The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress.

Excessive demands on the protein-folding capacity of the endoplasmic reticulum (ER) cause irremediable ER stress and contribute to cell loss in a number of cell degenerative diseases, including type 2 diabetes and neurodegeneration. The signals communicating catastrophic ER damage to the mitochondrial apoptotic machinery remain poorly understood. We used a biochemical approach to purify a cytosolic activity induced by ER stress that causes release of cytochrome c from isolated mitochondria. We discovered that the principal component of the purified pro-apoptotic activity is the proto-oncoprotein CRK (CT10-regulated kinase), an adaptor protein with no known catalytic activity. Crk(-/-) cells are strongly resistant to ER-stress-induced apoptosis. Moreover, CRK is cleaved in response to ER stress to generate an amino-terminal M(r)~14K fragment with greatly enhanced cytotoxic potential. We identified a putative BH3 (BCL2 homology 3) domain within this N-terminal CRK fragment, which sensitizes isolated mitochondria to cytochrome c release and when mutated significantly reduces the apoptotic activity of CRK in vivo. Together these results identify CRK as a pro-apoptotic protein that signals irremediable ER stress to the mitochondrial execution machinery

Phenotypically different cells in the nucleus of the solitary tract : expression of group I metabotropic glutamate receptors and activation by baroreflexes

"June 2008"Vita.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Thesis (Ph. D.) University of Missouri-Columbia 2008.Modulation and integration of visceral and central afferent information occurs in the nucleus of the solitary tract (NTS). The NTS is a heterogeneous nuclear region that contains afferent terminals, interneurons, and multiple synaptic receptors that process information before exiting the NTS to multiple nuclear regions within the brain. One such efferent pathway is to the caudal ventrolateral medulla (CVLM), which serves as the second central nuclear region of the arterial baroreflex. The exact nature of the modulation of the arterial baroreflex at the level of the NTS is still unknown. The studies presented here further clarify the role of Group I metabotropic glutamate receptors (mGluRs) on GABAergic, nitroxidergic and catecholaminergic neurons and neurons the project from the NTS to the CVLM. Additionally, we examine GABAergic, nitroxidergic and catecholaminergic neurons and neurons the project from the NTS to the CVLM activated i n the NTS through acute hypertension and hypotension. Finally, we proposed a study to examine the expression of Group I mGluRs on neurons activated by hypertension and hypotension and neurons that project the NTS from the CVLM. These studies suggest that Group I mGluRs are preferentially expressed on CVLM projecting neurons, and that hypertension and hypotension activate separate populations of neuron in the NTS.Includes bibliographical reference

Forming peculiarities and manifestation of tectonic faults in soft rocks

Features of distribution of tectonic structures in soft rocks confirm the presence of horizontal tectonic forces in the formation of faults and are based on the manifestation of their morphological features. Linear dependences of the amplitude on the length of tectonic dislocation in the area of wedging were obtained as a result of mathematical processing of the experimental data. Actual position of the crossing lines of fault plane with the seam were considered while studying the distribution of co-fault fracturing. Analysis of the data confirms that the distribution of faulting has an undulating character. Analysis of observations showed that the deviation of the crossing line of fault plane with the seam from the middle line is subject to the normal law of random variable distribution. Thus, the studies and the obtained results allow planning mining operations assessing the utility while developing fault areas

Hydrogen sulfide (H2S) augments synaptic neurotransmission in the nucleus of the solitary tract (NTS) [abstract]

Hydrogen sulfide (H2S) is a gasotransmitter generated through the metabolism of cysteine to serine. In the central nervous system, H2S is produced primarily by the enzyme cystanthionine [beta]-synthase (CBS). The brainstem nTS serves as the principal site for sensory afferent integration for cardiorespiratory regulation. We sought to determine the role of H2S, and its generation by CBS, in nTS excitability in normoxia and following chronic intermittent hypoxia (CIH), a rodent model of sleep apnea

A two-stage stochastic programming model for electric substation flood mitigation prior to an imminent hurricane

We present a stochastic programming model for informing the deployment of temporary flood mitigation measures to protect electrical substations prior to an imminent and uncertain hurricane. The first stage captures the deployment of a fixed number of mitigation resources, and the second stage captures grid operation in response to a contingency. The primary objective is to minimize expected load shed. We develop methods for simulating flooding induced by extreme rainfall and construct two geographically realistic case studies, one based on Tropical Storm Imelda and the other on Hurricane Harvey. Applying our model to those case studies, we investigate the effect of the mitigation budget on the optimal objective value and solutions. Our results highlight the sensitivity of the optimal mitigation to the budget, a consequence of those decisions being discrete. We additionally assess the value of having better mitigation options and the spatial features of the optimal mitigation.Comment: 35 pages, 12 figure

Die klinische Bedeutung von Biomarkern des Zelltodes und der Inflammation bei Patienten mit Leberzirrhose und hepatorenalem Syndrom

