The Biological Significance and Implications of Planar Cell Polarity for Nephrology

The orientation of cells in two-dimensional and three-dimensional space underpins how the kidney develops and responds to disease. The process by which cells orientate themselves within the plane of a tissue is termed planar cell polarity. In this Review, we discuss how planar cell polarity and the proteins that underpin it govern kidney organogenesis and pathology. The importance of planar cell polarity and its constituent proteins in multiple facets of kidney development is emphasised, including ureteric bud branching, tubular morphogenesis and nephron maturation. An overview is given of the relevance of planar cell polarity and its proteins for inherited human renal diseases, including congenital malformations with unknown aetiology and polycystic kidney disease. Finally, recent work is described outlining the influence of planar cell polarity proteins on glomerular diseases and highlight how this fundamental pathway could yield a new treatment paradigm for nephrology

Pulmonary ORMDL3 is critical for induction of Alternaria -induced allergic airways disease

Genome-wide association studies have identified the ORM (yeast)-like protein isoform 3 (ORMDL3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma. Objective We sought to investigate in vivo the functional role of ORMDL3 in disease inception. Methods An Ormdl3-deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata was determined. An adeno-associated viral vector was also used to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 knockout mice. Results Ormdl3 knockout mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response, and ORMDL3 was found to play a critical role in driving the activating transcription factor 6–mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum–associated degradation pathway. In addition, ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen–induced allergic airways disease. Conclusions This study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses

New and simple algorithms for stable flow problems

Stable flows generalize the well-known concept of stable matchings to markets in which transactions may involve several agents, forwarding flow from one to another. An instance of the problem consists of a capacitated directed network, in which vertices express their preferences over their incident edges. A network flow is stable if there is no group of vertices that all could benefit from rerouting the flow along a walk. Fleiner established that a stable flow always exists by reducing it to the stable allocation problem. We present an augmenting-path algorithm for computing a stable flow, the first algorithm that achieves polynomial running time for this problem without using stable allocation as a black-box subroutine. We further consider the problem of finding a stable flow such that the flow value on every edge is within a given interval. For this problem, we present an elegant graph transformation and based on this, we devise a simple and fast algorithm, which also can be used to find a solution to the stable marriage problem with forced and forbidden edges. Finally, we study the stable multicommodity flow model introduced by Kir\'{a}ly and Pap. The original model is highly involved and allows for commodity-dependent preference lists at the vertices and commodity-specific edge capacities. We present several graph-based reductions that show equivalence to a significantly simpler model. We further show that it is NP-complete to decide whether an integral solution exists

Memory consolidation in the cerebellar cortex

Several forms of learning, including classical conditioning of the eyeblink, depend upon the cerebellum. In examining mechanisms of eyeblink conditioning in rabbits, reversible inactivations of the control circuitry have begun to dissociate aspects of cerebellar cortical and nuclear function in memory consolidation. It was previously shown that post-training cerebellar cortical, but not nuclear, inactivations with the GABA(A) agonist muscimol prevented consolidation but these findings left open the question as to how final memory storage was partitioned across cortical and nuclear levels. Memory consolidation might be essentially cortical and directly disturbed by actions of the muscimol, or it might be nuclear, and sensitive to the raised excitability of the nuclear neurons following the loss of cortical inhibition. To resolve this question, we simultaneously inactivated cerebellar cortical lobule HVI and the anterior interpositus nucleus of rabbits during the post-training period, so protecting the nuclei from disinhibitory effects of cortical inactivation. Consolidation was impaired by these simultaneous inactivations. Because direct application of muscimol to the nuclei alone has no impact upon consolidation, we can conclude that post-training, consolidation processes and memory storage for eyeblink conditioning have critical cerebellar cortical components. The findings are consistent with a recent model that suggests the distribution of learning-related plasticity across cortical and nuclear levels is task-dependent. There can be transfer to nuclear or brainstem levels for control of high-frequency responses but learning with lower frequency response components, such as in eyeblink conditioning, remains mainly dependent upon cortical memory storage

Design of vaccine efficacy trials during public health emergencies

Public Health Emergencies (PHEs) provide a complex and challenging environment for vaccine evaluation. Under the R&D Blueprint Plan of Action, the World Health Organization (WHO) has convened a group of experts to agree on standard procedures to rapidly evaluate experimental vaccines during PHEs while maintaining the highest scientific and ethical standards. The Blueprint priority diseases, selected for their likelihood to cause PHEs and the lack of adequate medical countermeasures,were used to frame our methodological discussions. Here, we outline major vaccine study designs to be used in PHEs and summarize high-level recommendations for their use in this setting. We recognize that the epidemiology and transmission dynamics of the Blueprint priority diseasesmay be highly uncertain and that the unique characteristics of the vaccines and outbreak settings may affect our study design. To address these challenges, our group underscores the need for novel, flexible,and responsive trial designs. We conclude that assignment to study groups using randomization is a key principle underlying rigorous study design and should be utilized except in exceptional circumstances. Advance planning for vaccine trial designs is critical for rapid and effective response to a PHE and to advance knowledge to address and mitigate future PHEs

