Unequal Playing Time

Unequal Playing Time In his book The American College Town, Blake Gumprecht claims one of the defining features of college towns is that they are more progressive, liberal-minded, and socially-blended spaces. However, this is not the type of college town that appears in Marshall University’s collection of archives. Throughout the years, many groups of students were often overlooked due to minority population status. This presentation examines the lack of recognition for one such group, in particular, women’s athletics during the 1920’s. Student yearbooks published between 1920 and 1930 were analyzed for content featuring men versus women’s athletics. At the start of the decade in 1920, female athletes were given a one-page segment placed at the end of the athletics section which discussed the athletic classes offered to women. During that same year, there happened to be nine women and seven men on the yearbook’s editorial board. In the following years, the number of women on the editorial board decreased and despite the girl’s athletic association being the largest student organization on campus, so did the amount of recognition for the association. One could easily surmise that the men on the yearbook staff often overlooked women when it came to athletics. However, when men were the bulk of the yearbook editors, women were often most noted for their beauty and popularity, rather than their athletic achievements. Such inconsistencies directly contrast with Gumprecht’s definition of a college town being broadminded and socially incorporated

Westernmost Grand Canyon incision: Testing thermochronometric resolution

The timing of carving of Grand Canyon has been debated for over 100 years with competing endmember hypotheses advocating for either a 70 Ma (“old”) or <6 Ma (“young”) Grand Canyon. Several geological constraints appear to support a “young” canyon model, but thermochronometric measures of cooling history and corresponding estimates of landscape evolution have been in debate. In particular, 4He/3He thermochronometric data record the distribution of radiogenic 4He (from the 238U, 235U and 232Th decay series) within an individual apatite crystal and thus are highly sensitive to the thermal history corresponding to landscape evolution. However, there are several complicating factors that make interpreting such data challenging in geologic scenarios involving reheating. Here, we analyze new data that provide measures of the cooling of basement rocks at the base of westernmost Grand Canyon, and use these data as a testbed for exploring the resolving power and limitations of 4He/3He data in general. We explore a range of thermal histories and find that these data are most consistent with a “young” Grand Canyon. A problem with the recovered thermal history, however, is that burial temperatures are under predicted based on sedimentological evidence. A solution to this problem is to increase the resistance of alpha recoil damage to annealing, thus modifying He diffusion kinetics, allowing for higher temperatures throughout the thermal history. This limitation in quantifying radiation damage (and hence crystal retentivity) introduces non-uniqueness to interpreting time–temperature paths in rocks that resided in the apatite helium partial retention zone for long durations. Another source of non-uniqueness, is due to unknown U and Th distributions within crystals. We show that for highly zoned with a decrease in effective U of 20 ppm over the outer 80% of the radius of the crystal, the 4He/3He data could be consistent with an “old” canyon model. To reduce this non-uniqueness, we obtain U and Th zonation information for separate crystals from the same rock sample through LA-ICP-MS analysis. The observed U and Th distributions are relatively uniform and not strongly zoned, thus supporting a “young” canyon model interpretation of the 4He/3He data. Furthermore, we show that for the mapped zonation, the difference between predicted 4He/3He data for a uniform crystal and a 3D model of the crystal are minimal, highlighting that zonation is unlikely to lead us to falsely infer an “old” Grand Canyon

Expandable and Rapidly Differentiating Human Induced Neural Stem Cell Lines for Multiple Tissue Engineering Applications

Limited availability of human neurons poses a significant barrier to progress in biological and preclinical studies of the human nervous system. Current stem cell-based approaches of neuron generation are still hindered by prolonged culture requirements, protocol complexity, and variability in neuronal differentiation. Here we establish stable human induced neural stem cell (hiNSC) lines through the direct reprogramming of neonatal fibroblasts and adult adipose-derived stem cells. These hiNSCs can be passaged indefinitely and cryopreserved as colonies. Independently of media composition, hiNSCs robustly differentiate into TUJ1-positive neurons within 4 days, making them ideal for innervated co-cultures. In vivo, hiNSCs migrate, engraft, and contribute to both central and peripheral nervous systems. Lastly, we demonstrate utility of hiNSCs in a 3D human brain model. This method provides a valuable interdisciplinary tool that could be used to develop drug screening applications as well as patient-specific disease models related to disorders of innervation and the brain

Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy

Mesial temporal lobe epilepsy (mTLE) is the most common form of epilepsy, believed to arise in part from compromised GABAergic inhibition. The neuronal specific K+/Cl− co-transporter 2 (KCC2) is a critical determinant of the efficacy of GABAergic inhibition and deficits in its activity are observed in mTLE patients and animal models of epilepsy. To test if reductions of KCC2 activity directly contribute to the pathophysiology of mTLE, we locally ablated KCC2 expression in a subset of principal neurons within the adult hippocampus. Deletion of KCC2 resulted in compromised GABAergic inhibition and the development of spontaneous, recurrent generalized seizures. Moreover, local ablation of KCC2 activity resulted in hippocampal sclerosis, a key pathological change seen in mTLE. Collectively, our results demonstrate that local deficits in KCC2 activity within the hippocampus are sufficient to precipitate mTLE

KCC2 is required for the survival of mature neurons but not for their development

The K+/Cl- co-transporter KCC2 (SLC12A5) allows mature neurons in the CNS to maintain low intracellular Cl- levels that are critical in mediating fast hyperpolarizing synaptic inhibition via type A γ-aminobutyric acid receptors (GABAARs). In accordance with this, compromised KCC2 activity results in seizures, but whether such deficits directly contribute to the subsequent changes in neuronal structure and viability that lead to epileptogenesis, remains to be assessed. Canonical hyperpolarizing GABAAR currents develop postnatally which reflect a progressive increase in KCC2 expression levels and activity. To investigate the role that KCC2 plays in regulating neuronal viability and architecture we have conditionally ablated KCC2 expression in developing and mature neurons. Decreasing KCC2 expression in mature neurons resulted in the rapid activation of the extrinsic apoptotic pathway. Intriguingly, direct pharmacological inhibition of KCC2 in mature neurons was sufficient to rapidly induce apoptosis, an effect that was not abrogated via blockade of neuronal depolarization using Tetrodotoxin (TTX). In contrast, ablating KCC2 expression in immature neurons had no discernable effects on their subsequent development, arborization or dendritic structure. However, removing KCC2 in immature neurons was sufficient to ablate the subsequent postnatal development of hyperpolarizing GABAAR currents. Collectively, our results demonstrate that KCC2 plays a critical role in neuronal survival by limiting apoptosis, and mature neurons are highly sensitive to the loss of KCC2 function. In contrast, KCC2 appears to play a minimal role in mediating neuronal development or architecture

Advantages of doubly polished thin sections for the study of microfossils in volcanic rock

Doubly polished thin sections, originally prepared for fluid inclusion studies, present great advantages in the study of microfossils in volcanic rocks. Better visibility and light conditions, variation in thickness of the thin sections and the possibility to combine fluid inclusion studies with microfossil studies lead to a wide range of advantages over ordinary thin sections. This includes the study of morphology, internal microstructures, colonies, association with the substrate that microfossils are attached to and geological and environmental context in which the microfossil once lived. When meeting the criteria of microfossil recognition the advantages of doubly polished thin sections are substantial and can be crucial in distinguishing between biogenic microfossils and abiotically formed abiomorphs

External Learning Opportunities and the Diffusion of Process Innovations to Small Firms: The Case of Programmable Automation

In this chapter, we are concerned with explaining which types of firms have failed to adopt well-known improvements in process technology. This problem has, of course, been the underlying concern of all studies of diffusion “to rationalize why, if a new technology is superior, it is not taken up by all potential adopters” (Stoneman, 1983). Drawing on various theoretical perspectives, we identify a number of different barriers to adoption. With data collected from a 1987 nationally representative sample of US establishments in 21 metal-working and machinery manufacturing industries, we then construct a multivariate logistic regression model to empirically test for the effects of these factors on the likelihood of adoption of a particular process innovation, namely programmable automation (PA) machine tools

