Bone remodeling involves bone resorption by osteoclasts and synthesis by osteoblasts and is tightly regulated by the receptor activator of the NF-κB ligand (RANKL)/receptor activator of the NF-κB (RANK)/osteoprotegerin molecular triad. RANKL, a member of the TNF superfamily, induces osteoclast differentiation, activation and survival upon interaction with its receptor RANK. The decoy receptor osteoprotegerin inhibits osteoclast formation by binding to RANKL. Imbalance in this molecular triad can result in diseases, including osteoporosis and rheumatoid arthritis. In this study, we report the crystal structures of unliganded RANK and its complex with RANKL and elucidation of critical residues for the function of the receptor pair. RANK represents the longest TNFR with four full cysteine-rich domains (CRDs) in which the CRD4 is stabilized by a sodium ion and a rigid linkage with CRD3. On association, RANK moves via a hinge region between the CRD2 and CRD3 to make close contact with RANKL; a significant structural change previously unseen in the engagement of TNFR superfamily 1A with its ligand. The high-affinity interaction between RANK and RANKL, maintained by continuous contact between the pair rather than the patched interaction commonly observed, is necessary for the function because a slightly reduced affinity induced by mutation produces significant disruption of osteoclast formation. The structures of RANK and RANKL–RANK complex and the biological data presented in the paper are essential for not only our understanding of the specific nature of the signaling mechanism and of disease-related mutations found in patients but also structure based drug design.

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Preoperative α1-adrenoceptor antagonist has no benefit in maintaining intraoperative hemodynamic stability in patients with normotensive pheochromocytoma. It may increase the use of vasoactive drugs and colloid infusion.

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OBJECTIVE To study differences in baseline characteristics and outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line docetaxel-containing chemotherapy on prospective clinical studies (trial participants) versus those receiving this therapy outside of a clinical study (non-participants). PATIENTS AND METHODS Records from 247 consecutive chemotherapy-naive patients who were treated with docetaxel-containing chemotherapy for mCRPC at a single high-volume centre from 1998 to 2010 were reviewed. All patients received docetaxel either as clinical trial participants (n = 142; 11 separate studies) or as non-participants (n = 105). Univariable and multivariable Cox regression models predicted overall survival after chemotherapy initiation. RESULTS There was no significant difference between trial participation and non-participation with respect to patient age, type of primary treatment, tumour grade or clinical stage. Multivariable analyses showed a significantly lower risk of all-cause mortality (hazard ratio 0.567; P = 0.027) among trial participants vs non-participants. CONCLUSIONS Patients that were treated with docetaxel for mCRPC showed a significantly longer overall survival when enrolled in a clinical trial. Improved survival in trial participants may reflect the better medical oversight typically seen in patients enrolled in trials, more regimented follow-up schedules, or a positive effect on caregivers’ attitudes because of greater contact with medical services. With the retrospective nature of this analysis and the small study population, prospective studies are needed to validate the present findings and to further investigate the relationship between clinical trial participation and outcomes.

ABSTRACT. The plant-specific AWPM-19-domain proteins play important roles in plant development and stress responses. In the current study, OsPM19L1 encoding Oryza sativa AWPM-19-like protein 1 was isolated from rice. Tissue-specific gene expression analysis revealed that OsPM19L1 was highly expressed in the leaf sheath of rice. Interestingly, expression of OsPM19L1 was high at the early stage of panicle development and decreased thereafter. qRT-PCR analysis indicated that OsPM19L1 was dramatically induced by 20% PEG stress (>600-fold), exogenous abscisic acid (>350-fold), salt and cold stress. Subcellular localization assay suggested that the OsPM19L1-GFP (green fluorescent protein) fusion protein was localized in the membrane system in rice cells. Moreover, under stress conditions, OsPM19L1 expression was enhanced in an ABI5-Like1 (ABL1) deficiency rice mutant, abl1, suggesting that ABL1 negatively regulates OsPM19L1 gene expression. Thus, OsPM19L1 11995 OsPM19L1 is dramatically induced by osmotic stress in rice ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 11994-12005 (2015) appears to be closely associated with stress tolerance through ABAdependent pathway in rice.

Proteins interact with each other to fulfill their functions. The importance of weak protein-protein interactions has been increasingly recognized. However, owing to technical difficulties, ultra-weak interactions remain to be characterized. Phosphorylation can take place via a K(D)≈25 mM interaction between two bacterial enzymes. Using paramagnetic NMR spectroscopy and with the introduction of a novel Gd(III)-based probe, we determined the structure of the resulting complex to atomic resolution. The structure accounts for the mechanism of phosphoryl transfer between the two enzymes and demonstrates the physical basis for their ultra-weak interaction. Further, molecular dynamics (MD) simulations suggest that the complex has a lifetime in the micro- to millisecond regimen. Hence such interaction is termed a fleeting interaction. From mathematical modeling, we propose that an ultra-weak fleeting interaction enables rapid flux of phosphoryl signal, providing a high effective protein concentration.

The C2H2-type zinc finger proteins (ZFPs) are involved in a wide range of plant development and stress responses. Many studies have shown the positive roles of ZFP genes in stress tolerance. However, overexpression of ZFP genes usually leads to the side effect of growth retardation. Here we report a new member of the ZFP family, Oryza sativa drought-responsive zinc finger protein 1 (OsDRZ1), positively regulating both stress tolerance and plant architecture in rice (Oryza sativa L.). OsDRZ1 was expressed throughout all tissues examined and could be induced by multiple abiotic stresses. OsDRZ1 protein was localized mostly in the nucleus. Unlike most reported rice ZFPs functioning as transcriptional activators, OsDRZ1 is a transcriptional repressor. Overexpression of OsDRZ1 in rice increased seedling drought tolerance and the transgenic plants appeared to accumulate more free proline and fewer reactive oxygen species (ROS), and elevate the activities of antioxidant enzymes. In contrast, RNA interference (RNAi) of OsDRZ1 led to lower activities of antioxidative response and more sensitivity to drought. RNA sequencing analysis revealed that the genes down-regulated by OsDRZ1 were mostly down-regulated by drought, implying the critical role of OsDRZ1 in modulating drought-responsive gene expression. A cupin gene OsGLP1 (germin-like protein1) was identified as one of the potential target genes of OsDRZ1, as suggested by real-time PCR and transient expression analysis in rice protoplasts. Moreover, overexpression of OsDRZ1 did not lead to growth inhibition but the promotion of rice growth, implying the potential application prospective of OsDRZ1 in engineering drought-tolerant crops.