Inducible tumor difference between rapid and slow rat Nat2 congenic Fischer 344 rats administered methyl-nitrosourea.

Human arylamine N-acetyltransferase 1 (NAT1) is a well-known phase II metabolic enzyme that has been associated with carcinogenesis. Its role in the biotransformation of aromatic and heterocyclic amine carcinogens has been investigated for many years, but more recent investigations focus on a possible endogenous role of human NAT1 in cancer initiation and progression. We conducted in vivo studies using homozygous Fischer 344 rats, congenic at the rat Nat2 locus for high (rapid) and low (slow) activity. Wistar Kyoto inbred rats were used to breed in the slow activity rat Nat2 locus into the Fischer 344 inbred rat, which contains the rapid activity rat Nat2 locus. The rat Nat2 gene is a functional ortholog for the human NAT1 because it has similar sequence and substrate specificity to human NAT1. Chemically induced breast tumors are produced in the rat following administration of methyl-nitrosourea (MNU). In this thesis, rapid and slow acetylator female congenic rats were administrated a single dose of MNU (50 mg/kg) by intraperitoneal injection at three weeks of age. Weekly measurements of weights and palpable breast tumors were recorded. Palpable breast tumors showed a significantly shorter latency in rapid compared to slow acetylator congenic rats (p=0.040). At 23 weeks post MNUadministration, rats were euthanized, and tumor and adjacent non-tumor tissue were collected. Tumors were found in 78% of the rapid acetylator congenic rats with an average ± SEM of 1.78 ± 0.7 tumors per rat. In contrast, tumors were found in only 30% of slow acetylator congenic rats with an average of 0.5 ± 0.3 tumors per rat. Both tumor multiplicity and incidence approached significance (p=0.073 and 0.069, respectively) in this initial pilot experiment. Histopathology of the tumors classified the majority of the tumors as intraductal papillomas that were estrogen receptor positive by immunohistochemistry. The miRNA 574-3p was under expressed in intraductal papilloma breast tumors compared to normal tissues. These results suggest an important role for rat Nat2 in MNU-induced carcinogenesis and possibly carcinogenesis in general. Additional studies are proposed to confirm and understand the mechanism of rat Nat2’s involvement in carcinogenesis

Semigroup Closures of Finite Rank Symmetric Inverse Semigroups

We introduce the notion of semigroup with a tight ideal series and investigate their closures in semitopological semigroups, particularly inverse semigroups with continuous inversion. As a corollary we show that the symmetric inverse semigroup of finite transformations $\mathscr{I}_\lambda^n$ of the rank $\leqslant n$ is algebraically closed in the class of (semi)topological inverse semigroups with continuous inversion. We also derive related results about the nonexistence of (partial) compactifications of classes of semigroups that we consider.Comment: With the participation of the new coauthor - Jimmie Lawson - the manuscript has been substantially revised and expanded. Accordingly, we have also changed the manuscript titl

The Learning from the Large Scale Lotung Soil-Structure Interaction Experiments

Blind prediction analyses and subsequent correlation studies of a 1/4-scale reinforced concrete containment model constructed at Lotung, Taiwan subject to forced vibration tests and actual earthquakes are evaluated with the objective of validating soil-structure interaction (SSI) analysis methodologies commonly used in U.S. practice. The SSI methods used range from simple soil-spring representation to more complex finite-element methods and sub structuring techniques. Both forced vibration test (FVT) data and actual earthquake induced response data have been obtained for use in validating selected SSI analysis methodologies. Considering that for forced vibration tests only the stiffness and damping characteristics of the foundation are required (complexities of site response, wave scattering and stiffness degradation of soils are absent), the FVT evaluation shows that acceptable frequency predictions can be obtained by most of the methods; however, soil damping as obtained from geophysical methods does not seem to account for the total energy dissipation during SSI. A number of insights have been obtained with respect to the validity of SSI analysis methodologies for earthquake response. Among these are the following: vertical wave propagation assumption in performing SSI is adequate to describe the wave field; equivalent linear analysis of soil response for SSI analysis, such as performed by the SHAKE code, provides acceptable results; a significant but non-permanent degradation of soil modulus occurs during earthquakes; the development of soil stiffness degradation and damping curves as a function of strain, based on geophysical and laboratory tests, requires improvement to reduce variability and uncertainty; backfill stiffness plays an important role in determining impedance functions and possibly input motions; scattering of ground motion due to embedment is an important element in performing SSI analysis; more than the calculational techniques, the differences in response predictions are due to the modeling of the soil-structure system

Endothelin‐1 response to whole‐body vibration in obese and normal weight individuals

Upregulation of endothelin‐1 (ET‐1) is the hallmark of various cardiovascular diseases (CVD). The purpose of the present study was to assess the ET‐1 response to an acute bout of whole‐body vibration (WBV) in humans and to determine the role of adiposity. Twenty‐two participants volunteered for the study; they were grouped into overweight/obese [(OW/OB): n = 11, Age: 33 ± 4 years, Body mass index (BMI): 35 ± 10 kg/m(2)] or normal weight [(NW): n = 11, Age: 28 ± 7 years, BMI: 21 ± 2 kg/m(2)]. Participants engaged in 10 cycles of WBV exercise (1 cycle = 1 min WBV followed by 30 s of rest). Blood samples were analyzed for ET‐1 pre‐WBV (PRE), immediately post (POST), 1 h (1H), 3 h (3H), and 24 h (24H) post‐WBV. There was a significant time main effect of WBV on circulating ET‐1 (F = 12.5, p < 0.001); however, the ET‐1 response was similar (F = 0.180, p = 0.677) between groups. Specifically, compared to PRE, a significant increase in ET‐1 was observed at 1H (p = 0.017) and 3H (p = 0.025). In addition, concentrations of ET‐1 were significantly lower at 24H compared to PRE (p = 0.019), 1H (p < 0.001), and 3H (p < 0.001). Maximal oxygen uptake during WBV was similar between the two groups. Acute WBV resulted in an initial rise in ET‐1, followed by a significantly lower ET‐1 at 24H in both groups. Findings support the utility of routine WBV exercise to elicit a decrease in ET‐1 and improve CVD risk, similar to what has been reported with traditional modes of exercise

