The cell biology of polycystic kidney disease

Polycystic kidney disease is a common genetic disorder in which fluid-filled cysts displace normal renal tubules. Here we focus on autosomal dominant polycystic kidney disease, which is attributable to mutations in the PKD1 and PKD2 genes and which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis. The mechanisms that connect the underlying genetic defects to disease pathogenesis are poorly understood, but their exploration is shedding new light on interesting cell biological processes and suggesting novel therapeutic targets

Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption

To prevent dehydration, terrestrial animals and humans have developed a sensitive and versatile system to maintain their water homeostasis. In states of hypernatremia or hypovolemia, the antidiuretic hormone vasopressin (AVP) is released from the pituitary and binds its type-2 receptor in renal principal cells. This triggers an intracellular cAMP signaling cascade, which phosphorylates aquaporin-2 (AQP2) and targets the channel to the apical plasma membrane. Driven by an osmotic gradient, pro-urinary water then passes the membrane through AQP2 and leaves the cell on the basolateral side via AQP3 and AQP4 water channels. When water homeostasis is restored, AVP levels decline, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again. The action of AVP is counterbalanced by several hormones like prostaglandin E2, bradykinin, dopamine, endothelin-1, acetylcholine, epidermal growth factor, and purines. Moreover, AQP2 is strongly involved in the pathophysiology of disorders characterized by renal concentrating defects, as well as conditions associated with severe water retention. This review focuses on our recent increase in understanding of the molecular mechanisms underlying AVP-regulated renal water transport in both health and disease

Polycystic kidney diseases: From molecular discoveries to targeted therapeutic strategies

Polycystic kidney diseases (PKDs) represent a large group of progressive renal disorders characterized by the development of renal cysts leading to end-stage renal disease. Enormous strides have been made in understanding the pathogenesis of PKDs and the development of new therapies. Studies of autosomal dominant and recessive polycystic kidney diseases converge on molecular mechanisms of cystogenesis, including ciliary abnormalities and intracellular calcium dysregulation, ultimately leading to increased proliferation, apoptosis and dedifferentiation. Here we review the pathobiology of PKD, highlighting recent progress in elucidating common molecular pathways of cystogenesis. We discuss available models and challenges for therapeutic discovery as well as summarize the results from preclinical experimental treatments targeting key disease-specific pathways

Original quartz grain shape characteristics of the recent sediments of the Colorado River drainage basin

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Bibliography: leaves 72-74.Not availabl

Listeners prefer the laughs of children with autism to those of typically developing children

The purpose of this study was to investigate the impact of laugh sounds produced by 8- to 10-year-old children with and without autism on naïve listeners, and to evaluate if listeners could distinguish between the laughs of the two groups. Results showed that listeners rated the laughs of children with autism more positively than the laughs of typically developing children, and that they were slightly above chance levels at judging which group produced the laugh. A subset of participants who reported listening for uncontrolled or longer laughs were significantly better at discriminating between the laughs of the two groups. Our results suggest that the laughs of children with autism have the potential to promote the formation of relationships. © The Author(s) 2011

MagiXen: Combining Binary Translation and Virtualization

virtualization, dynamic binary translation, hypervisor, Xen Itanium, virtual appliances, virtual machine monitors Virtualization is emerging as an important technology in future systems, providing an extra layer of abstraction between the hardware and operating system. Previous work on virtualization has focused on the partitioning, isolation, and encapsulation features of virtual machines and their use for different applications, but mainly in the context of a specific processor architecture. In this paper, we argue for integrating an interface transformation layer to virtualization, specifically combining virtualization with a dynamic binary translator. This feature significantly increases the benefits from current applications of virtualization (e.g., for server consolidation and resource provisioning) while potentially enabling additional new uses of virtualization matched with emerging trends (e.g., virtual appliances and heterogeneous hardware). We have built MagiXen — pronounced “magician” — a prototype implementation of a Xen virtual machine monitor with integrated binary translation that can run IA-32 virtual machines on Itanium platforms. We present performance results for several typical benchmarks and discuss insights from our experiences with building the prototype

Transcendent Memory and Linux

Managing a fixed amount of memory (RAM) optimally is a long-solved problem in the Linux kernel. Managing RAM optimally in a virtual environment, however, is still a challenging problem because: (1) each guest kernel focuses solely on optimizing its entire fixed RAM allocation oblivious to the needs of other guests, and (2) very little information is exposed to the virtual machine manager (VMM) to enable it to decide if one guest needs RAM more than another guest. Mechanisms such as ballooning and hot-plug memory (Schopp, OLS’2006) allow RAM to be taken from a selfish guest and given to a needy guest, but these have significant known issues and, in any case, don’t solve the hard problem: Which guests are selfish and which are needy? IBM’s Collaborative Memory Management (Schwidefsky, OLS’2006) attempts to collect information from each guest and provide it to the VMM, but was deemed far too complex and attempts to upstream it have been mostly stymied. Transcendent Memory (tmem for short) is a new approach to optimize RAM utilization in a virtual environment. Underutilized RAM from each guest, plus RAM unassigned to any guest (fallow memory), is collected into a central pool. Indirect access to that RAM is then provided by the VMM through a carefully crafted, page-copy-based interface. Linux kernel changes are required but are relatively small and not only provide valuable information to the VMM, but also furnish additional "magic " memory to the kernel, provide performance benefits in the form of reduced I/O, and mitigate some of the issues that arise from ballooning/hotplug.