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Sample records for late-stage gambiense human

  1. Enantiospecific Reassessment of the Pharmacokinetics and Pharmacodynamics of Oral Eflornithine against Late-Stage Trypanosoma brucei gambiense Sleeping Sickness

    PubMed Central

    Björkman, S.; Doua, F.; Ashton, M.

    2014-01-01

    This study aimed to characterize the stereoselective pharmacokinetics of oral eflornithine in 25 patients with late-stage Trypanosoma brucei gambiense sleeping sickness. A secondary aim was to determine the concentrations of l- and d-eflornithine required in plasma or cerebrospinal fluid (CSF) for an efficient eradication of the T. brucei gambiense parasites. Patients were randomly allocated to receive either 100 (group I, n = 12) or 125 (group II, n = 13) mg/kg of body weight of drug every 6 h for 14 days. The concentrations of l- and d-eflornithine in the plasma and CSF samples were measured using a stereospecific liquid chromatographic method. Nonlinear mixed-effects modeling was used to characterize the plasma pharmacokinetics. The plasma concentrations of l-eflornithine were on average 52% (95% confidence interval [CI], 51, 54%; n = 321) of the d-enantiomer concentrations. The typical oral clearances of l- and d-eflornithine were 17.4 (95% CI, 15.5, 19.3) and 8.23 (95% CI, 7.36, 9.10) liters/h, respectively. These differences were likely due to stereoselective intestinal absorption. The distributions of eflornithine enantiomers to the CSF were not stereoselective. A correlation was found between the probability of cure and plasma drug exposure, although it was not more pronounced for the l-enantiomer than for that of total eflornithine. This study may explain why oral treatment for late-stage human African trypanosomiasis (HAT) patients with racemic eflornithine has previously failed; the more potent l-enantiomer is present at much lower concentrations in both plasma and CSF than those of the d-enantiomer. Eflornithine stereoselective pharmacokinetics needs to be considered if an oral dosage regimen is to be explored further. PMID:25512417

  2. Three Drug Combinations for Late-Stage Trypanosoma brucei gambiense Sleeping Sickness: A Randomized Clinical Trial in Uganda

    PubMed Central

    Priotto, Gerardo; Fogg, Carole; Balasegaram, Manica; Erphas, Olema; Louga, Albino; Checchi, Francesco; Ghabri, Salah; Piola, Patrice

    2006-01-01

    Objectives: Our objective was to compare the efficacy and safety of three drug combinations for the treatment of late-stage human African trypanosomiasis caused by Trypanosoma brucei gambiense. Design: This trial was a randomized, open-label, active control, parallel clinical trial comparing three arms. Setting: The study took place at the Sleeping Sickness Treatment Center run by Médecins Sans Frontières at Omugo, Arua District, Uganda Participants: Stage 2 patients diagnosed in Northern Uganda were screened for inclusion and a total of 54 selected. Interventions: Three drug combinations were given to randomly assigned patients: melarsoprol-nifurtimox (M+N), melarsoprol-eflornithine (M+E), and nifurtimox-eflornithine (N+E). Dosages were uniform: intravenous (IV) melarsoprol 1.8 mg/kg/d, daily for 10 d; IV eflornithine 400 mg/kg/d, every 6 h for 7 d; oral nifurtimox 15 (adults) or 20 (children <15 y) mg/kg/d, every 8 h for 10 d. Patients were followed up for 24 mo. Outcome Measures: Outcomes were cure rates and adverse events attributable to treatment. Results: Randomization was performed on 54 patients before enrollment was suspended due to unacceptable toxicity in one of the three arms. Cure rates obtained with the intention to treat analysis were M+N 44.4%, M+E 78.9%, and N+E 94.1%, and were significantly higher with N+E (p = 0.003) and M+E (p = 0.045) than with M+N. Adverse events were less frequent and less severe with N+E, resulting in fewer treatment interruptions and no fatalities. Four patients died who were taking melarsoprol-nifurtimox and one who was taking melarsoprol-eflornithine. Conclusions: The N+E combination appears to be a promising first-line therapy that may improve treatment of sleeping sickness, although the results from this interrupted study do not permit conclusive interpretations. Larger studies are needed to continue the evaluation of this drug combination in the treatment of T. b. gambiense sleeping sickness. PMID:17160135

  3. Mechanism of Trypanosoma brucei gambiense resistance to human serum.

    PubMed

    Uzureau, Pierrick; Uzureau, Sophie; Lecordier, Laurence; Fontaine, Frédéric; Tebabi, Patricia; Homblé, Fabrice; Grélard, Axelle; Zhendre, Vanessa; Nolan, Derek P; Lins, Laurence; Crowet, Jean-Marc; Pays, Annette; Felu, Cécile; Poelvoorde, Philippe; Vanhollebeke, Benoit; Moestrup, Soren K; Lyngsø, Jeppe; Pedersen, Jan Skov; Mottram, Jeremy C; Dufourc, Erick J; Pérez-Morga, David; Pays, Etienne

    2013-09-19

    The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases. T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b. brucei, the causative agent of nagana disease in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2), which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1). Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via the trypanosome receptor TbHpHbR (ref. 5), TLF-2 enters trypanosomes independently of TbHpHbR (refs 4, 5). APOL1 kills trypanosomes after insertion into endosomal/lysosomal membranes. Here we report that T. b. gambiense resists TLFs via a hydrophobic β-sheet of the T. b. gambiense-specific glycoprotein (TgsGP), which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According to such a multifactorial defence mechanism, transgenic expression of T. b. brucei TbHpHbR in T. b. gambiense did not cause parasite lysis in normal human serum. However, these transgenic parasites were killed in hypohaptoglobinaemic serum, after high TLF-1 uptake in the absence of haptoglobin (Hp) that competes for Hb and receptor binding. TbHpHbR inactivation preventing high APOL1 loading in hypohaptoglobinaemic serum may have evolved because of the overlapping endemic area of T. b. gambiense infection and malaria, the main cause of haemolysis-induced hypohaptoglobinaemia in western and central Africa. PMID:23965626

  4. Treatment options for second-stage gambiense human African trypanosomiasis

    PubMed Central

    Eperon, Gilles; Balasegaram, Manica; Potet, Julien; Mowbray, Charles; Valverde, Olaf; Chappuis, François

    2014-01-01

    Treatment of second-stage gambiense human African trypanosomiasis relied on toxic arsenic-based derivatives for over 50 years. The availability and subsequent use of eflornithine, initially in monotherapy and more recently in combination with nifurtimox (NECT), has drastically improved the prognosis of treated patients. However, NECT logistic and nursing requirements remain obstacles to its deployment and use in peripheral health structures in rural sub-Saharan Africa. Two oral compounds, fexinidazole and SCYX-7158, are currently in clinical development. The main scope of this article is to discuss the potential impact of new oral therapies to improve diagnosis-treatment algorithms and patients’ access to treatment, and to contribute to reach the objectives of the recently launched gambiense human African trypanosomiasis elimination program. PMID:25204360

  5. The TgsGP gene is essential for resistance to human serum in Trypanosoma brucei gambiense.

    PubMed

    Capewell, Paul; Clucas, Caroline; DeJesus, Eric; Kieft, Rudo; Hajduk, Stephen; Veitch, Nicola; Steketee, Pieter C; Cooper, Anneli; Weir, William; MacLeod, Annette

    2013-01-01

    Trypanosoma brucei gambiense causes 97% of all cases of African sleeping sickness, a fatal disease of sub-Saharan Africa. Most species of trypanosome, such as T. b. brucei, are unable to infect humans due to the trypanolytic serum protein apolipoprotein-L1 (APOL1) delivered via two trypanosome lytic factors (TLF-1 and TLF-2). Understanding how T. b. gambiense overcomes these factors and infects humans is of major importance in the fight against this disease. Previous work indicated that a failure to take up TLF-1 in T. b. gambiense contributes to resistance to TLF-1, although another mechanism is required to overcome TLF-2. Here, we have examined a T. b. gambiense specific gene, TgsGP, which had previously been suggested, but not shown, to be involved in serum resistance. We show that TgsGP is essential for resistance to lysis as deletion of TgsGP in T. b. gambiense renders the parasites sensitive to human serum and recombinant APOL1. Deletion of TgsGP in T. b. gambiense modified to uptake TLF-1 showed sensitivity to TLF-1, APOL1 and human serum. Reintroducing TgsGP into knockout parasite lines restored resistance. We conclude that TgsGP is essential for human serum resistance in T. b. gambiense. PMID:24098129

  6. The TgsGP Gene Is Essential for Resistance to Human Serum in Trypanosoma brucei gambiense

    PubMed Central

    DeJesus, Eric; Kieft, Rudo; Hajduk, Stephen; Veitch, Nicola; Steketee, Pieter C.; Cooper, Anneli; Weir, William; MacLeod, Annette

    2013-01-01

    Trypanosoma brucei gambiense causes 97% of all cases of African sleeping sickness, a fatal disease of sub-Saharan Africa. Most species of trypanosome, such as T. b. brucei, are unable to infect humans due to the trypanolytic serum protein apolipoprotein-L1 (APOL1) delivered via two trypanosome lytic factors (TLF-1 and TLF-2). Understanding how T. b. gambiense overcomes these factors and infects humans is of major importance in the fight against this disease. Previous work indicated that a failure to take up TLF-1 in T. b. gambiense contributes to resistance to TLF-1, although another mechanism is required to overcome TLF-2. Here, we have examined a T. b. gambiense specific gene, TgsGP, which had previously been suggested, but not shown, to be involved in serum resistance. We show that TgsGP is essential for resistance to lysis as deletion of TgsGP in T. b. gambiense renders the parasites sensitive to human serum and recombinant APOL1. Deletion of TgsGP in T. b. gambiense modified to uptake TLF-1 showed sensitivity to TLF-1, APOL1 and human serum. Reintroducing TgsGP into knockout parasite lines restored resistance. We conclude that TgsGP is essential for human serum resistance in T. b. gambiense. PMID:24098129

  7. Silent Human Trypanosoma brucei gambiense Infections around the Old Gboko Sleeping Sickness Focus in Nigeria

    PubMed Central

    Solomon Ngutor, Karshima; Idris, Lawal A.; Oluseyi Oluyinka, Okubanjo

    2016-01-01

    Trypanosoma brucei gambiense causes Gambian trypanosomosis, a disease ravaging affected rural parts of Sub-Saharan Africa. We screened 1200 human blood samples for T. b. gambiense using the card agglutination test for trypanosomosis, characterized trypanosome isolates with Trypanosoma gambiense serum glycoprotein-PCR (TgsGP-PCR), and analyzed our data using Chi square and odds ratio at 95% confidence interval for statistical association. Of the 1200 samples, the CATT revealed an overall infection rate of 1.8% which ranged between 0.0% and 3.5% across study sites. Age and sex based infection rates ranged between 1.2% and 2.3%. We isolated 7 (33.3%) trypanosomes from the 21 seropositive samples using immunosuppressed mice which were identified as T. b. gambiense group 1 by TgsGP-PCR. Based on study sites, PCR revealed an overall infection rate of 0.6% which ranged between 0.0% and 1.5%. Females and males revealed PCR based infection rates of 0.3% and 0.8%, respectively. Infection rates in adults (1.3%) and children (0.1%) varied significantly (p < 0.05). We observed silent T. b. gambiense infections among residents of this focus. Risks of disease development into the second fatal stage in these patients who may also serve as reservoirs of infection in the focus exist. PMID:26941995

  8. Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor.

    PubMed

    Kieft, Rudo; Capewell, Paul; Turner, C Michael R; Veitch, Nicola J; MacLeod, Annette; Hajduk, Stephen

    2010-09-14

    Human innate immunity against most African trypanosomes, including Trypanosoma brucei brucei, is mediated by a minor subclass of toxic serum HDL, called trypanosome lytic factor-1 (TLF-1). This HDL contains two primate specific proteins, apolipoprotein L-1 and haptoglobin (Hp)-related protein, as well as apolipoprotein A-1. These assembled proteins provide a powerful defense against trypanosome infection. Trypanosoma brucei rhodesiense causes human African sleeping sickness because it has evolved an inhibitor of TLF-1, serum resistance-associated (SRA) protein. Trypanosoma brucei gambiense lacks the SRA gene, yet it infects humans. As transfection of T. b. gambiense (group 1) is not possible, we initially used in vitro-selected TLF-1-resistant T. b. brucei to examine SRA-independent mechanisms of TLF-1 resistance. Here we show that TLF-1 resistance in T. b. brucei is caused by reduced expression of the Hp/Hb receptor gene (TbbHpHbR). Importantly, T. b. gambiense (group 1) also showed a marked reduction in uptake of TLF-1 and a corresponding decrease in expression of T. b. gambiense Hp/Hb receptor (TbgHpHbR). Ectopic expression of TbbHpHbR in TLF-1-resistant T. b. brucei rescued TLF-1 uptake, demonstrating that decreased TbbHpHbR expression conferred TLF-1 resistance. Ectopic expression of TbgHpHbR in TLF-1-resistant T. b. brucei failed to rescue TLF-1 killing, suggesting that coding sequence changes altered Hp/Hb receptor binding affinity for TLF-1. We propose that the combination of coding sequence mutations and decreased expression of TbgHpHbR directly contribute to parasite evasion of human innate immunity and infectivity of group 1 T. b. gambiense. PMID:20805508

  9. Molecular evidence of a Trypanosoma brucei gambiense sylvatic cycle in the human african trypanosomiasis foci of Equatorial Guinea

    PubMed Central

    Cordon-Obras, Carlos; Rodriguez, Yasmin Fermin; Fernandez-Martinez, Amalia; Cano, Jorge; Ndong-Mabale, Nicolas; Ncogo-Ada, Policarpo; Ndongo-Asumu, Pedro; Aparicio, Pilar; Navarro, Miguel; Benito, Agustin; Bart, Jean-Mathieu

    2015-01-01

    Gambiense trypanosomiasis is considered an anthroponotic disease. Consequently, control programs are generally aimed at stopping transmission of Trypanosoma brucei gambiense (T. b. gambiense) by detecting and treating human cases. However, the persistence of numerous foci despite efforts to eliminate this disease questions this strategy as unique tool to pursue the eradication. The role of animals as a reservoir of T. b. gambiense is still controversial, but could partly explain maintenance of the infection at hypo-endemic levels. In the present study, we evaluated the presence of T. b. gambiense in wild animals in Equatorial Guinea. The infection rate ranged from 0.8% in the insular focus of Luba to more than 12% in Mbini, a focus with a constant trickle of human cases. The parasite was detected in a wide range of animal species including four species never described previously as putative reservoirs. Our study comes to reinforce the hypothesis that animals may play a role in the persistence of T. b. gambiense transmission, being particularly relevant in low transmission settings. Under these conditions the integration of sustained vector control and medical interventions should be considered to achieve the elimination of gambiense trypanosomiasis. PMID:26257727

  10. Identifying Transmission Cycles at the Human-Animal Interface: The Role of Animal Reservoirs in Maintaining Gambiense Human African Trypanosomiasis

    PubMed Central

    Funk, Sebastian; Nishiura, Hiroshi; Heesterbeek, Hans; Edmunds, W. John; Checchi, Francesco

