Citation patterns were examined for Worm et al. 2006 (Science 314∶787–790), a high-impact paper that focused on relationships between marine biodiversity and ecosystem services. This paper sparked much controversy through its projection, highlighted in the press release, that all marine fisheries would be collapsed by 2048. Analysis of 664 citing papers revealed that only a small percentage (11%) referred to the 2048 projection, while 39% referred to fisheries collapse in general, and 40% to biodiversity and ecosystem services. The 2048 projection was mentioned more often in papers published soon after the original paper, in low-impact journals, and in journals outside of fields that would be expected to focus on biodiversity. Citing papers also mentioned the 2048 projection more often if they had few authors (28% of single-author papers vs. 2% of papers with 10 or more authors). These factors suggest that the more knowledgeable the authors of citing papers were about the controversy over the 2048 projection, the less likely they were to refer to it. A noteworthy finding was that if the original authors were also involved in the citing papers, they rarely (1 of 55 papers, 2%) mentioned the 2048 projection. Thus the original authors have emphasized the broader concerns about biodiversity loss, rather than the 2048 projection, as the key result of their study.
Species distribution models (SDMs) trained on presence-only data are frequently used in ecological research and conservation planning. However, users of SDM software are faced with a variety of options, and it is not always obvious how selecting one option over another will affect model performance. Working with MaxEnt software and with tree fern presence data from New Zealand, we assessed whether (a) choosing to correct for geographical sampling bias and (b) using complex environmental response curves have strong effects on goodness of fit. SDMs were trained on tree fern data, obtained from an online biodiversity data portal, with two sources that differed in size and geographical sampling bias: a small, widely-distributed set of herbarium specimens and a large, spatially clustered set of ecological survey records. We attempted to correct for geographical sampling bias by incorporating sampling bias grids in the SDMs, created from all georeferenced vascular plants in the datasets, and explored model complexity issues by fitting a wide variety of environmental response curves (known as “feature types” in MaxEnt). In each case, goodness of fit was assessed by comparing predicted range maps with tree fern presences and absences using an independent national dataset to validate the SDMs. We found that correcting for geographical sampling bias led to major improvements in goodness of fit, but did not entirely resolve the problem: predictions made with clustered ecological data were inferior to those made with the herbarium dataset, even after sampling bias correction. We also found that the choice of feature type had negligible effects on predictive performance, indicating that simple feature types may be sufficient once sampling bias is accounted for. Our study emphasizes the importance of reducing geographical sampling bias, where possible, in datasets used to train SDMs, and the effectiveness and essentialness of sampling bias correction within MaxEnt.
Clustering analysis has a growing role in the study of co-expressed genes for gene discovery. Conventional binary and fuzzy clustering do not embrace the biological reality that some genes may be irrelevant for a problem and not be assigned to a cluster, while other genes may participate in several biological functions and should simultaneously belong to multiple clusters. Also, these algorithms cannot generate tight clusters that focus on their cores or wide clusters that overlap and contain all possibly relevant genes. In this paper, a new clustering paradigm is proposed. In this paradigm, all three eventualities of a gene being exclusively assigned to a single cluster, being assigned to multiple clusters, and being not assigned to any cluster are possible. These possibilities are realised through the primary novelty of the introduction of tunable binarization techniques. Results from multiple clustering experiments are aggregated to generate one fuzzy consensus partition matrix (CoPaM), which is then binarized to obtain the final binary partitions. This is referred to as Binarization of Consensus Partition Matrices (Bi-CoPaM). The method has been tested with a set of synthetic datasets and a set of five real yeast cell-cycle datasets. The results demonstrate its validity in generating relevant tight, wide, and complementary clusters that can meet requirements of different gene discovery studies.
