Modified protein expression in the tectorial membrane of the cochlea reveals roles for the striated sheet matrix

The tectorial membrane (TM) of the mammalian cochlea is a complex extracellular matrix which, in response to acoustic stimulation, displaces the hair bundles of outer hair cells (OHCs), thereby initiating sensory transduction and amplification. Here, using TM segments from the basal, high-frequency region of the cochleae of genetically modified mice (including models of human hereditary deafness) with missing or modified TM proteins, we demonstrate that frequency-dependent stiffening is associated with the striated sheet matrix (SSM). Frequency-dependent stiffening largely disappeared in all three TM mutations studied where the SSM was absent either entirely or at least from the stiffest part of the TM overlying the OHCs. In all three TM mutations, dissipation of energy is decreased at low (<8 kHz) and increased at high (>8 kHz) stimulus frequencies. The SSM is composed of polypeptides carrying fixed charges, and electrostatic interaction between them may account for frequency-dependent stiffness changes in the material properties of the TM. Through comparison with previous in vivo measurements, it is proposed that implementation of frequency-dependent stiffening of the TM in the OHC attachment region facilitates interaction among tones, backward transmission of energy, and amplification in the cochlea

Toxicity of cancer therapy: what the cardiologist needs to know about angiogenesis inhibitors

Clinical outcomes for patients with a wide range of malignancies have improved substantially over the last two decades. Tyrosine kinase inhibitors (TKIs) are potent signalling cascade inhibitors and have been responsible for significant advances in cancer therapy. By inhibiting vascular endothelial growth factor receptor (VEGFR)-mediated tumour blood vessel growth, VEGFR-TKIs have become a mainstay of treatment for a number of solid malignancies. However, the incidence of VEGFR-TKI-associated cardiovascular toxicity is substantial and previously under-recognised. Almost all patients have an acute rise in blood pressure, and the majority develop hypertension. They are associated with the development of left ventricular systolic dysfunction (LVSD), heart failure and myocardial ischaemia and can have effects on myocardial repolarisation. Attention should be given to rigorous baseline assessment of patients prior to commencing VEGFR-TKIs, with careful consideration of baseline cardiovascular risk factors. Baseline blood pressure measurement, ECG and cardiac imaging should be performed routinely. Hypertension management currently follows national guidelines, but there may be a future role forendothelin-1 antagonism in the prevention or treatment of VEGFR-TKI-associated hypertension. VEGFR-TKI-associated LVSD appears to be independent of dose and is reversible. Patients who develop LVSD and heart failure should be managed with conventional heart failure therapies, but the role of prophylactic therapy is yet to be defined. Serial monitoring of left ventricular function and QT interval require better standardisation and coordinated care. Management of these complex patients requires collaborative, cardio-oncology care to allow the true therapeutic potential from cancer treatment while minimising competing cardiovascular effects

Intermolecular 1,3-dipolar cycloadditions of azomethine imines

Dipolar cycloadditions of azomethine imines, formed in situ from aldehydes and N1-alkyl-N2-acylhydrazines, with electron-deficient dipolarophiles produce pyrazolidines: mono-substituted dipolarophiles afford principally 4-substituted pyrazolidines

Colonization of Artificial Substrates at Dauphin Island, Alabama: A Comparison of Balanus (Cirripedia), Membranipora tenuis (Bryozoa), and Conopeum tenuissimum (Bryozoa) Settlement in 1999-2000 and 2010-12

Glass slides were used as artificial substrates to collect settling bryozoan and barnacle larvae during two collection periods, in 1999–2000 and 2010–12. This study follows up a previous report of Balanus settlement in Mobile Bay and now includes two bryozoan species. Slides were immersed at the Dauphin Island Sea Lab (Alabama) for 1 wk each month for 17–18 mo in each study, and then collected for staining and counting. The bryozoans Conopeum tenuissimum and Membranipora tenuis were both present in 1999–2000, though in 2010–12 C. tenuissimum was rarer and only six organisms were observed. In general the bryozoan colonization period extended throughout the spring, summer, and fall, with peak settlement in May–Aug. Barnacle cyprids and metamorphed stages colonized the substrates in July–Sept. and Feb.– March in 1999–2000, but in 2010–12 they were present in the summer and fall months and did not have a Feb.–March settlement. Colonization by both bryozoans and barnacles correlated statistically with temperature, and M. tenuis correlated negatively with salinity as its colonization density increased following the decreased salinity in the spring. In 1999–2000 only M. tenuis correlated with temperature. This study reports settlement periods for these invertebrates in Alabama and provides new data for colonization studies in Mobile Bay. Additionally, we document the successful colonization of substrates by these invertebrates immediately following the Deepwater Horizon oil spill

The Zn-finger domain of MdmX suppresses cancer progression by promoting genome stability in p53-mutant cells

