Effect of repetitive transcranial magnetic stimulation on trigeminal-mediated headshaking in 17 horses.

Background: Trigeminal-mediated headshaking is a neuropathic facial pain condition in horses. No treatment has been entirely successful. Repetitive transcranial magnetic stimulation (rTMS) is used in human medicine as a treatment for various neuropathic pain conditions, and good results have been achieved in cases of trigeminal neuralgia.

Arthrographic description of the canine carpal joint cavities and its recesses.

Joint effusion is diagnostically important. The canine carpal joint effusion, which is sometimes difficult to detect clinically, has received less attention in diagnostic ultrasound (US) studies. The aim of the present study was to provide a description of the morphological appearance of the canine carpal joint cavities and recesses using US, radiography, helical computed tomography (CT) and three-dimensional volume rendering technique (3D-VRT) images and to prove the applicability of musculoskeletal US for the detection of artificial carpal joint effusion in dogs.

Elasticity and Viscosity of DNA Liquid Crystals.

Concentrated solutions of blunt-ended DNA oligomer duplexes self-assemble in living polymers and order into lyotropic nematic liquid crystal phase. Using the optical torque provided by three distinct illumination geometries, we induce independent splay, twist, and bend deformations of the DNA nematic and measure the corresponding elastic coefficients , , and , and viscosities η, η, and η. We find the viscoelasticity of the system to be remarkably soft, as the viscoelastic coefficients are smaller than in other lyotropic liquid crystals.

Neutralizing Complement C5a Protects Mice with Pneumococcal Pulmonary Sepsis.

Background: Community-acquired pneumonia and associated sepsis cause high mortality despite antibiotic treatment. Uncontrolled inflammatory host responses contribute to the unfavorable outcome by driving lung and extrapulmonary organ failure. The complement fragment C5a holds significant proinflammatory functions and is associated with tissue damage in various inflammatory conditions.

CCL2/MCP-1 and CXCL12/SDF-1 blockade by L-aptamers improve pancreatic islet engraftment and survival in mouse.

The blockade of pro-inflammatory mediators is a successful approach to improve the engraftment after islet transplantation. L-aptamers are chemically synthesized, nonimmunogenic bio-stable oligonucleotides that bind and inhibit target molecules conceptually similar to antibodies. We aimed to evaluate if blockade-aptamer-based inhibitors of C-C Motif Chemokine Ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) and C-X-C Motif Chemokine Ligand 12/stromal cell-derived factor-1 (CXCL12/SDF-1) are able to favor islet survival in mouse models for islet transplantation and for type 1 diabetes.

CXCL12 blockade preferentially regenerates lost podocytes in cortical nephrons by targeting an intrinsic podocyte-progenitor feedback mechanism.

Insufficient podocyte regeneration after injury is a central pathomechanism of glomerulosclerosis and chronic kidney disease. Podocytes constitutively secrete the chemokine CXCL12, which is known to regulate homing and activation of stem cells; hence we hypothesized a similar effect of CXCL12 on podocyte progenitors. CXCL12 blockade increased podocyte numbers and attenuated proteinuria in mice with Adriamycin-induced nephropathy.

Nonenzymatic Polymerization into Long Linear RNA Templated by Liquid Crystal Self-Assembly.

Self-synthesizing materials, in which supramolecular structuring enhances the formation of new molecules that participate to the process, represent an intriguing notion to account for the first appearance of biomolecules in an abiotic Earth. We present here a study of the abiotic formation of interchain phosphodiester bonds in solutions of short RNA oligomers in various states of supramolecular arrangement and their reaction kinetics. We found a spectrum of conditions in which RNA oligomers self-assemble and phase separate into highly concentrated ordered fluid liquid crystal (LC) microdomains.

Effect of a calcitonin gene-related peptide-binding L-RNA aptamer on neuronal activity in the rat spinal trigeminal nucleus.

Background: Calcitonin gene-related peptide (CGRP) plays a major role in the pathogenesis of migraine and other primary headaches. Spinal trigeminal neurons integrate nociceptive afferent input from trigeminal tissues including intracranial afferents, and their activity is thought to reflect facial pain and headache in man. CGRP receptor inhibitors and anti-CGRP antibodies have been demonstrated to be therapeutically effective in migraine.

Reprint of "Dual blockade of the pro-inflammatory chemokine CCL2 and the homeostatic chemokine CXCL12 is as effective as high dose cyclophosphamide in murine proliferative lupus nephritis".

Induction therapy of proliferative lupus nephritis still requires the use of unselective immunosuppressive drugs with significant toxicities. In search of more specific drugs with equal efficacy but fewer side effects we considered blocking pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) and homeostatic chemokine stromal cell-derived factor-1 (SDF-1/CXCL12), which both contribute to the onset and progression of proliferative lupus nephritis yet through different mechanisms. We hypothesized that dual antagonism could be as potent on lupus nephritis as the unselective immunosuppressant cyclophosphamide (CYC).

Novel Tumor Pretargeting System Based on Complementary l-Configured Oligonucleotides.

Unnatural mirror image l-configured oligonucleotides (L-ONs) are a convenient substance class for the application as complementary in vivo recognition system between a tumor specific antibody and a smaller radiolabeled effector molecule in pretargeting approaches. The high hybridization velocity and defined melting conditions are excellent preconditions of the L-ON based methodology. Their high metabolic stability and negligible unspecific binding to endogenous targets are superior characteristics in comparison to their d-configured analogs.

A thermostable d-polymerase for mirror-image PCR.

