Search

Longitudinal growth of postnatal bone requires precise control of growth plate cartilage chondrocytes and subsequent osteogenesis and bone formation. Little is known about the role of angiogenesis and bone remodeling in maintenance of cartilaginous growth plate. Parathyroid hormone (PTH) stimulates bone remodeling by activating PTH receptor (PTH1R). Mice with conditional deletion of PTH1R in osteoblasts showed disrupted trabecular bone formation. The mice also exhibited postnatal growth retardation with profound defects in growth plate cartilage, ascribable predominantly to a decrease in number of hypertrophic chondrocytes, resulting in premature fusion of the growth plate and shortened long bones. Further characterization of hypertrophic zone and primary spongiosa revealed that endochondral angiogenesis and vascular invasion of the cartilage were impaired, which was associated with aberrant chondrocyte maturation and cartilage development. These studies reveal that PTH1R signaling in osteoblasts regulates cartilaginous growth plate for postnatal growth of bone.

Mesenchymal stem/progenitor cells (MSPCs) undergo rapid self-renewal and differentiation, contributing to fast skeletal growth during childhood and puberty. It remains unclear whether these cells change their properties during late puberty to young adulthood, when bone growth and accrual decelerate. Here we show that MSPCs in primary spongiosa of long bone in mice at late puberty undergo normal programmed senescence, characterized by loss of nestin expression. MSPC senescence is epigenetically controlled by the polycomb histone methyltransferase enhancer of zeste homolog 2 (Ezh2) and its trimethylation of histone H3 on Lysine 27 (H3K27me3) mark. Ezh2 maintains the repression of key cell senescence inducer genes through H3K27me3, and deletion of Ezh2 in early pubertal mice results in premature cellular senescence, depleted MSPCs pool, and impaired osteogenesis as well as osteoporosis in later life. Our data reveals a programmed cell fate change in postnatal skeleton and unravels a regulatory mechanism underlying this phenomenon., Mesenchymal stem cells are essential for bone development, but it is unclear if their activity is maintained after late puberty, when bone growth decelerates. The authors show that during late puberty in mice, these cells undergo senescence under the epigenetic control of Ezh2.

Metastatic or recurrent cervical cancer has limited treatment options and a high rate of mortality. Although anti-vascular endothelial growth factor drugs have shown great promise as a therapeutic target for treatment of advanced cervical cancer, drug resistance and class-specific side effects negate long-term benefits. The identification of alternative anti-angiogenic factors will be critical for future drug development for advanced or recurrent cervical cancer. In this study, we found that angiopoietins and Tie receptors were highly expressed in cervical cancer cells. Tie-2 expression in tumor cells predicted poorer prognosis. Wound closure assay and Transwell assay showed that upregulated or downregulated Ang-1 and Ang-2 expression promoted or reduced cervical cancer cell lines migration and invasion, respectively. In subcutaneous xenograft models of cervical cancer, downregulation of Ang-1 and Ang-2 attenuated tumor growth. The expression of vimentin and endomucin and microvessel density were all significantly decreased in the siAng-1 group and siAng-2 group relative to the infection control group. Our data support that dual inhibition of Ang-1 and Ang-2 may be an alternative target for anti-angiogenic adjuvant therapy in advanced or recurrent cervical squamous cell cancer.

The current article focuses on the impact for listeners of oral histories of persons with schizophrenia, presented to 241 audience members. Post-presentation feedback was obtained. Findings from a mixed-methods design combining chi-square analyses with qualitative presentation of emerging themes present evidence to support new learning, emotional impact, and motivational inspiration in listeners.

Acquired heterotopic ossification (HO) is a painful and debilitating disease characterized by extraskeletal bone formation after injury. The exact pathogenesis of HO remains unknown. Here we show that TGF-β initiates and promotes HO in mice. We find that calcified cartilage and newly formed bone resorb osteoclasts after onset of HO, which leads to high levels of active TGF-β that recruit mesenchymal stromal/progenitor cells (MSPCs) in the HO microenvironment. Transgenic expression of active TGF-β in tendon induces spontaneous HO, whereas systemic injection of a TGF-β neutralizing antibody attenuates ectopic bone formation in traumatic and BMP-induced mouse HO models, and in a fibrodysplasia ossificans progressive mouse model. Moreover, inducible knockout of the TGF-β type II receptor in MSPCs inhibits HO progression in HO mouse models. Our study points toward elevated levels of active TGF-β as inducers and promoters of ectopic bone formation, and suggest that TGF-β might be a therapeutic target in HO., Heterotopic ossification (HO) is a painful disease of unknown etiology characterized by extraskeletal bone formation after injury. Here the authors show that TGF-β is increased in HO lesions, where it promotes the early stages of HO pathology, and demonstrate that TGF-β inhibition ameliorates HO in mice.

This letter to the editor rebuts flawed analyses made by O'Reilly (2014) and points out duplicative comments that have already been rebutted in the peer-reviewed literature. O'Reilly (2014) provides little new scientific information on the source apportionment of polycyclic aromatic hydrocarbons (PAHs) in sediments, and the author stands by the results of her research.

Death may be exiled from the living room as we no longer keep parlors as dedicated space for ritual goodbyes and communion with our shrouded dead, but banished death has reappeared with a vengeance in our books, kindled and original paper, and channeled through our home entertainment centers, allowing us to once more meet our nemesis on common ground. We suggest that death is a root metaphor in horror fiction, and we highlight how fictional works about the undead allow us to face death and relate to it, as they move us to look more closely at the alliance between living and dead, provide us with a tangible adversary at end-of-life, and enable us to approach death with dialogic intimacy, acknowledgment, courage, and acceptance.

Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specific vessel subtype, strongly positive for CD31 and endomucin (CD31(hi)Emcn(hi)), couples angiogenesis and osteogenesis. Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts induces CD31(hi)Emcn(hi) vessel formation during bone modeling and remodeling. Mice with depletion of PDGF-BB in the tartrate-resistant acid phosphatase-positive cell lineage show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and fewer CD31(hi)Emcn(hi) vessels compared to wild-type mice. In the ovariectomy (OVX)-induced osteoporotic mouse model, serum and bone marrow levels of PDGF-BB and numbers of CD31(hi)Emcn(hi) vessels are significantly lower compared to sham-operated controls. Treatment with exogenous PDGF-BB or inhibition of cathepsin K to increase the number of preosteoclasts, and thus the endogenous levels of PDGF-BB, increases CD31(hi)Emcn(hi) vessel number and stimulates bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a new therapeutic target for treating osteoporosis by promoting angiogenesis and thus bone formation.

An updated checklist of cartilaginous and bony fishes from reefs and nearby areas around Clipperton Atoll (eastern Pacific) is presented. The register was compiled from field surveys between 1997 and 2012, an exhaustive literature review, and consultation of museum collections and databases. Records were then used to assess completeness of the local fish inventory using six nonparametric rarefaction formulations. A total of 197 species in 62 families was recorded, and of these 106 correspond to reef fishes; most of these are immigrants from the eastern and central Pacific, and only seven species were identified as endemics of the atoll. Estimated level of endemism in reef species (6.6%) is high for the eastern Pacific as a whole but intermediate when compared with data for other oceanic islands of the same region. From nonparametric tests it was estimated that expected number of reef fishes present at Clipperton is 110 + 4 species, and because the difference from the reported number from this ne...

To optimally manage an environment with predators, prey must correctly distinguish between cues that are risky and cues that are safe. Even a specific cue that is safe in one area or at a certain time may be dangerous in other situations, and vice versa. Latent inhibition is a cognitive mechanism by which animals fail to learn that a stimulus as risky because they have already learned it as non-threatening via previous encounters with the stimulus in the absence of negative consequences. Here, we demonstrate that latent inhibition of predator-recognition learning in wood frog tadpoles, Lithobates sylvaticus , depends on the timing of their learning opportunities. For 6 days, tadpoles were exposed daily to an initially novel stimulus (salamander odour), either in the morning (11.00–13.00 h) or evening (16.00–18.00 h). The following day, we conditioned tadpoles to recognize the salamander odour as a predator by pairing it with injured tadpole cues, either at the same time as their previous experience or at the opposite time. When tested the following day, latent inhibition occurred under each scenario where the timing of conditioning matched the timing of the pre-exposure. However, tadpoles tested in the morning showed learned fright responses when conditioned in the morning if their pre-exposure had occurred in the evening, whereas individuals tested in the evening showed learned fright responses when conditioned in the evening if their pre-exposure had occurred in the morning. This is the first report of time-dependent latent inhibition of predator-recognition learning, which is likely an important mechanism for correctly managing predation risk and safety.

During bone resorption, abundant factors previously buried in the bone matrix are released into the bone marrow microenvironment, which results in recruitment and differentiation of bone marrow mesenchymal stem cells (MSCs) for subsequent bone formation, temporally and spatially coupling bone remodeling. Parathyroid hormone (PTH) orchestrates the signaling of many pathways that direct MSC fate. The spatiotemporal release and activation of matrix TGF-β during osteoclast bone resorption recruits MSCs to bone-resorptive sites. Dysregulation of TGF-β alters MSC fate, uncoupling bone remodeling and causing skeletal disorders. Modulation of TGF-β or PTH signaling may reestablish coupled bone remodeling and be a potential therapy.

People with schizophrenia live their lives in the midst of misunderstanding and stigma from both the public and health-care providers, often fueled by media reports. Both laypersons and professiona...

Working in the Galapagos Islands and surrounding areas, we examined the relationship between population structure, a precursor to allopatric speciation, in species of reef fishes that exhibit different life history traits and three types of distributions in a nested setting: endemic (restricted to the Galapagos Islands), insular (Galapagos and neighboring islands), and Panamic (tropical eastern Pacific). We used a combination of population structure and coalescent approaches to assess the degree of genetic population structure in the three groups of fish species. In addition, we evaluated the level of inter-island genetic diversity in endemic species to determine if Galapagos fishes, like their terrestrial counterparts, could be used as a system to study allopatric speciation in the sea. We found that in general, there was no correlation between distribution ranges, life history traits, and population structure, except for Dialommus fuscus Gilbert, 1891, a Galapagos endemic that lives in the uppermost intertidal area, and as predicted, shows very strong population structure. We found the highest number of statistically significant population pairwise F ST comparisons in endemic species. In addition, three out of four endemic species showed significant population pairwise F ST [D. fuscus, Lepidonectes corallicola (Kendall and Radcliffe, 1912), and Lythrypnus gilbert (Heller and Snodgrass, 1903)]. These results suggest that endemic Galapagos Islands reef fishes may be a promising group of species to study phylogeographic patterns of speciation.

We describe an Introduction to Psychology (IP) demonstration of water dowsing and ideomotor action designed to enhance students’ critical thinking. An instructor demonstrated that metal rods crossed over an uncovered cup containing water but not one containing sugar. Student volunteers using the rods also saw them cross over the cup containing water, even after we covered the cup and surreptitiously replaced it with the cup containing sugar (illustrating ideomotor action). Five days later, students who saw the demonstration were (a) less convinced of the validity of dowsing and facilitated communication after reading anecdotal evidence and (b) more likely to suggest ideomotor action as an explanation for several ideomotor-related phenomena compared to students in the control sections of IP.

