Roles for the type III TGF-β receptor in human cancer

Transforming growth factor β (TGF-β) superfamily ligands have important roles in regulating cellular homeostasis, embryonic development, differentiation, proliferation, immune surveillance, angiogenesis, motility, and apoptosis in a cell type and context specific manner. TGF-β superfamily signaling pathways also have diverse roles in human cancer, functioning to either suppress or promote cancer progression. The TGF-β superfamily co-receptor, the type III TGF-β receptor (TβRIII, also known as betaglycan) mediates TGF-β superfamily ligand dependent as well as ligand independent signaling to both Smad and non-Smad signaling pathways. Loss of TβRIII expression during cancer progression and direct effects of TβRIII on regulating cell migration, invasion, proliferation, and angiogenesis support a role for TβRIII as a suppressor of cancer progression and/or as a metastasis suppressor. Defining the physiological function and mechanism of TβRIII action and alterations in TβRIII function during cancer progression should enable more effective targeting of TβRIII and TβRIII mediated functions for the diagnosis and treatment of human cancer.     

Genetic structure of the xerophilous bromeliad Pitcairnia geyskesii on inselbergs in French Guiana – a test of the forest refuge hypothesis

Inselbergs are isolated granitic rock outcrops that provide distinctive ecological conditions. In northern South America they rise above the surrounding rainforest. Among inselberg specialists, Pitcairnia geyskesii (Bromeliaceae) is restricted to these habitats in French Guiana. We studied populations from 12 inselbergs using 7 microsatellite loci to give a "reverse image" of the reduction-expansion of the rainforest in the context of the refuge hypothesis. Our analyses showed that populations are fragmented with dispersal occurring only over very short distances. Genetic diversity was higher in northern French Guiana, whereas specific alleles were observed in the south. The results point to the occurrence of a dry corridor in the north, as hypothesized by Tardy (1998) based on charcoal analyses, whereas de Granville's (1982) hypothesis of a unique past refuge is not confirmed. Moreover, our data suggests the importance of Oyapock River as a pathway for range expansion, arguing against the potential role of the Inini-Camopi Mountains as a physical barrier. Finally, in spite of a strongly argued scenario in favour of a north-to-south migration history, a clear genetic isolation of P. geyskesii populations living on inselbergs of the Mitaraka archipelago suggests a distinct ancestry of the most southern populations.     

Co-planting can phytoextract similar amounts of cadmium and zinc to mono-cropping from contaminated soils

Co-planting crops normally decreases the main crop yield due to the reduced soil surface area occupied by the main crop. However, in our previous experiments, co-planting Sedum alfredii, a shade-requiring, Cd and Zn-hyperaccumulating plant, with corn increased the biomass and metal phytoextraction of S. alfredii. This experiment was conducted to verify if co-planting another hyperaccumulator, Thlaspi caerulescens, with ryegrass (Lolium perenne) in a pot-trial could obtain a similar result. The soil was separated by two permeable nets with a 2 mm interface soil layer to obtain a shared rhizosphere zone. Soluble metal concentrations in the soil in different rooting zones were measured using 0.01 mol L^?1 CaCl₂ extraction. The results showed that the growth of T. caerulescens was significantly promoted by co-planting, with a growth increase of about 2-fold compared with monoculture growth. The total uptake of Cd and Zn by T. caerulescens was not decreased by co-planting, and resulted in similar phytoextraction rates for Cd (about 26.6% of the soil total Cd) and Zn (about 2.4% of the soil total Zn) when compared with monoculture, though the T. caerulescens population was decreased by 50% because of co-planting. Analysis of soil samples showed that T. caerulescens substantially reduced the concentrations of 0.01 mol L^?1 CaCl₂ extractable Cd and Zn throughout the soil, even in the interface area and the ryegrass rooting area. The ryegrass roots did not mobilize more metals for the co-planted T. caerulescens. Based on these results, existing grass on contaminated land could be partly left while planting metal hyperaccumulators for phytoremediation in order to reduce runoff from the contaminated soil. However a field scale trial would be required for these results to be verified.     

Application of matched filtering to identify behavioral modulation of brain oscillations

Brain oscillations modulated by motor behaviors are coupled to steady-state and other potentially unrelated to movement oscillations, with energy in the same frequency bands as the signals of interest. We applied matched filtering, a quasi-optimum signal detection technique, to decouple and extract movement-related signals from local field potentials (LFPs) recorded in monkey motor cortical areas during the execution of a visually instructed reach-out task. Using a matched-filterbank, we examined coupling and interference of pre-movement and initial steady-state oscillations with movement-induced signals. Once these signal contributions were eliminated, we were able to identify significant correlations of the residual signals with behavioral parameters, which appeared attenuated by pre-movement signal interference in the raw LFPs. Specifically, the maximum and minimum amplitudes of filtered LFPs were directly modulated by peak movement velocity and micro-movements, respectively, identified in recorded hand velocity profiles. In addition, we identified phase correlations between signals during the delay (when the instructional cue was presented) and movement intervals, as well as modulation of LFP phase by movement direction. For pairs of orthogonal movement directions, corresponding LFP signals were consistently out of phase. Finally, β-band energy which is typically reduced during movement execution, possibly partly due to destructive interference between the modulated by behavior signal and unrelated oscillations, appeared to be recovered in the filtered signals.     