Biological evolution resulted in a homochiral world in which nucleic acids consist exclusively of d-nucleotides and proteins made by ribosomal translation of l-amino acids. From the perspective of synthetic biology, however, particularly anabolic enzymes that could build the mirror-image counterparts of biological macromolecules such as l-DNA or l-RNA are lacking. Based on a convergent synthesis strategy, we have chemically produced and characterized a thermostable mirror-image polymerase that efficiently replicates and amplifies mirror-image (l)-DNA.

Liquid Crystal Ordering and Isotropic Gelation in Solutions of Four-Base-Long DNA Oligomers.

Liquid crystal ordering is reported in aqueous solutions of the oligomer 5'-ATTAp-3' and of the oligomer 5'-GCCGp-3'. In both systems, we quantitatively interpret ordering as stemming from the chaining of molecules via a "running-bond" type of pairing, a self-assembly process distinct from the duplex aggregation previously reported for longer oligonucleotides. While concentrated solutions of 5'-ATTAp-3' show only a columnar liquid crystal phase, solutions of 5'-GCCGp-3' display a rich phase diagram, featuring a chiral nematic phase analogous to those observed in solutions of longer oligonucleotides and two unconventional phases, a columnar crystal and, at high concentration, an isotropic amorphous gel.

Dual blockade of the pro-inflammatory chemokine CCL2 and the homeostatic chemokine CXCL12 is as effective as high dose cyclophosphamide in murine proliferative lupus nephritis.

Induction therapy of proliferative lupus nephritis still requires the use of unselective immunosuppressive drugs with significant toxicities. In search of more specific drugs with equal efficacy but fewer side effects we considered blocking pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) and homeostatic chemokine stromal cell-derived factor-1 (SDF-1/CXCL12), which both contribute to the onset and progression of proliferative lupus nephritis yet through different mechanisms. We hypothesized that dual antagonism could be as potent on lupus nephritis as the unselective immunosuppressant cyclophosphamide (CYC).

Expanding biohybrid-mediated asymmetric catalysis into the realm of RNA.

The recent development of biohybrid catalytic systems has allowed synthetic chemists to reach high levels of selectivity on a wide variety of valuable synthetic transformations. In this context, DNA-based catalysts have emerged as particularly appealing tools. Interestingly, while long RNA sequences (ribozymes) are known to catalyse specific biochemical reactions with remarkable efficiencies, RNA-based catalysts involving a catalytically active metal complex interacting in a non-covalent fashion with short sequences have never been evaluated to date.

Noncompetitive affinity assays of glucagon and amylin using mirror-image aptamers as affinity probes.

The ability to detect picomolar concentrations of glucagon and amylin using fluorescently labeled mirror-image aptamers, so-called Spiegelmers, is demonstrated. Spiegelmers rival the specificity of antibodies and overcome the problem of biostability of natural aptamers in a biological matrix. Using Spiegelmers as affinity probes, noncompetitive capillary electrophoresis affinity assays of glucagon and murine amylin were developed and optimized.

SDF-1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy.

Chronic rejection remains a major obstacle in transplant medicine. Recent studies suggest a crucial role of the chemokine SDF-1 on neointima formation after injury. Here, we investigate the potential therapeutic effect of inhibiting the SDF-1/CXCR4/CXCR7 axis with an anti-SDF-1 Spiegelmer (NOX-A12) on the development of chronic allograft vasculopathy.

Outwitting EF-Tu and the ribosome: translation with d-amino acids.

Key components of the translational apparatus, i.e. ribosomes, elongation factor EF-Tu and most aminoacyl-tRNA synthetases, are stereoselective and prevent incorporation of d-amino acids (d-aa) into polypeptides.

Intravitreal inhibition of complement C5a reduces choroidal neovascularization in mice.

Purpose: To investigate the influence of complement component C5a inhibition on laser-induced choroidal neovascularization (CNV) in mice using a C5a specific L-aptamer.

Methods: In C57BL/6 J mice CNV was induced by argon-laser, C5a-inhibitor (NOX-D20) was intravitreally injected in three concentrations: 0.3, 3.

Structural basis for the targeting of complement anaphylatoxin C5a using a mixed L-RNA/L-DNA aptamer.

L-Oligonucleotide aptamers (Spiegelmers) consist of non-natural L-configured nucleotides and are of particular therapeutic interest due to their high resistance to plasma nucleases. The anaphylatoxin C5a, a potent inflammatory mediator generated during complement activation that has been implicated with organ damage, can be efficiently targeted by Spiegelmers. Here, we present the first crystallographic structures of an active Spiegelmer, NOX-D20, bound to its physiological targets, mouse C5a and C5a-desArg.

Crystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2.

We report the crystal structure of a 40 mer mirror-image RNA oligonucleotide completely built from nucleotides of the non-natural L-chirality in complex with the pro-inflammatory chemokine L-CLL2 (monocyte chemoattractant protein-1), a natural protein composed of regular L-amino acids. The L-oligonucleotide is an L-aptamer (a Spiegelmer) identified to bind L-CCL2 with high affinity, thereby neutralizing the chemokine's activity. CCL2 plays a key role in attracting and positioning monocytes; its overexpression in several inflammatory diseases makes CCL2 an interesting pharmacological target.

Stereospecificity of oligonucleotide interactions revisited: no evidence for heterochiral hybridization and ribozyme/DNAzyme activity.

A major challenge for the application of RNA- or DNA-oligonucleotides in biotechnology and molecular medicine is their susceptibility to abundant nucleases. One intriguing possibility to tackle this problem is the use of mirror-image (l-)oligonucleotides. For aptamers, this concept has successfully been applied to even develop therapeutic agents, so-called Spiegelmers.

Neonatal ghrelin programs development of hypothalamic feeding circuits.

A complex neural network regulates body weight and energy balance, and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases, such as obesity. The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we evaluated the physiological and neurobiological contribution of ghrelin during development by specifically blocking ghrelin action during early postnatal development in mice.