Transforming growth factor β (TGFβ) is a multifunctional cytokine involved in skeletal development. Smad4 is the central intracellular mediator of TGFβ signaling. Our previous studies reveal that Smad4 is required for maintaining the normal development of chondrocytes in the growth plate. However, its biological function during postnatal bone remodeling is largely unknown. To investigate the role of Smad4 in maintaining bone homeostasis, we disrupted the Smad4 gene in differentiated osteoblasts using the Cre-loxP system. The Smad4 mutant mice exhibited lower bone mass up to 6 months of age. The proliferation and function of the mutant osteoblasts were significantly decreased. Bone mineral density, bone volume, bone formation rate and osteoblast numbers were remarkably reduced in Smad4 mutants. Intriguingly, the trabecular bone volume in Smad4 mutant mice older than 7 months was higher than that of controls whereas the calvarial and cortical bone remained thinner than in controls. This correlated with reduced bone resorption possibly caused by downregulation of TGFβ1 and alteration of the ligand receptor activator of NF-κB (RANKL)-osteoprotegerin (OPG) axis. These studies demonstrate essential roles of Smad4-mediated TGFβ signaling in coupling bone formation and bone resorption and maintaining normal postnatal bone homeostasis.

Two liquid chromatography mass spectrometric techniques, i.e. ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-Tof MS) and high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS), were used for quantification, confirmation or identification of six macrolide antibiotic residues and/or their degradation products in eggs, raw milk, and/or honey. Macrolides were extracted from food samples by acetonitrile or phosphate buffer (0.1 M, pH 8.0), and sample extracts were further cleaned up using solid-phase extraction cartridges. UPLC/Q-Tof data were acquired in Tof MS full scan mode that allowed both quantification and confirmation of macrolides, and identification of their degradation products. LC/MS/MS data acquisition was achieved using multiple reaction monitoring (MRM), i.e. two transitions, to provide a high degree of sensitivity and repeatability. Matrix-matched standard calibration curves with the use of roxithromycin as an internal standard were utilized to achieve the best accuracy of the method. Both techniques demonstrated good quantitative performance in terms of accuracy and repeatability. LC/MS/MS had advantages over UPLC/Q-Tof MS in that its limits of detection were lower and repeatability was somewhat better. UPLC/Q-Tof provided ultimate and unequivocal confirmation of positive findings, and allowed degradation product identification based on accurate mass. The combination of the two techniques can be very beneficial or complementary in routine analysis of macrolide antibiotic residues and their degradation products in food matrices to ensure the safety of food supply.

Organics are among the most abundant aerosol components in the atmosphere. However, there are still large uncertainties with emissions of primary organic aerosol (POA) and volatile organic compounds (VOCs) (precursor gases of secondary organic aerosol, SOA), formation of SOA, and chemical and physical properties (e.g., hygroscopicity) of POA and SOA. All these may have significant impacts on aerosol direct and indirect forcing estimated from global models. In this study a modal aerosol module (MAM) in the NCAR community atmospheric model (CAM) is used to examine sensitivities of aerosol indirect forcing to hygroscopicity (represented by a single parameter 'κ') of POA and SOA. Our model simulation indicates that in the present-day (PD) condition changing the 'κ' value of POA from 0 to 0.1 increases the number concentration of cloud condensational nuclei (CCN) at supersaturation S = 0.1% by 40-80% over the POA source regions, while changing the 'κ' value of SOA by ±50% (from 0.14 to 0.07 and 0.21) changes the CCN concentration within 40%. There are disproportionally larger changes in CCN concentration in the pre-industrial (PI) condition. Due to the stronger impact of organics hygroscopicity on CCN and cloud droplet number concentration at PI condition, global annual mean anthropogenic aerosol indirect forcing (AIF) between PD and PI conditions reduces with the increase of the hygroscopicity of organics. Global annual mean AIF varies by 0.4 W m −2 in the sensitivity runs with the control run of −1.3 W m −2 , highlighting the need for improved understanding of organics hygroscopicity and its representation in global models.

Cigarrette smoking as a triggering factor of hidradenitis suppurativa. Dermatology 198:261-4 Oswald F, Ta ¨uber B, Dobner T et al. (2001) p300 acts as a transcriptional coactivator for mammalian notch-1. Mol Cell Biol 21: 7761-74 Pan Y, Lin M, Tian X et al. (2004) Gammasecretase functions through Notch signalling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell 7:731-43 Revuz JE, Canoui-Poitrine F, Wolkenstein P et al. (2008) Prevalence and factors associated with hidradenitis suppurativa: results from two case-control studies.

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Manganese (Mn) deficiency can result in perosis in chicks, but the mechanism of Mn deficiency on tibia development remains poorly understood. Ninety one-day-old Arbor Acres male broiler chickens administered with control diet (60 mg Mn/kg) and Mn-deficient diets (40 mg Mn/kg, 8.7 mg Mn/kg) to investigate the effects of Mn deficiency on morphology of tibia and related signal transduction pathways in broiler chickens. At the age of 42 days, the bone trabecula, damaged osteoblasts and OPG/RANKL mRNA expression levels were investigated by histological assessment, electron microscopic examination and real-time quantitative PCR analysis, respectively. Results of histological observations showed that decreased trabecular thickness, trabecular number and trabecular bone area (%) together with increased trabecular bone separation were involved in perosis induced by Mn deficiency. The most striking ultrastructural modifications involved disruption of nuclear membrane and mitochondria outer membrane, loss of mitochondrion cristae and alteration in endoplasmic reticulum in osteoblasts of the Mn-deficient groups. Likewise, Mn deficiency results in a significant (P < 0.05) decrease in the relative mRNA expression levels of OPG and RANKL with a significantly higher RANKL/OPG ratio (P < 0.05). In conclusion, Mn deficiency can affect the development of tibia in broiler chickens, leading to metaphyseal osteoporosis which may be due to decreased OPG/RANKL mRNA expression.

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