Beneficial effects of l-arginine on reducing obesity: potential mechanisms and important implications for human health

Over the past 20 years, growing interest in the biochemistry, nutrition, and pharmacology of l-arginine has led to extensive studies to explore its nutritional and therapeutic roles in treating and preventing human metabolic disorders. Emerging evidence shows that dietary l-arginine supplementation reduces adiposity in genetically obese rats, diet-induced obese rats, finishing pigs, and obese human subjects with Type-2 diabetes mellitus. The mechanisms responsible for the beneficial effects of l-arginine are likely complex, but ultimately involve altering the balance of energy intake and expenditure in favor of fat loss or reduced growth of white adipose tissue. Recent studies indicate that l-arginine supplementation stimulates mitochondrial biogenesis and brown adipose tissue development possibly through the enhanced synthesis of cell-signaling molecules (e.g., nitric oxide, carbon monoxide, polyamines, cGMP, and cAMP) as well as the increased expression of genes that promote whole-body oxidation of energy substrates (e.g., glucose and fatty acids) Thus, l-arginine holds great promise as a safe and cost-effective nutrient to reduce adiposity, increase muscle mass, and improve the metabolic profile in animals and humans.     

Platelet derived growth factor B and epithelial mesenchymal transition of peritoneal mesothelial cells

Platelet derived growth factor (PDGF) is involved in wound healing in various organ systems. Its potential role in the context of peritoneal injury following long-term peritoneal dialysis is unclear. We used an adenovirus expressing the B chain of PDGF (AdPDGF-B) to assess its effect on pro-fibrotic pathways in the peritoneal membrane. To assess the transforming growth factor (TGF) β independent effects of PDGF, we over-expressed PDGF-B in the peritoneum of either wild-type mice (Smad3^+/+) or those with a deletion of the TGFβ signaling protein Smad3 (Smad3^?/?). PDGF-B induced sustained angiogenesis in both Smad3^+/+ and Smad3^?/? mice. Despite increased collagen gene expression, collagen accumulation was transient and fibrogenesis was associated with induction of collagenase activity. We observed epithelial to mesenchymal transition (EMT) involving the peritoneal mesothelial cells, as shown by increased SNAIL and decreased E-Cadherin expression with evidence of mesothelial cells expressing both epithelial and mesenchymal markers. Unlike TGFβ-induced EMT, PDGF-B exposure did not lead to mobilization of the mesothelial cells; they remained as a single monolayer throughout the observation period. This “non-invasive” EMT phenomenon is a novel finding and may have implications concerning the role of EMT in peritoneal fibrosis and injury to other organ systems. The observed effects were similar in Smad3^?/? and Smad3^+/+ animals, suggesting that the PDGF-B effects were independent of TGFβ or Smad signaling.     

Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis

The remarkable survival ability of Mycobacterium tuberculosis in infected hosts is related to the presence of cell wall-associated mycolic acids. Despite their importance, the mechanisms that modulate expression of these lipids in response to environmental changes are unknown. Here we demonstrate that the enoyl-ACP reductase activity of InhA, an essential enzyme of the mycolic acid biosynthetic pathway and the primary target of the anti-tubercular drug isoniazid, is controlled via phosphorylation. Thr-266 is the unique kinase phosphoacceptor, both in vitro and in vivo. The physiological relevance of Thr-266 phosphorylation was demonstrated using inhA phosphoablative (T266A) or phosphomimetic (T266D/E) mutants. Enoyl reductase activity was severely impaired in the mimetic mutants in vitro, as a consequence of a reduced binding affinity to NADH. Importantly, introduction of inhA_T266D/E failed to complement growth and mycolic acid defects of an inhA-thermosensitive Mycobacterium smegmatis strain, in a similar manner to what is observed following isoniazid treatment. This study suggests that phosphorylation of InhA may represent an unusual mechanism that allows M. tuberculosis to regulate its mycolic acid content, thus offering a new approach to future anti-tuberculosis drug development.     

Discovery of a novel class of biphenyl pyrazole sodium channel blockers for treatment of neuropathic pain

A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.