    2013-01-01

    Many infections can be transmitted between animals and humans. The epidemiological roles of different species can vary from important reservoirs to dead-end hosts. Here, we present a method to identify transmission cycles in different combinations of species from field data. We used this method to synthesise epidemiological and ecological data from Bipindi, Cameroon, a historical focus of gambiense Human African Trypanosomiasis (HAT, sleeping sickness), a disease that has often been considered to be maintained mainly by humans. We estimated the basic reproduction number of gambiense HAT in Bipindi and evaluated the potential for transmission in the absence of human cases. We found that under the assumption of random mixing between vectors and hosts, gambiense HAT could not be maintained in this focus without the contribution of animals. This result remains robust under extensive sensitivity analysis. When using the distributions of species among habitats to estimate the amount of mixing between those species, we found indications for an independent transmission cycle in wild animals. Stochastic simulation of the system confirmed that unless vectors moved between species very rarely, reintroduction would usually occur shortly after elimination of the infection from human populations. This suggests that elimination strategies may have to be reconsidered as targeting human cases alone would be insufficient for control, and reintroduction from animal reservoirs would remain a threat. Our approach is broadly applicable and could reveal animal reservoirs critical to the control of other infectious diseases. PMID:23341760

  11. Analysis of a model of gambiense sleeping sickness in humans and cattle.

    PubMed

    Ndondo, A M; Munganga, J M W; Mwambakana, J N; Saad-Roy, C M; van den Driessche, P; Walo, R O

    2016-01-01

    Human African Trypanosomiasis (HAT) and Nagana in cattle, commonly called sleeping sickness, is caused by trypanosome protozoa transmitted by bites of infected tsetse flies. We present a deterministic model for the transmission of HAT caused by Trypanosoma brucei gambiense between human hosts, cattle hosts and tsetse flies. The model takes into account the growth of the tsetse fly, from its larval stage to the adult stage. Disease in the tsetse fly population is modeled by three compartments, and both the human and cattle populations are modeled by four compartments incorporating the two stages of HAT. We provide a rigorous derivation of the basic reproduction number R0. For R0 < 1, the disease free equilibrium is globally asymptotically stable, thus HAT dies out; whereas (assuming no return to susceptibility) for R0 >1, HAT persists. Elasticity indices for R0 with respect to different parameters are calculated with baseline parameter values appropriate for HAT in West Africa; indicating parameters that are important for control strategies to bring R0 below 1. Numerical simulations with R0 > 1 show values for the infected populations at the endemic equilibrium, and indicate that with certain parameter values, HAT could not persist in the human population in the absence of cattle. PMID:27296784

  12. Untreated Human Infections by Trypanosoma brucei gambiense Are Not 100% Fatal

    PubMed Central

    Jamonneau, Vincent; Ilboudo, Hamidou; Kaboré, Jacques; Kaba, Dramane; Koffi, Mathurin; Solano, Philippe; Garcia, André; Courtin, David; Laveissière, Claude; Lingue, Kouakou; Büscher, Philippe; Bucheton, Bruno

    2012-01-01

    The final outcome of infection by Trypanosoma brucei gambiense, the main agent of sleeping sickness, has always been considered as invariably fatal. While scarce and old reports have mentioned cases of self-cure in untreated patients, these studies suffered from the lack of accurate diagnostic tools available at that time. Here, using the most specific and sensitive tools available to date, we report on a long-term follow-up (15 years) of a cohort of 50 human African trypanosomiasis (HAT) patients from the Ivory Coast among whom 11 refused treatment after their initial diagnosis. In 10 out of 11 subjects who continued to refuse treatment despite repeated visits, parasite clearance was observed using both microscopy and polymerase chain reaction (PCR). Most of these subjects (7/10) also displayed decreasing serological responses, becoming progressively negative to trypanosome variable antigens (LiTat 1.3, 1.5 and 1.6). Hence, in addition to the “classic” lethal outcome of HAT, we show that alternative natural progressions of HAT may occur: progression to an apparently aparasitaemic and asymptomatic infection associated with strong long-lasting serological responses and progression to an apparently spontaneous resolution of infection (with negative results in parasitological tests and PCR) associated with a progressive drop in antibody titres as observed in treated cases. While this study does not precisely estimate the frequency of the alternative courses for this infection, it is noteworthy that in the field national control programs encounter a significant proportion of subjects displaying positive serologic test results but negative results in parasitological testing. These findings demonstrate that a number of these subjects display such infection courses. From our point of view, recognising that trypanotolerance exists in humans, as is now widely accepted for animals, is a major step forward for future research in the field of HAT. PMID:22720107

  13. Embryonic hematopoietic stem cells and interstitial Cajal cells in the hindgut of late stage human embryos: evidence and hypotheses.

    PubMed

    Ilie, C A; Rusu, M C; Didilescu, A C; Motoc, A G M; Mogoantă, L

    2015-07-01

    There have been few studies on human embryos describing a specific pattern of hindgut colonization by hematopoietic stem cells (HSCs) and interstitial Cajal cells (ICCs). We aimed to study CD34, CD45 and CD117/c-kit expression in late stage human embryos, to attain observational data that could be related to studies on the aorta-gonad-mesonephros (AGM)-derived HSCs, and data on hindgut ICCs. Antibodies were also applied to identify alpha-smooth muscle actin and neurofilaments. Six human embryos of 48-56 days were used. In the 48 day embryo, the hindgut was sporadically populated by c-kit+ ICCs, but, in all other embryos, a layer of myenteric ICCs had been established. Intraneural c-kit+ cells were found in pelvic nerves and vagal trunks, suggesting that the theory of Ramon y Cajal assuming that ICCs may be primitive neurons may not be so invalid. Also in the 48 day embryo, c-kit+/CD45+ perivascular cells were found along the pelvic neurovascular axes, suggesting that not only liver, but also other organs could be seeded with HSCs from the AGM region. CD45+ cells with dendritic morphologies were found in all hindgut layers, including the epithelium. This last evidence is suggestive of an AGM contribution to the tissue resident macrophages and could be related to processes of sprouting angiogenesis which, in turn, have been found to be guided by filopodia of endothelial tip cells. Further studies on human embryonic and fetal material should be performed to attempt to clarify whether the hindgut colonization with HSCs is a transitory or definitive process. PMID:25723517

  14. The CD3-zeta chimeric antigen receptor overcomes TCR Hypo-responsiveness of human terminal late-stage T cells.

    PubMed

    Rappl, Gunter; Riet, Tobias; Awerkiew, Sabine; Schmidt, Annette; Hombach, Andreas A; Pfister, Herbert; Abken, Hinrich

    2012-01-01

    Adoptive therapy of malignant diseases with tumor-specific cytotoxic T cells showed remarkable efficacy in recent trials. Repetitive T cell receptor (TCR) engagement of target antigen, however, inevitably ends up in hypo-responsive cells with terminally differentiated KLRG-1(+) CD57(+) CD7(-) phenotype limiting their therapeutic efficacy. We here revealed that hypo-responsiveness of CMV-specific late-stage CD8(+) T cells is due to reduced TCR synapse formation compared to younger cells. Membrane anchoring of TCR components contributes to T cell hypo-responsiveness since dislocation of galectin-3 from the synapse by swainsonine restored both TCR synapse formation and T cell response. Transgenic expression of a CD3-zeta signaling chimeric antigen receptor (CAR) recovered hypo-responsive T cells to full effector functions indicating that the defect is restricted to TCR membrane components while synapse formation of the transgenic CAR was not blocked. CAR engineered late-stage T cells released cytokines and mediated redirected cytotoxicity as efficiently as younger effector T cells. Our data provide a rationale for TCR independent, CAR mediated activation in the adoptive cell therapy to avoid hypo-responsiveness of late-stage T cells upon repetitive antigen encounter. PMID:22292024

  15. TLTF in Cerebrospinal Fluid for Detection and Staging of T. b. gambiense Infection

    PubMed Central

    Abdulla, Maha-Hamadien; Bakhiet, Moiz; Lejon, Veerle; Andersson, Jan; McKerrow, James; Al-Obeed, Omar; Harris, Robert A.

    2013-01-01

    Background Trypanosome-derived lymphocyte triggering factor (TLTF) is a molecule released by African trypanosomes that interacts with the host immune system, resulting in increased levels of IFN-γ production. Methodology/Principal findings TLTF and anti-TLTF antibodies were assessed in sera and cerebrospinal fluid (CSF) from patients infected with Trypanosoma brucei gambiense (T. b. gambiense) in an attempt to identify alternative markers for diagnosis and stage determination of human African trypanosomiasis or sleeping sickness. Seventy-four serum and sixty-one CSF samples from patients with parasitologically confirmed infection and known disease stage along with 13 sera and CSF from uninfected controls were tested. In serum the levels of anti-TLTF antibodies were unrelated to the disease stage. In contrast, levels of anti-TLTF antibodies in CSF were higher in intermediate/late stages than in early stage disease patients. Specificity of the detected antibodies was assessed by inhibition of TLTF bioactivity as represented by its ability to induce IFN-γ production. Additionally, TLTF was detected in CSF from late stage patients by Western blotting with the anti-TLTF specific monoclonal antibody MO3. Conclusions/Significance These findings suggest a new possibility for disease diagnosis with focus on involvement of the CNS through detection of TLTF and anti-TLTF antibodies in the CSF. PMID:24260185

  16. The miRNA and mRNA Signatures of Peripheral Blood Cells in Humans Infected with Trypanosoma brucei gambiense

    PubMed Central

    Leong, Smiths; Simo, Gustave; Camara, Mamadou; Jamonneau, Vincent; Kabore, Jacques; Ilboudo, Hamidou; Bucheton, Bruno; Hoheisel, Jörg D.; Clayton, Christine

    2013-01-01

    Simple, reliable tools for diagnosis of human African Trypanosomiases could ease field surveillance and enhance patient care. In particular, current methods to distinguish patients with (stage II) and without (stage I) brain involvement require samples of cerebrospinal fluid. We describe here an exploratory study to find out whether miRNAs from peripheral blood leukocytes might be useful in diagnosis of human trypanosomiasis, or for determining the stage of the disease. Using microarrays, we measured miRNAs in samples from Trypanosoma brucei gambiense-infected patients (9 stage I, 10 stage II), 8 seronegative parasite-negative controls and 12 seropositive, but parasite-negative subjects. 8 miRNAs (out of 1205 tested) showed significantly lower expression in patients than in seronegative, parasite-negative controls, and 1 showed increased expression. There were no clear differences in miRNAs between patients in different disease stages. The miRNA profiles could not distinguish seropositive, but parasitologically negative samples from controls and results within this group did not correlate with those from the trypanolysis test. Some of the regulated miRNAs, or their predicted mRNA targets, were previously reported changed during other infectious diseases or cancer. We conclude that the changes in miRNA profiles of peripheral blood lymphocytes in human African trypanosomiasis are related to immune activation or inflammation, are probably disease-non-specific, and cannot be used to determine the disease stage. The approach has little promise for diagnostics but might yield information about disease pathology. PMID:23826264

  17. Acute paretic syndrome in juvenile White Leghorn chickens resembles late stages of acute inflammatory demyelinating polyneuropathies in humans

    PubMed Central

    2010-01-01

    Background Sudden limb paresis is a common problem in White Leghorn flocks, affecting about 1% of the chicken population before achievement of sexual maturity. Previously, a similar clinical syndrome has been reported as being caused by inflammatory demyelination of peripheral nerve fibres. Here, we investigated in detail the immunopathology of this paretic syndrome and its possible resemblance to human neuropathies. Methods Neurologically affected chickens and control animals from one single flock underwent clinical and neuropathological examination. Peripheral nervous system (PNS) alterations were characterised using standard morphological techniques, including nerve fibre teasing and transmission electron microscopy. Infiltrating cells were phenotyped immunohistologically and quantified by flow cytometry. The cytokine expression pattern was assessed by quantitative real-time PCR (qRT-PCR). These investigations were accomplished by MHC genotyping and a PCR screen for Marek's disease virus (MDV). Results Spontaneous paresis of White Leghorns is caused by cell-mediated, inflammatory demyelination affecting multiple cranial and spinal nerves and nerve roots with a proximodistal tapering. Clinical manifestation coincides with the employment of humoral immune mechanisms, enrolling plasma cell recruitment, deposition of myelin-bound IgG and antibody-dependent macrophageal myelin-stripping. Disease development was significantly linked to a 539 bp microsatellite in MHC locus LEI0258. An aetiological role for MDV was excluded. Conclusions The paretic phase of avian inflammatory demyelinating polyradiculoneuritis immunobiologically resembles the late-acute disease stages of human acute inflammatory demyelinating polyneuropathy, and is characterised by a Th1-to-Th2 shift. PMID:20109187

  18. SRR-SB3, a disulfide-containing macrolide that inhibits a late stage of the replicative cycle of human immunodeficiency virus.

    PubMed Central

    Witvrouw, M; Balzarini, J; Pannecouque, C; Jhaumeer-Laulloo, S; Esté, J A; Schols, D; Cherepanov, P; Schmit, J C; Debyser, Z; Vandamme, A M; Desmyter, J; Ramadas, S R; de Clercq, E

    1997-01-01

    From a series of macrocyclic diamides possessing the disulfide linkage, only SRR-SB3, a compound that complexes with zinc, was found to inhibit human immunodeficiency virus type 1 (HIV-1; strain IIIB) replication at a concentration of 1.8 to 6.5 micrograms/ml in MT-4, CEM, and peripheral blood mononuclear cells. SRR-SB3 was toxic to MT-4 cells at a concentration of 15.9 micrograms/ml, resulting in a selectivity index of 9 in these cells. This macrolide was also effective against various other HIV-1 strains, including clinical isolates and HIV-1 strains resistant to protease inhibitors and nucleoside and nonnucleoside reverse transcriptase inhibitors. It was also active against various HIV-2 strains, simian immunodeficiency virus (strain MAC251), and Moloney murine sarcoma virus, but not against viruses other than retroviruses. In addition, the compound was found to inhibit chronic HIV-1 infections in vitro. The compound in combination with other antiviral agents, such as zidovudine, zalcitabine, and stavudine, showed an effect that was between additive and synergistic. Time-of-addition experiments indicated that SRR-SB3 acts at a late stage of the HIV-1 replicative cycle. PMID:9021177

  19. TGF-β inhibits metastasis in late stage human squamous cell carcinoma of the skin by a mechanism that does not involve Id1.

    PubMed

    Ganapathy, Anu; Paterson, Ian C; Prime, Stephen S; Eveson, John W; Pring, Miranda; Price, Nicky; Threadgold, Suzy P; Davies, Maria

    2010-12-01

    It is now generally accepted that TGF-β acts as a pro-metastatic factor in advanced human breast cancer. However, it is well documented, that TGF-β is context dependent, and whether the TGF-β pathway switches to promote metastasis during the progression of squamous cell carcinoma (SCC) is unknown. This study examined the role of TGF-β signalling in SCC using a series of genetically related keratinocyte cell lines representing later stages of the disease, stably transduced with a dominant negative TβRII cDNA (dnTβRII). We demonstrated that clones expressing dnTβRII lost their growth inhibitory response to TGF-βin vitro, while ligand expression remained unchanged. Following transplantation of transduced cells to athymic mice in vivo, we showed that attenuation of the TGF-β signal resulted in a loss of differentiation and increased metastasis. In human tissue samples loss of TGF-β signal transduction as measured by pSmad2 activity also correlated with a loss of differentiation. Id1, previously shown to be down regulated by TGF-β, an inhibitor of differentiation and associated with metastasis, was weakly expressed in focal areas of a small number of human tumours but expression did not correlate with low levels of pSmad2. Our data demonstrate that TGF-β does not switch to promote metastasis in late stage human SCC of the skin and that inhibition of TGF-β signalling results in a loss of differentiation and increased metastasis in the later stages of this disease. PMID:20663607

  20. Neural-Dural Transition at the Thoracic and Lumbar Spinal Nerve Roots: A Histological Study of Human Late-Stage Fetuses

    PubMed Central

    Cho, Kwang Ho; Jin, Zhe Wu; Abe, Hiroshi; Shibata, Shunichi; Murakami, Gen; Rodríguez-Vázquez, Jose Francisco

    2016-01-01

    Epidural blocks have been used extensively in infants. However, little histological information is available on the immature neural-dural transition. The neural-dural transition was histologically investigated in 12 late-stage (28–30 weeks) fetuses. The dural sheath of the spinal cord was observed to always continue along the nerve roots with varying thicknesses between specimens and segments, while the dorsal root ganglion sheath was usually very thin or unclear. Immature neural-dural transitions were associated with effective anesthesia. The posterior radicular artery was near the dorsal root ganglion and/or embedded in the nerve root, whereas the anterior radicular artery was separated from the nearest nerve root. The anterior radicular artery was not associated with the dural sheath but with thin mesenchymal tissue. The numbers of radicular arteries tended to become smaller in larger specimens. Likewise, larger specimens of the upper thoracic and lower lumbar segments did not show the artery. Therefore, elimination of the radicular arteries to form a single artery of Adamkiewicz was occurring in late-stage fetuses. The epidural space was filled with veins, and the loose tissue space extended ventrolaterally to the subpleural tissue between the ribs. Consequently, epidural blocks in infants require special attention although immature neural-dural transitions seemed to increase the effect. PMID:27069926

  1. Neural-Dural Transition at the Thoracic and Lumbar Spinal Nerve Roots: A Histological Study of Human Late-Stage Fetuses.

