A study of age-related architectural changes that are most damaging to bones

Osteoporosis-related bone damage causes major socioeconomic problems. For efficient use of therapeutic agents, it is necessary to be able to reliably identify patients with high propensity for nontraumatic fracture. Age-related bone loss imposes several architectural changes in bone; one of the few ways to estimate damage due to individual changes, and hence determine the most serious types of damage, is via the analysis of suitable mathematical models. Anatomical sites such as the vertebral body, proximal femur, and distal radius are locations where most age-related fractures occur. The inner porous (or trabecular) bone from these sites, which resemble disordered cubic networks, play a significant role in load transmission at these sites. Analysis of a mathematical model of porous bone is used to show that perforation of elements of the network is the most damaging architectural change to a bone. We also show that an expression for bone strength, derived on this basis, can capture changes in strength caused by the inclusion of other features like thinning of trabecular bone and the anisotropy of the network. We finally argue that bone density, which is currently the most routinely used diagnostic, cannot be a reliable surrogate for bone strength.     

The p75 neurotrophin receptor enhances TrkA signalling by binding to Shc and augmenting its phosphorylation

Nerve growth factor (NGF) is an important neuronal survival factor, especially during development. Optimal sensitivity of the survival response to NGF requires the presence of TrkA and the p75 neurotrophin receptor, p75(NTR). Signalling pathways used by TrkA are well established, but the mechanisms by which p75(NTR) enhances NGF signalling remain far from clear. A prevalent view is that p75(NTR) and TrkA combine to form a high-affinity receptor, but definitive evidence for this is still lacking. We therefore investigated the possibility that p75(NTR) and TrkA interact via their signal transduction pathways. Using antisense techniques to down-regulate p75(NTR) and TrkA, we found that p75(NTR) specifically enhanced phosphorylation of the 46- and 52-kDa isoforms of Shc during nerve growth factor-induced TrkA activation. p75(NTR) did not enhance tyrosine phosphorylation of other TrkA substrates. Serine phosphorylation of Akt, downstream of Shc activation, was also p75(NTR)-dependent. We consistently detected co-immunoprecipitation of p75(NTR) and Shc. These data indicate that p75(NTR) interacts with Shc physically, via a binding interaction, and functionally, by assisting its phosphorylation. Whilst providing evidence that p75(NTR) augments TrkA signal transduction, these results do not preclude the presence of a p75(NTR)-TrkA high-affinity NGF receptor.     

The human homologue of the Drosophila melanogaster flightless-I gene (flil) maps within the Smith-Magenis microdeletion critical region in 17p11.2.

The Smith-Magenis syndrome (SMS) appears to be a contiguous-gene-deletion syndrome associated with a proximal deletion of the short arm of chromosome 17 in band p11.2. The spectrum of clinical findings includes short stature, brachydactyly, developmental delay, dysmorphic features, sleep disturbances, and behavioral problems. The complex phenotypic features suggest deletion of several contiguous genes. However, to date, no protein-encoding gene has been mapped to the SMS critical region. Recently, the Drosophila melanogaster flightless-I gene, fliI, and the homologous human cDNA have been isolated. Mutations in fliI result in loss of flight ability and, when severe, cause lethality due to incomplete cellularization with subsequent abnormal gastrulation. Here, we demonstrate that the human homologue (FLI) maps within the SMS critical region. Genomic cosmids were used as probes for FISH, which localized this gene to the 17p11.2 region. Somatic-cell hybrid-panel mapping further localized this gene to the SMS critical region. Southern blot analysis of somatic-cell hybrids and/or FISH analysis of lymphoblastoid cell lines from 12 SMS patients demonstrates the deletion of one copy of FLI in all SMS patients analyzed.     

Loss of ABCA8B decreases myelination by reducing oligodendrocyte precursor cells in mice

The myelin sheath, which is wrapped around axons, is a lipid-enriched structure produced by mature oligodendrocytes. Disruption of the myelin sheath is observed in several neurological diseases, such as multiple sclerosis. A crucial component of myelin is sphingomyelin, levels of which can be increased by ABCA8, a member of the ATP-binding cassette transporter family. ABCA8 is highly expressed in the cerebellum, specifically in oligodendroglia. However, whether ABCA8 plays a role in myelination and mechanisms that would underlie this role remain unknown. Here, we found that the absence of Abca8b, a mouse ortholog of ABCA8, led to decreased numbers of cerebellar oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes in mice. We show that in oligodendrocytes, ABCA8 interacts with chondroitin sulfate proteoglycan 4 (CSPG4), a molecule essential for OPC proliferation, migration, and myelination. In the absence of Abca8b, localization of CSPG4 to the plasma membrane was decreased, contributing to reduced cerebellar CSPG4 expression. Cerebellar CSPG4+ OPCs were also diminished, leading to decreased mature myelinating oligodendrocyte numbers and cerebellar myelination levels in Abca8b^?/? mice. In addition, electron microscopy analyses showed that the number of nonmyelinated cerebellar axons was increased, whereas cerebellar myelin thickness (g-ratio), myelin sheath periodicity, and axonal diameter were all decreased, indicative of disordered myelin ultrastructure. In line with disrupted cerebellar myelination, Abca8b^?/? mice showed lower cerebellar conduction velocity and disturbed locomotion. In summary, ABCA8 modulates cerebellar myelination, in part through functional regulation of the ABCA8-interacting protein CSPG4. Our findings suggest that ABCA8 disruption may contribute to the pathophysiology of myelin disorders.     

Temporal variability of forest communities: empirical estimates of population change in 4000 tree species

Long‐term surveys of entire communities of species are needed to measure fluctuations in natural populations and elucidate the mechanisms driving population dynamics and community assembly. We analysed changes in abundance of over 4000 tree species in 12 forests across the world over periods of 6–28 years. Abundance fluctuations in all forests are large and consistent with population dynamics models in which temporal environmental variance plays a central role. At some sites we identify clear environmental drivers, such as fire and drought, that could underlie these patterns, but at other sites there is a need for further research to identify drivers. In addition, cross‐site comparisons showed that abundance fluctuations were smaller at species‐rich sites, consistent with the idea that stable environmental conditions promote higher diversity. Much community ecology theory emphasises demographic variance and niche stabilisation; we encourage the development of theory in which temporal environmental variance plays a central role.     

Effective models of periodically driven networks

Circadian rhythms are governed by a highly coupled, complex network of genes. Due to feedback within the network, any modification of the system's state requires coherent changes in several nodes. A model of the underlying network is necessary to compute these modifications. We use an effective modeling approach for this task. Rather than inferred biochemical interactions, our method utilizes microarray data from a group of mutants for its construction. With simulated data, we develop an effective model for a circadian network in a peripheral tissue, subject to driving by the suprachiasmatic nucleus, the mammalian pacemaker. The effective network can predict time-dependent gene expression levels in other mutants.