High concentrations of polycyclic aromatic hydrocarbons (PAHs) are accumulating in many urban stormwater ponds in Minnesota, resulting in either expensive disposal of the excavated sediment or deferred maintenance by economically challenged municipalities. Fifteen stormwater ponds in the Minneapolis—St. Paul, MN, metropolitan area were studied to determine sources of PAHs to bed sediments through the application of several environmental forensic techniques, including a contaminant mass balance receptor model. The model results were quite robust and indicated that coal tar-based sealant (CT-sealant) particulate washoff and dust sources were the most important sources of PAHs (67.1 %), followed by vehicle-related sources (29.5 %), and pine wood combustion particles (3.4 %). The distribution of 34 parent and alkylated PAHs was also evaluated regarding ancillary measurements of black carbon, total organic carbon, and particle size classes. None of these parameters were significantly different based on major land-use classifications (i.e., residential, commercial, and industrial) for pond watersheds. PAH contamination in three stormwater ponds was high enough to present a risk to benthic invertebrates, whereas nine ponds exceeded human health risk-based benchmarks that would prompt more expensive disposal of dredged sediment. The State of Minnesota has been addressing the broader issue of PAH-contaminated stormwater ponds by encouraging local municipalities to ban CT-sealants (29 in all) and to promote pollution prevention alternatives to businesses and homeowners, such as switching to asphalt-based sealants. A statewide CT-sealant ban was recently enacted. Other local and regional jurisdictions may benefit from using Minnesota’s approach where CT-sealants are still used.

When different species have common predators, selection should favor individuals that respond to alarm cues from the other species. The Ozark zigzag salamander (Plethodon angusticlavius) occupies microhabitats under rocks and logs during wet conditions, and uses subterranean burrows during harsh environmental periods. Using the vomeronasal organ, these salamanders can assess chemical cues in their environment, including cues from predators and alarm secretions from conspecific and heterospecific salamanders. Ozark zigzag salamanders live syntopically with earthworms which are abundant and vulnerable to the same predators. We tested whether salamanders would respond to alarm secretion from earthworms in ways that are consistent with antipredator behaviour. We obtained alarm secretions from earthworms by simulating a predator attack (grasping them with forceps) and collecting the stimuli in water. When exposed to alarm secretions, salamanders increased their time spent in escape behaviour, decreased their c...

Balancing bone resorption and formation is the quintessential component for the prevention of osteoporosis. Signals that determine the recruitment, replication, differentiation, function, and apoptosis of osteoblasts and osteoclasts direct bone remodeling and determine whether bone tissue is gained, lost, or balanced. Therefore, understanding the signaling pathways involved in the coupling process will help develop further targets for osteoporosis therapy, by blocking bone resorption or enhancing bone formation in a space- and time-dependent manner. Insulin-like growth factor type 1 (IGF-1) has long been known to play a role in bone strength. It is one of the most abundant substances in the bone matrix, circulates systemically and is secreted locally, and has a direct relationship with bone mineral density. Recent data has helped further our understanding of the direct role of IGF-1 signaling in coupling bone remodeling which will be discussed in this review. The bone marrow microenvironment plays a critical role in the fate of mesenchymal stem cells and hematopoietic stem cells and thus how IGF-1 interacts with other factors in the microenvironment are equally important. While previous clinical trials with IGF-1 administration have been unsuccessful at enhancing bone formation, advances in basic science studies have provided insight into further mechanisms that should be considered for future trials. Additional basic science studies dissecting the regulation and the function of matrix IGF-1 in modeling and remodeling will continue to provide further insight for future directions for anabolic therapies for osteoporosis.

Mutations in low-density lipoprotein receptor-related protein 6 (LRP6) are associated with human skeletal disorders. LRP6 is required for parathyroid hormone (PTH)-stimulated signaling pathways in osteoblasts. We investigated whether LRP6 in osteoblasts directly regulates bone remodeling and mediates the bone anabolic effects of PTH by specifically deleting LRP6 in mature osteoblasts in mice (LRP6 KO). Three-month-old LRP6 KO mice had a significant reduction in bone mass in the femora secondary spongiosa relative to their wild-type littermates, whereas marginal changes were found in femoral tissue of 1-month-old LRP6 KO mice. The remodeling area of the 3-month-old LRP6 KO mice showed a decreased bone formation rate as detected by Goldner's Trichrome staining and calcein double labeling. Bone histomorphometric and immumohistochemical analysis revealed a reduction in osteoblasts but little change in the numbers of osteoclasts and osteoprogenitors/osteoblast precursors in LRP6 KO mice compared with wild-type littermates. In addition, the percentage of the apoptotic osteoblasts on the bone surface was higher in LRP6 KO mice compared with wild-type littermates. Intermittent injection of PTH had no effect on bone mass or osteoblastic bone formation in either trabecular and cortical bone in LRP6 KO mice, whereas all were enhanced in wild-type littermates. Additionally, the anti-apoptotic effect of PTH on osteoblasts in LRP6 KO mice was less significant compared with wild-type mice. Therefore, our findings demonstrate that LRP6 in osteoblasts is essential for osteoblastic differentiation during bone remodeling and the anabolic effects of PTH.

Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for the condition because of limited understanding of its pathogenesis. We show that transforming growth factor β1 (TGF-β1) is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis. TGF-β1 concentrations are also high in subchondral bone from humans with osteoarthritis. High concentrations of TGF-β1 induced formation of nestin-positive mesenchymal stem cell (MSC) clusters, leading to formation of marrow osteoid islets accompanied by high levels of angiogenesis. We found that transgenic expression of active TGF-β1 in osteoblastic cells induced osteoarthritis, whereas inhibition of TGF-β activity in subchondral bone attenuated the degeneration of articular cartilage. In particular, knockout of the TGF-β type II receptor (TβRII) in nestin-positive MSCs led to less development of osteoarthritis relative to wild-type mice after ACLT. Thus, high concentrations of active TGF-β1 in subchondral bone seem to initiate the pathological changes of osteoarthritis, and inhibition of this process could be a potential therapeutic approach to treating this disease.

Intervertebral disc (IVD) degeneration is the leading cause of disability with no disease-modifying treatment. IVD degeneration is associated with instable mechanical loading in the spine, but little is known about how mechanical stress regulates nucleus notochordal (NC) cells to maintain IVD homeostasis. Here we report that mechanical stress can result in excessive integrin αvβ6-mediated activation of transforming growth factor beta (TGFβ), decreased NC cell vacuoles, and increased matrix proteoglycan production, and results in degenerative disc disease (DDD). Knockout of TGFβ type II receptor (TβRII) or integrin αv in the NC cells inhibited functional activity of postnatal NC cells and also resulted in DDD under mechanical loading. Administration of RGD peptide, TGFβ, and αvβ6-neutralizing antibodies attenuated IVD degeneration. Thus, integrin-mediated activation of TGFβ plays a critical role in mechanical signaling transduction to regulate IVD cell function and homeostasis. Manipulation of this signaling pathway may be a potential therapeutic target to modify DDD.