    PubMed

    Cho, Kwang Ho; Jin, Zhe Wu; Abe, Hiroshi; Shibata, Shunichi; Murakami, Gen; Rodríguez-Vázquez, Jose Francisco

    2016-01-01

    Epidural blocks have been used extensively in infants. However, little histological information is available on the immature neural-dural transition. The neural-dural transition was histologically investigated in 12 late-stage (28-30 weeks) fetuses. The dural sheath of the spinal cord was observed to always continue along the nerve roots with varying thicknesses between specimens and segments, while the dorsal root ganglion sheath was usually very thin or unclear. Immature neural-dural transitions were associated with effective anesthesia. The posterior radicular artery was near the dorsal root ganglion and/or embedded in the nerve root, whereas the anterior radicular artery was separated from the nearest nerve root. The anterior radicular artery was not associated with the dural sheath but with thin mesenchymal tissue. The numbers of radicular arteries tended to become smaller in larger specimens. Likewise, larger specimens of the upper thoracic and lower lumbar segments did not show the artery. Therefore, elimination of the radicular arteries to form a single artery of Adamkiewicz was occurring in late-stage fetuses. The epidural space was filled with veins, and the loose tissue space extended ventrolaterally to the subpleural tissue between the ribs. Consequently, epidural blocks in infants require special attention although immature neural-dural transitions seemed to increase the effect. PMID:27069926

  2. Trypanosoma brucei gambiense Group 1 Is Distinguished by a Unique Amino Acid Substitution in the HpHb Receptor Implicated in Human Serum Resistance

    PubMed Central

    Sistrom, Mark; Agbebakun, Kehinde; Balmer, Oliver; Gibson, Wendy; Aksoy, Serap; Caccone, Adalgisa

    2012-01-01

    Trypanosoma brucei rhodesiense (Tbr) and T. b. gambiense (Tbg), causative agents of Human African Trypanosomiasis (sleeping sickness) in Africa, have evolved alternative mechanisms of resisting the activity of trypanosome lytic factors (TLFs), components of innate immunity in human serum that protect against infection by other African trypanosomes. In Tbr, lytic activity is suppressed by the Tbr-specific serum-resistance associated (SRA) protein. The mechanism in Tbg is less well understood but has been hypothesized to involve altered activity and expression of haptoglobin haemoglobin receptor (HpHbR). HpHbR has been shown to facilitate internalization of TLF-1 in T.b. brucei (Tbb), a member of the T. brucei species complex that is susceptible to human serum. By evaluating the genetic variability of HpHbR in a comprehensive geographical and taxonomic context, we show that a single substitution that replaces leucine with serine at position 210 is conserved in the most widespread form of Tbg (Tbg group 1) and not found in related taxa, which are either human serum susceptible (Tbb) or known to resist lysis via an alternative mechanism (Tbr and Tbg group 2). We hypothesize that this single substitution contributes to reduced uptake of TLF and thus may play a key role in conferring serum resistance to Tbg group 1. In contrast, similarity in HpHbR sequence among isolates of Tbg group 2 and Tbb/Tbr provides further evidence that human serum resistance in Tbg group 2 is likely independent of HpHbR function. PMID:22802982

  3. Anaplastic, plasmablastic, and plasmacytic plasmacytomas of mice: relationships to human plasma cell neoplasms and late-stage differentiation of normal B cells.

    PubMed

    Qi, Chen-Feng; Zhou, Jeff X; Lee, Chang Hoon; Naghashfar, Zohreh; Xiang, Shao; Kovalchuk, Alexander L; Fredrickson, Torgny N; Hartley, Janet W; Roopenian, Derry C; Davidson, Wendy F; Janz, Siegfried; Morse, Herbert C

    2007-03-15

    We have compared histologic features and gene expression profiles of newly identified plasmacytomas from NFS.V(+) congenic mice with plasmacytomas of IL6 transgenic, Fasl mutant, and SJL-beta2M(-/-) mice. NFS.V(+) tumors comprised an overlapping morphologic spectrum of high-grade/anaplastic, intermediate-grade/plasmablastic, and low-grade/plasmacytic cases with similarities to subsets of human multiple myeloma and plasmacytoma. Microarray and immunohistochemical analyses of genes expressed by the most prevalent tumors, plasmablastic plasmacytomas, showed them to be most closely related to immunoblastic lymphomas, less so to plasmacytomas of Fasl mutant and SJL mice, and least to plasmacytic plasmacytomas of IL6 transgenic mice. Plasmablastic tumors seemed to develop in an inflammatory environment associated with gene signatures of T cells, natural killer cells, and macrophages not seen with plasmacytic plasmacytomas. Plasmablastic plasmacytomas from NFS.V(+) and SJL-beta2M(-/-) mice did not have structural alterations in Myc or T(12;15) translocations and did not express Myc at high levels, regular features of transgenic and pristane-induced plasmacytomas. These findings imply that, as for human multiple myeloma, Myc-independent routes of transformation contribute to the pathogenesis of these tumors. These findings suggest that plasma cell neoplasms of mice and humans exhibit similar degrees of complexity. Mouse plasmacytomas, previously considered to be homogeneous, may thus be as diverse as their human counterparts with respect to oncogenic mechanisms of plasma cell transformation. Selecting specific types of mouse plasmacytomas that relate most closely to subtypes of human multiple myeloma may provide new opportunities for preclinical testing of drugs for treatment of the human disease. PMID:17363561

  4. Epitope-Specific Evolution of Human B Cell Responses to Borrelia burgdorferi VlsE Protein from Early to Late Stages of Lyme Disease.

    PubMed

    Jacek, Elzbieta; Tang, Kevin S; Komorowski, Lars; Ajamian, Mary; Probst, Christian; Stevenson, Brian; Wormser, Gary P; Marques, Adriana R; Alaedini, Armin

    2016-02-01

    Most immunogenic proteins of Borrelia burgdorferi, the causative agent of Lyme disease, are known or expected to contain multiple B cell epitopes. However, the kinetics of the development of human B cell responses toward the various epitopes of individual proteins during the course of Lyme disease has not been examined. Using the highly immunogenic VlsE as a model Ag, we investigated the evolution of humoral immune responses toward its immunodominant sequences in 90 patients with a range of early to late manifestations of Lyme disease. The results demonstrate the existence of asynchronous, independently developing, Ab responses against the two major immunogenic regions of the VlsE molecule in the human host. Despite their strong immunogenicity, the target epitopes were inaccessible to Abs on intact spirochetes, suggesting a lack of direct immunoprotective effect. These observations document the association of immune reactivity toward specific VlsE sequences with different phases of Lyme disease, demonstrating the potential use of detailed epitope mapping of Ags for staging of the infection, and offer insights regarding the pathogen's possible immune evasion mechanisms. PMID:26718339

  5. Epitope-Specific Evolution of Human B Cell Responses to Borrelia burgdorferi VlsE Protein from Early to Late Stages of Lyme Disease

    PubMed Central

    Jacek, Elzbieta; Tang, Kevin S.; Komorowski, Lars; Ajamian, Mary; Probst, Christian; Stevenson, Brian; Wormser, Gary P.; Marques, Adriana R.

    2016-01-01

    Most immunogenic proteins of Borrelia burgdorferi, the causative agent of Lyme disease, are known or expected to contain multiple B cell epitopes. However, the kinetics of the development of human B cell responses toward the various epitopes of individual proteins during the course of Lyme disease has not been examined. Using the highly immunogenic VlsE as a model Ag, we investigated the evolution of humoral immune responses toward its immunodominant sequences in 90 patients with a range of early to late manifestations of Lyme disease. The results demonstrate the existence of asynchronous, independently developing, Ab responses against the two major immunogenic regions of the VlsE molecule in the human host. Despite their strong immunogenicity, the target epitopes were inaccessible to Abs on intact spirochetes, suggesting a lack of direct immunoprotective effect. These observations document the association of immune reactivity toward specific VlsE sequences with different phases of Lyme disease, demonstrating the potential use of detailed epitope mapping of Ags for staging of the infection, and offer insights regarding the pathogen’s possible immune evasion mechanisms. PMID:26718339

  6. The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular Mechanisms Differently Affected by Rab5a in the Early and Late Stages.

    PubMed

    Maroni, Paola; Bendinelli, Paola; Resnati, Massimo; Matteucci, Emanuela; Milan, Enrico; Desiderio, Maria Alfonsina

    2016-01-01

    Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and isolation-membrane initiation, remain controversial; molecular mechanisms involve the small-GTPase Rab5a, which regulates vesicle traffic for autophagosome formation. We examined Rab5a involvement in the function of key members of ubiquitin-conjugation systems, Atg7 and LC3-lipidated, interacting with the scaffold-protein p62. Immunohistochemistry of Rab5a was performed in human specimens of bone metastasis and pair-matched breast carcinoma; the autophagic-molecular mechanisms affected by Rab5a were evaluated in human 1833 bone metastatic cells, derived from breast-carcinoma MDA-MB231 cells. To clarify the role of Rab5a, 1833 cells were transfected transiently with Rab5a-dominant negative, and/or stably with the short-hairpin RNA Atg7, were exposed to two inhibitors of autolysosome function, and LC3II and p62 expression was measured. We showed basal autophagy in bone-metastatic cells and the pivotal role of Rab5a together with Beclin 1 between the early stages, elongation of isolation membrane/closed autophagosome mediated by Atg7, and the late-degradative stages. This regulatory network might occur in bone-metastasis and in high-grade dysplastic lesions, preceding invasive-breast carcinoma and conferring phenotypic characteristics for dissemination. PMID:27023526

  7. The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular Mechanisms Differently Affected by Rab5a in the Early and Late Stages

    PubMed Central

    Maroni, Paola; Bendinelli, Paola; Resnati, Massimo; Matteucci, Emanuela; Milan, Enrico; Desiderio, Maria Alfonsina

    2016-01-01

    Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and isolation-membrane initiation, remain controversial; molecular mechanisms involve the small-GTPase Rab5a, which regulates vesicle traffic for autophagosome formation. We examined Rab5a involvement in the function of key members of ubiquitin-conjugation systems, Atg7 and LC3-lipidated, interacting with the scaffold-protein p62. Immunohistochemistry of Rab5a was performed in human specimens of bone metastasis and pair-matched breast carcinoma; the autophagic-molecular mechanisms affected by Rab5a were evaluated in human 1833 bone metastatic cells, derived from breast-carcinoma MDA-MB231 cells. To clarify the role of Rab5a, 1833 cells were transfected transiently with Rab5a-dominant negative, and/or stably with the short-hairpin RNA Atg7, were exposed to two inhibitors of autolysosome function, and LC3II and p62 expression was measured. We showed basal autophagy in bone-metastatic cells and the pivotal role of Rab5a together with Beclin 1 between the early stages, elongation of isolation membrane/closed autophagosome mediated by Atg7, and the late-degradative stages. This regulatory network might occur in bone-metastasis and in high-grade dysplastic lesions, preceding invasive-breast carcinoma and conferring phenotypic characteristics for dissemination. PMID:27023526

  8. Bioluminescence Imaging to Detect Late Stage Infection of African Trypanosomiasis.

    PubMed

    Burrell-Saward, Hollie; Ward, Theresa H

    2016-01-01

    Human African trypanosomiasis (HAT) is a multi-stage disease that manifests in two stages; an early blood stage and a late stage when the parasite invades the central nervous system (CNS). In vivo study of the late stage has been limited as traditional methodologies require the removal of the brain to determine the presence of the parasites. Bioluminescence imaging is a non-invasive, highly sensitive form of optical imaging that enables the visualization of a luciferase-transfected pathogen in real-time. By using a transfected trypanosome strain that has the ability to produce late stage disease in mice we are able to study the kinetics of a CNS infection in a single animal throughout the course of infection, as well as observe the movement and dissemination of a systemic infection. Here we describe a robust protocol to study CNS infections using a bioluminescence model of African trypanosomiasis, providing real time non-invasive observations which can be further analyzed with optional downstream approaches. PMID:27284970

  9. Late-stage sinking of plutons

    USGS Publications Warehouse

    Glazner, A.F.; Miller, D.M.

    1997-01-01

    Many granodiorite to diorite plutons in the Great Basin of western North America are surrounded by rim monoclines or anticlines that suggest relative downward movement of the plutons while wall rocks were hot and ductile. We propose that such plutons rise to a level of approximately neutral buoyancy and then founder as their densities increase ??? 40% during crystallization. Late-stage sinking of intermediate to mafic plutons should be common when wall rocks are rich in weak, low-density minerals such as quartz and calcite. Structures related to sinking will overprint those related to initial pluton emplacement and may be mistaken for regional tectonic structures.

