The JAK1/STAT3/SOCS3 axis in bone development,physiology, and pathology

Bone growth and the maintenance of bone structure are controlled by multiple endocrine and paracrine factors, including cytokines expressed locally within the bone microenvironment and those that are elevated, both locally and systemically, under inflammatory conditions. This review focuses on those bone-active cytokines that initiate JAK–STAT signaling, and outlines the discoveries made from studying skeletal defects caused by induced or spontaneous modifications in this pathway. Specifically, this review describes defects in JAK1, STAT3, and SOCS3 signaling in mouse models and in humans, including mutations designed to modify these pathways downstream of the gp130 coreceptor. It is shown that osteoclast formation is generally stimulated indirectly by these pathways through JAK1 and STAT3 actions in inflammatory and other accessory cells, including osteoblasts. In addition, in bone remodeling, osteoblast differentiation is increased secondary to stimulated osteoclast formation through an IL-6-dependent pathway. In growth plate chondrocytes, STAT3 signaling promotes the normal differentiation process that leads to bone lengthening. Within the osteoblast lineage, STAT3 signaling promotes bone formation in normal physiology and in response to mechanical loading through direct signaling in osteocytes. This activity, particularly that of the IL-6/gp130 family of cytokines, must be suppressed by SOCS3 for the normal formation of cortical bone.Subject terms: Growth factor signalling, Metabolic bone disease     

Biomimetic synthesis of the racemic angucyclinones of the aquayamycin and WP 3688-2 types

The first synthesis of the racemic 8-deoxy WP3688-2 angucycline antibiotic (3), with characteristic cis-hydroxy groups at C-4 a and C-12b, is reported. Key steps involve the coupling, mediated by samarium diiodide, of the bicyclic trione 37 to the tricyclic cis-diol 39. Biomimetic aldol cyclization of the corresponding dione 41 gave a mixture of the tetracyclic cis- and trans-3,4a-diols 42 and 43, which were oxidized by cerium ammonium nitrate to the quinones 45 and 3. The synthetic compounds 45 and 3 corresponded in configuration to the angucycline antibiotics aquayamicin (1) and WP 3688-2 (2), respectively.     

Light Irradiation of Mouse Spermatozoa: Stimulation of In Vitro Fertilization and Calcium Signals

Irradiation of mouse spermatozoa by 630 nm He-Ne laser was found to enhance the intracellular calcium levels and fertilizing potential of these cells. The effect of light on calcium transport and on fertilization rate was abrogated in the absence of Ca²⁺during the irradiation time, indicating that the effect of light is Ca²⁺dependent. The stimulatory effect of light on Ca²⁺uptake was abolished in the presence of a voltage-dependent Ca²⁺-channel inhibitor nifedipine, indicating the involvement of a plasma membrane voltage-dependent Ca²⁺channel. Furthermore, the stimulatory effect of light was completely inhibited by the mitochondrial uncoupler FCCP, indicating that laser irradiation might affect the mitochondrial Ca²⁺transport mechanisms. A causal association between laser irradiation, reactive oxygen species (ROS) generation and sperm function was indicated by studies with ROS scavengers, superoxide dismutase (SOD) and catalase, and exogenous hydrogen peroxide. The SOD treatment, which enhanced H₂O₂ production, resulted in increased Ca²⁺uptake and enhanced fertilization rate. On the other hand, catalase, which decomposes H₂O₂, impaired the light-induced stimulation in Ca²⁺uptake and the fertilization rate. Taken together, the data suggest that H₂O₂ might be involved in the irradiation effects, and indeed laser irradiation enhances the production of H₂O₂, by spermatozoa. These results indicate that the effect of 630 nm He-Ne laser irradiation is mediated through the generation of H₂O₂ by the spermatozoa and that this effect plays a significant role in the augmentation of the sperm cells' capability to fertilize metaphase H-arrested eggs in vitro.     