The MDMX (MDM4) oncogene is amplified or overexpressed in a significant percentage of human tumors. MDMX is thought to function as an oncoprotein by binding p53 tumor suppressor protein to inhibit p53-mediated transcription, and by complexing with MDM2 oncoprotein to promote MDM2-mediated degradation of p53. However, down-regulation or loss of functional MDMX has also been observed in a variety of human tumors that are mutated for p53, often correlating with more aggressive cancers and a worse patient prognosis. We have previously reported that endogenous levels of MdmX can suppress proliferation and promote pseudo-bipolar mitosis in primary and tumor cells derived from p53-deficient mice, and that MdmX-p53 double deficient mice succumb to spontaneously formed tumors more rapidly than p53-deficient mice. These results suggest that the MdmX oncoprotein may act as a tumor-suppressor in cancers with compromised p53 function. By using orthotopic transplantation and lung colonization assays in mice we now establish a p53-independent anti-oncogenic role for MdmX in tumor progression. We also demonstrate that the roles of MdmX in genome stability and in proliferation are two distinct functions encoded by the separate MdmX protein domains. The central Zn-finger domain suppresses multipolar mitosis and chromosome loss, whereas the carboxy-terminal RING domain suppresses proliferation of p53-deficient cells. Furthermore, we determine that it is the maintenance of genome stability that underlies MdmX role in suppression of tumorigenesis in hyperploid p53 mutant tumors. Our results offer a rationale for the increased metastatic potential of p53 mutant human cancers with aberrant MdmX function and provide a caveat for the application of anti-MdmX treatment of tumors with compromised p53 activity

Cyclin-dependent kinase 5 regulates PSD-95 ubiquitination in neurons

Cyclin-dependent kinase 5 (Cdk5) and its activator p35 have been implicated in drug addiction, neurodegenerative diseases such as Alzheimer\u27s, learning and memory, and synapse maturation and plasticity. However, the molecular mechanisms by which Cdk5 regulates synaptic plasticity are still unclear. PSD-95 is a major postsynaptic scaffolding protein of glutamatergic synapses that regulates synaptic strength and plasticity. PSD-95 is ubiquitinated by the ubiquitin E3 ligase Mdm2, and rapid and transient PSD-95 ubiquitination has been implicated in NMDA receptor-induced AMPA receptor endocytosis. Here we demonstrate that genetic or pharmacological reduction of Cdk5 activity increases the interaction of Mdm2 with PSD-95 and enhances PSD-95 ubiquitination without affecting PSD-95 protein levels in vivo in mice, suggesting a nonproteolytic function of ubiquitinated PSD-95 at synapses. We show that PSD-95 ubiquitination correlates with increased interaction with beta-adaptin, a subunit of the clathrin adaptor protein complex AP-2. This interaction is increased by genetic reduction of Cdk5 activity or NMDA receptor stimulation and is dependent on Mdm2. Together these results support a function for Cdk5 in regulating PSD-95 ubiquitination and its interaction with AP-2 and suggest a mechanism by which PSD-95 may regulate NMDA receptor-induced AMPA receptor endocytosis

Ice loads acting on a model podded propeller blade (OMAE2005-67416)

With the increase in popularity of podded propulsors and arctic navigation, understanding the interaction between a podded propulsor and ice has become more important. Propeller-ice interaction itself is a complicated process with a high level of uncertainty resulting from the uncertainties associated with the properties of the ice and with the propeller-ice interaction conditions. Model tests provide relatively well-controlled ice properties and interaction conditions to reduce the uncertainties. In order to improve the understanding of this interaction and to develop numerical models of it, a model podded propulsor was used in “Puller” mode, and ice loads were measured on its instrumented blade and propeller shaft. The results of the experiments conducted to simulate the interactions (milling) of the instrumented blade with ice in different operating conditions are reported in this paper. Loads measured during the milling consist of ice milling loads, “inseparable” hydrodynamic loads, and “separable” hydrodynamic loads. The sample results presented here include ice milling and inseparable hydrodynamic loads for various advance coefficients and depths of cut (amount of blade penetration into ice). Some results are compared with existing ice load models

Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells

Dicer, an enzyme involved in microRNA (miRNA) maturation, is required for proper cell differentiation and embryogenesis in mammals. Recent evidence indicates that Dicer and miRNA may also regulate tumorigenesis. To better characterize the role of miRNA in primary cell growth, we generated Dicer-conditional mice. Ablation of Dicer and loss of mature miRNAs in embryonic fibroblasts up-regulated p19Arf and p53 levels, inhibited cell proliferation, and induced a premature senescence phenotype that was also observed in vivo after Dicer ablation in the developing limb and in adult skin. Furthermore, deletion of the Ink4a/Arf or p53 locus could rescue fibroblasts from premature senescence induced by Dicer ablation. Although levels of Ras and Myc oncoproteins appeared unaltered, loss of Dicer resulted in increased DNA damage and p53 activity in these cells. These results reveal that loss of miRNA biogenesis activates a DNA damage checkpoint, up-regulates p19Arf-p53 signaling, and induces senescence in primary cells