Angiogenesis is an essential process for normal skeletal muscle function. There is a growing body of evidence suggesting that thrombospondin-1 (TSP-1), a potent antiangiogenic protein in tumorigenesis, is an important regulator of both physiological and pathological skeletal muscle angiogenesis. We tested the hypothesis that chronic exposure to a TSP-1 mimetic (ABT-510), which targets the CD36 TSP-1 receptor, would decrease skeletal muscle capillarity as well as alter the balance between positive and negative angiogenic proteins under basal conditions. Osmotic minipumps with either ABT-510 or vehicle (5% dextrose) were implanted subcutaneously in the subscapular region of C57/BL6 mice for 14 days. When compared to the vehicle treated mice, the ABT-510 group had a 20% decrease in capillarity in the superficial region of the gastrocnemius (GA), 11% decrease in the plantaris (PLT), and a 35% decrease in the soleus (SOL). ABT-510 also decreased muscle protein expression of vascular endothelial growth factor (VEGF) in both the GA (−140%) and SOL (−62%); however there was no change in VEGF in the PLT. Serum VEGF was not altered in ABT-510 treated animals. Endogenous TSP-1 protein expression in all muscles remained unaltered. Tunnel staining revealed no difference in muscle apoptosis between ABT-510 and vehicle treated groups. These data provide evidence that the anti-angiogenic effects of TSP-1 are mediated, at least in part, via the CD36 receptor. It also suggests that under physiologic conditions the TSP-1/CD36 axis plays a role in regulating basal skeletal muscle microvessel density.
Aeroplysinin-1 is a brominated antibiotic used by some sponges for defense against bacterial pathogen invasion. Aeroplysinin-1 has a wide spectrum of anti-tumoral action and behaves as a potent anti-angiogenic compound for bovine aortic endothelial cells. In this study, we demonstrate anti-angiogenic effects of aeroplysinin-1 on human endothelial cells. Furthermore, the response of angiogenesis related genes to aeroplysinin-1 treatment was studied in human endothelial cells by using gene arrays. The major changes were observed in thrombospondin 1 (TSP-1) and monocyte chemoattractant protein-1 (MCP-1), both of which were down-regulated. These inhibitory effects of aeroplysinin-1 were confirmed by using independent experimental approaches. To have a deeper insight on the anti-inflammatory effects of aeroplysinin-1 in endothelial cells, cytokine arrays were also used. This experimental approach confirmed effects on MCP-1 and TSP-1 and showed down-regulation of several other cytokines. Western blotting experiments confirmed down-regulation of ELTD1 (EGF, latrophilin and seven transmembrane domain-containing protein 1), interleukin 1α and matrix metalloproteinase 1 (MMP-1). These results along with our observation of a dramatic inhibitory effect of aeroplysinin-1 on cyclooxygenase-2 protein expression levels in endothelial cells and a human monocyte cell line suggest that aeroplysinin-1 could be a novel anti-inflammatory compound with potential pharmacological interest.
Studies of mimicry among tropical reef-fishes usually give little or no consideration to alternative explanations for behavioral associations between unrelated, look-alike species that benefit the supposed mimic. I propose and assess such an alternative explanation. With mimicry the mimic resembles its model, evolved to do so in response to selection by the mimicry target, and gains evolved benefits from that resemblance. In the alternative, the social-trap hypothesis, a coincidental resemblance of the model to the “mimic” inadvertently attracts the latter to it, and reinforcement of this social trapping by learned benefits leads to the “mimic” regularly associating with the model. I examine three well known cases of supposed aggressive mimicry among reef-fishes in relation to nine predictions from these hypotheses, and assess which hypothesis offers a better explanation for each. One case, involving precise and complex morphological and behavioral resemblance, is strongly consistent with mimicry, one is inconclusive, and one is more consistent with a social-trap based on coincidental, imprecise resemblance. Few cases of supposed interspecific mimicry among tropical reef fishes have been examined in depth, and many such associations may involve social traps arising from generalized, coincidental resemblance. Mimicry may be much less common among these fishes than is generally thought.