STM Spectroscopy of ultra-flat graphene on hexagonal boron nitride

Graphene has demonstrated great promise for future electronics technology as well as fundamental physics applications because of its linear energy-momentum dispersion relations which cross at the Dirac point. However, accessing the physics of the low density region at the Dirac point has been difficult because of the presence of disorder which leaves the graphene with local microscopic electron and hole puddles, resulting in a finite density of carriers even at the charge neutrality point. Efforts have been made to reduce the disorder by suspending graphene, leading to fabrication challenges and delicate devices which make local spectroscopic measurements difficult. Recently, it has been shown that placing graphene on hexagonal boron nitride (hBN) yields improved device performance. In this letter, we use scanning tunneling microscopy to show that graphene conforms to hBN, as evidenced by the presence of Moire patterns in the topographic images. However, contrary to recent predictions, this conformation does not lead to a sizable band gap due to the misalignment of the lattices. Moreover, local spectroscopy measurements demonstrate that the electron-hole charge fluctuations are reduced by two orders of magnitude as compared to those on silicon oxide. This leads to charge fluctuations which are as small as in suspended graphene, opening up Dirac point physics to more diverse experiments than are possible on freestanding devices.Comment: Nature Materials advance online publication 13/02/201

Heterologous expression screens in Nicotiana benthamiana identify a candidate effector of the wheat Yellow Rust Pathogen that associates with processing bodies

Rust fungal pathogens of wheat (Triticum spp.) affect crop yields worldwide. The molecular mechanisms underlying the virulence of these pathogens remain elusive, due to the limited availability of suitable molecular genetic research tools. Notably, the inability to perform high-throughput analyses of candidate virulence proteins (also known as effectors) impairs progress. We previously established a pipeline for the fast-forward screens of rust fungal candidate effectors in the model plant Nicotiana benthamiana. This pipeline involves selecting candidate effectors in silico and performing cell biology and protein-protein interaction assays in planta to gain insight into the putative functions of candidate effectors. In this study, we used this pipeline to identify and characterize sixteen candidate effectors from the wheat yellow rust fungal pathogen Puccinia striiformis f sp tritici. Nine candidate effectors targeted a specific plant subcellular compartment or protein complex, providing valuable information on their putative functions in plant cells. One candidate effector, PST02549, accumulated in processing bodies (P-bodies), protein complexes involved in mRNA decapping, degradation, and storage. PST02549 also associates with the P-body-resident ENHANCER OF mRNA DECAPPING PROTEIN 4 (EDC4) from N. benthamiana and wheat. We propose that P-bodies are a novel plant cell compartment targeted by pathogen effectors

EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2013 . Scientific opinion on Dietary Reference Values for fluoride

Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies (NDA) derived Dietary Reference Values (DRVs) for fluoride, which are provided as Adequate Intake (AI) from all sources, including non-dietary sources. Fluoride is not an essential nutrient. Therefore, no Average Requirement for the performance of essential physiological functions can be defined. Nevertheless, the Panel considered that the setting of an AI is appropriate because of the beneficial effects of dietary fluoride on prevention of dental caries. The AI is based on epidemiological studies (performed before the 1970s) showing an inverse relationship between the fluoride concentration of water and caries prevalence. As the basis for defining the AI, estimates of mean fluoride intakes of children via diet and drinking water with fluoride concentrations at which the caries preventive effect approached its maximum whilst the risk of dental fluorosis approached its minimum were chosen. Except for one confirmatory longitudinal study in US children, more recent studies were not taken into account as they did not provide information on total dietary fluoride intake, were potentially confounded by the use of fluoride-containing dental hygiene products, and did not permit a conclusion to be drawn on a dose-response relationship between fluoride intake and caries risk. The AI of fluoride from all sources (including non-dietary sources) is 0.05 mg/kg body weight per day for both children and adults, including pregnant and lactating women. For pregnant and lactating women, the AI is based on the body weight before pregnancy and lactation. Reliable and representative data on the total fluoride intake of the European population are not available

Adaptive transaction scheduling for transactional memory systems

Transactional memory systems are expected to enable parallel programming at lower programming complexity, while delivering improved performance over traditional lock-based systems. Nonetheless, there are certain situations where transactional memory systems could actually perform worse. Transactional memory systems can outperform locks only when the executing workloads contain sufficient parallelism. When the workload lacks inherent parallelism, launching excessive transactions can adversely degrade performance. These situations will actually become dominant in future workloads when large-scale transactions are frequently executed. In this thesis, we propose a new paradigm called adaptive transaction scheduling to address this issue. Based on the parallelism feedback from applications, our adaptive transaction scheduler dynamically dispatches and controls the number of concurrently executing transactions. In our case study, we show that our low-cost mechanism not only guarantees that hardware transactional memory systems perform no worse than a single global lock, but also significantly improves performance for both hardware and software transactional memory systems.M.S.Committee Chair: Lee, Hsien-Hsin; Committee Member: Blough, Douglas; Committee Member: Yalamanchili, Sudhaka

The contributions of diverse sense organs in the control of leg movement by a walking insect

Cruse H, Dean J, Suilmann M. The contributions of diverse sense organs in the control of leg movement by a walking insect. Journal of Comparative Physiology, A. 1984;154(5):695-705