Neophobia, the fear of novel stimuli, plays a major role in animal ecology. Here, we review studies on predator neophobia and explore its underlying patterns within an ecological framework. Predator neophobia is typically assessed by observing behaviours in novel areas that bring potential risk from unknown predators, or by observing behaviours towards certain kinds of objects and odours that are novel. We conducted a literature review across taxa, surveying research on baseline and induced neophobia versus controls. We calculated effect sizes for the intensity of neophobic responses, and categorized data according to six factors (taxa, age class, background type, trophic position, test cue type and experimental treatment type). While accounting for each of the other factors, we found that baseline neophobia was stronger among birds and mammals, and towards novel areas, relative to other taxa and cue types. Baseline neophobia was lower for wild-caught animals and for those that were higher in trophic position, compared with those reared in captivity and from lower trophic levels. By contrast, induced neophobia was similar in intensity across taxa, background types and testing cue types, while again being lower among upper trophic-level members and among juvenile animals. Although induced neophobia occurred across all treatment types, brain lesions induced stronger neophobia than predation risk or social isolation. We discuss potential mechanisms underlying these results and highlight gaps in the literature.

Parathyroid hormone (PTH) regulates bone remodeling by activating PTH type 1 receptor (PTH1R) in osteoblasts/osteocytes. Insulin-like growth factor type 1 (IGF-1) stimulates mesenchymal stem cell differentiation to osteoblasts. However, little is known about the signaling mechanisms that regulates the osteoblast-to-osteocyte transition. Here we report that PTH and IGF-I synergistically enhance osteoblast-to-osteocyte differentiation. We identified that a specific tyrosine residue, Y494, on the cytoplasmic domain of PTH1R can be phosphorylated by insulin-like growth factor type I receptor (IGF1R) in vitro. Phosphorylated PTH1R localized to the barbed ends of actin filaments and increased actin polymerization during morphological change of osteoblasts into osteocytes. Disruption of the phosphorylation site reduced actin polymerization and dendrite length. Mouse models with conditional ablation of PTH1R in osteoblasts demonstrated a reduction in the number of osteoctyes and dendrites per osteocyte, with complete overlap of PTH1R with phosphorylated-PTH1R positioning in osteocyte dendrites in wild-type mice. Thus, our findings reveal a novel signaling mechanism that enhances osteoblast-to-osteocyte transition by direct phosphorylation of PTH1R by IGF1R., Bone formation: Hormone and growth factor work together A key hormone and growth factor work together to help turn bone-forming cells into mature bone. Janet Crane and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, tested the effects of parathyroid hormone (PTH) and insulin like-growth factor type 1 (IGF-1) signaling on the differentiation of bone-forming osteoblasts by modulating the activity of their receptors in genetically engineered mice. They found a specific part of the PTH type 1 receptor has a phosphate group added to it by the IGF-1 receptor. This chemical tagging leads to changes in the cytoskeleton of osteoblasts that enhance the formation of mature bone cells known as osteocytes. Mice without this PTH receptor had reduced numbers of osteocytes in their bone. The findings reveal a novel signaling mechanism behind this cellular transition during bone building.

Through time, the activity patterns, morphology, and development of both predators and prey change, which in turn alter the relative vulnerability of prey to their coexisting predators. Recognizing these changes can thus allow prey to make optimal decisions by projecting risk trends into the future. We used tadpoles (Lithobates sylvaticus) to test the hypothesis that tadpoles can extrapolate information about predation risk from past information. We exposed tadpoles to an odour that represented either a temporally consistent risk or an increasing risk. When tested for their response to the odour, the initial antipredator behaviour of tadpoles did not differ, appearing to approach the limit of their maximum response, but exposure to increasing risk induced longer retention of these responses. When repeating the experiment using lower risk levels, heightened responses occurred for tadpoles exposed to increasing risk, and the strongest responses were exhibited by those that received an abrupt increase compared to a steady increase. Our results indicate that tadpoles can assess risk trends through time and adjust their antipredator responses in a way consistent with an extrapolated trend. This is a sophisticated method for prey to avoid threats that are becoming more (or less) dangerous over part of their lifespan.

We apply new perspectives on how organisms burrow by examining the association of in situ variation in sediment mechanical properties with burrowing ability and species distribution of two sympatric lugworms, Abarenicola pacifica and Abarenicola claparedi. We quantified the sediment's resistance to penetration and its grain size distribution at sites inhabited by each species. Abarenicola pacifica individuals were found in significantly harder to penetrate, more heterogeneous sediments. We compared worm burrowing ability using reciprocal transplant experiments. Worms from firmer sediments, A. pacifica, were able to make successful steep burrows in sediments characteristic of either species. In contrast, A. claparedi individuals often failed to complete successful burrows in the firmer A. pacifica sediment. To examine how morphological differences could explain these patterns, we compared body wall musculature and measured how well individuals support their own bodies when draped over a cantilever. Lugworms from the firmer sediment had thicker body wall musculature and held their bodies more rigidly than did worms from softer sediments. Additionally, we observed subtle differences in the papillae on the proboscises' surfaces, which could affect worm–sediment interactions, but we found no differences in the chaetae of the two species. Abarenicola claparedi produced more mucus, which could be important in shoring up burrow walls in their shifting, sandy habitat. This study presents the first example of using field-based experiments to determine how sediment mechanical properties and worm burrowing ability could act to determine organismal distribution. Our findings have broader ecological implications because of the role of lugworms as ecosystem engineers.

