Aquifer Heterogeneity Characterization with Oscillatory Pumping: Sensitivity Analysis and Imaging Potential

[1] Periodic pumping tests, in which a fluid is extracted during half a period, then reinjected, have been used historically to estimate effective aquifer properties. In this work, we suggest a modified approach to periodic pumping test analysis in which one uses several periodic pumping signals of different frequencies as stimulation, and responses are analyzed through inverse modeling using a “steady-periodic” model formulation. We refer to this strategy as multifrequency oscillatory hydraulic imaging. Oscillating pumping tests have several advantages that have been noted, including no net water extraction during testing and robust signal measurement through signal processing. Through numerical experiments, we demonstrate additional distinct advantages that multifrequency stimulations have, including: (1) drastically reduced computational cost through use of a steady-periodic numerical model and (2) full utilization of the aquifer heterogeneity information provided by responses at different frequencies. We first perform fully transient numerical modeling for heterogeneous aquifers and show that equivalent results are obtained using a faster steady-periodic heterogeneous numerical model of the wave phasor. The sensitivities of observed signal response to aquifer heterogeneities are derived using an adjoint state-based approach, which shows that different frequency stimulations provide complementary information. Finally, we present an example 2-D application in which sinusoidal signals at multiple frequencies are used as a data source and are inverted to obtain estimates of aquifer heterogeneity. These analyses show the different heterogeneity information that can be obtained from different stimulation frequencies, and that data from several sinusoidal pumping tests can be rapidly inverted using the steady-periodic framework

Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis

Cyclin D1 is an important molecular driver of human breast cancer but better understanding of its oncogenic mechanisms is needed, especially to enhance efforts in targeted therapeutics. Currently, pharmaceutical initiatives to inhibit cyclin D1 are focused on the catalytic component since the transforming capacity is thought to reside in the cyclin D1/CDK activity. We initiated the following study to directly test the oncogenic potential of catalytically inactive cyclin D1 in an in vivo mouse model that is relevant to breast cancer. Herein, transduction of cyclin D1(-/-) mouse embryonic fibroblasts (MEFs) with the kinase dead KE mutant of cyclin D1 led to aneuploidy, abnormalities in mitotic spindle formation, autosome amplification, and chromosomal instability (CIN) by gene expression profiling. Acute transgenic expression of either cyclin D1(WT) or cyclin D1(KE) in the mammary gland was sufficient to induce a high CIN score within 7 days. Sustained expression of cyclin D1(KE) induced mammary adenocarcinoma with similar kinetics to that of the wild-type cyclin D1. ChIP-Seq studies demonstrated recruitment of cyclin D1(WT) and cyclin D1(KE) to the genes governing CIN. We conclude that the CDK-activating function of cyclin D1 is not necessary to induce either chromosomal instability or mammary tumorigenesis

The Pathology of EMT in Mouse Mammary Tumorigenesis

Epithelial-mesenchymal-transition (EMT) tumorigenesis in the mouse was first described over 100 years ago using various terms such as carcinosarcoma and without any comprehension of the underlying mechanisms. Such tumors have been considered artifacts of transplantation and of tissue culture. Recently, EMT tumors have been recognized in mammary glands of genetically engineered mice. This review provides a historical perspective leading to the current status in the context of some of the key molecular biology. The biology of mouse mammary EMT tumorigenesis is discussed with comparisons to human breast cancer

Expanding boundaries in psychiatry: uncertainty in the context of diagnosis-seeking and negotiation

Psychiatric diagnosis has become pervasive in modern culture, exerting an increasing influence on notions of personhood, identity practices and forms of self‐governing. The broadening of diagnostic categories and increasing awareness regarding popular diagnostic categories has led to an increased demand for formal diagnosis within clinical encounters. However, there is continuing ‘epistemological uncertainty’ (Fox 2000) surrounding these entities, in part due to their lack of associated clinical biomarkers and their ‘fuzzy boundaries’. Meanwhile, this diagnostic expansion has encountered resistance from those concerned with the alleged ‘over‐pathologisation’ of emotional distress. Drawing upon the concepts of ‘diagnostic cultures’ (Brinkmann 2016) and the ‘looping effects of human kinds’ (Hacking 1995), this article considers some of the competing forces acting upon the contested boundaries of diagnostic categories as they play out within diagnostic interactions. The study involved ethnographic observations of diagnostic encounters within several UK‐based mental health clinics. By focusing on interactions where diagnosis is negotiated, findings illustrate the role played by different kinds of diagnostic uncertainty in shaping these negotiations. It is argued that diagnostic reification plays a key role in the moral categorisation of patients, particularly where there is uncertainty regarding individual diagnostic status

Proteotypic classification of spontaneous and transgenic mammary neoplasms

INTRODUCTION: Mammary tumors in mice are categorized by using morphologic and architectural criteria. Immunolabeling for terminal differentiation markers was compared among a variety of mouse mammary neoplasms because expression of terminal differentiation markers, and especially of keratins, provides important information on the origin of neoplastic cells and their degree of differentiation. METHODS: Expression patterns for terminal differentiation markers were used to characterize tumor types and to study tumor progression in transgenic mouse models of mammary neoplasia (mice overexpressing Neu (Erbb2), Hras, Myc, Notch4, SV40-TAg, Tgfa, and Wnt1), in spontaneous mammary carcinomas, and in mammary neoplasms associated with infection by the mouse mammary tumor virus (MMTV). RESULTS: On the basis of the expression of terminal differentiation markers, three types of neoplasm were identified: first, simple carcinomas composed exclusively of cells with a luminal phenotype are characteristic of neoplasms arising in mice transgenic for Neu, Hras, Myc, Notch4, and SV40-TAg; second, 'complex carcinomas' displaying luminal and myoepithelial differentiation are characteristic of type P tumors arising in mice transgenic for Wnt1, neoplasms arising in mice infected by the MMTV, and spontaneous adenosquamous carcinomas; and third, 'carcinomas with epithelial to mesenchymal transition (EMT)' are a characteristic feature of tumor progression in Hras-, Myc-, and SV40-TAg-induced mammary neoplasms and PL/J and SJL/J mouse strains, and display de novo expression of myoepithelial and mesenchymal cell markers. In sharp contrast, EMT was not detected in papillary adenocarcinomas arising in BALB/cJ mice, spontaneous adenoacanthomas, neoplasms associated with MMTV-infection, or in neoplasms arising in mice transgenic for Neu and Wnt1. CONCLUSIONS: Immunohistochemical profiles of complex neoplasms are consistent with a stem cell origin, whereas simple carcinomas might originate from a cell committed to the luminal lineage. In addition, these results suggest that the initiating oncogenic events determine the morphologic features associated with cancer progression because EMT is observed only in certain types of neoplasm