  10. The Natural Progression of Gambiense Sleeping Sickness: What Is the Evidence?

    PubMed Central

    Checchi, Francesco; Filipe, João A. N.; Barrett, Michael P.; Chandramohan, Daniel

    2008-01-01

    Gambiense human African trypanosomiasis (HAT, sleeping sickness) is widely assumed to be 100% pathogenic and fatal. However, reports to the contrary exist, and human trypano-tolerance has been postulated. Furthermore, there is uncertainty about the actual duration of both stage 1 and stage 2 infection, particularly with respect to how long a patient remains infectious. Understanding such basic parameters of HAT infection is essential for optimising control strategies based on case detection. We considered the potential existence and relevance of human trypano-tolerance, and explored the duration of infectiousness, through a review of published evidence on the natural progression of gambiense HAT in the absence of treatment, and biological considerations. Published reports indicate that most gambiense HAT cases are fatal if untreated. Self-resolving and asymptomatic chronic infections probably constitute a minority if they do indeed exist. Chronic carriage, however, deserves further study, as it could seed renewed epidemics after control programmes cease. PMID:19104656

  11. Late stage trifluoromethylthiolation strategies for organic compounds.

    PubMed

    Barata-Vallejo, Sebastian; Bonesi, Sergio; Postigo, Al

    2016-07-26

    Substitution by the CF3S group allows for an increase in lipophilicity and electron-withdrawing properties along with an improvement in the bioavailability of medicinal targets; consequently, the late stage introduction of CF3S moieties into medicinal scaffolds is a sought-after strategy in synthetic organic chemistry. Different newly-developed electrophilic and nucleophilic reagents are used to effect the trifluoromethylthiolation of (hetero)aromatic compounds, aliphatic compounds (alkyl, alkenyl, alkynyl substrates), the trifluoromethylthiolation at the α- and β-carbonyl positions, and heteroatoms (N- and S-). Such reactions can involve homolytic substitutions, or functional-group substitutions (ipso). Addition reactions of electrophilic reagents to double and triple bonds followed by ring-cyclizations will be shown to yield relevant CF3S-substituted heteroaromatic compounds with relevant pharmacological action. PMID:27354317

  12. A Primate APOL1 Variant That Kills Trypanosoma brucei gambiense.

    PubMed

    Cooper, Anneli; Capewell, Paul; Clucas, Caroline; Veitch, Nicola; Weir, William; Thomson, Russell; Raper, Jayne; MacLeod, Annette

    2016-08-01

    Humans are protected against infection from most African trypanosomes by lipoprotein complexes present in serum that contain the trypanolytic pore-forming protein, Apolipoprotein L1 (APOL1). The human-infective trypanosomes, Trypanosoma brucei rhodesiense in East Africa and T. b. gambiense in West Africa have separately evolved mechanisms that allow them to resist APOL1-mediated lysis and cause human African trypanosomiasis, or sleeping sickness, in man. Recently, APOL1 variants were identified from a subset of Old World monkeys, that are able to lyse East African T. b. rhodesiense, by virtue of C-terminal polymorphisms in the APOL1 protein that hinder that parasite's resistance mechanism. Such variants have been proposed as candidates for developing therapeutic alternatives to the unsatisfactory anti-trypanosomal drugs currently in use. Here we demonstrate the in vitro lytic ability of serum and purified recombinant protein of an APOL1 ortholog from the West African Guinea baboon (Papio papio), which is able to lyse examples of all sub-species of T. brucei including T. b. gambiense group 1 parasites, the most common agent of human African trypanosomiasis. The identification of a variant of APOL1 with trypanolytic ability for both human-infective T. brucei sub-species could be a candidate for universal APOL1-based therapeutic strategies, targeted against all pathogenic African trypanosomes. PMID:27494254

  13. A Primate APOL1 Variant That Kills Trypanosoma brucei gambiense

    PubMed Central

    Cooper, Anneli; Capewell, Paul; Clucas, Caroline; Veitch, Nicola; Weir, William; Thomson, Russell; Raper, Jayne; MacLeod, Annette

    2016-01-01

    Humans are protected against infection from most African trypanosomes by lipoprotein complexes present in serum that contain the trypanolytic pore-forming protein, Apolipoprotein L1 (APOL1). The human-infective trypanosomes, Trypanosoma brucei rhodesiense in East Africa and T. b. gambiense in West Africa have separately evolved mechanisms that allow them to resist APOL1-mediated lysis and cause human African trypanosomiasis, or sleeping sickness, in man. Recently, APOL1 variants were identified from a subset of Old World monkeys, that are able to lyse East African T. b. rhodesiense, by virtue of C-terminal polymorphisms in the APOL1 protein that hinder that parasite’s resistance mechanism. Such variants have been proposed as candidates for developing therapeutic alternatives to the unsatisfactory anti-trypanosomal drugs currently in use. Here we demonstrate the in vitro lytic ability of serum and purified recombinant protein of an APOL1 ortholog from the West African Guinea baboon (Papio papio), which is able to lyse examples of all sub-species of T. brucei including T. b. gambiense group 1 parasites, the most common agent of human African trypanosomiasis. The identification of a variant of APOL1 with trypanolytic ability for both human-infective T. brucei sub-species could be a candidate for universal APOL1-based therapeutic strategies, targeted against all pathogenic African trypanosomes. PMID:27494254

  14. High Calcium (~80mol%) Late Stage Carbonate in ALH84001

    NASA Astrophysics Data System (ADS)

    Gildea, K. J.; Holland, G.; Lyon, I. C.; Chatzitheodoridis, E.; Burgess, R.

    2006-03-01

    Brief petrological, chemical and textural description of previously undescribed high Ca late stage carbonate in Martian meteorite ALH84001. This carbonate surrounds Mg rich carbonates and rosette fragments.

  15. Skull counting in late stages after internal contamination by actinides.

    PubMed

    Tani, Kotaro; Shutt, Arron; Kurihara, Osamu; Kosako, Toshiso

    2015-02-01

    Monitoring preparation for internal contamination with actinides (e.g. Pu and Am) is required to assess internal doses at nuclear fuel cycle-related facilities. In this paper, the authors focus on skull counting in case of single-incident inhalation of (241)Am and propose an effective procedure for skull counting with an existing system, taking into account the biokinetic behaviour of (241)Am in the human body. The predicted response of the system to skull counting under a certain counting geometry was found to be only ∼1.0 × 10(-5) cps Bq(-1) 1y after intake. However, this disadvantage could be remedied by repeated measurements of the skull during the late stage of the intake due to the predicted response reaching a plateau at about the 1000th day after exposure and exceeding that in the lung counting. Further studies are needed for the development of a new detection system with higher sensitivity to perform reliable internal dose estimations based on direct measurements. PMID:24920571

  16. [Report on l7 years of studies of human African trypanosomiasis caused by T. gambiense in children 0-6 years of age].

    PubMed

    Triolo, N; Trova, P; Fusco, C; Le Bras, J

    1985-01-01

    The authors present 227 cases of human African trypanosomiasis in children between 0 and 6 years, which have been observed for 17 years in the hyperendemic area of Fontem, Cameroon. These cases deal with a subject seldom described in medical literature. The authors especially insist on the velocity of both the contamination and involvement of the nervous system, as well as on the difficulty in settling a diagnosis when failing consider the notion of endemic area. On the other hand, they stress the fact that the efficiency of arsenical treatment is not more dangerous for children than for adults. Finally, they confirm the existence of congenital trypanosomiasis, which proves to be as important from the epidemiological point of view than from the strategical means to be used to identify this disease. PMID:4068971

  17. Late-stage clinical development in lower urogenital targets: sexual dysfunction

    PubMed Central

    Azam, Usman

    2006-01-01

    In recent years, late-stage clinical drug development that primarily focuses on urogenital targets has centered around four areas of medical need (both unmet need and aiming to improve on existing therapies). These include male sexual dysfunction (MSD), female sexual dysfunction (FSD), prostatic pathology (neoplastic, pre-neoplasitic, and non-neoplastic), and improvement in lower urinary tract symptoms. Despite the regulatory approval of compounds to treat erectile dysfunction (ED), benign prostatic hyperplasia, a number of treatments for overactive bladder, and stress urinary incontinence, there remains a deficiency in addressing a number of conditions that arise out of pathophysiological dysfunction resulting in lower urogenital tract sexual conditions. In terms of late-stage clinical development, significant progress has most recently been made in MSD development, especially in understanding further a common and complex sexual dysfunction – that of premature ejaculation. The search also continues for compounds that improve ED in terms of better efficacy and superior safety profile compared to the currently marketed phosphodiesterase-5-inhibitors. Whilst there are no approved medications to treat the subtypes of FSD, there has been significant progress in attempting to better understand how to appropriately assess treatment benefit in clinical trial settings for this difficult to diagnose and treat condition. This review will focus on late-stage human clinical development pertaining to MSD and FSD. PMID:16465180

  18. Functionalized Metallated Cavitands via Imidation and Late-Stage Elaboration

    PubMed Central

    Zhao, Yanchuan

    2015-01-01

    Efficient methods for the preparation of functionalized metallated cavitands are described. Functional groups can be either introduced by an imidation of metal-oxo complexes or by a late-stage elaboration of the imido ligands. By using diversified iminophosphorane (PPh3=NR) reagents, π-conjugated pyrene, redox active ferrocene and polymerizable norbornene moieties were successfully introduced. Furthermore, the iodo and alkynyl groups on the imido ligands are capable of undergoing efficient Sonogashira cross-coupling and copper-catalyzed azide alkyne cycloaddition reactions, thereby providing facile access to complex architectures containing metallated cavitands. PMID:26962300

  19. Middle-Aged More Often Diagnosed with Late-Stage Lung Cancer

    MedlinePlus

    ... Middle-Aged More Often Diagnosed With Late-Stage Lung Cancer British study highlights the need for better early ... more likely to be diagnosed with late-stage lung cancer than those who are slightly older, a new ...

  20. Genomic predictors for treatment of late stage prostate cancer.

    PubMed

    Shevrin, Daniel H

    2016-01-01

    In spite of the development of new treatments for late stage prostate cancer, significant challenges persist to match individuals with effective targeted therapies. Genomic classification using high-throughput sequencing technologies has the potential to achieve this goal and make precision medicine a reality in the management of men with castrate-resistant prostate cancer. This chapter reviews some of the most recent studies that have resulted in significant progress in determining the landscape of somatic genomic alterations in this cohort and, more importantly, have provided clinically actionable information that could guide treatment decisions. This chapter reviews the current understanding of common alterations such as alterations of the androgen receptor and PTEN pathway, as well as ETS gene fusions and the growing importance of PARP inhibition. It also reviews recent studies that characterize the evolution to neuroendocrine tumors, which is becoming an increasingly important clinical problem. Finally, this chapter reviews recent innovative studies that characterize the compelling evolutionary history of lethal prostate cancer evidenced by polyclonal seeding and interclonal cooperation between metastasis and the importance of tumor clone dynamics measured serially in response to treatment. The genomic landscape of late stage prostate cancer is becoming better defined, and the prospect for assigning clinically actionable data to inform rationale treatment for individuals with this disease is becoming a reality. PMID:27030083

  1. Genomic predictors for treatment of late stage prostate cancer

    PubMed Central

    Shevrin, Daniel H

    2016-01-01

    In spite of the development of new treatments for late stage prostate cancer, significant challenges persist to match individuals with effective targeted therapies. Genomic classification using high-throughput sequencing technologies has the potential to achieve this goal and make precision medicine a reality in the management of men with castrate-resistant prostate cancer. This chapter reviews some of the most recent studies that have resulted in significant progress in determining the landscape of somatic genomic alterations in this cohort and, more importantly, have provided clinically actionable information that could guide treatment decisions. This chapter reviews the current understanding of common alterations such as alterations of the androgen receptor and PTEN pathway, as well as ETS gene fusions and the growing importance of PARP inhibition. It also reviews recent studies that characterize the evolution to neuroendocrine tumors, which is becoming an increasingly important clinical problem. Finally, this chapter reviews recent innovative studies that characterize the compelling evolutionary history of lethal prostate cancer evidenced by polyclonal seeding and interclonal cooperation between metastasis and the importance of tumor clone dynamics measured serially in response to treatment. The genomic landscape of late stage prostate cancer is becoming better defined, and the prospect for assigning clinically actionable data to inform rationale treatment for individuals with this disease is becoming a reality. PMID:27030083

  2. Patellar tendinopathy: late-stage results from surgical treatment☆

    PubMed Central

    Cenni, Marcos Henrique Frauendorf; Silva, Thiago Daniel Macedo; do Nascimento, Bruno Fajardo; de Andrade, Rodrigo Cristiano; Júnior, Lúcio Flávio Biondi Pinheiro; Nicolai, Oscar Pinheiro

    2015-01-01

    Objective To evaluate the late-stage results from surgical treatment of patellar tendinopathy (PT), using the Visa score (Victorian Institute of Sport Tendon Study Group) and the Verheyden method. Methods This was a retrospective study in which the postoperative results from 12 patients (14 knees) who were operated between July 2002 and February 2011 were evaluated. The patients included in the study presented patellar tendinopathy that was refractory to conservative treatment, without any other concomitant lesions. Patients who were not properly followed up during the postoperative period were excluded. Results Using the Verheyden method, nine patients were considered to have very good results, two had good results and one had poor results. In relation to Visa, the mean was 92.4 points and only two patients had scores less than 70 points (66 and 55 points). Conclusion When surgical treatment for patellar tendinopathy is correctly indicated, it has good long-term results. PMID:26535202

  3. Late stage modification of receptors identified from dynamic combinatorial libraries.

    PubMed

    Pinkin, Nicholas K; N Power, Amanie; Waters, Marcey L

    2015-11-28

    Small molecule receptors are attractive potential sensors of post-translational modifications, including methylated lysine and methylated arginine. Using dynamic combinatorial chemistry (DCC), our lab previously identified a suite of receptors that bind to Kme3 with a range of affinities ranging from low micromolar to high nanomolar, each with a unique selectivity for Kme3 over the lower methylation states. To enable these receptors to have broad application as Kme3 sensors, we have developed a method for their late-stage modification, which we used to synthesize biotinylated derivatives of A2B, A2D, and A2G in a single step. For our most attractive receptor for applications, A2N, we needed to develop an alternative method for its selective functionalization, which we achieved by "activating" the carboxylic acids on the constituent monomer A or N by pre-functionalizing them with glycine (Gly). Using the resulting Gly-A and Gly-N monomers, we synthesized the novel A2N variants A2Gly-N, Gly-A2N, and Gly-A2Gly-N, which enabled the late stage biotinylation of A2N wherever Gly was incorporated. Finally, we performed ITC and NMR binding experiments to study the effect that carboxylate spacing has on the affinity and selectivity of A2Gly-N and Gly-A2N for KmeX guests compared to A2N. These studies revealed the proximity of the carboxylates to play a complex role in the molecular recognition event, despite their positioning on the outside of the receptor. PMID:26384269

  4. Trypanosoma brucei gambiense Infections in Mice Lead to Tropism to the Reproductive Organs, and Horizontal and Vertical Transmission

    PubMed Central

    Biteau, Nicolas; Asencio, Corinne; Izotte, Julien; Rousseau, Benoit; Fèvre, Muriel; Pillay, Davita; Baltz, Théo

    2016-01-01

    Trypanosoma brucei gambiense, transmitted by the tsetse fly, is the main causative agent of Human African trypanosomosis in West Africa and poses a significant health risk to 70 million people. Disease progression varies depending on host immunity, but usually begins with a haemo-lymphatic phase, followed by parasite invasion of the central nervous system. In the current study, the tropism of T. b. gambiense 1135, causing a low level chronic ‘silent’ infection, was monitored in a murine model using bioluminescence imaging and PCR. A tropism to the reproductive organs, in addition to the central nervous system, after 12–18 months of infection was observed. Bioluminescent analysis of healthy females crossed with infected males showed that 50%, 62.5% and 37.5% of the female mice were subsequently positive for parasites in their ovaries, uteri and brain respectively. Although PCR confirmed the presence of parasites in the uterus of one of these mice, the blood of all mice was negative by PCR and LAMP. Subsequently, bioluminescent imaging of the offspring of infected female mice crossed with healthy males indicated parasites were present in the reproductive organs of both male (80%) and female (60%) offspring. These findings imply that transmission of T. b. gambiense 1135 occurs horizontally, most probably via sexual contact, and vertically in a murine model, which raises the possibility of a similar transmission in humans. This has wide reaching implications. Firstly, the observations made in this study are likely to be valid for wild animals acting as a reservoir for T. b. gambiense. Also, the reproductive organs may act as a refuge for parasites during drug treatment in a similar manner to the central nervous system. This could leave patients at risk of a relapse, ultimately allowing them to act as a reservoir for subsequent transmission by tsetse and possibly, horizontally and vertically. PMID:26735855

  5. Trypanosoma brucei gambiense Infections in Mice Lead to Tropism to the Reproductive Organs, and Horizontal and Vertical Transmission.