Some aquatic species are able to learn to recognize chemical cues from predators through classical conditioning. In previous tests, laboratory-reared larval hellbenders (Cryptobranchus alleganiensis) showed weak antipredator responses to introduced predators (trout) compared to responses to their native predators, such as bass and sculpin. However, hellbender larvae that were conditioned with conspecific alarm cues at six months of age learned to recognize trout odour, but the responses of younger larvae to alarm cues have not been tested and the ontogeny of learning abilities is not known. In this study, we successfully trained younger larval hellbenders (4 months old) to recognize trout. Moreover, we found that the learned responses of younger hellbenders (decreased activity) are different from those of the older hellbenders (increased activity) in the previous study. This ontogenetic shift in behaviour may result from larvae increasing locomotor and sensory abilities and becoming more visible during the 4-6 month time period.

Most cells that have been tested have two trans plasma membrane electron transport systems for the oxidation of cytosolic NADH. The first is an oxidase which transfers electrons from NADH to oxygen through dehydrogenases to coenzyme Q and a terminal reduced coenzyme Q oxidase. The second system for trans membrane electrontransport from NADH is a protein complex called porin or Voltage Dependent Anion Channel (VDAC). It transfers electrons across the 32 F. L. Crane et al. membrane on a pair of SH groups which line the channel. It does not react directly with oxygen but transfers electrons to an external artificial acceptor such as ferricyanide. The natural acceptor is most likely to be semidehydroascorbic acid which would be reduced to ascorbate which can be oxidized by ascorbate oxidase acting as the terminal oxidase. Activation of NADH oxidation in serum deficient media stimulates growth of cultured cells. Which oxidase contributes to the growth stimulation has not been determined. Here we consider inhibitors which can help define which NADH oxidation controls growth Growth stimulation is much greater with transformed tumor cells than with untransformed cells. Inhibitors of transmembrane electron transport inhibit growth and a wide group of well known anti tumor drugs are excellent inhibitors of the transmembrane electron transport in tumor cells and are less inhibitory in untransformed cells. The terminal oxidase copper protein, referred to as tNOX or ECTO-NOX, appears to be modified with cell transformation so that it is less firmly attached to the outer surface of the cell and is released into the sera more than c NOX.1 Activation of the trans membrane electron transport increases the NAD+ concentration inside the cell by oxidation of NADH. Since the reduction of pyruvate , which also increases cytosolic NAD, can stimulate growth a function of NAD in growth control is indicated which could involve activation of sirtuin 1 by NAD in the cytoplasm. Sirtuin 1 is known to control the cell cycle and apoptosis.

Thirty-eight hospitals participated in falls prevention team training, followed by coaching and mentoring over 3 months to develop unit-based initiatives to reduce falls. Initiatives centered on fall risk assessment, rounding, or postfall assessment. Paired t test of the pre-/postintervention fall rates of 23 of the hospitals revealed reduced fall rates (P < .01). The estimated mean decrease was 1.7 falls per 1000 patient days (95% confidence limits of 0.7-2.7).

The dynamic relationship between reefs and the people who utilize them at a subsistence level is poorly understood. This paper characterizes atoll-scale patterns in shallow coral reef habitat and fish community structure, and correlates these with environmental characteristics and anthropogenic factors, critical to conservation efforts for the reefs and the people who depend on them. Hierarchical clustering analyses by site for benthic composition and fish community resulted in the same 3 major clusters: cluster 1-oceanic (close proximity to deep water) and uninhabited (low human impact); cluster 2-oceanic and inhabited (high human impact); and cluster 3-lagoonal (facing the inside of the lagoon) and inhabited (highest human impact). Distance from village, reef exposure to deep water and human population size had the greatest effect in predicting the fish and benthic community structure. Our study demonstrates a strong association between benthic and fish community structure and human use across the Ulithi Atoll (Yap State, Federated States of Micronesia) and confirms a pattern observed by local people that an 'opportunistic' scleractinian coral (Montipora sp.) is associated with more highly impacted reefs. Our findings suggest that small human populations (subsistence fishing) can nevertheless have considerable ecological impacts on reefs due, in part, to changes in fishing practices rather than overfishing per se, as well as larger global trends. Findings from this work can assist in building local capacity to manage reef resources across an atoll-wide scale, and illustrates the importance of anthropogenic impact even in small communities.

Mesenchymal stem cells (MSCs) participate in the repair/remodelling of many tissues, where MSCs commit to different lineages dependent on the cues in the local microenvironment. Here we show that TGFβ-activated RhoA/ROCK signalling functions as a molecular switch regarding the fate of MSCs in arterial repair/remodelling after injury. MSCs differentiate into myofibroblasts when RhoA/ROCK is turned on, endothelial cells when turned off. The former is pathophysiologic resulting in intimal hyperplasia, whereas the latter is physiological leading to endothelial repair. Further analysis revealed that MSC RhoA activation promotes formation of an extracellular matrix (ECM) complex consisting of connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF). Inactivation of RhoA/ROCK in MSCs induces matrix metalloproteinase-3-mediated CTGF cleavage, resulting in VEGF release and MSC endothelial differentiation. Our findings uncover a novel mechanism by which cell–ECM interactions determine stem cell lineage specificity and offer additional molecular targets to manipulate MSC-involved tissue repair/regeneration., It is unclear what regulates the fate of mesenchymal stem cells (MSCs) in arterial repair following injury. Here, the authors show that MSC differentiation following injury is triggered by RhoA which in turn stimulates the release of connective tissue growth factor and vascular endothelial growth factor.

