Disruption of the V-ATPase functionality as a way to uncouple bone formation and resorption - a novel target for treatment of osteoporosis

The unique ability of the osteoclasts to resorb the calcified bone matrix is dependent on secretion of hydrochloric acid. This process is mediated by a vacuolar H+ ATPase (V-ATPase) and a chloride-proton antiporter. The structural subunit of the V-ATPase, a3, is highly specific for osteoclasts, and mutations in a3 lead to infantile malignant osteopetrosis, a phenomenon characterized by increased bone mass, an increased number of non-resorbing osteoclasts, and a complete lack of bone resorption. Importantly, these individuals have normal or even increased osteoblast numbers and bone formation suggesting that the osteoclasts, but not their resorptive capability, relay an anabolic signal, and, hence, that bone formation can be uncoupled from bone resorption when the a3 subunit is eliminated by mutations, or possibly by pharmacological intervention. The pharmacological profile of the a3 subunit as a highly specific target with a mode of action profile augmenting uncoupling and sustained bone formation, as derived from osteopetrotic patients and mice, highlights the relevance of the V-ATPase in future osteoporosis drug development. However, as illustrated by numerous attempts at developing specific inhibitors of the osteoclastic V-ATPase it is a very difficult target to work with, and an inhibitor possessing the desired profile remains elusive, although highly promising approaches recently have been launched.     

Optimization of PDMS network for a fast response and sensitive actuation material applied in a MEMS spatial light modulator

The cross-linked networks of linear vinyl-terminated poly(dimethylsiloxane) (PDMS) with trimethylsiloxy-terminated methyhydrosiloxane–dimethylsiloxane copolymer (cross-linker) were investigated by tuning the cross-linker concentration, the chain length of linear PDMS and the functionality of the cross-linker. Response time and elastic modulus of the cross-linked PDMS elastomer were characterized by home-made measurement systems and analyzed based on their network topologies. An optimized PDMS elastomer, which has response time of 9 μs and elastic modulus of 601 kPa, was utilized as the actuation material in a MEMS spatial light modulator (SLM). The fabrication processes were described. This polymer based SLM has shown fast response time (9 μs) and successfully diffracted light into higher orders with 84% first-order diffraction efficiency.     

Julia Sets in Parameter Spaces

Given a complex number λ of modulus 1, we show that the bifurcation locus of the one parameter family {f _b (z)=λz+b z ²+z ³} _{b ∈ ℂ} contains quasi-conformal copies of the quadratic Julia set J(λz+z ²). As a corollary, we show that when the Julia set J(λz+z ²) is not locally connected (for example when z↦λz+z ² has a Cremer point at 0), the bifurcation locus is not locally connected. To our knowledge, this is the first example of complex analytic parameter space of dimension 1, with connected but non-locally connected bifurcation locus. We also show that the set of complex numbers λ of modulus 1, for which at least one of the parameter rays has a non-trivial accumulation set, contains a dense G _δ subset of S ¹. Received: 22 September 2000 / Accepted: 16 January 2001     

Using impedance measurements to detect and quantify the effect of air leaks on the attenuation of earplugs

The impedance of a simple artificial ear occluded with an earplug and bypassed with narrow air leaks was measured along with the attenuation of sound through the air leaks. A lumped element model is suggested for the simple occluded artificial ear with an air leak. The suggested model was adapted to the impedance measurements and the attenuation was predicted from the model. The attenuation predictions were compared to the attenuation measurements and were found to be within [-3.5,+3] dB of the measured attenuation over the frequency range of 50-1000 Hz and an attenuation range of -2-38 dB. The average difference between the measured and predicted attenuation for four different leaks in the frequency range of 50-1000 Hz was -0.7 dB, indicating a very slight underestimation of the attenuation.     

Dihydroxy Phenylselenonium p-Toluenesulfonate; Preparation and Use in the Recycling of Selenium Reagents

Dihydroxy phenylselenonium p-toluenesulfonate is prepared by oxidation of diphenyl diselenide with hydrogen peroxide in the presence of p-toluenesulfonic acid. The process which is carried out as a titration has been applied as the key step in a preparation of very pure diphenyl diselenide and in the recycling of benzeneseleninic acid.     