Protective role of Cav-1 in pneumolysin-induced endothelial barrier dysfunction

Pneumolysin (PLY) is a bacterial pore forming toxin and primary virulence factor of Streptococcus pneumonia, a major cause of pneumonia. PLY binds cholesterol-rich domains of the endothelial cell (EC) plasma membrane resulting in pore assembly and increased intracellular (IC) Ca2+ levels that compromise endothelial barrier integrity. Caveolae are specialized plasmalemma microdomains of ECs enriched in cholesterol. We hypothesized that the abundance of cholesterol-rich domains in EC plasma membranes confers cellular susceptibility to PLY. Contrary to this hypothesis, we found increased PLY-induced IC Ca2+ following membrane cholesterol depletion. Caveolin-1 (Cav-1) is an essential structural protein of caveolae and its regulation by cholesterol levels suggested a possible role in EC barrier function. Indeed, Cav-1 and its scaffolding domain peptide protected the endothelial barrier from PLY-induced disruption. In loss of function experiments, Cav-1 was knocked-out using CRISPR-Cas9 or silenced in human lung microvascular ECs. Loss of Cav-1 significantly enhanced the ability of PLY to disrupt endothelial barrier integrity. Rescue experiments with re-expression of Cav-1 or its scaffolding domain peptide protected the EC barrier against PLY-induced barrier disruption. Dynamin-2 (DNM2) is known to regulate caveolar membrane endocytosis. Inhibition of endocytosis, with dynamin inhibitors or siDNM2 amplified PLY induced EC barrier dysfunction. These results suggest that Cav-1 protects the endothelial barrier against PLY by promoting endocytosis of damaged membrane, thus reducing calcium entry and PLY-dependent signaling

Structure and photophysics of indigoids for singlet fission: Cibalackrot

We report an investigation of structure and photophysics of thin layers of cibalackrot, a sturdy dye derived from indigo by double annulation at the central double bond. Evaporated layers contain up to three phases, two crystalline and one amorphous. Relative amounts of all three have been determined by a combination of X-ray diffraction and FT-IR reflectance spectroscopy. Initially, excited singlet state rapidly produces a high yield of a transient intermediate whose spectral properties are compatible with charge-transfer nature. This intermediate more slowly converts to a significant yield of triplet, which, however, does not exceed 100% and may well be produced by intersystem crossing rather than singlet fission. The yields were determined by transient absorption spectroscopy and corrected for effects of partial sample alignment by a simple generally applicable procedure. Formation of excimers was also observed. In order to obtain guidance for improving molecular packing by a minor structural modification, calculations by a simplified frontier orbital method were used to find all local maxima of singlet fission rate as a function of geometry of a molecular pair. The method was tested at 48 maxima by comparison with the ab initio Frenkel-Davydov exciton model. Published under license by AIP Publishing

Implementation and Characterization of Vibrotactile Interfaces

While a standard approach is more or less established for rendering basic vibratory cues in consumer electronics, the implementation of advanced vibrotactile feedback still requires designers and engineers to solve a number of technical issues. Several off-the-shelf vibration actuators are currently available, having different characteristics and limitations that should be considered in the design process. We suggest an iterative approach to design in which vibrotactile interfaces are validated by testing their accuracy in rendering vibratory cues and in measuring input gestures. Several examples of prototype interfaces yielding audio-haptic feedback are described, ranging from open-ended devices to musical interfaces, addressing their design and the characterization of their vibratory output

Functional kinds: a skeptical look

The functionalist approach to kinds has suffered recently due to its association with law-based approaches to induction and explanation. Philosophers of science increasingly view nomological approaches as inappropriate for the special sciences like psychology and biology, which has led to a surge of interest in approaches to natural kinds that are more obviously compatible with mechanistic and model-based methods, especially homeostatic property cluster theory. But can the functionalist approach to kinds be weaned off its dependency on laws? Dan Weiskopf has recently offered a reboot of the functionalist program by replacing its nomological commitments with a model-based approach more closely derived from practice in psychology. Roughly, Weiskopf holds that the natural kinds of psychology will be the functional properties that feature in many empirically successful cognitive models, and that those properties need not be localized to parts of an underlying mechanism. I here skeptically examine the three modeling practices that Weiskopf thinks introduce such non-localizable properties: fictionalization, reification, and functional abstraction. In each case, I argue that recognizing functional properties introduced by these practices as autonomous kinds comes at clear cost to those explanations’ counterfactual explanatory power. At each step, a tempting functionalist response is parochialism: to hold that the false or omitted counterfactuals fall outside the modeler’s explanatory aims, and so should not be counted against functional kinds. I conclude by noting the dangers this attitude poses to scientific disagreement, inviting functionalists to better articulate how the individuation conditions for functional kinds might outstrip the perspective of a single modeler

RNAi screen identifies a role for adaptor protein AP-3 in sorting to the regulated secretory pathway

AP-3 concentrates proteins within large dense-core vesicles to promote regulated exocytosis