Parathyroid hormone (PTH) stimulates bone remodeling and induces differentiation of bone marrow mesenchymal stromal/stem cells (MSCs) by orchestrating activities of local factors such as bone morphogenetic proteins (BMPs). The activity and specificity of different BMP ligands are controlled by various extracellular antagonists that prevent binding of BMPs to their receptors. Low-density lipoprotein receptor-related protein 6 (LRP6) has been shown to interact with both the PTH and BMP extracellular signaling pathways by forming a complex with parathyroid hormone 1 receptor (PTH1R) and sharing common antagonists with BMPs. We hypothesized that PTH-enhanced differentiation of MSCs into the osteoblast lineage through enhancement of BMP signaling occurs by modifying the extracellular antagonist network via LRP6. In vitro studies using multiple cell lines, including Sca-1(+) CD45(-) CD11b(-) MSCs, showed that a single injection of PTH enhanced phosphorylation of Smad1 and could also antagonize the inhibitory effect of noggin. PTH treatment induced endocytosis of a PTH1R/LRP6 complex and resulted in enhancement of phosphorylation of Smad1 that was abrogated by deletion of PTH1R, β-arrestin, or chlorpromazine. Deletion of LRP6 alone led to enhancement of pSmad1 levels that could not be further increased with PTH treatment. Finally, knockdown of LRP6 increased the exposure of endogenous cell-surface BMP receptor type II (BMPRII) significantly in C2C12 cells, and PTH treatment significantly enhanced cell-surface binding of (125) I-BMP2 in a dose- and time-dependent manner, implying that LRP6 organizes an extracellular network of BMP antagonists that prevent access of BMPs to BMP receptors. In vivo studies in C57BL/6J mice and of transplanted green fluorescent protein (GFP)-labeled Sca-1(+) CD45(-) CD11b(-) MSCs into the bone marrow cavity of Rag2(-/-) immunodeficient mice showed that PTH enhanced phosphorylation of Smad1 and increased commitment of MSCs to osteoblast lineage, respectively. These data demonstrate that PTH enhancement of MSC differentiation to the osteoblast lineage occurs through a PTH- and LRP6-dependent pathway by endocytosis of the PTH1R/LRp6 complex, allowing enhancement of BMP signaling.

Calcium binding to the regulatory domain of cardiac troponin C (cNTnC) causes a conformational change that exposes a hydrophobic surface to which troponin I (cTnI) binds, prompting a series of protein-protein interactions that culminate in muscle contraction. A number of cTnC variants that alter the Ca(2+) sensitivity of the thin filament have been linked to disease. Tikunova and Davis engineered a series of cNTnC mutations that altered Ca(2+) binding properties and studied the effects on the Ca(2+) sensitivity of the thin filament and contraction [Tikunova, S. B., and Davis, J. P. (2004) J. Biol. Chem. 279, 35341-35352]. One of the mutations they engineered, the L48Q variant, resulted in a pronounced increase in the cNTnC Ca(2+) binding affinity and Ca(2+) sensitivity of cardiac muscle force development. In this work, we sought structural and mechanistic explanations for the increased Ca(2+) sensitivity of contraction for the L48Q cNTnC variant, using an array of biophysical techniques. We found that the L48Q mutation enhanced binding of both Ca(2+) and cTnI to cTnC. Nuclear magnetic resonance chemical shift and relaxation data provided evidence that the cNTnC hydrophobic core is more exposed with the L48Q variant. Molecular dynamics simulations suggest that the mutation disrupts a network of crucial hydrophobic interactions so that the closed form of cNTnC is destabilized. The findings emphasize the importance of cNTnC's conformation in the regulation of contraction and suggest that mutations in cNTnC that alter myofilament Ca(2+) sensitivity can do so by modulating Ca(2+) and cTnI binding.

Given evolving imaging technologies, we noted significant variation in the diagnostic evaluation of pediatric choledochal cysts (CDC). To streamline the diagnostic approach to CDC, and minimize associated expenses, we compared typing accuracy and costs of ultrasound (US), intraoperative cholangiography (IOC), and magnetic resonance cholangiopancreatography (MRCP).Records of 30 consecutive pediatric CDC patients were reviewed. Blinded to all clinical data, two pediatric radiologists reviewed all US, MRCPs, and IOCs to type CDCs according to the Todani classification. When compared with pathologic findings, the concordance between and accuracy of each diagnostic test were determined. Inflation-adjusted procedure charges and collections for imaging modalities were analyzed.Mean typing accuracy overlapped for US, IOC, and MRCP. Inter-rater reliability was 87 % for US (κ = 0.77), 80 % for IOC (κ = 0.62), and 60 % for MRCP (κ = 0.37). MRCP procedure charges ($1204.69) and collections ($420.85) exceeded IOC and US combined ($264.80 charges, p = 0.0002; $93.40 collections, p = 0.0021).Our data support the use of US alone in the diagnosis of pediatric CDC when no intrahepatic biliary ductal dilatation is visualized. However, when dilated intrahepatic ducts are encountered on US, MRCP should be utilized to distinguish a type I from a type IV CDC, which may alter the operative approach.

Many aspects of animal behavior can be socially facilitated, including foraging behavior, exploration behavior, and antipredator behavior. Although larvae of the ringed salamander (Ambystoma annulatum) are not gregarious, they can live in high densities and face intense predation pressure during a short period following hatching. In a predator-recognition experiment, we found that these salamanders responded to chemical cues from dragonfly nymphs (Family: Libellulidae) with appropriate antipredator behavior (decreased activity), and this response was absent when salamanders were exposed to chemical cues from nonpredatory mayfly nymphs (Family: Heptageniidae). In a second experiment, we tested whether antipredator behavior in response to chemical cues of dragonflies could be socially facilitated by larval ringed salamanders. We placed an “observer” salamander into a central arena with four “demonstrator” salamanders behind clear barriers around an arena. The barriers ensured that chemical cues would not be detected by the observer. When demonstrators were exposed to chemical cues from dragonflies, the data were consistent with the hypothesis that both demonstrators and observers decreased activity relative to a blank control. Our results provide evidence that social facilitation can occur in larval ringed salamanders, a nonsocial species.