A model for transition of 5 '-nuclease domain of DNA polymerase I from inert to active modes

Bacteria contain DNA polymerase I (PolI), a single polypeptide chain consisting of similar to 930 residues, possessing DNA-dependent DNA polymerase, 3'-5' proofreading and 5'-3' exonuclease (also known as flap endonuclease) activities. PolI is particularly important in the processing of Okazaki fragments generated during lagging strand replication and must ultimately produce a double-stranded substrate with a nick suitable for DNA ligase to seal. PolI's activities must be highly coordinated both temporally and spatially otherwise uncontrolled 5'-nuclease activity could attack a nick and produce extended gaps leading to potentially lethal double-strand breaks. To investigate the mechanism of how PolI efficiently produces these nicks, we present theoretical studies on the dynamics of two possible scenarios or models. In one the flap DNA substrate can transit from the polymerase active site to the 5'-nuclease active site, with the relative position of the two active sites being kept fixed; while the other is that the 5'-nuclease domain can transit from the inactive mode, with the 5'-nuclease active site distant from the cleavage site on the DNA substrate, to the active mode, where the active site and substrate cleavage site are juxtaposed. The theoretical results based on the former scenario are inconsistent with the available experimental data that indicated that the majority of 5'-nucleolytic processing events are carried out by the same PolI molecule that has just extended the upstream primer terminus. By contrast, the theoretical results on the latter model, which is constructed based on available structural studies, are consistent with the experimental data. We thus conclude that the latter model rather than the former one is reasonable to describe the cooperation of the PolI's polymerase and 5'-3' exonuclease activities. Moreover, predicted results for the latter model are presented

Parameter identification problems in the modelling of cell motility

We present a novel parameter identification algorithm for the estimation of parameters in models of cell motility using imaging data of migrating cells. Two alternative formulations of the objective functional that measures the difference between the computed and observed data are proposed and the parameter identification problem is formulated as a minimisation problem of nonlinear least squares type. A Levenberg–Marquardt based optimisation method is applied to the solution of the minimisation problem and the details of the implementation are discussed. A number of numerical experiments are presented which illustrate the robustness of the algorithm to parameter identification in the presence of large deformations and noisy data and parameter identification in three dimensional models of cell motility. An application to experimental data is also presented in which we seek to identify parameters in a model for the monopolar growth of fission yeast cells using experimental imaging data. Our numerical tests allow us to compare the method with the two different formulations of the objective functional and we conclude that the results with both objective functionals seem to agree

Effects of gemcitabine on APE/ref-1 endonuclease activity in pancreatic cancer cells, and the therapeutic potential of antisense oligonucleotides

Apurinic/apyrimidinic endonuclease (APE) is a key enzyme involved in DNA base excision repair (BER) that is often expressed at elevated levels in human cancers. Pancreatic cancer cells treated with the nucleoside analogue gemcitabine (2′, 2′-difluoro-2′deoxycytidine) showed increases in APE/redox effector factor (ref-1) protein levels (approximately two-fold for Panc-1 and six-fold for MiaPaCa-2), with corresponding increases in endonuclease activity. These results suggested that the activation of APE/ref-1 might be an adaptive response that contributes to gemcitabine resistance by facilitating BER. To test this hypothesis, we examined the effects of disrupting APE/ref-1 using antisense on gemcitabine toxicity. Antisense oligonucleotides decreased protein levels three-fold in MiaPaCa-2 and five-fold in Panc-1 in comparison to controls, associated with reduced endonuclease activity. Combination treatments with antisense oligonucleotides and gemcitabine partially suppressed the increase in APE/ref-1 activity seen in cells exposed to gemcitabine alone. While clonogenic assays showed only slight decreases in colony formation in cells treated with either antisense oligonucleotides or gemcitabine alone, the combination with APE/ref-1 antisense resulted in a 2-log enhancement of gemcitabine toxicity in Panc-1 cells. Overall these findings suggest that APE/ref-1 plays a significant role in gemcitabine resistance in some pancreatic cancer cells, and support the further investigation of novel treatments that target this protein