Hydrotris(triazolyl)borate complexes as functional models for Cu nitrite reductase: the electronic influence of distal nitrogens

Hydrotris(triazolyl)borate (Ttz) ligands form CuNO(x) (x = 2, 3) complexes for structural and functional models of copper nitrite reductase. These complexes have distinct properties relative to complexes of hydrotris(pyrazolyl)borate (Tp) and neutral tridentate N-donor ligands. The electron paramagnetic resonance spectra of five-coordinate copper complexes show rare nitrogen superhyperfine couplings with the Ttz ligand, indicating strong σ donation. The copper(I) nitrite complex [PPN](+)[(Ttz(tBu,Me))Cu(I)NO(2)](-) has been synthesized and characterized and allows for the stoichiometric reduction of NO(2)(-) to NO with H(+) addition. Anionic Cu(I) nitrite complexes are unusual and are stabilized here for the first time because Ttz is a good π acceptor.     

Optimal dividend strategies in a Cramér-Lundberg model with capital injections

We consider a classical risk model with dividend payments and capital injections. Thereby, the surplus has to stay positive. Like in the classical de Finetti problem, we want to maximise the discounted dividend payments minus the penalised discounted capital injections. We derive the Hamilton-Jacobi-Bellman equation for the problem and show that the optimal strategy is a barrier strategy. We explicitly characterise when the optimal barrier is at 0 and find the solution for exponentially distributed claim sizes.     

New aspects of diphenylbutadiene photochemistry. Regiospecific hula-twist photoisomerization

In EPA glass at liquid nitrogen temperature, the E,E isomer of diphenylbutadiene (DPB) was photostable, while both the Z,E and Z,Z isomers underwent selective HT isomerization at center 1 giving the stable conformer of the double-bond isomerized trans product. That HT-1 was involved rather than the OBF process was shown by results of o,o'-dimethyl-DPB. Formation of unstable trans product corresponded to simultaneous configurational and conformational isomerization. The regioselectivity was found not sensitive to a substituent effect, as shown by the similar reactivity in p,p'- or o,o'-bistrifluoromethyl-DPB.     

Assembly intermediates in polyketide biosynthesis: enantioselective syntheses of beta-hydroxycarbonyl compounds

A versatile approach for the enantioselective synthesis of functionalised beta-hydroxy N-acetylcysteamine thiol esters has been developed which allows the facile incorporation of isotopic labels. It has been shown that a remarkable reversal of selectivity occurs in the titanium mediated aldol reaction of acyloxazolidinone using either (S)- or (R)-tert-butyldimethylsilyloxybutanal. The aldol products are valuable intermediates in the synthesis of 4-hydroxy-6-substituted delta-lactones.     

Towards a Characterization of Self-Similar Tilings in Terms of Derived Voronoï Tessellations

In this paper, a technique for analyzing levels of hierarchy in a tiling of Euclidean space is presented. Fixing a central configuration P of tiles in , a `derived Voronoï' tessellation _P is constructed based on the locations of copies of P in . A family of derived Voronoï tilings is formed by allowing the central configurations to vary through an infinite number of possibilities. The family will normally be an infinite one, but we show that for a self-similar tiling it is finite up to similarity. In addition, we show that if the family is finite up to similarity, then is pseudo-self-similar. The relationship between self-similarity and pseudo-self-similarity is not well understood, and this is the obstruction to a complete characterization of self-similarity via our method. A discussion and conjecture on the connection between the two forms of hierarchy for tilings is provided.     

The stereochemistry of spiropiperidine cyclizations (histrionicotoxin,part I)

The spirocyclization of straingt-chain triketo-intermediates, similar to possible biogenetic precursors of histrionicotoxin, is shown to be stereoselective, generating the non-natural configuration at C-2. Aiming at an sp²-center in this position, triketo-brassylic ester was treated with ammonia at room temperature and was shown to cleanly and efficiently yield a spiroketone.