With the resurgence of nuclear power and increased interest in advanced nuclear reactors as an option to supply abundant energy without the associated greenhouse gas emissions of the more conventional fossil fuel energy sources, there is a need to establish internationally recognized standards for the verification and validation (V&V) of software used to calculate the thermal–hydraulic behavior of advanced reactor designs for both normal operation and hypothetical accident conditions. To address this need, ASME (American Society of Mechanical Engineers) Standards and Certification has established the V&V 30 Committee, under the jurisdiction of the V&V Standards Committee, to develop a consensus standard for verification and validation of software used for design and analysis of advanced reactor systems. The initial focus of this committee will be on the V&V of system analysis and computational fluid dynamics (CFD) software for nuclear applications. To limit the scope of the effort, the committee will further limit its focus to software to be used in the licensing of High-Temperature Gas-Cooled Reactors. Although software verification will be an important and necessary part of the standard, much of the initial effort of the committee will be focused on the validation of existing software and new models that could be used in the licensing process. In this framework, the Standard should conform to Nuclear Regulatory Commission (NRC) and other regulatory practices, procedures and methods for licensing of nuclear power plants as embodied in the United States (U.S.) Code of Federal Regulations and other pertinent documents such as Regulatory Guide 1.203, “Transient and Accident Analysis Methods” and NUREG-0800, “NRC Standard Review Plan”. In addition, the Standard should be consistent with applicable sections of ASME NQA-1-2008 “Quality Assurance Requirements for Nuclear Facility Applications (QA)”. This paper describes the general requirements for the proposed V&V 30 Standard, which includes: (a) applicable NRC and other regulatory requirements for defining the operational and accident domain of a nuclear system that must be considered if the system is to be licensed, (b) the corresponding calculation domain of the software that should encompass the nuclear operational and accident domain to be used to study the system behavior for licensing purposes, (c) the definition of the scaled experimental data set required to provide the basis for validating the software, (d) the ensemble of experimental data sets required to populate the validation matrix for the software in question, and (e) the practices and procedures to be used when applying a validation standard. Although this initial effort will focus on software for licensing of High-Temperature Gas-Cooled Reactors, it is anticipated that the practices and procedures developed for this Standard can eventually be extended to other nuclear and non-nuclear applications.

Parasites are known to affect an array of characteristics of their hosts, including morphology, physiology and behaviour. We examined the foraging and antipredator behaviour of rainbow darters, Etheostoma caeruleum, that were parasitized by glochidia larvae of freshwater mussels (Ptychobranchus occidentalis and Venustaconcha pleasii: Unionidae). Glochidia attach to the gills of the host and become encapsulated in host tissue. Over a period of days or weeks the larvae develop into free-living juveniles, which then leave the host. Parasitized darters increased ventilation rates (either early in the infestation or at the height of the infestation), were less active during foraging trials, lost more body size than nonparasitized darters and showed significantly weaker responses to predation risk (signalled by the presence of a chemical alarm cue). Therefore, even for a relatively short-term infection, parasitized darters may pay a cost in terms of decreased growth and decreased probability of survival.

Biogeographic boundaries are the meeting zone of broadly distributed faunas, or the actual cause of a faunal break. In the latter case, closely related sister species should be found across such a boundary. To achieve such a situation, preliminary stages are expected, where phylogeographic breaks followed by genetic cryptic speciation would be observed. Biogeographic boundaries, in the Cape Point/Cape Agulhas region of southern Africa, offer an ideal system to test such predictions. Here, we studied two intertidal clinid fish species that are endemic to southern Africa, Clinus superciliosus (n = 127) and Muraenoclinus dorsalis (n = 114). Using mitochondrial control region, 16S rRNA, 12S rRNA and NADH2 genes and the nuclear rhodopsin and the first intron of the S7 ribosomal protein gene, we show both phylogeographic breaks and likely cryptic speciation in each species. Pairwise Φst results suggest population genetic structuring for both species, with higher levels for M. dorsalis (Φst = 0.34–0.93) than for C. superciliosus (Φst = 0.1–0.74). Further, we recover two and three distinct lineages within M. dorsalis and C. superciliosus, respectively. Phylogenetic topologies, concordance between nuclear and mitochondrial markers and levels of sequence divergence, which are consistent with closely related sister species pairs, suggest the presence of cryptic species. Our results therefore meet the expectation for reduced gene flow at a biogeographic barrier, which translates into significant genetic breaks and cryptic sister species.

Although salamanders have been shown to respond to classical conditioning, spatial learning has been largely unstudied. We tested whether salamanders could learn to locate foraging areas by using landmarks. We trained 10 salamanders Plethodon angusticlavius to use landmarks (small rocks) to locate patches within the arena containing food (blackworms Lum-briculus variegatus). At the corners of each square testing arena were four plastic dishes, one containing blackworms and the other three empty. A rock was placed in front of the dish containing blackworms, and the location of the food-dish was randomly chosen for each training trial. A control group was also trained to feed on blackworms in the presence of a rock, but the rock was positioned randomly among the four dish locations so that the rock was not a reliable landmark for the worms. Although the length of the training period for individual salamanders varied (22–38 trainings per individual), the mean number of trainings for salamanders in the control and experimental groups was equal (30 training trials). During testing, no blackworms were present to eliminate any visual or chemical cues emanating directly from the prey. Individuals trained with the rock landmarks spent significantly more time in the area of the landmark than did control salamanders.

For species with declining populations, captive rearing with subsequent release into natural habitats (“head-starting”) is often used as part of a conservation strategy. One challenge to head-starting programs is that head-started individuals can suffer high rates of postrelease predation. Head-starting programs are currently being established for hellbenders (Cryptobrancus alleganeinsis), large aquatic salamanders that are experiencing population declines throughout much of the species' range. Although hellbenders have innate recognition of many predators, inexperienced juveniles show only weak recognition of introduced trout. We used a classical conditioning protocol to train captive-reared hellbender larvae to show fright responses to the scent of trout. We exposed hellbender larvae to trout-scented water plus a hellbender distress secretion during training trials. In a subsequent test, these larvae responded to trout cues alone with a fright response; control larvae that were trained with the trout scent plus a blank control did not show a fright response to the trout cues. Learning was specific to trout because trained larvae did not respond to water that had been scented by a suckermouth catfish. Although a number of details remain to be addressed concerning standardized procedures, we recommend that head-starting programs for hellbenders include trout-recognition training. Zoo Biol 30:611–622, 2011. © 2010 Wiley Periodicals, Inc.

