Hypoxia-inducible factor-2α mediates senescence-associated intrinsic mechanisms of age-related bone loss

Aging is associated with cellular senescence followed by bone loss leading to bone fragility in humans. However, the regulators associated with cellular senescence in aged bones need to be identified. Hypoxia-inducible factor (HIF)−2α regulates bone remodeling via the differentiation of osteoblasts and osteoclasts. Here, we report that HIF-2α expression was highly upregulated in aged bones. HIF-2α depletion in male mice reversed age-induced bone loss, as evidenced by an increase in the number of osteoblasts and a decrease in the number of osteoclasts. In an in vitro model of doxorubicin-mediated senescence, the expression of Hif-2α and p21, a senescence marker gene, was enhanced, and osteoblastic differentiation of primary mouse calvarial preosteoblast cells was inhibited. Inhibition of senescence-induced upregulation of HIF-2α expression during matrix maturation, but not during the proliferation stage of osteoblast differentiation, reversed the age-related decrease in Runx2 and Ocn expression. However, HIF-2α knockdown did not affect p21 expression or senescence progression, indicating that HIF-2α expression upregulation in senescent osteoblasts may be a result of aging rather than a cause of cellular senescence. Osteoclasts are known to induce a senescent phenotype during in vitro osteoclastogenesis. Consistent with increased HIF-2α expression, the expression of p16 and p21 was upregulated during osteoclastogenesis of bone marrow macrophages. ChIP following overexpression or knockdown of HIF-2α using adenovirus revealed that p16 and p21 are direct targets of HIF-2α in osteoclasts. Osteoblast-specific (Hif-2α^fl/fl;Col1a1-Cre) or osteoclast-specific (Hif-2α^fl/fl;Ctsk-Cre) conditional knockout of HIF-2α in male mice reversed age-related bone loss. Collectively, our results suggest that HIF-2α acts as a senescence-related intrinsic factor in age-related dysfunction of bone homeostasis.Subject terms: Cell biology, Diseases     

Exercise type and muscle fiber specific induction of caveolin-1 expression for insulin sensitivity of skeletal muscle

It is well known that exercise can have beneficial effects on insulin resistance by activation of glucose transporter. Following up our previous report that caveolin-1 plays an important role in glucose uptake in L6 skeletal muscle cells, we examined whether exercise alters the expression of caveolin-1, and whether exercise-caused changes are muscle fiber and exercise type specific. Fifty week-old Sprague Dawley (SD) rats were trained to climb a ladder and treadmill for 8 weeks and their soleus muscles (SOL) and extensor digitorum longus muscles (EDL) were removed after the last bout of exercise and compared with those from non-exercised animals. We found that the expression of insulin related proteins and caveolins did not change in SOL muscles after exercise. However, in EDL muscles, the expression of insulin receptor beta (IR beta) and glucose transporter-4 (GLUT-4) as well as phosphorylation of AKT and AMPK increased with resistance exercise but not with aerobic exercise. Also, caveolin-1 and caveolin-3 increased along with insulin related proteins only in EDL muscles by resistance exercise. These results suggest that upregulation of caveolin-1 in the skeletal muscle is fiber specific and exercise type specific, implicating the requirement of the specific mode of exercise to improve insulin sensitivity.     

Single-pulse coherent diffraction imaging using soft x-ray laser

We report a coherent diffraction imaging (CDI) using a single 8 ps soft x-ray laser pulse at a wavelength of 13.9 nm. The soft x-ray pulse was generated by a laboratory-scale intense pumping laser providing coherent x-ray pulses up to the level of 10(11) photons/pulse. A spatial resolution below 194 nm was achieved with a single pulse, and it was shown that a resolution below 55 nm is feasible with improved detector capability. The single-pulse CDI might provide a way to investigate dynamics of nanoscale molecules or particles.     

Improved prewhitening method for linear frequency modulation reverberation using dechirping transformation

This letter presents an autoregressive (AR) prewhitener for linear frequency modulation (LFM) reverberation to enhance the target signal. The proposed method uses a dechirping transformation to inversely compensate the frequency chirp rate of the LFM and give the LFM reverberation a stationary frequency property in each data block. The left or right beam signal adjacent to the current beam is then used as the reference signal, and the frequency response of each data block modeled using the AR coefficients. Finally, these coefficients are used to implement the inverse filter and efficiently prewhiten the LFM reverberation of the current beam.     

