Load Regulates Bone Formation and Sclerostin Expression through a TGFβ-Dependent Mechanism

Bone continually adapts to meet changing physical and biological demands. Osteoblasts, osteoclasts, and osteocytes cooperate to integrate these physical and biochemical cues to maintain bone homeostasis. Although TGFβ acts on all three of these cell types to maintain bone homeostasis, the extent to which it participates in the adaptation of bone to mechanical load is unknown. Here, we investigated the role of the TGFβ pathway in load-induced bone formation and the regulation of Sclerostin, a mechanosensitive antagonist of bone anabolism. We found that mechanical load rapidly represses the net activity of the TGFβ pathway in osteocytes, resulting in reduced phosphorylation and activity of key downstream effectors, Smad2 and Smad3. Loss of TGFβ sensitivity compromises the anabolic response of bone to mechanical load, demonstrating that the mechanosensitive regulation of TGFβ signaling is essential for load-induced bone formation. Furthermore, sensitivity to TGFβ is required for the mechanosensitive regulation of Sclerostin, which is induced by TGFβ in a Smad3-dependent manner. Together, our results show that physical cues maintain bone homeostasis through the TGFβ pathway to regulate Sclerostin expression and the deposition of new bone.     

CNS stem cells: Where's the biology (a.k.a. beef)?

Central nervous system (CNS) stem cells have become the subject of many laboratories' efforts, presentations, and publications. Yet, in the stem cell world, CNS cells are viewed with skepticism. This is likely due to a dearth of biology (in vivo function) to accompany a flurry of phenomenological and restorative neurology studies. In this article, we compare and contrast the biological knowledge of adult forebrain epidermal growth factor-responsive neural stem cells that has emerged from our laboratories with that of hematopoietic stem cells, using two recent papers in the latter field as specific examples. A comparison of stem cell location, lineage, and repopulation suggests that our understanding of CNS stem cell biology is immature. We conclude that a greater focus on in vivo biology will enhance our knowledge and understanding of CNS stem cells. © 1998 John Wiley & Sons, Inc. J Neurobiol 36: 307–314, 1998     

A. A. Ukhtomskiĭ and I. P. Pavlov: a controversy or a dialogue?

Pavlov's concept of conditioned reflexes and Ukhtomskii theory of dominanta fall within the biological line in physiology. They unravel the integral adaptive and active nature of the organism behavior in the environment. It is impossible to develop modern concepts about the determinants of goal-directed behavior of animals and voluntary activity of humans without in-depth study of the achievements of these Russian physiological schools which not only formed the methodological basis for the current studies but also directed the way for their further development.     

Monitoring HIV Viral Load in Resource Limited Settings: Still a Matter of Debate?

Introduction

Consequences of lack of viral monitoring in predicting the effects of development of HIV drug resistance mutations during HAART in resource-limited settings (RLS) is still a matter of debate.

Design

To assess, among HIV+ patients receiving their first-line HAART, prevalence of virological failure and genotypic resistance mutations pattern in a Médécins Sans Frontières/Ministry of Health programme in Busia District (Kenya).

Methods

Patients with HAART treatment for ≥12 months were eligible for the study and those with HIV-RNA ≥5000 copies/ml underwent genotypic study. Total HIV-1 RNA from Dried Blood Spots was extracted using Nuclisens method.

Results

926 patients were included. Among 274 (29.6%) patients with detectable viral load, 55 (5.9%) experienced treatment failure (viral load >5.000 copies/ml); 61.8% were female and 10 (18.2%) had clinical failure. Median CD4 cell count was 116 cell/mm3 (IQR: 54–189). Median HIV-RNA was 32,000 copies/ml (IQR: 11000–68000). Eighteen out of 55 (33%) samples could be sequenced on PR and RT genes, with resistance associated mutations (RAMs) in 15 out of 18 samples (83%). Among patients carrying RAMs, 12/15 (81%) harboured RAMs associated to thymidine analogues (TAMs). All of them (100%) showed M184V resistance associated mutation to lamivudine as well as NNRTI''s RAMS.

Conclusions

Virological failure rate in resource-limited settings are similar to those observed in developed countries. Resistance mutation patterns were concordant with HAART received by failing patients. Long term detectable viral load confers greater probability of developing resistance and as a consequence, making difficult to find out a cost-effective subsequent treatment regimen.     

K. H. Rechinger — a life devoted to botany

K. H. Rechinger's great botanical life-work and its impulses on plant geography and taxonomy are estimated.Address toKarl Heinz Rechinger, held on October 18, 1986.     

Flora von Meran im März a. c.

Ohne Zusammenfassung     

Intravenous Magnesium Sulfate With and Without EDTA as a Magnesium Load Test—Is Magnesium Deficiency Widespread?

Serum/plasma measurements do not reflect magnesium deficits in clinical situations, and magnesium load tests are used as a more accurate method to identify magnesium deficiency in a variety of disease states as well as in subclinical conditions. The objective of this study was to determine if people are indeed magnesium deficient or if the apparent magnesium deficiency is due to the composition of the infusate used in the load test. Magnesium load tests were performed on seven patients using three different Mg solution infusions-a Mg-EDTA (ethylene diamine tetraacetic acid)-nutrient cocktail used in EDTA chelation therapy containing several components including vitamins and minerals, and the same cocktail without EDTA and an infusion of an identical amount of magnesium in normal saline solution. There was no significant difference in the amount of magnesium retained in the 24 h after infusion among the three infusates. All infusates resulted in very high magnesium retention compared to previous published magnesium load studies. Magnesium deficiency may be widespread, and the relationship of Mg deficiency to related diseases requires further study.     