    PubMed

    Biteau, Nicolas; Asencio, Corinne; Izotte, Julien; Rousseau, Benoit; Fèvre, Muriel; Pillay, Davita; Baltz, Théo

    2016-01-01

    Trypanosoma brucei gambiense, transmitted by the tsetse fly, is the main causative agent of Human African trypanosomosis in West Africa and poses a significant health risk to 70 million people. Disease progression varies depending on host immunity, but usually begins with a haemo-lymphatic phase, followed by parasite invasion of the central nervous system. In the current study, the tropism of T. b. gambiense 1135, causing a low level chronic 'silent' infection, was monitored in a murine model using bioluminescence imaging and PCR. A tropism to the reproductive organs, in addition to the central nervous system, after 12-18 months of infection was observed. Bioluminescent analysis of healthy females crossed with infected males showed that 50%, 62.5% and 37.5% of the female mice were subsequently positive for parasites in their ovaries, uteri and brain respectively. Although PCR confirmed the presence of parasites in the uterus of one of these mice, the blood of all mice was negative by PCR and LAMP. Subsequently, bioluminescent imaging of the offspring of infected female mice crossed with healthy males indicated parasites were present in the reproductive organs of both male (80%) and female (60%) offspring. These findings imply that transmission of T. b. gambiense 1135 occurs horizontally, most probably via sexual contact, and vertically in a murine model, which raises the possibility of a similar transmission in humans. This has wide reaching implications. Firstly, the observations made in this study are likely to be valid for wild animals acting as a reservoir for T. b. gambiense. Also, the reproductive organs may act as a refuge for parasites during drug treatment in a similar manner to the central nervous system. This could leave patients at risk of a relapse, ultimately allowing them to act as a reservoir for subsequent transmission by tsetse and possibly, horizontally and vertically. PMID:26735855

  6. Loop Mediated Isothermal Amplification for Detection of Trypanosoma brucei gambiense in Urine and Saliva Samples in Nonhuman Primate Model

    PubMed Central

    Ngotho, Maina; Kagira, John Maina; Gachie, Beatrice Muthoni; Karanja, Simon Muturi; Waema, Maxwell Wambua; Maranga, Dawn Nyawira; Maina, Naomi Wangari

    2015-01-01

    Human African trypanosomiasis (HAT) is a vector-borne parasitic zoonotic disease. The disease caused by Trypanosoma brucei gambiense is the most prevalent in Africa. Early diagnosis is hampered by lack of sensitive diagnostic techniques. This study explored the potential of loop mediated isothermal amplification (LAMP) and polymerase chain reaction (PCR) in the detection of T. b. gambiense infection in a vervet monkey HAT model. Six vervet monkeys were experimentally infected with T. b. gambiense IL3253 and monitored for 180 days after infection. Parasitaemia was scored daily. Blood, cerebrospinal fluid (CSF), saliva, and urine samples were collected weekly. PCR and LAMP were performed on serum, CSF, saliva, and urine samples. The detection by LAMP was significantly higher than that of parasitological methods and PCR in all the samples. The performance of LAMP varied between the samples and was better in serum followed by saliva and then urine samples. In the saliva samples, LAMP had 100% detection between 21 and 77 dpi, whereas in urine the detection it was slightly lower, but there was over 80% detection between 28 and 91 dpi. However, LAMP could not detect trypanosomes in either saliva or urine after 140 and 126 dpi, respectively. The findings of this study emphasize the importance of LAMP in diagnosis of HAT using saliva and urine samples. PMID:26504841

  7. [Ethical and legal issues in late stage of dementia].

    PubMed

    Fernandes, Lia

    2008-01-01

    As we enter the 21st century, growth of the elderly population, the costs of care, and the advances of medical science and technology will continue to have an impact on the patient-physician relationship. Transformation of the health care system will also raise ethical issues inherent to changing roles. The special nature of Alzheimer's patients and the natural course of their disease require special care on the part of physicians to meet the ethical challenges and establish medical goals, in conjunction with their patients and their families. In spite of these rapid advances in biomedical sciences, were not sufficiently developed in the most fitness answers, regarding special moral and ethical attitudes, which must be taken into account, in particular when we try to understand the experience of people with dementia. This article explores emerging issues in relation to awareness in dementia and its impact on legal and ethical matters. The different approaches and principles demonstrated in relation to ethical issues are discussed, with an exploration of the concepts of mental capacity, testamentary capacity, power of attorney, court of protection, advance directives, decision making, participation in research and treatment, informed consent and older people driving. The tensions that exist between the imperatives of doing no harm and of maintaining autonomy in addressing legal and ethical issues are highlighted. The review emphasizes the importance of considering competency and awareness as being multi-faceted, to be understood in the context of social interaction, trying to deal with the challenge of protecting, but not overprotecting, people with dementia. Late stage of dementia is a terminal disease where the goal of the care may not be prolongation of life at all costs, but rather achievement: quality of life, dignity and comfort. In the initial late dementia, quality of life is the target, treating medical problems and psychiatric symptoms. The dignity of

  8. Placental transport of lindane during early and late stages of gestation in rats

    SciTech Connect

    Khanna, R.N.; Kunwar, K.; Gupta, R.; Gupta, G.S.D. )

    1991-10-01

    Lindane (gamma-isomer of hexachlorocyclohexane, gamma-HCH), an organochlorine pesticide, is widely used as an agricultural pesticide especially in developing countries. Human exposure is likely because of its use in some pharmaceutical preparations and in public health for pest control purpose. It has been detected in human milk and fat samples in India and in many developed countries. The accumulation of lindane over a long period in fat samples and its presence in milk suggests that the human fetus may be exposed to lindane at some time during gestation from the maternal tissue stores. The present study was, therefore, undertaken to determine the placental transfer of lindane in rats during early and late stages of gestation.

  9. Capitellocondylar total elbow replacement in late-stage rheumatoid arthritis.

    PubMed

    Ovesen, Janne; Olsen, Bo Sanderhoff; Johannsen, Hans Viggo; Søjbjerg, Jens Ole

    2005-01-01

    Between 1994 and 2000, 51 capitellocondylar elbow replacements were inserted in 41 patients. All patients had late-stage rheumatoid arthritis. The mean age at operation was 56 years (range, 25-78 years). There were 12 men and 29 women. At follow-up, 6 patients had died of unrelated causes with the implant in situ and without radiographic loosening, and 1 patient was lost to follow-up. The remaining 43 elbows in 34 patients were followed up clinically and radiographically at a mean of 6.9 years (range, 26-119 months). Relief of pain was complete in 91% of the surviving elbows, and in 9%, there was only mild pain. Pain-free range of motion at follow-up was significantly improved. Flexion increased a mean of 43 degrees ; extension, 16 degrees ; supination, 24 degrees and pronation, 26 degrees . Of the elbows, 7 underwent revision, 3 because of deep infection, 1 for aseptic loosening, and 3 because of instability. Other complications included 2 maltracking elbows, 2 triceps tendon ruptures, 2 cases of operative olecranon bursitis, and 2 ulnar nerve palsies. One elbow showed radiolucent lines of more than 1 mm in the circumference of the ulnar component; none of the other elbows showed any signs of progressive radiographic loosening. At a mean follow-up of 6.9 years, a functional prosthesis was retained in 82.7% of the elbows, and the mean survival of the implant was 8.6 years (95% CI, 7.8-9.5 years). PMID:16015242

  10. Trypanosome-induced Interferon-γ production in whole blood stimulation assays is associated with latent Trypanosoma brucei gambiense infections.

    PubMed

    Ilboudo, Hamidou; Jamonneau, Vincent; Koffi, Mathurin; Kaboré, Jacques; Amoussa, Roukiyath; Holzmuller, Philippe; Garcia, André; Bucheton, Bruno; Courtin, David

    2016-06-01

    Control of human African trypanosomiasis (HAT) is highly dependent on the ability to detect and treat infected individuals. However, a number of individuals exposed to Trypanosoma brucei gambiense are able to control infection to undetectable levels in blood. They are long-term potential reservoirs and thus a threat for control strategies. Cytokine responses in whole blood stimulation assays were quantified in individuals with contrasting HAT status. Trypanosome-induced IFN-γ production was only observed in "trypanotolerant" subjects suspected of harboring latent infections. This result contributes new insights into the immune responses associated with infection control and opens novel diagnosis perspectives regarding HAT elimination. PMID:26993030

  11. A single amino acid substitution in the group 1 Trypanosoma brucei gambiense haptoglobin-hemoglobin receptor abolishes TLF-1 binding.

    PubMed

    DeJesus, E; Kieft, R; Albright, B; Stephens, N A; Hajduk, S L

    2013-01-01

    Critical to human innate immunity against African trypanosomes is a minor subclass of human high-density lipoproteins, termed Trypanosome Lytic Factor-1 (TLF-1). This primate-specific molecule binds to a haptoglobin-hemoglobin receptor (HpHbR) on the surface of susceptible trypanosomes, initiating a lytic pathway. Group 1 Trypanosoma brucei gambiense causes human African Trypanosomiasis (HAT), escaping TLF-1 killing due to reduced uptake. Previously, we found that group 1 T. b. gambiense HpHbR (TbgHpHbR) mRNA levels were greatly reduced and the gene contained substitutions within the open reading frame. Here we show that a single, highly conserved amino acid in the TbgHpHbR ablates high affinity TLF-1 binding and subsequent endocytosis, thus evading TLF-1 killing. In addition, we show that over-expression of TbgHpHbR failed to rescue TLF-1 susceptibility. These findings suggest that the single substitution present in the TbgHpHbR directly contributes to the reduced uptake and resistance to TLF-1 seen in these important human pathogens. PMID:23637606

  12. A Single Amino Acid Substitution in the Group 1 Trypanosoma brucei gambiense Haptoglobin-Hemoglobin Receptor Abolishes TLF-1 Binding

    PubMed Central

    DeJesus, E.; Kieft, R.; Albright, B.; Stephens, N. A.; Hajduk, S. L.

    2013-01-01

    Critical to human innate immunity against African trypanosomes is a minor subclass of human high-density lipoproteins, termed Trypanosome Lytic Factor-1 (TLF-1). This primate-specific molecule binds to a haptoglobin-hemoglobin receptor (HpHbR) on the surface of susceptible trypanosomes, initiating a lytic pathway. Group 1 Trypanosoma brucei gambiense causes human African Trypanosomiasis (HAT), escaping TLF-1 killing due to reduced uptake. Previously, we found that group 1 T. b. gambiense HpHbR (TbgHpHbR) mRNA levels were greatly reduced and the gene contained substitutions within the open reading frame. Here we show that a single, highly conserved amino acid in the TbgHpHbR ablates high affinity TLF-1 binding and subsequent endocytosis, thus evading TLF-1 killing. In addition, we show that over-expression of TbgHpHbR failed to rescue TLF-1 susceptibility. These findings suggest that the single substitution present in the TbgHpHbR directly contributes to the reduced uptake and resistance to TLF-1 seen in these important human pathogens. PMID:23637606

  13. Expression of Trypanosoma brucei gambiense Antigens in Leishmania tarentolae. Potential for Use in Rapid Serodiagnostic Tests (RDTs)

    PubMed Central

    Rooney, Barrie; Piening, Turid; Büscher, Philippe; Rogé, Stijn; Smales, C. Mark

    2015-01-01

    The development of rapid serodiagnostic tests for sleeping sickness and other diseases caused by kinetoplastids relies on the affordable production of parasite-specific recombinant antigens. Here, we describe the production of recombinant antigens from Trypanosoma brucei gambiense (T.b. gambiense) in the related species Leishmania tarentolae (L. tarentolae), and compare their diagnostic sensitivity and specificity to native antigens currently used in diagnostic kits against a panel of human sera. A number of T.b. gambiense protein antigen candidates were chosen for recombinant expression in L. tarentolae based on current diagnostics in field use and recent findings on immunodiagnostic antigens found by proteomic profiling. In particular, the extracellular domains of invariant surface glycoprotein 65 (ISG65), variant surface glycoproteins VSG LiTat 1.3 and VSG LiTat 1.5 were fused with C-terminal histidine tags and expressed as soluble proteins in the medium of cultured, recombinant L. tarentolae. Using affinity chromatography, on average 10 mg/L of recombinant protein was purified from cultures and subsequently tested against a panel of sera from sleeping sickness patients from controls, i.e. persons without sleeping sickness living in HAT endemic countries. The evaluation on sera from 172 T.b. gambiense human African trypanosomiasis (HAT) patients and from 119 controls showed very high diagnostic potential of the two recombinant VSG and the rISG65 fragments with areas under the curve between 0.97 and 0.98 compared to 0.98 and 0.99 with native VSG LiTat 1.3 and VSG LiTat 1.5 (statistically not different). Evaluation on sera from 78 T.b. rhodesiense HAT patients and from 100 controls showed an acceptable diagnostic potential of rISG65 with an area under the curve of 0.83. These results indicate that a combination of these recombinant antigens has the potential to be used in next generation rapid serodiagnostic tests. In addition, the L. tarentolae expression system

  14. Imagable 4T1 model for the study of late stage breast cancer

    PubMed Central

    Tao, Kai; Fang, Min; Alroy, Joseph; Sahagian, G Gary

    2008-01-01

    Background The 4T1 mouse mammary tumor cell line is one of only a few breast cancer models with the capacity to metastasize efficiently to sites affected in human breast cancer. Here we describe two 4T1 cell lines modified to facilitate analysis of tumor growth and metastasis and evaluation of gene function in vivo. New information regarding the involvement of innate and acquired immunity in metastasis and other characteristics of the model relevant to its use in the study of late stage breast cancer are reported. Methods The lines were engineered for stable expression of firefly luciferase to allow tracking and quantitation of the cells in vivo. Biophotonic imaging was used to characterize growth and metastasis of the lines in vivo and an improved gene expression approach was used to characterize the basis for the metastatic phenotype that was observed. Results Growth of cells at the primary site was biphasic with metastasis detected during the second growth phase 5–6 weeks after introduction of the cells. Regression of growth, which occurred in weeks 3–4, was associated with extensive necrosis and infiltration of leukocytes. Biphasic tumor growth did not occur in BALB/c SCID mice indicating involvement of an acquired immune response in the effect. Hematopoiesis in spleen and liver and elevated levels of circulating leukocytes were observed at week 2 and increased progressively until death at week 6–8. Gene expression analysis revealed an association of several secreted factors including colony stimulatory factors, cytokines and chemokines, acute phase proteins, angiogenesis factors and ECM modifying proteins with the 4T1 metastatic phenotype. Signaling pathways likely to be responsible for production of these factors were also identified. Conclusion The production of factors that stimulate angiogenesis and ECM modification and induce hematopoiesis, recruitment and activation of leukocytes suggest that 4T1 tumor cells play a more direct role than previously

  15. Changes in the corpus callosum in women with late-stage bipolar disorder

    PubMed Central

    Lavagnino, Luca; Cao, Bo; Mwangi, Benson; Wu, Mon-Ju; Sanches, Marsal; Zunta-Soares, Giovana B; Kapczinski, Flavio; Soares, Jair

    2015-01-01

    Objective The present study investigated the differences in corpus callosum (CC) volumes between women with early stage and late stage bipolar I (BP I) disorder using the criteria previously described in the literature. Method We compared women with early and late stage BP I using criteria described in the Staging Systems Task Force Report of the International Society for Bipolar Disorders. We included 20 patients with early stage and 21 patients with late stage BP Iand a group of 25 healthy controls. Patients and controls underwent structural magnetic resonance imaging. Information on the clinical features of bipolar disorder was collected using a standardized questionnaire. Anatomical volumes of 5 regions of CC were compared between the three groups. Results Women with late-stage BP I disorder had reduced posterior CC volumes compared to early stage bipolar I patients and controls (F=6.05; P=0.004). The difference was significant after controlling for age, comorbidity with post-traumatic stress disorder, psychotic symptoms during mood episodes, and current use of medication. Conclusion The posterior CC was significantly decreased in volume in women with late-stage bipolar disorder. These findings suggest that CC may be an anatomical target of neuroprogression in the course of bipolar disorder in women. PMID:25640667

  16. In vitro investigation of Brazilian Cerrado plant extract activity against Plasmodium falciparum, Trypanosoma cruzi and T. brucei gambiense.