The focus of this study was on gifted adults' perceptions of multigenerational giftedness in their families. Participants have been surveyed annually since their high school graduation in 1988. The purpose of the longitudinal study is to gain insight into the career and life development of gifted individuals post-high school. For the present follow-up study, data were collected via the Internet and mailed surveys and analyzed by a 5-member research team. Participants reported their perceptions of whether or not their parents and children were gifted and the areas of giftedness. The number of participants who perceived both parents to be gifted was roughly equal to those stating that neither parent was gifted. Areas of perceived giftedness differed between mothers and fathers. The majority of participants identified at least one of their children as gifted. Specific areas of giftedness perceived in participants' children and parents are described. Implications of the findings are discussed.

Violent behavior on college campuses has been a long-standing problem that has received increased attention due to recent shootings. At present, the factors that predict college students' violent behavior are not well understood. To increase knowledge in this area, two studies were conducted that examined the prevalence and predictors of college students' fears of committing violent behavior. Data from a single university indicated that less than 2% of the general student body possessed strong fears of acting violently and more than 80% of students had no such fears. Among clients at the university counseling center, 7% expressed strong fears of acting violently whereas 71% of clients had no such fears. Similar prevalence rates were found in a sample of 27,616 clients from 66 university counseling centers. Predictors of fears of acting violently included low academic motivation, suicidal ideation, irritable feelings, fears of having a panic attack in public, having harmed another person previously, having...

The purpose of this study was to learn about gifted adults' experiences in advanced classes and attitudes about advanced classes or gifted programs for their children. Participants were 88 adults (33 men and 55 women) who have been participating in a longitudinal study of academically talented individuals since their high-school graduation in 1988. Participants responded to open-ended questions via mailed surveys. Eighty-five percent of participants described their academic experiences in advanced classes as positive, whereas slightly fewer participants (59%) described their interpersonal experiences in advanced classes as positive. Seventy-five percent of participants with children described signs of giftedness in their children, and 88% of participants indicated that they would support advanced placement for their children if it were recommended by the school. Implications of the findings were discussed and directions for future research were provided.

The discovery and the rediscovery of plastoquinone (PQ) are described together with the definition of its structure as a 2,3-dimethyl 5 solanosyl benzoquinone. The discovery, by M. Kofler, was a result of a search for Vitamin K. Its rediscovery was made by me, when I was at The Enzyme Institute of the University of Wisconsin, analyzing animals and plants for the newly discovered coenzyme Q. In green plants, I found another lipophilic quinone in addition to coenzyme Q. Some misleading evidence suggested as if the new quinone had coenzyme Q activity in mitochondria, but improved methods gave negative results. When I found that the quinone was concentrated in chloroplasts, I considered a role for it in photosynthesis analogous to the role of coenzyme Q in mitochondria. After moving to the Chemistry Department, University of Texas at Austin, I used a plain light bulb and some spinach chloroplasts to show that PQ could be involved in photosynthetic redox reactions. This effect was supported by Norman Bishop's restoration of chloroplast electron transport after solvent extraction, with PQ and photoreduction studies by E. R. Redfern and J. Friend in R. A. Morton's laboratory in Liverpool, UK. We also found an additional analog of PQ in addition to a second analog found in Wisconsin. We called the new analogs PQB and PQC. Although we found some restoration effects with PQC, the discovery by W. T. Griffiths in Morton's laboratory, that PQB and PQC consisted of six forms of PQ each, made it more likely that the new analogs were breakdown products. Morton's group established the structure of the PQCs as a series of PQs, with a hydroxyl group on the prenyl side chain, and the PQB series as having fatty acids esterified to the hydroxyl groups of PQC. Possible functions of the analogs are also discussed in this article.

Females of some temperate-zone snake species appear to exhibit thermophilic behavior during gestation, resulting in differential habitat use between gravid and nongravid individuals. We investigated thermoregulation of 13 female cottonmouths (Agkistrodon piscivorus) near their northwestern range limit in southwestern Missouri during mid-summer. Mean preferred body temperature (23.4 C) and preferred body temperature range (Tset, 20.0-26.5 C) measured in a laboratory thermal gradient were lower than those reported for most snake species. Physical models demonstrated that Tset consistently was available to snakes during the study period, although the frequency of availability varied among habitats. The relatively high thermal quality of the environment (based on Tset availability) allowed snakes to achieve field body temperatures (Tb) closely matching laboratory preferences. Gravid females exploited the thermal environment more efficiently than nongravid females by preferentially occupying the most thermally favorable microhabitats. Accordingly, gravid females consistently maintained higher Tb than nongravid females, demonstrating a functional link between habitat use and thermoregulation. Differences in Tb between gravid and nongravid females were greatest at low ambient temperatures, highlighting their different thermoregulatory strategies. Maintenance of low Tb in nongravid females is consistent with an energy conservation strategy benefiting reproductive investment.

Naturally occurring deuterium ((2)H) in biota can be used to trace movement, migration and geographic origin of a range of organisms. However, to evaluate movements of animals using δ(2)H measurements of tissues, it is necessary to establish the turnover time of (2)H in the tissues and the extent of isotopic discrimination from different environmental (2)H sources to those tissues. We investigated the turnover of (2)H in lake sturgeon (Acipenser fulvescens) blood by manipulating both environmental water δ(2)H and diet δ(2)H over a four-month period. The half-life of deuterium in lake sturgeon blood was 37.9 days after an increase in the environmental water δ(2)H of +714 ‰. However, no clear turnover in blood (2)H occurred over the same period in a separate trial following a change of -63.8 ‰ or +94.2 ‰ in diet. These findings suggest that environmental water (2)H exchanges much faster with blood than diets and that blood δ(2)H values can be used to trace movements of sturgeon and other fish moving among isotopically distinct waters.