How reliable are results on spatial distribution of biodiversity based on databases? Many studies have evidenced the uncertainty related to this kind of analysis due to sampling effort bias and the need for its quantification. Despite that a number of methods are available for that, little is known about their statistical limitations and discrimination capability, which could seriously constrain their use. We assess for the first time the discrimination capacity of two widely used methods and a proposed new one (FIDEGAM), all based on species accumulation curves, under different scenarios of sampling exhaustiveness using Receiver Operating Characteristic (ROC) analyses. Additionally, we examine to what extent the output of each method represents the sampling completeness in a simulated scenario where the true species richness is known. Finally, we apply FIDEGAM to a real situation and explore the spatial patterns of plant diversity in a National Park. FIDEGAM showed an excellent discrimination capability to distinguish between well and poorly sampled areas regardless of sampling exhaustiveness, whereas the other methods failed. Accordingly, FIDEGAM values were strongly correlated with the true percentage of species detected in a simulated scenario, whereas sampling completeness estimated with other methods showed no relationship due to null discrimination capability. Quantifying sampling effort is necessary to account for the uncertainty in biodiversity analyses, however, not all proposed methods are equally reliable. Our comparative analysis demonstrated that FIDEGAM was the most accurate discriminator method in all scenarios of sampling exhaustiveness, and therefore, it can be efficiently applied to most databases in order to enhance the reliability of biodiversity analyses.
Accidental or therapeutic total body exposure to ionizing radiation has profound pathophysiological consequences including acute radiation syndrome. Currently only investigational drugs are available in case of radiological or nuclear accidents or terrorism. Lack of selective radioprotectants for normal tissues also limits the therapeutic doses that can be delivered to treat cancers. CD47 is a receptor for the secreted protein thrombospondin-1. Blockade of thrombospondin-1 or CD47 provides local radioprotection of soft tissues and bone marrow. We now report that suppression of CD47 using an antisense morpholino increases survival of mice exposed to lethal total body irradiation. Increased survival is associated with increased peripheral circulating blood cell counts and increased proliferative capacity of bone marrow derived cells. Moreover, CD47 blockade decreased cell death while inducing a protective autophagy response in radiosensitive gastrointestinal tissues. Thus, CD47 is a new target for radiomitigation that prevents both hematopoietic and gastrointestinal radiation syndromes.
Recent studies show the importance of interactions between CD47 expressed on acute myeloid leukemia (AML) cells and the inhibitory immunoreceptor, signal regulatory protein-alpha (SIRPα) on macrophages. Although AML cells express SIRPα, its function has not been investigated in these cells. In this study we aimed to determine the role of the SIRPα in acute myeloid leukemia.
Design and Methods
We analyzed the expression of SIRPα, both on mRNA and protein level in AML patients and we further investigated whether the expression of SIRPα on two low SIRPα expressing AML cell lines could be upregulated upon differentiation of the cells. We determined the effect of chimeric SIRPα expression on tumor cell growth and programmed cell death by its triggering with an agonistic antibody in these cells. Moreover, we examined the efficacy of agonistic antibody in combination with established antileukemic drugs.
By microarray analysis of an extensive cohort of primary AML samples, we demonstrated that SIRPα is differentially expressed in AML subgroups and its expression level is dependent on differentiation stage, with high levels in FAB M4/M5 AML and low levels in FAB M0–M3. Interestingly, AML patients with high SIRPα expression had a poor prognosis. Our results also showed that SIRPα is upregulated upon differentiation of NB4 and Kasumi cells. In addition, triggering of SIRPα with an agonistic antibody in the cells stably expressing chimeric SIRPα, led to inhibition of growth and induction of programmed cell death. Finally, the SIRPα-derived signaling synergized with the activity of established antileukemic drugs.
Our data indicate that triggering of SIRPα has antileukemic effect and may function as a potential therapeutic target in AML.