    PubMed

    Charneau, Sébastien; de Mesquita, Mariana Laundry; Bastos, Izabela Marques Dourado; Santana, Jaime Martins; de Paula, José Elias; Grellier, Philippe; Espindola, Laila Salmen

    2016-06-01

    The threatened Brazilian Cerrado biome is an important biodiversity hotspot but still few explored that constitutes a potential reservoir of molecules to treat infectious diseases. We selected eight Cerrado plant species for screening against the erythrocytic stages of Plasmodium falciparum, human intracellular stages of Trypanosoma cruzi and bloodstream forms of T. brucei gambiense, and for their cytotoxicity upon the rat L6-myoblast cell line. Bioassays were performed with 37 hexane, ethyl acetate and ethanol extracts prepared from different plant organs. Activities against parasites were observed for 24 extracts: 9 with anti-P. falciparum, 4 with anti-T. cruzi and 11 with anti-T. brucei gambiense activities. High anti-protozoal activity (IC50 values < 10 μg/mL) without obvious cytotoxicity to L6 cells was observed for eight extracts from plants: Connarus suberosus, Blepharocalyx salicifolius, Psidium laruotteanum and Myrsine guianensis. Overall, studies of plant extracts will contribute to increase the biodiversity knowledge essential for Cerrado conservation and sustainable development. PMID:26222897

  17. Screening of Trypanosoma brucei gambiense in Domestic Livestock and Tsetse Flies from an Insular Endemic Focus (Luba, Equatorial Guinea)

    PubMed Central

    Cordon-Obras, Carlos; García-Estébanez, Carmen; Ndong-Mabale, Nicolás; Abaga, Simón; Ndongo-Asumu, Pedro; Benito, Agustín; Cano, Jorge

    2010-01-01

    Background Sleeping sickness is spread over 36 Sub-Saharan African countries. In West and Central Africa, the disease is caused by Trypanosoma brucei gambiense, which produces a chronic clinical manifestation. The Luba focus (Bioko Island, Equatorial Guinea) has not reported autochthonous sleeping sickness cases since 1995, but given the complexity of the epidemiological cycle, the elimination of the parasite in the environment is difficult to categorically ensure. Methodology/Principal Findings The aim of this work is to assess, by a molecular approach (Polymerase Chain Reaction, PCR), the possible permanence of T. b. gambiense in the vector (Glossina spp.) and domestic fauna in order to improve our understanding of the epidemiological situation of the disease in an isolated focus considered to be under control. The results obtained show the absence of the parasite in peridomestic livestock but its presence, although at very low rate, in the vector. On the other hand, interesting entomological data highlight that an elevated concentration of tsetse flies was observed in two out of the ten villages considered to be in the focus. Conclusions These findings demonstrate that even in conditions of apparent control, a complete parasite clearance is difficult to achieve. Further investigations must be focused on animal reservoirs which could allow the parasites to persist without leading to human cases. In Luba, where domestic livestock are scarcer than other foci in mainland Equatorial Guinea, the epidemiological significance of wild fauna should be assessed to establish their role in the maintenance of the infection. PMID:20544031

  18. Implications of Heterogeneous Biting Exposure and Animal Hosts on Trypanosomiasis brucei gambiense Transmission and Control.

    PubMed

    Stone, Chris M; Chitnis, Nakul

    2015-10-01

    The gambiense form of sleeping sickness is a neglected tropical disease, which is presumed to be anthroponotic. However, the parasite persists in human populations at levels of considerable rarity and as such the existence of animal reservoirs has been posited. Clarifying the impact of animal host reservoirs on the feasibility of interrupting sleeping sickness transmission through interventions is a matter of urgency. We developed a mathematical model allowing for heterogeneous exposure of humans to tsetse, with animal populations that differed in their ability to transmit infections, to investigate the effectiveness of two established techniques, screening and treatment of at-risk populations, and vector control. Importantly, under both assumptions, an integrated approach of human screening and vector control was supported in high transmission areas. However, increasing the intensity of vector control was more likely to eliminate transmission, while increasing the intensity of human screening reduced the time to elimination. Non-human animal hosts played important, but different roles in HAT transmission, depending on whether or not they contributed as reservoirs. If they did not serve as reservoirs, sensitivity analyses suggested their attractiveness may instead function as a sink for tsetse bites. These outcomes highlight the importance of understanding the ecological and environmental context of sleeping sickness in optimizing integrated interventions, particularly for moderate and low transmission intensity settings. PMID:26426854

  19. Implications of Heterogeneous Biting Exposure and Animal Hosts on Trypanosomiasis brucei gambiense Transmission and Control

    PubMed Central

    Stone, Chris M.; Chitnis, Nakul

    2015-01-01

    The gambiense form of sleeping sickness is a neglected tropical disease, which is presumed to be anthroponotic. However, the parasite persists in human populations at levels of considerable rarity and as such the existence of animal reservoirs has been posited. Clarifying the impact of animal host reservoirs on the feasibility of interrupting sleeping sickness transmission through interventions is a matter of urgency. We developed a mathematical model allowing for heterogeneous exposure of humans to tsetse, with animal populations that differed in their ability to transmit infections, to investigate the effectiveness of two established techniques, screening and treatment of at-risk populations, and vector control. Importantly, under both assumptions, an integrated approach of human screening and vector control was supported in high transmission areas. However, increasing the intensity of vector control was more likely to eliminate transmission, while increasing the intensity of human screening reduced the time to elimination. Non-human animal hosts played important, but different roles in HAT transmission, depending on whether or not they contributed as reservoirs. If they did not serve as reservoirs, sensitivity analyses suggested their attractiveness may instead function as a sink for tsetse bites. These outcomes highlight the importance of understanding the ecological and environmental context of sleeping sickness in optimizing integrated interventions, particularly for moderate and low transmission intensity settings. PMID:26426854

  20. Reorganization of Nuclear Pore Complexes and the Lamina in Late-Stage Parvovirus Infection.

    PubMed

    Mäntylä, Elina; Niskanen, Einari A; Ihalainen, Teemu O; Vihinen-Ranta, Maija

    2015-11-01

    Canine parvovirus (CPV) infection induces reorganization of nuclear structures. Our studies indicated that late-stage infection induces accumulation of nuclear pore complexes (NPCs) and lamin B1 concomitantly with a decrease of lamin A/C levels on the apical side of the nucleus. Newly formed CPV capsids are located in close proximity to NPCs on the apical side. These results suggest that parvoviruses cause apical enrichment of NPCs and reorganization of nuclear lamina, presumably to facilitate the late-stage infection. PMID:26311881

  1. Reorganization of Nuclear Pore Complexes and the Lamina in Late-Stage Parvovirus Infection

    PubMed Central

    Mäntylä, Elina; Niskanen, Einari A.; Ihalainen, Teemu O.

    2015-01-01

    Canine parvovirus (CPV) infection induces reorganization of nuclear structures. Our studies indicated that late-stage infection induces accumulation of nuclear pore complexes (NPCs) and lamin B1 concomitantly with a decrease of lamin A/C levels on the apical side of the nucleus. Newly formed CPV capsids are located in close proximity to NPCs on the apical side. These results suggest that parvoviruses cause apical enrichment of NPCs and reorganization of nuclear lamina, presumably to facilitate the late-stage infection. PMID:26311881

  2. Identification of miR-1 as a micro RNA that supports late-stage differentiation of growth cartilage cells.

    PubMed

    Sumiyoshi, Kumi; Kubota, Satoshi; Ohgawara, Toshihiro; Kawata, Kazumi; Nishida, Takashi; Shimo, Tsuyoshi; Yamashiro, Takashi; Takigawa, Masaharu

    2010-11-12

    The process of endochondral ossification is strictly regulated by a variety of extracellular and intracellular factors. Recently, it has become recognized that specific miRNAs are involved in this process by regulating the expression of the relevant genes at the post-transcriptional level. In this present study we obtained the first evidence of the involvement of a specific micro RNA (miRNA) in the regulation of the chondrocyte phenotype during late stages of differentiation. By use of the microarray technique, miR-1 was identified as this miRNA, the expression of which was most repressed upon hypertrophic differentiation. Transfection of human chondrocytic HCS-2/8 cells and chicken normal chondrocytes with miR-1 led to repressed expression of aggrecan, the major cartilaginous proteoglycan gene. Therefore, miR-1 was found to be involved in the regulation of the chondrocytic phenotype and thus to play an important role in chondrocytes during the late stage of the differentiation process, maintaining the integrity of the cartilage tissue. PMID:20937250

  3. Art in Alzheimer's care: promoting well-being in people with late-stage Alzheimer's disease.

    PubMed

    Walsh, Sandra M; Lamet, Ann R; Lindgren, Carolyn L; Rillstone, Pam; Little, Daniel J; Steffey, Christine M; Rafalko, Sharon Y; Sonshine, Rosanne

    2011-01-01

    The purpose of this qualitative study was to explore the responses of people with late-stage Alzheimer's disease (AD) to a creative bonding intervention (CBI). The CBI consisted of simple art activities. Guided by Reed's self-transcendence theory, research questions were "Will persons with late-stage AD show evidence of self-transcendence during the CBI?" and "Will persons with late-stage AD show evidence of well-being during the CBI?" Twelve CBI sessions, documented by videotape and field notes, were conducted with four participants. Themes emerged within two clusters: trusting/thirsting/following and choosing/connecting/reminiscing. An overarching category of "cocooning" described participants' world during the CBI as they displayed evidence of self-transcendence and well-being. The CBI is a strategy that can be implemented by staff families, and volunteers. Nurses are positioned to provide transformation leadership for implementation of creative approaches during care of people with late-stage AD, but administrative and financial support are needed. PMID:21473563

  4. Noradrenergic Action in Prefrontal Cortex in the Late Stage of Memory Consolidation

    ERIC Educational Resources Information Center

    Tronel, Sophie; Feenstra, Matthijs G. P.; Sara, Susan J.

    2004-01-01

    These experiments investigated the role of the noradrenergic system in the late stage of memory consolidation and in particular its action at beta receptors in the prelimbic region (PL) of the prefrontal cortex in the hours after training. Rats were trained in a rapidly acquired, appetitively motivated foraging task based on olfactory…

  5. Chemotherapy for Late-Stage Cancer Patients: Meta-Analysis of Complete Response Rates

    PubMed Central

    Ashdown, Martin L.; Robinson, Andrew P.; Yatomi-Clarke, Steven L.; Ashdown, M. Luisa; Allison, Andrew; Abbott, Derek; Markovic, Svetomir N.; Coventry, Brendon J.

    2015-01-01

    Complete response (CR) rates reported for cytotoxic chemotherapy for late-stage cancer patients are generally low, with few exceptions, regardless of the solid cancer type or drug regimen. We investigated CR rates reported in the literature for clinical trials using chemotherapy alone, across a wide range of tumour types and chemotherapeutic regimens, to determine an overall CR rate for late-stage cancers. A total of 141 reports were located using the PubMed database. A meta-analysis was performed of reported CR from 68 chemotherapy trials (total 2732 patients) using standard agents across late-stage solid cancers—a binomial model with random effects was adopted. Mean CR rates were compared for different cancer types, and for chemotherapeutic agents with different mechanisms of action, using a logistic regression. Our results showed that the CR rates for chemotherapy treatment of late-stage cancer were generally low at 7.4%, regardless of the cancer type or drug regimen used. We found no evidence that CR rates differed between different chemotherapy drug types, but amongst different cancer types small CR differences were evident, although none exceeded a mean CR rate of 11%. This remarkable concordance of CR rates regardless of cancer or therapy type remains currently unexplained, and motivates further investigation. PMID:26834979

  6. Middle-Aged More Often Diagnosed with Late-Stage Lung Cancer

    MedlinePlus

    ... Middle-Aged More Often Diagnosed With Late-Stage Lung Cancer British study highlights the need for better early detection, researchers say To use the sharing features on this page, please enable JavaScript. (*this news item will not ...

  7. Familial aggregation of Trypanosoma brucei gambiense trypanosomiasis in a very high incidence community in Zaire.

    PubMed

    Khonde, N; Pépin, J; Niyonsenga, T; De Wals, P

    1997-01-01

    Familial aggregation of Trypanosoma brucei gambiense human African trypanosomiasis (HAT) was investigated in 3 adjacent villages of central Zaire where 318/1431 inhabitants had previously suffered from HAT. Neither spatial nor familial aggregation was detected when analysing the distribution of cases in the whole community using Poisson, negative binomial and pairwise odds ratio models. However, clustering of cases was observed when specific familial relationships were examined. The risk of HAT for a child was significantly increased if the mother had also had HAT, but it was not influenced by a past history of HAT in the father. Sisters and brothers of cases of HAT had a higher risk of HAT than siblings of individuals who had never had HAT, but no such association was documented for half-sisters and half-brothers. Among married couples, a past history of HAT in one spouse had no impact on the other spouse's risk of HAT. Indirect arguments suggested that familial clustering was a consequence of shared exposure, either sequential or simultaneous, rather than of genetic susceptibility. The existence of familial clustering should be kept in mind when implementing passive or active case-finding activities. PMID:9463655

  8. Late Stage Freiberg Infraction in a Division I Collegiate Tennis Player

    PubMed Central

    Faircloth, Johnnie; Mitchell, Jennifer J; Edwards, David S

    2015-01-01

    Introduction: Freiberg infraction is a relatively rare osteochondrosis of the metatarsal head. The etiology of Freiberg infraction is poorly understood but likely involves factors such as, repetitive trauma and vascular compromise. When discovered early, Freiberg infraction can be cured with conservative measures but late presentations require surgical intervention. We present a case of stage V Freiberg infraction in a Division I collegiate tennis player that responded to conservative treatment. Case Report: A 20 year old female tennis player presented with worsening of her chronic foot pain. She had tenderness to palpation and diminished range of motion at the second metatarsophalangeal joint. Radiographs revealed late stage Freiberg infraction of the second metatarsal. This patient’s pain was successfully treated with conservative measures; prolonging her collegiate tennis career. Conclusion: Surgical intervention is required for definitive treatment of late stage Freiberg infraction. Conservative treatment can be effective in prolonging the athlete’s career. PMID:27299057

  9. Synthesis of highly functionalized oligobenzamide proteomimetic foldamers by late stage introduction of sensitive groups.

    PubMed

    Burslem, George M; Kyle, Hannah F; Prabhakaran, Panchami; Breeze, Alexander L; Edwards, Thomas A; Warriner, Stuart L; Nelson, Adam; Wilson, Andrew J

    2016-04-12

    α-Helix proteomimetics represent an emerging class of ligands that can be used to inhibit an array of helix mediated protein-protein interactions. Within this class of inhibitor, aromatic oligobenzamide foldamers have been widely and successfully used. This manuscript describes alternative syntheses of these compounds that can be used to access mimetics that are challenging to synthesize using previously described methodologies, permitting access to compounds functionalized with multiple sensitive side chains and accelerated library assembly through late stage derivatisation. PMID:27005701

  10. Distinct Signaling Requirements for the Establishment of ESC Pluripotency in Late-Stage EpiSCs

    PubMed Central

    Illich, Damir Jacob; Zhang, Miao; Ursu, Andrei; Osorno, Rodrigo; Kim, Kee-Pyo; Yoon, Juyong; Araúzo-Bravo, Marcos J.; Wu, Guangming; Esch, Daniel; Sabour, Davood; Colby, Douglas; Grassme, Kathrin S.; Chen, Jiayu; Greber, Boris; Höing, Susanne; Herzog, Wiebke; Ziegler, Slava; Chambers, Ian; Gao, Shaorong; Waldmann, Herbert; Schöler, Hans R.

