LSD1 is essential for oocyte meiotic progression by regulating CDC25B expression in mice

Mammalian oocytes are arrested at prophase I until puberty when hormonal signals induce the resumption of meiosis I and progression to meiosis II. Meiotic progression is controlled by CDK1 activity and is accompanied by dynamic epigenetic changes. Although the signalling pathways regulating CDK1 activity are well defined, the functional significance of epigenetic changes remains largely unknown. Here we show that LSD1, a lysine demethylase, regulates histone H3 lysine 4 di-methylation (H3K4me2) in mouse oocytes and is essential for meiotic progression. Conditional deletion of Lsd1 in growing oocytes results in precocious resumption of meiosis and spindle and chromosomal abnormalities. Consequently, most Lsd1-null oocytes fail to complete meiosis I and undergo apoptosis. Mechanistically, upregulation of CDC25B, a phosphatase that activates CDK1, is responsible for precocious meiotic resumption and also contributes to subsequent spindle and chromosomal defects. Our findings uncover a functional link between LSD1 and the major signalling pathway governing meiotic progression

Calibration of erodibility testing devices for bridge design support

In order to promote bridge safety under flood conditions, the U. S. Federal Highway Administration (FHWA) has been developing more reliable bridge scour evaluation methods that take into account bridge site specific flow conditions and stream bed material properties. The FHWA is currently developing two such devices: the Ex-situ Scour Testing Device (ESTD) and the laboratory version of an In-situ Scour Testing Device (Lab-ISTD), both test erodibility of stream bed material under specific flow conditions. To maintain portability and robustness, the Lab-ISTD has evolved into a compact cylindrical device that uses a radial flow pattern towards the center of the device to mobilize the foundation material and carrying it away. In this study the previously calibrated ESTD is used as a reference to characterize the performance of the Lab-ISTD, and therefore establish a calibration procedure that enables the Lab-ISTD to produce necessary parameters for better bridge scour evaluation and foundation design

A field erodibility testing device for scour evaluation of bridges

Evaluation of scour in cohesive soil requires a good understanding of hydraulic erosion power from stream flow and the erosion resistance of the soil. In order to develop more reliable scour evaluation methods, the US Federal Highway Administration is investigating a few approaches for evaluating erosion resistance of cohesive soil. The In-situ Scour Testing Device (ISTD) produces a horizontal flow to simulate the flood conditions in an open channel and test the soil for erodibility. The erosion head assembly is compact in size and fits into the steel casing commonly used with hollow stem augers in a routine geotechnical subsurface exploration. The ISTD can be deployed to any depth that pier scour may reach to test the local material for erosion resistance. This device is calibrated using lab erosion testing devices and has been tested in the field

A computational approach to the study of the stability of pier riprap at the Middle Fork Feather River

This paper discusses the use of various technologies and advanced computational modeling techniques that were combined for monitoring the performance of pier riprap on the basis of a field case study – Pier 3 of a bridge over the Middle Fork Feather River – in northern California, USA. The first phase involved capturing the field condition of the bridge site using sonar instrumentation technology in order to obtain high resolution bathymetry data. The second phase entailed enhancement and transformation of the scanned bathymetric data into a 3D CAD model to be used as the initial geometry for numerical modeling. A Fluid Structure Interaction (FSI) numerical approach was applied to simulate the rock incipient motion i.e. shear failure by coupling Computational Fluid Dynamics (CFD) software STAR-CCM+ and a Computational Structural Mechanics (CSM) software LS-DYNA. Several coupled simulations have been performed with varying flow conditions to identify shear failure conditions for the riprap apron

Shallow foundations for the support of vertical-wall bridge abutments: interaction between riprap and contraction scour

The database from flume experiments focused on the performance of riprap layouts based on field installations and FHWA HEC-23 design guidelines against clear-water abutment scour combined with Computational Fluid Dynamics (CFD) is used to investigate how flow fields at single span bridge openings, dominated by flow contraction, adjust in response to variations of bed roughness and cross-section geometry due to riprap installations. These adjustments increase bed shear stress magnitudes on the unprotected erodible bed leading to underestimated contraction scour depths therefore creating instability, and ultimately causing edge failure of the riprap. Based on the combined physical/numerical modeling approach an edge failure-resistant riprap layout is proposed. Furthermore, the CFD approach provides an insight into shear stress magnitudes within a nonuniform bed roughness in the bridge opening, and a comprehensive flowdepth-riprap interaction model to define limits for “hydraulically narrow” bridge openings that might be prone to edge failure of the scour protecting riprap

Rosiglitazone and glimeperide: review of clinical results supporting a fixed dose combination

Type 2 diabetes has become a major burden to the health care systems worldwide. Among the drugs approved for this indication, glimepiride and rosiglitazone have gained substantial importance in routine use. While glimepiride stimulates β-cell secretion and leads to reduction of blood glucose values, rosiglitazone activates PPARγ and improves insulin resistance, at the vascular and metabolically active cells. Therefore, the combination of the two drugs may be an interesting approach to improve glycemic control and lower cardiovascular risk. A fixed combination of both drugs has been approved for clinical use in the US and EU. The combination of glimepiride and rosiglitazone is generally well tolerated and the use of a fixed combination may lead to improved adherence of the patients to their therapy. The purpose of this review is to evaluate the clinical data that have been published on this combination, appearing to represent a convenient way to obtain therapeutic targets in patients with type 2 diabetes mellitus

Productive Parvovirus B19 Infection of Primary Human Erythroid Progenitor Cells at Hypoxia Is Regulated by STAT5A and MEK Signaling but not HIFα

Human parvovirus B19 (B19V) causes a variety of human diseases. Disease outcomes of bone marrow failure in patients with high turnover of red blood cells and immunocompromised conditions, and fetal hydrops in pregnant women are resulted from the targeting and destruction of specifically erythroid progenitors of the human bone marrow by B19V. Although the ex vivo expanded erythroid progenitor cells recently used for studies of B19V infection are highly permissive, they produce progeny viruses inefficiently. In the current study, we aimed to identify the mechanism that underlies productive B19V infection of erythroid progenitor cells cultured in a physiologically relevant environment. Here, we demonstrate an effective reverse genetic system of B19V, and that B19V infection of ex vivo expanded erythroid progenitor cells at 1% O2 (hypoxia) produces progeny viruses continuously and efficiently at a level of approximately 10 times higher than that seen in the context of normoxia. With regard to mechanism, we show that hypoxia promotes replication of the B19V genome within the nucleus, and that this is independent of the canonical PHD/HIFα pathway, but dependent on STAT5A and MEK/ERK signaling. We further show that simultaneous upregulation of STAT5A signaling and down-regulation of MEK/ERK signaling boosts the level of B19V infection in erythroid progenitor cells under normoxia to that in cells under hypoxia. We conclude that B19V infection of ex vivo expanded erythroid progenitor cells at hypoxia closely mimics native infection of erythroid progenitors in human bone marrow, maintains erythroid progenitors at a stage conducive to efficient production of progeny viruses, and is regulated by the STAT5A and MEK/ERK pathways