Targeting the podocyte to treat glomerular kidney disease.

The majority of chronic kidney disease (CKD) cases have their origin in the glomerulus, the microvascular unit of the nephron that serves as a filter tasked with forming primary urine. This selective filtration process is determined to a large extent by the functional capacity of the podocyte, a highly differentiated cell type that enwraps the outer aspect of the glomerular capillary wall. In this short review, we describe the biology of the podocyte, its central role in the etiology of various glomerulopathies and highlight current and future opportunities to exploit the unique properties of this cell type for developing kidney-specific therapeutics.

microRNA-34a regulates neurite outgrowth, spinal morphology, and function.

The p53 family member TAp73 is a transcription factor that plays a key role in many biological processes, including neuronal development. In particular, we have shown that p73 drives the expression of miR-34a, but not miR-34b and c, in mouse cortical neurons. miR-34a in turn modulates the expression of synaptic targets including synaptotagmin-1 and syntaxin-1A.

Neuropsin cleaves EphB2 in the amygdala to control anxiety.

A minority of individuals experiencing traumatic events develop anxiety disorders. The reason for the lack of correspondence between the prevalence of exposure to psychological trauma and the development of anxiety is unknown. Extracellular proteolysis contributes to fear-associated responses by facilitating neuronal plasticity at the neuron-matrix interface.

Ryanodine receptor-2 upregulation and nicotine-mediated plasticity.

Nicotine, the major psychoactive component of cigarette smoke, modulates neuronal activity to produce Ca2+-dependent changes in gene transcription. However, the downstream targets that underlie the long-term effects of nicotine on neuronal function, and hence behaviour, remain to be elucidated. Here, we demonstrate that nicotine administration to mice upregulates levels of the type 2 ryanodine receptor (RyR2), a Ca2+-release channel present on the endoplasmic reticulum, in a number of brain areas associated with cognition and addiction, notably the cortex and ventral midbrain.

Different pathways lead to mitochondrial fragmentation during apoptotic and excitotoxic cell death in primary neurons.

Mitochondrial fragmentation is recognized to be an important event during the onset of apoptosis. In this current study, we have used single cell imaging to investigate the role of the mitochondrial fission protein DRP-1 on mitochondrial morphology and mitochondrial fragmentation in primary hippocampal neurons undergoing necrotic or apoptotic cell death. Treatment of neurons with 500 nM staurosporine (apoptosis) or 30 μM glutamate (l-Glu; excitotoxic necrosis) produced a fragmentation and condensation of mitochondria, which although occurred over markedly different time frames appeared broadly similar in appearance.

The impact of 4-Poster deer self-treatment devices at three locations in Maryland.

From 1998-2002 twenty-five deer self-treatment devices (4-Posters), using 2% amitraz, were operated at three locations in Maryland to determine their effectiveness in controlling blacklegged ticks, Ixodes scapularis Say, and lone star ticks, Amblyomma americanum (L.). Each treatment site was approximately 518 ha and paired with a similar site lacking 4-Posters.

Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells.

Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells.

N-methyl-D-aspartate receptors mediate the phosphorylation and desensitization of muscarinic receptors in cerebellar granule neurons.

Changes in synaptic strength mediated by ionotropic glutamate N-methyl-D-asparate (NMDA) receptors is generally considered to be the molecular mechanism underlying memory and learning. NMDA receptors themselves are subject to regulation through signaling pathways that are activated by G-protein-coupled receptors (GPCRs). In this study we investigate the ability of NMDA receptors to regulate the signaling of GPCRs by focusing on the G(q/11)-coupled M(3)-muscarinic receptor expressed endogenously in mouse cerebellar granule neurons.

Mitochondrial Ca2+ signalling in hippocampal neurons.

High-resolution fluorescent imaging of mitochondrial-targeted probes was used to examine the ability of mitochondria to decode complex spatial and temporal Ca2+ signals evoked in synaptically active networks of hippocampal neurons. Green-to-red photoconversion of the mitochondrial-targeted probe, mito-Kaede, demonstrated that mitochondria were present as discrete organelles 2-6 microm in length. Real-time imaging of mitochondrial-targeted ratiometric pericam (2 mtRP) visualised rapid, repetitive, transient mitochondrial Ca2+ fluxes in response to periods of synaptic activation.

Muscarinic acetylcholine receptor activation enhances hippocampal neuron excitability and potentiates synaptically evoked Ca(2+) signals via phosphatidylinositol 4,5-bisphosphate depletion.

Using single cell Ca(2+) imaging and whole cell current clamp recordings, this study aimed to identify the signal transduction mechanisms involved in mACh receptor-mediated, enhanced synaptic signaling in primary cultures of hippocampal neurons. Activation of M(1) mACh receptors produced a 2.48 +/- 0.

NMDA-receptor regulation of muscarinic-receptor stimulated inositol 1,4,5-trisphosphate production and protein kinase C activation in single cerebellar granule neurons.

Inositol 1,4,5-trisphosphate (InsP(3)) production in single cerebellar granule neurons (CGNs) grown in culture was measured using the PH domain of phospholipase C delta1 tagged with enhanced green fluorescent protein (eGFP-PH(PLCdelta1)). These measurements were correlated with changes in intracellular free Ca2+ determined by single cell imaging. In control CGNs, intracellular Ca2+ stores appeared replete.

Visualizing phosphoinositide signalling in single neurons gets a green light.

There is now substantial evidence, from single-cell imaging, that complex patterns of release from Ca(2+) stores play an important role in regulating synaptic efficacy and plasticity. Moreover, the major mechanism of store release depends on the generation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] through the action of phospholipase(s) C on phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)], and several neurotransmitters can enhance receptor-mediated activation of this enzyme. The recent development of techniques to image real-time changes in PtdIns(4,5)P(2) hydrolysis according to generation of Ins(1,4,5)P(3) and diacylglycerol in single cells has significantly advanced our ability to investigate these signalling pathways, particularly in relation to single-cell Ca(2+) signals.

Ca2+/calmodulin-dependent translocation of sphingosine kinase: role in plasma membrane relocation but not activation.

Activation of sphingosine kinase (SPHK), thereby increasing cellular levels of sphingosine 1-phosphate (S1P), may be involved in a variety of intracellular responses including Ca(2+) signaling. This study uses mammalian SPHK1a, tagged with enhanced green fluorescent protein (eGFP), to examine whether translocation of this enzyme is linked with Ca(2+)-mobilizing responses. Real-time confocal imaging of SPHK1a-eGFP in human SH-SY5Y neuroblastoma cells visualized a relocation of the enzyme from the cytosol to the plasma membrane in response to Ca(2+)-mobilizing stimuli (muscarinic M(3)- or lysophosphatidic acid receptor activation, and thapsigargin-mediated store release).