    2016-01-01

    Summary It has previously been reported that mouse epiblast stem cell (EpiSC) lines comprise heterogeneous cell populations that are functionally equivalent to cells of either early- or late-stage postimplantation development. So far, the establishment of the embryonic stem cell (ESC) pluripotency gene regulatory network through the widely known chemical inhibition of MEK and GSK3beta has been impractical in late-stage EpiSCs. Here, we show that chemical inhibition of casein kinase 1alpha (CK1alpha) induces the conversion of recalcitrant late-stage EpiSCs into ESC pluripotency. CK1alpha inhibition directly results in the simultaneous activation of the WNT signaling pathway, together with inhibition of the TGFbeta/SMAD2 signaling pathway, mediating the rewiring of the gene regulatory network in favor of an ESC-like state. Our findings uncover a molecular mechanism that links CK1alpha to ESC pluripotency through the direct modulation of WNT and TGFbeta signaling. PMID:27149845

  11. On the transition of base flow recession from early stage to late stage

    NASA Astrophysics Data System (ADS)

    Ghosh, Debapi K.; Wang, Dingbao; Zhu, Tingju

    2016-02-01

    This paper is focused on the transition of base flow recession from early stage to late stage. The volume flow rate that takes place when such a transition occurs is identified for each of the twenty-three recession events observed at the Panola Mountain Research Watershed (PMRW) in Georgia, USA, using a newly developed cumulative regression analysis method. Meanwhile, the flow at the watershed outlet, which was recorded when the discharge at the perennial stream head diminishes to zero, is identified for each recession event. As evidenced by a correlation coefficient of 0.90, these two characteristic flows are found to be highly correlated, suggesting a fundamental linkage between the transition of base flow recession from early stage to late stage and the drying up of ephemeral streams. During the early stage, the contraction of ephemeral streams largely controls the recession behavior, whereas in the late stage when perennial streams dominate the flowing streams, the contraction of flowing streams is minimal and groundwater hydraulics governs the recession behavior.

  12. Root Morphology Was Improved in a Late-Stage Vigor Super Rice Cultivar

    PubMed Central

    Huang, Min; Chen, Jiana; Cao, Fangbo; Jiang, Ligeng; Zou, Yingbin

    2015-01-01

    This study aimed to test the hypothesis that root morphology might be improved and consequently contributing to superior post-heading shoot growth and grain yield in late-stage vigor super rice. A pot experiment was carried out to compare yield attributes, shoot growth and physiological properties and root morphological traits between a late-stage vigor super rice cultivar (Y-liangyou 087) and an elite rice cultivar (Teyou 838). Grain yield and total shoot biomass were 7–9% higher in Y-liangyou 087 than in Teyou 838. Y-liangyou 087 had 60–64% higher post-heading shoot growth rate and biomass production than Teyou 838. Average relative chlorophyll concentration and net photosynthetic rate in flag leaves were 7–11% higher in Y-liangyou 087 than in Teyou 838 during heading to 25 days after heading. Y-liangyou 087 had 41% higher post-heading shoot N uptake but 17–25% lower root biomass and root-shoot ratio at heading and maturity than Teyou 838. Specific root length and length and surface area of fine roots were higher in Y-liangyou 087 than in Teyou 838 at heading and maturity by more than 15%. These results indicated that root-shoot relationships were well balanced during post-heading phase in the late-stage vigor super rice cultivar Y-liangyou 087 by improving root morphology including avoiding a too great root biomass and developing a large fine root system. PMID:26566229

  13. Comparative analysis of cerebrospinal fluid from the meningo-encephalitic stage of T. b. gambiense and rhodesiense sleeping sickness patients using TMT quantitative proteomics.

    PubMed

    Tiberti, Natalia; Sanchez, Jean-Charles

    2015-09-01

    The quantitative proteomics data here reported are part of a research article entitled "Increased acute immune response during the meningo-encephalitic stage of Trypanosoma brucei rhodesiense sleeping sickness compared to Trypanosoma brucei gambiense", published by Tiberti et al., 2015. Transl. Proteomics 6, 1-9. Sleeping sickness (human African trypanosomiasis - HAT) is a deadly neglected tropical disease affecting mainly rural communities in sub-Saharan Africa. This parasitic disease is caused by the Trypanosoma brucei (T. b.) parasite, which is transmitted to the human host through the bite of the tse-tse fly. Two parasite sub-species, T. b. rhodesiense and T. b. gambiense, are responsible for two clinically different and geographically separated forms of sleeping sickness. The objective of the present study was to characterise and compare the cerebrospinal fluid (CSF) proteome of stage 2 (meningo-encephalitic stage) HAT patients suffering from T. b. gambiense or T. b. rhodesiense disease using high-throughput quantitative proteomics and the Tandem Mass Tag (TMT(®)) isobaric labelling. In order to evaluate the CSF proteome in the context of HAT pathophysiology, the protein dataset was then submitted to gene ontology and pathway analysis. Two significantly differentially expressed proteins (C-reactive protein and orosomucoid 1) were further verified on a larger population of patients (n=185) by ELISA, confirming the mass spectrometry results. By showing a predominant involvement of the acute immune response in rhodesiense HAT, the proteomics results obtained in this work will contribute to further understand the mechanisms of pathology occurring in HAT and to propose new biomarkers of potential clinical utility. The mass spectrometry raw data are available in the Pride Archive via ProteomeXchange through the identifier PXD001082. PMID:26306311

  14. Predictors of neighborhood risk for late-stage melanoma: addressing disparities through spatial analysis and area-based measures.

    PubMed

    Hu, Shasa; Sherman, Recinda; Arheart, Kristopher; Kirsner, Robert S

    2014-04-01

    Minority populations have disproportionately more advanced stage melanoma and worse survival. To clarify the impact of race and ethnicity on late-stage melanoma diagnosis, we performed spatial analysis of geocoded melanoma cases diagnosed in Florida, 1999-2008, to identify geographic clusters of higher-than-expected incidence of late-stage melanoma and developed predictive models for melanoma cases in high-risk neighborhoods accounting for area-based poverty, race/ethnicity, patient insurance status, age, and gender. In the adjusted model, Hispanic ethnicity and census tract-level poverty are the strongest predictors for clustering of late-stage melanoma. Hispanic whites were 43% more likely to live in neighborhoods with excessive late-stage melanoma (P<0.001) compared with non-Hispanic whites (NHW). For every 1% increase in population living in poverty, there is a 2% increase in late-stage melanoma clustering (P<0.001). Census tract-level poverty predicted late-stage melanoma similarly among NHW and Hispanic whites. The impact of insurance coverage varied among populations; the most consistent trend was that Medicaid coverage is associated with higher odds for late-stage melanoma. The finding that Hispanics are most likely to reside in high-risk neighborhoods, independent of poverty and insurance status, underscores the importance of addressing, and overcoming community-level barriers to melanoma care. PMID:24335896

  15. Latent Trypanosoma brucei gambiense foci in Uganda: a silent epidemic in children and adults?

    PubMed

    Wastling, S L; Picozzi, K; Wamboga, C; VON Wissmann, B; Amongi-Accup, C; Wardrop, N A; Stothard, J R; Kakembo, A; Welburn, S C

    2011-10-01

    Trypanosoma brucei gambiense sleeping sickness follows a long asymptomatic phase and persists in ancient foci from which epidemic clinical disease arises. A putative focus of T. b. gambiense infections has been identified, initially in mothers and young children, on the Lake Albert shoreline of Western Uganda leading to mass screening of 6207 individuals in September 2008. T. b. gambiense infections were identified by Card Agglutination Test for Trypanosomiasis (CATT) and sub-species-specific PCR although parasitological methods failed to confirm any patent trypanosome infections. In April 2009, CATT positives were re-visited; diagnosis of individuals by CATT and PCR was unstable over the two time points and parasites remained undetected, even using mini Anion Exchange Centrifugation Technique (mAECT). These observations suggest the possibility of a silent focus of disease, where all infected individuals are in a latent stage, and highlight our limited understanding of the local natural history and disease progression of T. b. gambiense in children and adults. PMID:21554841

  16. Late-stage galaxy mergers in cosmos to z ∼ 1

    SciTech Connect

    Lackner, C. N.; Silverman, J. D.; Salvato, M.; Kampczyk, P.; Kartaltepe, J. S.; Sanders, D.; Lee, N.; Capak, P.; Scoville, N.; Civano, F.; Halliday, C.; Ilbert, O.; Le Fèvre, O.; Jahnke, K.; Koekemoer, A. M.; Liu, C. T.; Sheth, K.

    2014-12-01

    The role of major mergers in galaxy and black hole formation is not well-constrained. To help address this, we develop an automated method to identify late-stage galaxy mergers before coalescence of the galactic cores. The resulting sample of mergers is distinct from those obtained using pair-finding and morphological indicators. Our method relies on median-filtering of high-resolution images to distinguish two concentrated galaxy nuclei at small separations. This method does not rely on low surface brightness features to identify mergers, and is therefore reliable to high redshift. Using mock images, we derive statistical contamination and incompleteness corrections for the fraction of late-stage mergers. The mock images show that our method returns an uncontaminated (<10%) sample of mergers with projected separations between 2.2 and 8 kpc out to z∼1. We apply our new method to a magnitude-limited (m{sub FW} {sub 814}<23) sample of 44,164 galaxies from the COSMOS HST/ACS catalog. Using a mass-complete sample with logM{sub ∗}/M{sub ⊙}>10.6 and 0.25late-stage mergers. Correcting for incompleteness and contamination, the fractional merger rate increases strongly with redshift as r{sub merge}∝(1+z){sup 3.8±0.9}, in agreement both with earlier studies and with dark matter halo merger rates. Separating the sample into star-forming and quiescent galaxies shows that the merger rate for star-forming galaxies increases strongly with redshift, (1+z){sup 4.5±1.3}, while the merger rate for quiescent galaxies is consistent with no evolution, (1+z){sup 1.1±1.2}. The merger rate also becomes steeper with decreasing stellar mass. Limiting our sample to galaxies with spectroscopic redshifts from zCOSMOS, we find that the star formation rates and X-ray selected active galactic nucleus (AGN) activity in likely late-stage mergers are higher by factors of ∼2 relative to those of a control sample. Combining our sample with more

  17. Ethical issues for late-stage trials of multipurpose prevention technologies for HIV and pregnancy.

    PubMed

    Cohen, Jessica A; Mastroianni, Anna C; Macklin, Ruth

    2014-11-01

    Multipurpose prevention technologies (MPTs) designed to simultaneously prevent pregnancy and HIV could provide urgently needed tools to address unmet sexual and reproductive health needs of women worldwide. Late-stage clinical trials will be complex given the need to demonstrate efficacy for HIV and contraceptive indications simultaneously from a single product. Currently, HIV and pregnancy prevention trials have distinctive design features that will need to be reconciled in MPT trials. This article identifies several ethical issues uniquely associated with this research that will benefit from future deliberation and guidance to ensure that this globally important research can proceed efficiently and expeditiously. PMID:25113651

  18. Late-stage kinetics of laser-induced photochemical deposition in liquid solutions

    NASA Astrophysics Data System (ADS)

    Hugonnot, Emmanuel; Muller, Xavier; Delville, Jean-Pierre

    2002-11-01

    Using a reaction-diffusion equation involving the one-photon excitation of a two-level system, we propose a rate equation that describes the late-stage growth of laser-induced photochemical deposits. With appropriate scaling, we show that the kinetics can be reduced to a single master curve for large beam radii. To experimentally illustrate the model, we investigate the coarsening of the deposit induced by a reaction with chromates photoactivated by a continuous Ar+ laser wave. Predicted growth laws are confirmed and the universal single-scaled dynamics is experimentally demonstrated.

  19. Ethical issues for late-stage trials of multipurpose prevention technologies for HIV and pregnancy

    PubMed Central

    Cohen, Jessica A.; Mastroianni, Anna C.; Macklin, Ruth

    2014-01-01

    Multipurpose prevention technologies (MPTs) designed to simultaneously prevent pregnancy and HIV could provide urgently needed tools to address unmet sexual and reproductive health needs of women worldwide. Late-stage clinical trials will be complex given the need to demonstrate efficacy for HIV and contraceptive indications simultaneously from a single product. Currently, HIV and pregnancy prevention trials have distinctive design features that will need to be reconciled in MPT trials. This article identifies several ethical issues uniquely associated with this research that will benefit from future deliberation and guidance to ensure that this globally important research can proceed efficiently and expeditiously. PMID:25113651

  20. New insights on late stage volcanism in the Pigafetta basin, western Pacific

    NASA Astrophysics Data System (ADS)

    Stadler, T.; Tominaga, M.

    2014-12-01

    We document observations of late stage volcanism in the western Pacific Pigafetta Basin by integrating previously published and new multichannel seismic (MCS) reflection profiles, Ocean Drilling Program (ODP) drill core, and well log data. We examine data from three seismic experiments (FM35-12, MESOPAC II, and MTr5) conducted in the Pigafetta Basin, one of the oldest, deepest abyssal basins in the world, where crustal age is suggested to range from M29 (~157 Ma) to M44 (~169.8 Ma) based on Japanese Mesozoic magnetic lineations. We use a total of ~2150 km of MCS lines along with core and wire-line logging data from ODP Hole 801C. As a basis for our interpretation, we use previously defined seismic stratigraphy for the Pigafetta Basin, including Horizon B (basement) and lower transparent unit (volcaniclastic turbidites) terminology. We build synthetic seismograms from density and p-wave velocity logs using OpendTect v 4.6.0 tie well to seismic feature. We then incorporate energy and similarity attributes of the MCS profiles with the modeled seismogram to correlate reflectors to ODP Hole 801C lithostratigraphy. From this correlation, to be consistent with previous studies, we assign lithology and age to prominent sedimentary and basement reflectors throughout all survey lines. We characterize widely distributed deformation of Horizon B and lower sedimentary unit reflectors based on coherency of wiggle traces, lateral and vertical energy attenuation, and dip of reflectors over a range of scales (>10 km to <1 km). Our findings provide new evidence of late stage volcanism occurring in the Pigafetta Basin during the mid-Cretaceous (110 - 90 Ma). We classify late stage volcanism into 3 types of volcanic related features: (1) seamounts, (2) sills, and (3) vertical seismic disturbance zones (<<1 km wide) characterized by bilateral upward drag of reflectors (indicating a thin, vertical volcanic intrusion). The distribution of these features provide new insights into

  1. A review of late-stage CNS drug candidates for the treatment of obesity.

    PubMed

    Heal, D J; Gosden, J; Smith, S L

    2013-01-01

    Obesity is an important causative factor in morbidity, disability and premature death. Increasing levels of obesity will impose enormous health, financial and social burdens on worldwide society unless effective interventions are implemented. For many obese individuals, diet and behavioural modification need to be supplemented by pharmacotherapy. Preclinical research has revealed a greater understanding of the complex nature of the hypothalamic regulation of food intake and has generated a wide range of new molecular targets for the development of drug candidates for obesity treatment. As shown by the clinical results that have been obtained with this next generation of therapies, some approaches, for example, fixed-dose drug combinations, have already demonstrated an ability to deliver levels of efficacy that are not achievable with the current antiobesity drug therapies. The regulatory and marketing landscape for development, registration and commercialisation of novel centrally acting drugs for treatment of obesity and related metabolic disorders has changed substantially in recent years. Now a much greater emphasis is placed on tolerability and safety, as well as efficacy. In this review we briefly describe the therapeutic approaches to tackle obesity that are in late-stage clinical development. We then discuss drugs in late-stage development for the treatment of obesity and also future directions. PMID:22410963

  2. Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine via Late-Stage Oxidation of (+)-Fendleridine Derivatives.