Cochlear blood flow regulation is important to prevent hearing loss caused by ischemia and oxidative stress. Cochlear blood supply is provided by the spiral modiolar artery (SMA). The myogenic tone of the SMA is enhanced by the nitric oxide synthase (NOS) blocker L-NG-Nitro-Arginine (LNNA) in males, but not in females. Here, we investigated whether this gender difference is based on differences in the cytosolic Ca2+ concentration and/or the Ca2+ sensitivity of the myofilaments. Vascular diameter, myogenic tone, cytosolic Ca2+, and Ca2+ sensitivity were evaluated in pressurized SMA segments isolated from male and female gerbils using laser-scanning microscopy and microfluorometry. The gender difference of the LNNA-induced tone was compared, in the same vessel segments, to tone induced by 150 mM K+ and endothelin-1, neither of which showed an apparent gender-difference. Interestingly, LNNA-induced tone in male SMAs was observed in protocols that included changes in intramural pressure, but not when the intramural pressure was held constant. LNNA in male SMAs did not increase the global Ca2+ concentration in smooth muscle cells but increased the Ca2+ sensitivity. This increase in the Ca2+ sensitivity was abolished in the presence of the guanylyl cyclase inhibitor ODQ or by extrinsic application of either the nitric oxide (NO)-donor DEA-NONOate or the cGMP analog 8-pCPT-cGMP. The rho-kinase blocker Y27632 decreased the basal Ca2+ sensitivity and abolished the LNNA-induced increase in Ca2+ sensitivity in male SMAs. Neither LNNA nor Y27632 changed the Ca2+ sensitivity in female SMAs. The data suggest that the gender difference in LNNA-induced tone is based on a gender difference in the regulation of rho-kinase mediated Ca2+ sensitivity. Rho-kinase and NO thus emerge as critical factors in the regulation of cochlear blood flow. The larger role of NO-dependent mechanisms in male SMAs predicts greater restrictions on cochlear blood flow under conditions of impaired endothelial cell function.
In many fisheries multiple species are simultaneously caught while stock assessments and fishing quota are defined at species level. Yet species caught together often share habitat and resources, resulting in interspecific resource competition. The consequences of resource competition on population dynamics and revenue of simultaneously harvested species has received little attention due to the historical single stock approach in fisheries management. Here we present the results of a modelling study on the interaction between resource competition of sole (Solea solea) and slaice (Pleuronectus platessa) and simultaneous harvesting of these species, using a stage-structured population model. Three resources were included of which one is shared with a varied competition intensity. We find that plaice is the better competitor of the two species and adult plaice are more abundant than adult sole. When competition is high sole population biomass increases with increasing fishing effort prior to plaice extinction. As a result of this increase in the sole population, the revenue of the stocks combined as function of effort becomes bimodal with increasing resource competition. When considering a single stock quota for sole, its recovery with increasing effort may result in even more fishing effort that would drive the plaice population to extinction. When sole and plaice compete for resources the highest revenue is obtained at effort levels at which plaice is extinct. Ignoring resource competition promotes overfishing due to increasing stock of one species prior to extinction of the other species. Consequently, efforts to mitigate the decline in one species will not be effective if increased stock in the other species leads to increased quota. If a species is to be protected against extinction, management should not only be directed at this one species, but all species that compete with it for resource as well.
Local adaptation along steep environmental gradients likely contributes to plant diversity in the Cape Region of South Africa, yet existing analyses of trait divergence are limited to static measurements of functional traits rather than trajectories of individual development. We explore whether five taxa of evergreen shrubs (Protea section Exsertae) differ in their developmental trajectories and capacity for plasticity using two environmentally-distinct common gardens in South Africa. We measured seedlings in the summer-dry season and winter-wet season of each of two consecutive years to characterize ontogeny and plasticity within years, as same-age leaf cohorts mature, and between years, i.e., from leaf one cohort to the next. We compared patterns of development between gardens to assess whether trait trajectories are programmed versus plastic and examined whether developmental differences covaried with characteristics of a seedling’s home environment. We detected plasticity in developmental trajectories for leaf area, stomatal size, stomatal pore index, and to a limited extent specific leaf area, but not for stomatal density. We showed that the species growing in the harshest environments exhibits both the smallest increase in leaf area between years and the least change in SLA and photosynthetic rates as leaves age within years. These results show that within this clade, species have diverged in developmental trajectories and plasticity as well as in mean trait values. Some of these differences may be associated with adaptation to cold and drought stress within an environmentally-complex region.