Purification and Characterization of Agarase from Marine Bacteria <Emphasis Type="Italic">Acinetobacter</Emphasis> sp. PS12B and Its Use for Preparing Bioactive Hydrolysate from Agarophyte Red Seaweed <Emphasis Type="Italic">Gracilaria verrucosa</Emphasis>

Acinetobacter strain PS12B was isolated from marine sediment and was found to be a good candidate to degrade agar and produce agarase enzyme. The extracellular agarase enzyme from strain PS12B was purified by ammonium sulfate precipitation followed by DEAE-cellulose ion-exchange chromatography. The specific activity of the crude enzyme which was 1.52 U increased to 45.76 U, after two-stage purification, with an enzyme yield of 9.76%. Purified enzyme had a molecular mass of 24 kDa. The optimum pH and temperature for activity of purified agarase were found to be 8.0 and 40 °C, respectively. The K_m and V_max values for agarase were 4.69 mg/ml and 0.5 μmol/min, respectively. Treatment with EDTA reduced the agarase activity by 58% at 5 mM concentration. The enzyme activity was stimulated by the presence of Fe²⁺, Mn²⁺, and Ca2⁺ ions while reducing reagents (β-mercaptoethanol and dithiothreitol, DTT) enhanced its activity by 30–40%. The purified agarase exhibited tolerance to both detergents and organic solvents. Major hydrolysis products of agar were DP4 and also a mixture of longer oligosaccharides DP6 and DP7. The enzyme hydrolysed seaweed (Gracilaria verrucosa) exhibited strong antioxidant activity in vitro. Successful hydrolysis of seaweed indicates the potential use of the enzyme to produce seaweed hydrolysate having health benefits as well as the industrial application like the production of biofuels.     

Prolonged bone marrow T1-relaxation in acute leukaemia. In vivo tissue characterization by magnetic resonance imaging

In vivo tissue characterization by measurement of T1- and T2-relaxation processes is one of the greatest potentials of magnetic resonance imaging (MRI). This may be especially useful in the evaluation of bone marrow disorders as the MRI-signal from bone marrow is not influenced by the overlying osseous tissue. Nine patients with acute leukaemia, one patient with myelodysplastic syndrome, and ten normal volunteers were included in the study. The T1- and T2-relaxation processes were measured in the lumbar spine bone marrow using a wholebody superconductive MR-scanner operating at 1.5 Tesla. In the patients MRI was done at the time of diagnosis and during follow-up of chemotherapy and related to bone marrow biopsies taken within three days of the MRI. At the time of diagnosis T1-relaxation time was increased two to three times in the patients (range 0.7-3.0 sec.) compared to the controls (range 0.38-0.60 sec.). No significant difference was seen in the T2-relaxation process. In relation to chemotherapy T1 decreased towards the normal range in the patients who obtained complete remission, whereas T1 remained prolonged in the patients who did not respond successfully to the treatment. The results indicate that MRI may be a non-invasive clinically useful tool in the evaluation of acute leukaemia especially as a follow-up control of chemotherapy.     

Crystallographic structure and defects in epitaxial bismuth films grown on mica

Atomic force microscopy is used to image the surface relief of epitaxial Bi films grown on mica substrates. Monatomic terrace steps are readily resolved, which provide detailed information on crystal growth and defect structures. The films grow from the coalescence of isolated three-dimensional islands, however, each island grows layer-by-layer. The islands are triangular in shape and when they coalesce to form a continuous film, their structures are either in-phase, and consequently large crystallites are formed, or they are out-of-phase and defect structures are formed. The most common defects observed are twinning and stacking faults. Images showing the microscopic details of stacking faults, twinning, and grain boundaries are observed as a result of islands coalescing to form a continuous film.     

A general theory of structure spaces with applications to spaces of prime ideals

A structure space is a quadrupleX=(X, d, A, P), where for some setR, X A=2 ^R ,d:X×X A is defined byd(I, J)=J–I, andP is the family of cofinite subsets ofR. Forr P, I X, N _r (I)={J X: d(I, J) r},To(X)={Q X: if x Q there is anr P such thatN _r (x) Q}. ThenTo(X) is a (not usually Hausdorff) topology onX called the hull-kernel topology. Replacing d byd ^*, whered ^* (I, J)=d(J, I), or byd ^s, whered ^s (I, J.)=d(I, J) d ^* (I, J), and proceeding in the obvious way yields thedual hull-kernel topology To(X ^*) andsymmetric topology To(X ^s ). The latter is always a zero-dimensional Hausdorff space. When R is a commutative ring with identity andX is a collection of proper prime ideals ofR, To(X ^s ) is usually called thepatch topology. Our generality enables us to improve on known results in the case of space of prime ideals and to apply this theory to a wide variety of algebraic structures. In particular, we establish criteria for a subspace of a structure space to be closed in the symmetric topology; we establish a duality between families of maximal elements in the hull-kernel topology and families of minimal elements in the dual hull-kernel topology of subspaces that are closed in the symmetric topology; we use topological constructions to generalize certain ring theoretic notions, such as radical ideals an annihilator ideals; we use this theory to obtain new results about subspaces of the space prime ideals of a reduced, commutative ring.Presented by F. E. J. Linton.This author's research was supported by a grant from the CUNY-PSC research award program.