Drought and Oxidative Load in the Leaves of C3 Plants: a Predominant Role for Photorespiration?

Although active oxygen species are produced at high rates inboth the chloroplasts and peroxisomes of the leaves of C₃ plants,most attention has focused on the potentially damaging consequencesof enhanced chloroplastic production in stress conditions suchas drought. This article attempts to provide quantitative estimatesof the relative contributions of the chloroplast electron transportchain and the glycolate oxidase reaction to the oxidative loadplaced on the photosynthetic leaf cell. Rates of photorespiratoryH₂O₂ production were obtained from photosynthetic and photorespiratoryflux rates, derived from steady-state leaf gas exchange measurementsat varying irradiance and ambient CO₂. Assuming a 10 % allocationof photosynthetic electron flow to the Mehler reaction, photorespiratoryH₂O₂ production would account for about 70 % of total H₂O₂ formedat all irradiances measured. When chloroplastic CO₂ concentrationrates are decreased, photorespiration becomes even more predominantin H₂O₂ generation. At the increased flux through photorespirationobserved at lower ambient CO₂, the Mehler reaction would haveto account for more than 35 % of the total photosynthetic electronflow in order to match the rate of peroxisomal H₂O₂ production.The potential signalling role of H₂O₂ produced in the peroxisomesis emphasized, and it is demonstrated that photorespiratoryH₂O₂ can perturb the redox states of leaf antioxidant pools.We discuss the interactions between oxidants, antioxidants andredox changes leading to modified gene expression, particularlyin relation to drought, and call attention to the potentialsignificance of photorespiratory H₂O₂ in signalling and acclimation.     

Holocene timber-line dynamics at Bachalpsee, a lake at 2265 m a.s.l. in the northern Swiss Alps

Palaeobotanical analysis and radiocarbon dating of lake sediments from Bachalpsee (2265 m a.s.l.), a small lake above the present-day timber-line in the northern Swiss Alps reveals that the region was already deglaciated during the Younger Dryas. The sediment record is dominated by long-distance transported pollen that originates from lowland vegetation but the plant macrofossils give evidence of the local vegetation development. Comparison with palaeobotanical results from three sites along an altitudinal transect permits the reconstruction of the regional timber-line history. Throughout the entire Holocene the catchment of Bachalpsee consisted of a mosaic of open meadows and dwarf shrubs (Salix, Vaccinium, Rhododendron). Chironomid and cladoceran assemblages suggest that the early to mid-Holocene was the warmest interval at Bachalpsee. Comparison of the palaeobotanical results with those from the mire “Feld” (2130 m a.s.l.) in the vicinity of Bachalpsee showed that during the mid-Holocene the timber-line was formed by Pinus cembra and Picea abies with some scattered Abies alba trees and was situated close to Bachalpsee but never reached its catchment. The maximum timber-line in the Northern Alps was reached between 6000 and 3000 cal b.p. which is several millennia later than in the Central Alps. The species composition of the tree-line (Abies alba, Pinus cembra and the absence of Larix decidua) points to less continental and moister climatic conditions compared with the central Alps during the early to mid-Holocene. From 3000 cal b.p. onwards the timber-line was lowered by human deforestation with the most intense pulses of human impact occurring since the Middle Ages. The catchment of Bachalpsee has been used as alpine pasture since the Bronze Age.     

Babjevia gen. nov. — a new genus of the Lipomycetaceae

The species described asLipomyces anomalus Babjeva & Gorin shows significant genetic and phenotypic divergence from the type speciesLipomyces starkeyi Lodder & Kreger-van Rij in terms of rRNA base sequence substitution and ascosporal and septal ultrastructure. The species is consequently reclassified in the new, unispecific genusBabjevia, asBabjevia anomala.     

Oleuropein Aglycone Protects Transgenic C. elegans Strains Expressing Aβ42 by Reducing Plaque Load and Motor Deficit

The presence of amyloid aggregates of the 42 amino acid peptide of amyloid beta (Aβ42) in the brain is the characteristic feature of Alzheimer’s disease (AD). Amyloid beta (Aβ deposition is also found in muscle fibers of individuals affected by inclusion body myositis (sIBM), a rare muscular degenerative disease affecting people over 50. Both conditions are presently lacking an effective therapeutic treatment. There is increasing evidence to suggest that natural polyphenols may prevent the formation of toxic amyloid aggregates; this applies also to oleuropein aglycone (OLE), the most abundant polyphenol in extra virgin olive oil, previously shown to hinder amylin and Aβ aggregation. Here we evaluated the ability of OLE to interfere with Aβ proteotoxicity in vivo by using the transgenic CL2006 and CL4176 strains of Caenorhabditis elegans, simplified models of AD and of sIBM, which express human Aβ in the cytoplasm of body wall muscle cells. OLE-fed CL2006 worms displayed reduced Aβ plaque deposition, less abundant toxic Aβ oligomers, remarkably decreased paralysis and increased lifespan with respect to untreated animals. A protective effect was also observed in CL4176 worms but only when OLE was administered before the induction of the Aβ transgene expression. These effects were specific, dose-related, and not mediated by the known polyphenolic anti-oxidant activity, suggesting that, in this model organism, OLE interferes with the Aβ aggregation skipping the appearance of toxic species, as already shown in vitro for Aβ42.