There is renewed interest in implementing surrogate species approaches in conservation planning due to the large number of species in need of management but limited resources and data. One type of surrogate approach involves selection of one or a few species to represent a larger group of species requiring similar management actions, so that protection and persistence of the selected species would result in conservation of the group of species. However, among the criticisms of surrogate approaches is the need to test underlying assumptions, which remain rarely examined. In this study, we tested one of the fundamental assumptions underlying use of surrogate species in recovery planning: that there exist groups of threatened and endangered species that are sufficiently similar to warrant similar management or recovery criteria. Using a comprehensive database of all plant species listed under the U.S. Endangered Species Act and tree-based random forest analysis, we found no evidence of species groups based on a set of distributional and biological traits or by abundances and patterns of decline. Our results suggested that application of surrogate approaches for endangered species recovery would be unjustified. Thus, conservation planning focused on individual species and their patterns of decline will likely be required to recover listed species.
Multivalent effects dictate the binding affinity of multiple ligands on one molecular entity to receptors. Integrins are receptors that mediate cell attachment through multivalent binding to peptide sequences within the extracellular matrix, and overexpression promotes the metastasis of some cancers. Multivalent display of integrin antagonists enhances their efficacy, but current scaffolds have limited ranges and precision for the display of ligands. Here we present an approach to study multivalent effects across wide ranges of ligand number, density, and three-dimensional arrangement. Using L-lysine γ-substituted peptide nucleic acids, the multivalent effects of an integrin antagonist were examined over a range of 1 to 45 ligands. The optimal construct improves the inhibitory activity of the antagonist by two orders of magnitude against the binding of melanoma cells to the extracellular matrix in both in vitro and in vivo models.
Copper is an essential element in various metabolisms. The investigation was carried out to evaluate acute gastroprotective effects of the Copper (II) complex against ethanol-induced superficial hemorrhagic mucosal lesions in rats.
Rats were divided into 7 groups. Groups 1 and 2 were orally administered with Tween 20 (10% v/v). Group 3 was orally administered with 20 mg/kg omeprazole (10% Tween 20). Groups 4–7 received 10, 20, 40, and 80 mg/kg of the complex (10% Tween 20), respectively. Tween 20 (10% v/v) was given orally to group 1 and absolute ethanol was given orally to groups 2–7, respectively. Rats were sacrificed after 1 h. Group 2 exhibited severe superficial hemorrhagic mucosal lesions. Gastric wall mucus was significantly preserved by the pre-treatment complex. The results showed a significant increase in glutathione (GSH), superoxide dismutase (SOD), nitric oxide (NO), and Prostaglandin E2 (PGE2) activities and a decrease in malondialdehyde (MDA) level. Histology showed marked reduction of hemorrhagic mucosal lesions in groups 4–7. Immunohistochemical staining showed up-regulation of Hsp70 and down-regulation of Bax proteins. PAS staining of groups 4–7 showed intense stain uptake of gastric mucosa. The acute toxicity revealed the non-toxic nature of the compound.
The gastroprotective effect of the Copper (II) complex may possibly be due to preservation of gastric wall mucus; increase in PGE2 synthesis; GSH, SOD, and NO up-regulation of Hsp70 protein; decrease in MDA level; and down-regulation of Bax protein.