107 Blätter, Illustrationen, Diagramm

On Simplices with a Given Barycenter That Are Enclosed by the Standard Simplex

We present an optimization model defined on the manifold of the set of stochastic matrices. Geometrically, the model is akin to identifying a maximum-volume $n$-dimensional simplex that has a given barycenter and is enclosed by the $n$-dimensional standard simplex. Maximizing the volume of a simplex is equivalent to maximizing the determinant of its corresponding matrix. In our model, we employ trace maximization as a linear alternative to determinant maximization. We identify the analytical form of a solution to this model. We prove the solution is optimal and present necessary and sufficient conditions for it to be the unique optimal solution. Additionally, we show the identified optimal solution is an inverse $M$-matrix, and that its eigenvalues are the same as its diagonal entries. We demonstrate how the model and its solutions apply to the task of synthesizing conditional cumulative distribution functions (CDFs) that, in tandem with a given discrete marginal distribution, coherently preserve a given CDF

A unique academic leadership modality and mentoring model in an online, competency-based, graduate nursing program

Session presented on Tuesday, September 20, 2016: This presentation will examine an academic leadership modality in a competency-based nursing program that offers an innovative and authentic method of delivering education in a virtual setting. In this competency based nursing program, the mentoring model takes a radical departure from the traditional education model. When supported by this intentional academic mentoring model, students experience a profound change in attitudes toward course content, online technologies, teamwork, and applied nursing practice (Barkley, 2014; Parker, 2013). The unique mentoring model is utilized to enhance the development of leadership skills in faculty and in graduate nursing students. Faculty Course Mentors develop the necessary leadership skills to prioritize and personalize student academic mentoring strategies. Graduate nursing students learn collaborative leadership skills to serve as effective change agents in their healthcare organizations to achieve desired outcomes. Academic mentoring by Course Mentor faculty offers an innovative and authentic method of delivering education in a virtual setting. In this technology driven setting, a unique and modern approach to academic leadership is coupled with input from external partners and leaders in the health care industry. This input enhances and promotes the student-centered experience (Jones-Schenk, 2014). The curriculum design integrates a faculty leadership and mentoring model that promotes ongoing student-faculty mentor interaction and faculty mentor-program manager interaction. The integration of the ongoing mentoring also fosters authentic learning, collaborative scholarly inquiry, and enhancement of student success. The faculty model consists of clearly delineated, disaggregated faculty roles which include Program Managers, Course Mentors, Student Mentors, and Evaluators who are committed to student achievement of nursing program outcomes that align with the CCNE Essentials of Master\u27s Education in Nursing. Program Managers collaborate with mentors to ensure ongoing professional growth and development. The Program Manager continually applies metric-driven strategies to promote effective mentoring and enhance student outcomes. Course Mentors are accountable for the quality and integrity of educational programs, and consistently provide relevant and innovative academic resources to meet the needs of a diverse student population. Course Mentors are subject matter experts who support students as they engage in specific sections of the curriculum. Through intentional, individualized interactions, faculty mentors identify academic needs, embrace diversity, and promote scholarly pursuits. Student Mentors provide foundational and ongoing support for successful student growth. Student mentors advise and coach students throughout the program and offer academic guidance and coaching to promote work-school-life balance. Additionally, the advice provided assists students in successfully navigating their educational experience by utilizing all available resources. Resources include services identified through referrals to the student support center, the center for writing excellence, and individualized wellness programs. Evaluators are subject matter experts tasked with reviewing assessment submissions in a fair and unbiased manner to determine if competency has been demonstrated. Evaluators have no contact with faculty mentors nor students in order to preserve objectivity and reduce bias in the evaluation process. Written feedback is provided to enhance student performance. Student-student, student-mentor, and student-stakeholder interactions are supported by multiple communication technologies such as web conferencing, cohorts, emails, short video recordings, and telephone conversations. Quality mentoring communications support students in overcoming barriers and increase student retention rates through the development of a strong sense of connectedness (Irani, Wilson, Slough & Rieger, 2014; LaBarbera, 2013). Student outcomes demonstrate heightened student satisfaction with 93% satisfied/very satisfied with this academic mentoring leadership model (Jones-Schenk, 2014). Student reflections have also revealed the positive effects of this academic leadership modality. The authenticity of the mentoring creates a deep sense of connectedness between the students, stakeholders, course mentors, and student mentors, and \u27brings out the best\u27 in each learner. Students learn to work collaboratively, think creatively, and move beyond their comfort zone. Students also reported a new awareness of the complexity of healthcare systems that transformed their nursing practice and enhanced their role as a clinical/academic nurse leader within organizations

Threat and decision models for informing power grid resilience under uncertainty

The electric power grid is lifeline infrastructure and a cornerstone of modern society. The ability of the grid to withstand severe contingencies is essential for the well-being of individuals, businesses, and communities as a whole, and recent extreme weather events have highlighted vulnerabilities that subject those parties to risk. As factors like climate change, renewable penetration, and mass electrification guide the transformation of power grids, improving or at least maintaining its resilience is crucial. In this work, we present end-to-end frameworks for simulating the uncertain effects of extreme weather on a power grid and then leveraging the simulations to guide resilience decision-making via optimization under uncertainty. The benefits of our frameworks are highlighted through a variety of case studies built on simulations of tropical storm and winter storm events and power flow optimization modeling.Mechanical Engineerin