

Oracle-based optimization applied to climate model calibration

In this paper, we show how oracle-based optimization can be effectively used for the calibration of an intermediate complexity climate model. In a fully developed example, we estimate the 12 principal parameters of the C-GOLDSTEIN climate model by using an oracle- based optimization tool, Proximal-ACCPM. The oracle is a procedure that finds, for each query point, a value for the goodness-of-fit function and an evaluation of its gradient. The difficulty in the model calibration problem stems from the need to undertake costly calculations for each simulation and also from the fact that the error function used to assess the goodness-of-fit is not convex. The method converges to a Fbest fit_ estimate over 10 times faster than a comparable test using the ensemble Kalman filter. The approach is simple to implement and potentially useful in calibrating computationally demanding models based on temporal integration (simulation), for which functional derivative information is not readily available

Narrative inquiry into (re)imagining alternative schools: a case study of Kevin Gonzales.

Although there are many alternative schools that strive for the successful education for their students, negative images of alternative schools persist. While some alternative schools are viewed as “idealistic havens,” many are viewed as “dumping grounds,” or “juvenile detention centers.” Employing narrative inquiry, this article interrogates how a student, Kevin Gonzales, experiences his alternative education and raises questions about the role of alternative schools. Kevin Gonzales’s story is presented in a literary form of biographical journal to provide a “metaphoric loft” that helps us imagine other students like Kevin. This, in turn, provokes us to examine our current educational practice, and to (re)imagine ways in which alternative education can provide the best possible educational experiences for disenfranchised students who are increasingly underserved by the public education system

Multiple excitation modes in Hf 163

Excited states of Hf163 were populated using the Zr94(Ge74,5n) reaction and the decay γ rays were measured with the Gammasphere spectrometer. Two previously known bands were extended to higher spins, and nine new bands were identified. In addition to bands associated with three- and five-quasiparticle configurations, two γ-vibrational bands coupled to the i13/2 excitation were also observed. The lowest level of a newly identified, negative-parity band is proposed to be the ground state of the nucleus. A systematic delay of the high-spin proton crossing frequency with increasing quadrupole deformation from Hf162 to Hf172 was established. Extensive band searches failed to reveal a triaxial, strongly deformed structure in Hf163 similar to the one observed in several nuclei around A∼165

A Model for the Development of the Rhizobial and Arbuscular Mycorrhizal Symbioses in Legumes and Its Use to Understand the Roles of Ethylene in the Establishment of these two Symbioses

We propose a model depicting the development of nodulation and arbuscular mycorrhizae. Both processes are dissected into many steps, using Pisum sativum L. nodulation mutants as a guideline. For nodulation, we distinguish two main developmental programs, one epidermal and one cortical. Whereas Nod factors alone affect the cortical program, bacteria are required to trigger the epidermal events. We propose that the two programs of the rhizobial symbiosis evolved separately and that, over time, they came to function together. The distinction between these two programs does not exist for arbuscular mycorrhizae development despite events occurring in both root tissues. Mutations that affect both symbioses are restricted to the epidermal program. We propose here sites of action and potential roles for ethylene during the formation of the two symbioses with a specific hypothesis for nodule organogenesis. Assuming the epidermis does not make ethylene, the microsymbionts probably first encounter a regulatory level of ethylene at the epidermis–outermost cortical cell layer interface. Depending on the hormone concentrations there, infection will either progress or be blocked. In the former case, ethylene affects the cortex cytoskeleton, allowing reorganization that facilitates infection; in the latter case, ethylene acts on several enzymes that interfere with infection thread growth, causing it to abort. Throughout this review, the difficulty of generalizing the roles of ethylene is emphasized and numerous examples are given to demonstrate the diversity that exists in plants

Reply to: Possible overestimation of isomer depletion due to contamination

We appreciate the interest of Guo et al., the points that they raise, and the opportunity that we have to provide additional details that are not included in ref. This allows us to strengthen our experimental case while, in parallel, recent developments are improving our theoretical understanding of nuclear excitation by electron capture (NEEC), such as the exploration of a substantial increase in predicted NEEC probability when considering capture by an ion in an excited state (S. Gargiulo et al., submitted) or the impact of the momentum distribution of target electrons (J.R. et al., submitted). In the accompanying Comment, Guo et al. focus on whether potential background contributions were underestimated in our analysis. As discussed below, these concerns are mostly unwarranted; aside from a small systematic uncertainty that could possibly slightly reduce our reported NEEC excitation probability of Pexc = 0.010(3), our original conclusions still stand