A novel behaviorally dependent dosing (BDD) schedule was used to examine the relationship between doses of cocaine self-administered by rats and brain drug levels within a session. The BDD schedule used a hold-down response to activate a syringe pump. The length of time the lever was held down determined the duration that the syringe pump was activated. In the first experiment, rats self-administered cocaine for daily 3 h sessions and brain levels of cocaine were modeled using well-established parameters. Although analysis revealed that rats self-administered doses within a predicted range, one extremely large dose was consistently observed at the beginning of each session when brain levels of cocaine were low. In the second experiment, we introduced a range of timeout periods (10–25 min) in order to produce variability in brain-cocaine concentrations. Animals self-administered larger doses immediately following each timeout period and the dose size was inversely correlated with the length of the timeout. These results show that the dose of cocaine that rats self-administer within a session is inversely related to the amount of drug on board.
cocaine; self-administration; reinforcing efficacy; regulation; unit dose; hold down; addiction & substance abuse; animal models; behavioral science; psychopharmacology; cocaine; self-administration; reinforcing efficacy; regulation; unit doseKeywords:cocaine; self-administration; reinforcing efficacy; regulation; unit dose; hold down
Anti-1-amino-2-[18F]fluorocyclopentane-1-carboxylic acid (anti-2-[18F]FACPC) is an unnatural alicyclic amino acid radiotracer with high uptake in the DU-145 prostate cancer cell line in vitro. Our goal was to determine if anti-2-[18F]FACPC is useful in the detection of prostate carcinoma.
Five patients with elevated PSA (1.1–20.5 ng/mL) after curative therapy for prostate carcinoma underwent 60 min dynamic positron emission tomography (PET) of the pelvis after IV injection of 193–340 MBq of anti-2-[18F]FACPC. Uptake was compared against PET scans in the same patients with the leucine analog, anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-[18F]FACBC), at similar time points and validated via pathology, clinical, and imaging follow-up.
At 5 min, average (±SD) SUVmax of malignant lesions is 4.1(±1.3) for anti-2-[18F] FACPC and 4.3(±1.1) for anti-[18F]FACBC. Yet, blood pool activity at 5 min is significantly higher for anti-2-[18F]FACPC with average (±SD) lesion/blood pool SUVmax/SUVmean ratio of 1.4 (±0.5) vs. 3.0 (±0.9) for anti-[18F]FACBC. At 20 min, average (±SD) SUVmax of malignant lesions is 2.6 (±1.0) for anti-2-[18F]FACPC and 3.4 (±0.8) for anti-[18F]FACBC. Yet, bladder activity at 20 min is significantly more intense for anti-2-[18F] FACPC with average (±SD) lesion/bladder SUVmax/SUVmean ratio of 0.3 (±0.8) vs. 2.3 (±1.4) for anti-[18F]FACBC.
While prostate bed lesions are visible on early imaging with anti-2-[18F]FACPC, there is high blood pool activity obscuring nodes. As blood pool fades, nodal uptake decreases and high bladder activity then obscures pelvic structures. Compared with anti-[18F]FACBC, imaging characteristics for anti-2-[18F]FACPC are unfavorable for pelvic recurrent prostate carcinoma detection.
FACPC; FACBC; Prostate; PET
Schemes designed to make farming landscapes less hostile to wildlife have been questioned because target taxa do not always respond in the expected manner. Microbats are often overlooked in this process, yet persist in agricultural landscapes and exert top-down control of crop pests. We investigated the relationship between microbats and measures commonly incorporated into agri-environment schemes, to derive management recommendations for their ongoing conservation. We used acoustic detectors to quantify bat species richness, activity, and feeding in 32 linear remnants and adjacent fields across an agricultural region of New South Wales, Australia. Nocturnal arthropods were simultaneously trapped using black-light traps. We recorded 91,969 bat calls, 17,277 of which could be attributed to one of the 13 taxa recorded, and 491 calls contained feeding buzzes. The linear remnants supported higher bat activity than the fields, but species richness and feeding activity did not significantly differ. We trapped a mean 87.6 g (±17.6 g SE) of arthropods per night, but found no differences in biomass between land uses. Wider linear remnants with intact native vegetation supported more bat species, as did those adjacent to unsealed, as opposed to sealed roads. Fields of unimproved native pastures, with more retained scattered trees and associated hollows and logs, supported the greatest bat species richness and activity. We conclude that the juxtaposition of linear remnants of intact vegetation and scattered trees in fields, coupled with less-intensive land uses such as unimproved pastures will benefit bat communities in agricultural landscapes, and should be incorporated into agri-environment schemes. In contrast, sealed roads may act as a deterrent. The “wildlife friendly farming” vs “land sparing” debate has so far primarily focussed on birds, but here we have found evidence that the integration of both approaches could particularly benefit bats.
