Clinical development of anti-RANKL therapy

The receptor activator of nuclear factor-κB ligand (RANKL), its cognate receptor RANK, and its natural decoy receptor osteoprotegerin have been identified as the final effector molecules of osteoclastic bone resorption. This has provided an ideal target for therapeutic interventions in metabolic bone disease. As described in previous reviews in this supplement, RANKL signaling is required for osteoclast differentiation, activation, and survival. Furthermore, in vivo inhibition of RANKL leads to immediate osteoclast apoptosis, and there are no in vivo models of bone resorption that are refractory to RANKL inhibition. Thus, the only step remaining in the development of a clinical intervention is the generation of a safe, effective, and specific drug that can inhibit RANKL in humans. Here we review the clinical development of denosumab (formerly known as AMG 162), which is a fully human mAb directed against RANKL. This discussion includes the breadth of 21 human studies that have led to the current phase 3 clinical trials seeking approval for use of this agent to treat postmenopausal women with low bone mineral density (osteoporosis) and patients with metastatic lytic bone lesions (multiple myeloma, and prostate and breast cancer)

Dynamic nuclear structure emerges from chromatin crosslinks and motors

The cell nucleus houses the chromosomes, which are linked to a soft shell of lamin filaments. Experiments indicate that correlated chromosome dynamics and nuclear shape fluctuations arise from motor activity. To identify the physical mechanisms, we develop a model of an active, crosslinked Rouse chain bound to a polymeric shell. System-sized correlated motions occur but require both motor activity {\it and} crosslinks. Contractile motors, in particular, enhance chromosome dynamics by driving anomalous density fluctuations. Nuclear shape fluctuations depend on motor strength, crosslinking, and chromosome-lamina binding. Therefore, complex chromatin dynamics and nuclear shape emerge from a minimal, active chromosome-lamina system.Comment: 18 pages, 21 figure

Analysis of secondary growth in the Arabidopsis shoot reveals a positive role of jasmonate signalling in cambium formation

After primary growth, most dicotyledonous plants undergo secondary growth. Secondary growth involves an increase in the diameter of shoots and roots through formation of secondary vascular tissue. A hallmark of secondary growth initiation in shoots of dicotyledonous plants is the initiation of meristematic activity between primary vascular bundles, i.e. in the interfascicular regions. This results in establishment of a cylindrical meristem, namely the vascular cambium. Surprisingly, despite its major implications for plant growth and the accumulation of biomass, the molecular regulation of secondary growth is only poorly understood. Here, we combine histological, molecular and genetic approaches to characterize interfascicular cambium initiation in the Arabidopsis thaliana inflorescence shoot. Using genome-wide transcriptional profiling, we show that stress-related and touch-inducible genes are up-regulated in stem regions where secondary growth takes place. Furthermore, we show that the products of COI1, MYC2, JAZ7 and the touch-inducible gene JAZ10, which are components of the JA signalling pathway, are cambium regulators. The positive effect of JA application on cambium activity confirmed a stimulatory role of JA in secondary growth, and suggests that JA signalling triggers cell divisions in this particular context

Exploring Satellite-Derived Relationships between Cloud Droplet Number Concentration and Liquid Water Path Using a Large-Domain Large-Eddy Simulation

Important aspects of the adjustments to aerosol-cloud interactions can be examined using the relationship between cloud droplet number concentration (Nd) and liquid water path (LWP). Specifically, this relation can constrain the role of aerosols in leading to thicker or thinner clouds in response to adjustment mechanisms. This study investigates the satellite retrieved relationship between Nd and LWP for a selected case of mid-latitude continental clouds using high-resolution Large-eddy simulations (LES) over a large domain in weather prediction mode. Since the satellite retrieval uses the adiabatic assumption to derive the Nd, we have also considered adiabatic Nd (NAd) from the LES model for comparison. The joint histogram analysis shows that the NAd-LWP relationship in the LES model and the satellite is in approximate agreement. In both cases, the peak conditional probability (CP) is confined to lower NAd and LWP; the corresponding mean LWP (LWP) shows a weak relation with NAd. The CP shows a larger spread at higher NAd (>50 cm–3), and the LWP increases non-monotonically with increasing NAd in both cases. Nevertheless, both lack the negative NAd-LWP relationship at higher NAd, the entrainment effect on cloud droplets. In contrast, the model simulated Nd-LWP clearly illustrates a much more nonlinear (an increase in LWP with increasing Nd and a decrease in LWP at higher Nd) relationship, which clearly depicts the cloud lifetime and the entrainment effect. Additionally, our analysis demonstrates a regime dependency (marine and continental) in the NAd-LWP relation from the satellite retrievals. Comparing local vs large-scale statistics from satellite data shows that continental clouds exhibit only a weak nonlinear NAd-LWP relationship. Hence a regime-based Nd-LWP analysis is even more relevant when it comes to warm continental clouds and their comparison to satellite retrievals