A biogentic-type synthesis of dendrolasin

Dendrolasin¹ was synthesized from farnesol via biogenetic-type intermediates.     

Lithiated cyclopropanone ketals

The ketene acetal I reacted with dibromocarbene yielding the dibromocyclopropanone ketal II, which was reduced to the monobromide III by treatment with tri-n-butyltin hydride. Reaction of III with n-butyllithium at ?78°C yielded the lithiated cyclopropanone ketal IV, which yielded adducts with acetone, cyclohexanone, cyclohexenone, 3,3,3-trimethoxybutan-2-one, 2-butanone, and 3-pentanone.     

Development of a high-precision image-processing automatic measurement system for MRI visceral fat images acquired using a binomial RF-excitation pulse

Development of a rapid and accurate method for visceral fat measurement is an important task, given the recent increase in the number of patients with metabolic syndrome. In this study, we optimized the Fast Low Angle Shot (FLASH) sequence using a binominal radiofrequency excitation pulse, in which the acquisition time is short, and measured changes in the amount of visceral fat in subjects after a period of wearing clothes with a fat-reducing effect during walking. We solved the reproducibility problem associated with the number of slices, and developed automatic measurement software for high-precision separation and extraction of abdominal visceral fat images. This software was developed using intensity correction with the coil position, derivation of a threshold by histogram analysis and fat separation by template matching for abdominal images. The cross-sectional area of a single slice varies for every acquisition due to visceral organ movement, but the relative error largely converged for seven slices. The measured amount of abdominal fat tended to be consistent with changes in the body fat and waist circumference of the subjects. The correlation coefficients between automatic extraction using the measurement software and manual extraction were 0.9978 for subcutaneous fat and 0.9972 for visceral fat, showing very strong positive correlations. The consistency rates were 0.9502±0.0167 for subcutaneous fat and 0.9395±0.0147 for visceral fat, and the shapes of the regions were also extracted very accurately. These results show that the magnetic resonance imaging acquisition method and image processing system developed in this study are beneficial for measurement of abdominal visceral fat. Therefore, this method may have a major role in future diagnosis of metabolic syndrome.     

Engineering the Internal Structure of Magnetic Silica Nanoparticles by Thermal Control

Calcination of hydrated iron salts in the pores of both spherical and rod‐shaped mesoporous silica nanoparticles (NPs) changes the internal structure from an ordered 2D hexagonal structure into a smaller number of large voids in the particles with sizes ranging from large hollow cores down to ten nanometer voids. The voids only form when the heating rate is rapid at a rate of 30 °C min^?1. The sizes of the voids are controlled reproducibly by the final calcination temperature; as the temperature is decreased the number of voids decreases as their size increases. The phase of the iron oxide NPs is α‐Fe₂O₃ when annealed at 500 °C, and Fe₃O₄ when annealed at lower temperatures. The water molecules in the hydrated iron (III) chloride precursor salts appear to play important roles by hydrolyzing Si? O? Si bonding, and the resulting silanol is mobile enough to affect the reconstruction into the framed hollow structures at high temperature. Along with hexahydrates, trivalent Fe³⁺ ions are assumed to contribute to the structure disruption of mesoporous silica by replacing tetrahedral Si⁴⁺ ions and making Fe? O? Si bonding. Volume fraction tomography images generated from transmission electron microscopy (TEM) images enable precise visualization of the structures. These results provide a controllable method of engineering the internal shapes in silica matrices containing superparamagnetic NPs.     

Targeted and sustained delivery of aclarubicin to lymphatics by lactic acid-oligomer microsphere in rat

We examined targeted delivery of an anticancer drug, aclarubicin (ACR), to the lymphatic system in rats by encapsulation of the drug in microsphere (MS) prepared from nontoxic and biodegradable L-lactic acid-oligomer with an average molecular weight (Mw) of 3600. ACR was released at an almost constant rate from two kinds of ACR-MSs having different size (1-5 microns and less than 1 micron) over 20 d in phosphate-buffered saline at 37 degrees C. The intraperitoneal administration of both ACR-MSs (dose of ACR; 5 mg/kg) to rats sustained an almost constant ACR level (300-400 and 400-600 ng/ml) in the lymph of the thoracic duct during over 10 d, and the ACR level in the blood was extremely low, although intraperitoneal injection of ACR alone gave lower level of ACR in the lymph than in the blood level within 12 h.