Intraoperative visual fluorescence imaging (vFI) has emerged as a promising aid to surgical guidance, but does not fully exploit the potential of the fluorescent agents that are currently available. Here, we introduce a quantitative fluorescence imaging (qFI) approach that converts spectrally-resolved data into images of absolute fluorophore concentration pixel-by-pixel across the surgical field of view (FOV). The resulting estimates are linear, accurate, and precise relative to true values, and spectral decomposition of multiple fluorophores is also achieved. Experiments with protoporphyrin IX in a glioma rodent model demonstrate in vivo quantitative and spectrally-resolved fluorescence imaging of infiltrating tumor margins for the first time. Moreover, we present images from human surgery which detect residual tumor not evident with state-of-the-art vFI. The wide-field qFI technique has broad implications for intraoperative surgical guidance because it provides near real-time quantitative assessment of multiple fluorescent biomarkers across the operative field.
Disseminated Candida albicans infection results in high morbidity and mortality despite treatment with existing antifungal drugs. Recent studies suggest that modulating the host immune response can improve survival, but specific host targets for accomplishing this goal remain to be identified. The extracellular matrix protein thrombospondin-1 is released at sites of tissue injury and modulates several immune functions, but its role in C. albicans pathogenesis has not been investigated. Here, we show that mice lacking thrombospondin-1 have an advantage in surviving disseminated candidiasis and more efficiently clear the initial colonization from kidneys despite exhibiting fewer infiltrating leukocytes. By examining local and systemic cytokine responses to C. albicans and other standard inflammatory stimuli, we identify a crucial function of phagocytes in this enhanced resistance. Subcutaneous air pouch and systemic candidiasis models demonstrated that endogenous thrombospondin-1 enhances the early innate immune response against C. albicans and promotes activation of inflammatory macrophages (inducible nitric oxide synthase+, IL-6high, TNF-αhigh, IL-10low), release of the chemokines MIP-2, JE, MIP-1α, and RANTES, and CXCR2-driven polymorphonuclear leukocytes recruitment. However, thrombospondin-1 inhibited the phagocytic capacity of inflammatory leukocytes in vivo and in vitro, resulting in increased fungal burden in the kidney and increased mortality in wild type mice. Thus, thrombospondin-1 enhances the pathogenesis of disseminated candidiasis by creating an imbalance in the host immune response that ultimately leads to reduced phagocytic function, impaired fungal clearance, and increased mortality. Conversely, inhibitors of thrombospondin-1 may be useful drugs to improve patient recovery from disseminated candidiasis.
The intracellular enzyme urea amidolyase (Dur1,2p) enables C. albicans to utilize urea as a sole nitrogen source. Because deletion of the DUR1,2 gene reduces survival of C. albicans co-cultured with a murine macrophage cell line, we investigated the role of Dur1,2p in pathogenesis using a mouse model of disseminated candidiasis. A dur1,2Δ/dur1,2Δ strain was significantly less virulent than the wild-type strain, showing significantly higher survival rate, better renal function, and decreased and less sustained fungal colonization in kidney and brain. Complementation of the mutant restored virulence. DUR1,2 deletion resulted in a milder host inflammatory reaction. Immunohistochemistry, flow cytometry, and magnetic resonance imaging showed decreased phagocytic infiltration into infected kidneys. Systemic cytokine levels of wild-type mice infected with the dur1,2 mutant showed a more balanced systemic pro-inflammatory cytokine response. Host gene expression and protein analysis in infected kidneys revealed parallel changes in the local immune response. Significant differences were observed in the kidney IL-1 inflammatory pathway, IL-15 signaling, MAP kinase signaling, and the alternative complement pathway. We conclude that Dur1,2p is important for kidney colonization during disseminated candidiasis and contributes to an unbalanced host inflammatory response and subsequent renal failure. Therefore, this Candida-specific enzyme may represent a useful drug target to protect the host from kidney damage associated with disseminated candidiasis.
