Kettering University

About: Kettering University is a education organization based out in Flint, Michigan, United States. It is known for research contribution in the topics: Cancer & RNA. The organization has 6842 authors who have published 7689 publications receiving 337503 citations. The organization is also known as: GMI Engineering & Management Institute & General Motors Institute.

Cryo-EM structures of fungal and metazoan mitochondrial calcium uniporters.

Abstract: The mitochondrial calcium uniporter (MCU) is a highly selective calcium channel and a major route of calcium entry into mitochondria How the channel catalyses ion permeation and achieves ion selectivity are not well understood, partly because MCU is thought to have a distinct architecture in comparison to other cellular channels Here we report cryo-electron microscopy reconstructions of MCU channels from zebrafish and Cyphellophora europaea at 85 A and 32 A resolutions, respectively In contrast to a previous report of pentameric stoichiometry for MCU, both channels are tetramers The atomic model of C europaea MCU shows that a conserved WDXXEP signature sequence forms the selectivity filter, in which calcium ions are arranged in single file Coiled-coil legs connect the pore to N-terminal domains in the mitochondrial matrix In C europaea MCU, the N-terminal domains assemble as a dimer of dimers; in zebrafish MCU, they form an asymmetric crescent The structures define principles that underlie ion permeation and calcium selectivity in this unusual channel

Morphogenesis of the node and notochord: The cellular basis for the establishment and maintenance of left–right asymmetry in the mouse

Abstract: Establishment of left-right asymmetry in the mouse embryo depends on leftward laminar fluid flow in the node, which initiates a signaling cascade that is confined to the left side of the embryo. Leftward fluid flow depends on two cellular processes: motility of the cilia that generate the flow and morphogenesis of the node, the structure where the cilia reside. Here, we provide an overview of the current understanding and unresolved questions about the regulation of ciliary motility and node structure. Analysis of mouse mutants has shown that the motile cilia must have a specific structure and length, and that they must point posteriorly to generate the necessary leftward fluid flow. However, the precise structure of the motile cilia is not clear and the mechanisms that position cilia on node cells have not been defined. The mouse node is a teardrop-shaped pit at the distal tip of the early embryo, but the morphogenetic events that create the mature node from cells derived from the primitive streak are only beginning to be characterized. Recent live imaging experiments support earlier scanning electron microscopy (SEM) studies and show that node assembly is a multi-step process in which clusters of node precursors appear on the embryo surface as overlying endoderm cells are removed. We present additional SEM and confocal microscopy studies that help define the transition stages during node morphogenesis. After the initiation of left-sided signaling, the notochordal plate, which is contiguous with the node, generates a barrier at the embryonic midline that restricts the cascade of gene expression to the left side of the embryo. The field is now poised to dissect the genetic and cellular mechanisms that create and organize the specialized cells of the node and midline that are essential for left-right asymmetry.

The transformation of the model organism: a decade of developmental genetics.

Abstract: The past decade has seen the development of powerful techniques to dissect the molecular processes that regulate development. New tools have been used to reveal the basis of cell polarity, morphogen gradients and regulation of signaling in developing animals. Cell biology and developmental biology have become closely intertwined, and many genes that had been thought of as regulators of general cell biological (housekeeping) functions have been shown to act as specific developmental regulators. Vertebrate developmental genetics is now flourishing, with forward and reverse genetics in both zebrafish and the mouse providing new dimensions to our understanding of development.

Clinical results of treatment with E. coli L-asparaginase in adults with leukemia, lymphoma, and solid tumors

Abstract: E. coli L-asparaginase (A-ase) was administered to 163 adults with different forms of leukemia, lymphoma, and solid tumors. Six of 11 patients with acute lymphoblastic leukemia and 4 of 32 patients with acute myeloblastic, myelomonoblastic, or undifferentiated leukemia had complete or good partial remissions. Doses of 10 to 5000 IU/kg/day were used, but there was no clear correlation between dose and therapeutic response, nor with any particular preparation of A-ase. Some of the others had transient physical and/or hematologic improvement, but remission was not achieved. Nineteen patients with myeloblastic leukemia, 4 with lymphoblastic and 3 with undifferentiated, had no response. Eight patients with acute leukemia (7 lymphoblastic and one myeloblastic), who were already in complete remission induced with other agents, were treated with 1000 IU/kg/day or higher doses of A-ase for one month or longer. Seven were given no further therapy. The disease relapsed within 2-5 months in 6 patients, but one is still in remission after 8 months. The eighth patient is still in remission after 3 months but is receiving other chemotherapy. Partial hematologic responses occurred in one patient with untreated chronic granulocytic leukemia, in 4 of 5 patients in a blastic phase of chronic granulocytic leukemia, and in 2 of 3 patients with chronic lymphocytic leukemia, but in none of these patients was the response of substantial clinical benefit. Two patients with disseminated lymphosarcoma or reticulum cell sarcoma had excellent therapeutic responses to A-ase, and 4 others showed some improvement while 14 had no detectable response. Eight patients with advanced Hodgkin's disease showed no response. One patient with malignant melanoma with multiple cutaneous metastases had temporary regression of his metastatic nodules with A-ase on several occasions, but evaluation of this case was complicated by other chemotherapy. Twenty-nine other patients with melanoma had no response nor did 45 patients with other types of solid tumors. Some toxic manifestations of A-ase occurred in almost all patients; these were generally more severe and sometimes were intolerable at higher dosage levels. The toxicity will be discussed in detail in an accompanying report.