Sex-biased dispersal is widespread in the animal kingdom and is affected by numerous factors including mating system, social factors and environmental conditions. Unlike birds and mammals, there is no common trend in amphibians and explaining the direction and degree of sex-biased dispersal in species-specific cases is difficult. We conducted a study on dispersal of the Chinese piebald odorous frog (Odorrana schmackeri) in a fragmented landscape associated with dam construction. Ten microsatellite loci were used to analyze 382 samples sourced from 14 fragmented ‘islands’. Assignment tests indicated a significant pattern of female-biased dispersal on one island with inconsistencies in the strength and direction of this pattern between nearby islands. The effects of four island attributes and two potential impact factors on the pattern of sex-biased dispersal were examined. We found that the extent of isolation from the mainland and the number of breeding sites both showed a negative correlation with female biased dispersal, such that the closer an island is to the mainland the more likely it is to display female biased dispersal, and the more breeding sites on an island the more male immigrants. Based on these results, we conclude that geographic isolation and limited breeding resources are the most likely explanation for the patterns of dispersal observed in this fragmented population of amphibians.
The chemo-preventative effects of dithiolethione compounds are attributed to their activation of anti-oxidant response elements (ARE) by reacting with the Nrf2/Keap1 protein complex. In this study, we demonstrate anti-proliferative effects of the dithiolethione compound ACS-1 in human cancer cell lines (A549 and MDA-MB-231) by increasing the activity of the tumor suppressor PP2A. ACS-1 inhibited EGF-induced cellular proliferation in a concentration and time-dependent manner. Akt activation, as determined by serine-473 phosphorylation, was inhibited by ACS-1 in cells stimulated with either EGF or fibronectin. Furthermore, ACS-1 inhibited mTOR signaling and decreased c-myc protein levels. ACS-1 did not proximally alter EGFR or integrin signaling, but caused a concentration-dependent increase in PP2A activity. The effect of ACS-1 on Akt activation was not observed in the presence of the PP2A inhibitor okadaic acid. ACS-1 effects on PP2A activity were independent of ARE activation and cAMP formation. In addition to ACS-1, other dithiolethione compounds showed similar effects in reducing Akt activation, suggesting that this class of compounds may have other effects beyond chemoprevention.
Dithiolethione; PP2A; Akt; cancer; breast; lung
Background and purpose
Primary spontaneous osteonecrosis of the knee is a painful lesion in the elderly without any known cause. The onset of pain is usually acute. The prognosis is poor with high frequency of osteoarthritis, joint surface collapse, and subsequent knee surgery. In the present study, we determined whether bisphosphonates can prevent the joint surface collapse by delaying the post-necrotic remodeling.
Patients and methods
Between 2006 and 2009, 17 consecutive patients (mean age 68 years) with clinical and radiographic signs of knee osteonecrosis were identified and given alendronate, 70 mg perorally, once a week for a minimum of 6 months. The patients were followed clinically, radiographically, and by MRI.
10 of the 17 patients did not develop osteoarthritis (group A), 4 patients developed mild osteoarthritis but no knee joint surface collapse (group B), and 3 patients had a joint surface collapse (group C). 2 of the 3 patients in group C—as compared to none in the other groups—stopped medication prematurely, due to side effects.
Compared to a previous, untreated series of osteonecrosis patients at our hospital, the clinical results in the present series appeared better. 59% of the patients had a complete radiographic recovery, as compared to 25% in the original study. 12% were failures regarding need to undergo surgery when bisphosphonates were given, as compared to 32% in the previous untreated series. An anticatabolic drug delaying the remodeling might be an effective treatment in osteonecrosis of the knee but further (preferably randomized) studies are necessary.