    PubMed

    White, Kolby L; Movassaghi, Mohammad

    2016-09-01

    We report the first total syntheses of (+)-haplocidine and its N1-amide congener (+)-haplocine. Our concise synthesis of these alkaloids required the development of a late-stage and highly selective C-H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide-directed ortho-acetoxylation of indoline amides enabled our implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions. An electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provided access to hexacyclic C19-hemiaminal ether alkaloids (+)-fendleridine, (+)-acetylaspidoalbidine, and (+)-propionylaspidoalbidine. A highly effective enzymatic resolution of a non-β-branched primary alcohol (E = 22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. Our synthetic strategy provides succinct access to hexacyclic aspidosperma derivatives, including the antiproliferative alkaloid (+)-haplocidine. PMID:27510728

  3. Radiosyntheses using Fluorine-18: the Art and Science of Late Stage Fluorination

    PubMed Central

    Cole, Erin L.; Stewart, Megan N.; Littich, Ryan; Hoareau, Raphael; Scott, Peter J. H.

    2014-01-01

    Positron (β+) emission tomography (PE) is a powerful, noninvasive tool for the in vivo, three-dimensional imaging of physiological structures and biochemical pathways. The continued growth of PET imaging relies on a corresponding increase in access to radiopharmaceuticals (biologically active molecules labeled with short-lived radionuclides such as fluorine-18). This unique need to incorporate the short-lived fluorine-18 atom (t1/2 = 109.77 min) as late in the synthetic pathway as possible has made development of methodologies that enable rapid and efficient late stage fluorination an area of research within its own right. In this review we describe strategies for radiolabeling with fluorine-18, including classical fluorine-18 radiochemistry and emerging techniques for late stage fluorination reactions, as well as labeling technologies such as microfluidics and solid-phase radiochemistry. The utility of fluorine-18 labeled radiopharmaceuticals is showcased through recent applications of PET imaging in the healthcare, personalized medicine and drug discovery settings. PMID:24484425

  4. Sonication-facilitated Immunofluorescence Staining of Late-stage Embryonic and Larval Drosophila Tissues In Situ

    PubMed Central

    Wawersik, Matthew

    2014-01-01

    Studies performed in Drosophila melanogaster embryos and larvae provide crucial insight into developmental processes such as cell fate specification and organogenesis. Immunostaining allows for the visualization of developing tissues and organs. However, a protective cuticle that forms at the end of embryogenesis prevents permeation of antibodies into late-stage embryos and larvae. While dissection prior to immunostaining is regularly used to analyze Drosophila larval tissues, it proves inefficient for some analyses because small tissues may be difficult to locate and isolate. Sonication provides an alternative to dissection in larval Drosophila immunostaining protocols. It allows for quick, simultaneous processing of large numbers of late-stage embryos and larvae and maintains in situ morphology. After fixation in formaldehyde, a sample is sonicated. Sample is then subjected to immunostaining with antigen-specific primary antibodies and fluorescently labeled secondary antibodies to visualize target cell types and specific proteins via fluorescence microscopy. During the process of sonication, proper placement of a sonicating probe above the sample, as well as the duration and intensity of sonication, is critical. Additonal minor modifications to standard immunostaining protocols may be required for high quality stains. For antibodies with low signal to noise ratio, longer incubation times are typically necessary. As a proof of concept for this sonication-facilitated protocol, we show immunostains of three tissue types (testes, ovaries, and neural tissues) at a range of developmental stages. PMID:25146311

  5. Cryopreservation of the late stage embryos of Spodoptera exigua (Lepidoptera: Noctuidae).

    PubMed

    Luo, Li; Pang, Yi; Chen, Qijin; Li, Guanghong

    2006-01-01

    Genetic devolution, genetic drift and contamination are all threats to maintain germplasm stability during mass rearing of many insects. Cryopreservation of beet armworm (Spodoptera exigua) embryos was studied to provide information to improve mass rearing. A series of experiments was conducted on late-stage embryos (45-48 h at 27 degree C) of the beet armyworm, which included evaluation of cryoprotectants (CPAs), their toxicity and glass-forming tendency and optimization of experimental procedures. The results showed that ethylene glycol (EG) was the best CPA with comparatively low toxicity compared to the other six CPAs tested (methanol, 1,3-propanediol, glycerol, 2-amino-1-ethanol, 3-amino-1-propanol 3-methoxy-1 and 2-propanediol). The highest hatching rate of 8.8 degree was attained after freezing with a 3-step loading procedure and a 1-step unloading procedure, but the hatched larvae from frozen-thawed embryos did not actively feed and could not develop to a later stage. This was attributed to injuries from freezing in late stage embryos of S. exigua which had formed midguts. PMID:17256068

  6. Divergent natural selection promotes immigrant inviability at early and late stages of evolutionary divergence.

    PubMed

    Ingley, Spencer J; Johnson, Jerald B

    2016-03-01

    Natural selection's role in speciation has been of fundamental importance since Darwin first outlined his theory. Recently, work has focused on understanding how selection drives trait divergence, and subsequently reproductive isolation. "Immigrant inviability," a barrier that arises from selection against immigrants in their nonnative environment, appears to be of particular importance. Although immigrant inviability is likely ubiquitous, we know relatively little about how selection acts on traits to drive immigrant inviability, and how important immigrant inviability is at early-versus-late stages of divergence. We present a study evaluating the role of predation in the evolution of immigrant inviability in recently diverged population pairs and a well-established species pair of Brachyrhaphis fishes. We evaluate performance in a high-predation environment by assessing survival in the presence of a predator, and swimming endurance in a low-predation environment. We find strong signatures of local adaptation and immigrant inviability of roughly the same magnitude both early and late in divergence. We find remarkably conserved selection for burst-speed swimming (important in predator evasion), and selection for increased size in low-predation environments. Our results highlight the consistency with which selection acts during speciation, and suggest that similar factors might promote initial population differentiation and maintain differentiation at late stages of divergence. PMID:26831519

  7. In vivo evaluation of sixteen plant extracts on mice inoculated with Trypanosoma brucei gambiense.

    PubMed Central

    Youan, B. B.; Coulibaly, S.; Miezan, T. B.; Doua, F.; Bamba, M.

    1997-01-01

    After examination of the drugs used by traditional practitioners in Côte d'lvoire, nine formulas prescribed in the treatment of African human trypanosomiasis (AHT) were selected for investigation. These formulas made use of 40 plants, 16 of which were studied because of their properties, as described in the literature, and their frequent use by practitioners. The plant extracts were administered, after maceration or decoction, either orally or intraperitoneally to Swiss mice that had previously been inoculated with Trypanosoma brucei gambiense (Tbg), strain MHOM/Cl/81/Dal 083. The parasitaemia in each mouse was followed for three consecutive days and compared with that in control mice, which had been given either a saline solution (SS: negative control) or well-known drugs (melarsoprol, difluoromethylornithine, and pentamidine: positive control). Our investigations led to the following conclusions. (a) None of the plant extracts revealed trypanocidal or trypanostatic activity relative to SS controls (P > 0.05). In fact, the mice that received the extracts died on the third day after inoculation, with 0% survival and an average parasitaemia of 10.8 +/- 2 x 10(7) trypanosomes/ml. (b) The treated positive controls, relative to SS, showed 100% survival and no parasitaemia (P < 0.05). Melarsoprol appeared to be active when given orally at a dose of 3.6 mg/kg body weight twice a day for 3 days. This method of testing the sensitivity of trypanosomes to plant extracts is easy and inexpensive, and could be applied to other areas of research on tropical diseases. PMID:9342893

  8. Regulation of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling during late stage osteoclast differentiation

    SciTech Connect

    Zawawi, M.S.F.; Dharmapatni, A.A.S.S.K.; Cantley, M.D.; McHugh, K.P.; Haynes, D.R.; Crotti, T.N.

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer Calcineurin/NFAT inhibitors FK506 and VIVIT treated human PBMC derived osteoclasts in vitro. Black-Right-Pointing-Pointer Differential regulation of ITAM receptors and adaptor molecules by calcineurin/NFAT inhibitors. Black-Right-Pointing-Pointer FK506 and VIVIT suppress ITAM factors during late phase osteoclast differentiation. -- Abstract: Osteoclasts are specialised bone resorptive cells responsible for both physiological and pathological bone loss. Osteoclast differentiation and activity is dependent upon receptor activator NF-kappa-B ligand (RANKL) interacting with its receptor RANK to induce the transcription factor, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway has been identified as a co-stimulatory pathway in osteoclasts. Osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells (TREM2) are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FcR{gamma}) and DNAX-activating protein 12 kDa (DAP12) respectively to induce calcium signalling. Treatment with calcineurin-NFAT inhibitors, Tacrolimus (FK506) and the 11R-VIVIT (VIVIT) peptide, reduces NFATc1 expression consistent with a reduction in osteoclast differentiation and activity. This study aimed to investigate the effects of inhibiting calcineurin-NFAT signalling on the expression of ITAM factors and late stage osteoclast genes including cathepsin K (CathK), Beta 3 integrin ({beta}3) and Annexin VIII (AnnVIII). Human peripheral blood mononuclear cells (PBMCs) were differentiated with RANKL and macrophage-colony stimulating factor (M-CSF) over 10 days in the presence or absence of FK506 or VIVIT. Osteoclast formation (as assessed by tartrate resistant acid phosphatase (TRAP)) and activity (assessed by dentine pit resorption) were significantly reduced with treatment. Quantitative real

  9. [Serological evidence of the existence of a wild reservoir of Trypanosoma brucei gambiense in the Pendjari biosphere reservation in the Republic of Benin].

    PubMed

    Guedegbe, B; Verhulst, A; Van Meirvenne, N; Pandey, V S; Doko, A

    1992-06-01

    In the national park of Pendjari, situated in the North-West of Benin, 91 wild animals, belonging to seven species, were darted. Thick and thin blood smears were examined for trypanosomes and plasma for trypanolytic antibodies against 6 antigenic variants of Trypanosoma brucei gambiense. Parasites were found in 13.92% and trypanolytic antibodies in 20.88% of the samples. A total of 28.57% of animals were positive by at least one of the two test systems used. Morphologically Trypanosoma congolense, T. vivax and T. brucei were identified. Overall prevalence was 40% in Adenota kob (n: 50), 13.63% in Alcelaphus buselaphus (n: 22), 10% in Hippotragus equinus (n: 10), 33% in Kobus defassa (n: 3), 0% in Phacochoerus aethiopicus (n: 3) and in Syncerus caffer (n: 2). The only lion (Panthera leo) examined was serologically positive. The results indicate that the wild animals are reservoirs of animal trypanosomes and suggest that among them Adenota kob and Panthera leo are carriers of T. brucei gambiense, one of the etiological aspects of human trypanosomiasis. PMID:1417158

  10. The Biting Midge Culicoides sonorensis (Diptera: Ceratopogonidae) Is Capable of Developing Late Stage Infections of Leishmania enriettii

    PubMed Central

    Seblova, Veronika; Sadlova, Jovana; Vojtkova, Barbora; Votypka, Jan; Carpenter, Simon; Bates, Paul Andrew; Volf, Petr

    2015-01-01

    Background Despite their importance in animal and human health, the epidemiology of species of the Leishmania enriettii complex remains poorly understood, including the identity of their biological vectors. Biting midges of the genus Forcipomyia (Lasiohelea) have been implicated in the transmission of a member of the L. enriettii complex in Australia, but the far larger and more widespread genus Culicoides has not been investigated for the potential to include vectors to date. Methodology/Principal Findings Females from colonies of the midges Culicoides nubeculosus Meigen and C. sonorensis Wirth & Jones and the sand fly Lutzomyia longipalpis Lutz & Nevia (Diptera: Psychodidae) were experimentally infected with two different species of Leishmania, originating from Australia (Leishmania sp. AM-2004) and Brazil (Leishmania enriettii). In addition, the infectivity of L. enriettii infections generated in guinea pigs and golden hamsters for Lu. longipalpis and C. sonorensis was tested by xenodiagnosis. Development of L. enriettii in Lu. longipalpis was relatively poor compared to other Leishmania species in this permissive vector. Culicoides nubeculosus was not susceptible to infection by parasites from the L. enriettii complex. In contrast, C. sonorensis developed late stage infections with colonization of the thoracic midgut and the stomodeal valve. In hamsters, experimental infection with L. enriettii led only to mild symptoms, while in guinea pigs L. enriettii grew aggressively, producing large, ulcerated, tumour-like lesions. A high proportion of C. sonorensis (up to 80%) feeding on the ears and nose of these guinea pigs became infected. Conclusions/Significance We demonstrate that L. enriettii can develop late stage infections in the biting midge Culicoides sonorensis. This midge was found to be susceptible to L. enriettii to a similar degree as Lutzomyia longipalpis, the vector of Leishmania infantum in South America. Our results support the hypothesis that some

  11. Video-assisted thoracoscopic decortication for the management of late stage pleural empyema, is it feasible?

    PubMed Central

    Hajjar, Waseem M.; Ahmed, Iftikhar; Al-Nassar, Sami A.; Alsultan, Rawan K.; Alwgait, Waad A.; Alkhalaf, Hanoof H.; Bisht, Shekhar C.

    2016-01-01

    BACKGROUND: Video-assisted thoracoscopic surgical decortication (VATSD) is widely applicable in fibrinopurulent Stage II empyema. While, more chronic thick walled Stage III empyema (organizing stage) needs conversion to open thoracotomy, and existing reports reveal a lacuna in the realm of late stage empyema patient's management through VATS utilization, particularly Stage III empyema. We prospectively evaluated the application of VATSD regardless of the stage of pleural empyema for the effective management of late stage empyema in comparison to open decortications (ODs) to minimize the adverse effects of the disease. METHODS: All patients with pyogenic pleural empyema (Stage II and Stage III) in King Khalid University Hospital (KKUH) (admitted from January 2009 to December 2013) who did not respond to chest tube/pigtail drainage and/or antibiotic therapy were treated with VATSD and/or open thoracotomy. Prospective evaluation was carried out, and the effect of this technique on perioperative outcomes was appraised to evaluate our technical learning with the passage of time and experience with VATS for late stage empyema management. RESULTS: Out of total 63 patients, 26 had Stage II empyema and 37 had Stage III empyema. VATSD was employed on all empyema patients admitted in the KKUH. VATSD was successful in all patients with Stage II empyema. Twenty-five patients (67.6%) with Stage III empyema completed VATSD successfully. However, only 12 cases (32.4%) required conversions to open (thoracotomy) drainage (OD). The median hospital stay for Stage III VATSD required 9.65 ± 4.1 days. Whereas, patients who underwent open thoracotomy took longer time (21.82 ± 16.35 days). Similarly, Stage III VATSD and Stage III open surgery cases showed significance difference among chest tube duration (7.84 ± 3.33 days for VATS and 15.92 ± 8.2 days for open thoracotomy). Significantly, lower postoperative complications were detected in patients treated with VATSD in terms of

  12. Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer.

    PubMed

    Moughon, Diana L; He, Huanhuan; Schokrpur, Shiruyeh; Jiang, Ziyue Karen; Yaqoob, Madeeha; David, John; Lin, Crystal; Iruela-Arispe, M Luisa; Dorigo, Oliver; Wu, Lily

    2015-11-15

    Malignant ascites is a common complication in the late stages of epithelial ovarian cancer (EOC) that greatly diminishes the quality of life of patients. Malignant ascites is a known consequence of vascular dysfunction, but current approved treatments are not effective in preventing fluid accumulation. In this study, we investigated an alternative strategy of targeting macrophage functions to reverse the vascular pathology of malignant ascites using fluid from human patients and an immunocompetent murine model (ID8) of EOC that mirrors human disease by developing progressive vascular disorganization and leakiness culminating in massive ascites. We demonstrate that the macrophage content in ascites fluid from human patients and the ID8 model directly correlates with vascular permeability. To further substantiate macrophages' role in the pathogenesis of malignant ascites, we blocked macrophage function in ID8 mice using a colony-stimulating factor 1 receptor kinase inhibitor (GW2580). Administration of GW2580 in the late stages of disease resulted in reduced infiltration of protumorigenic (M2) macrophages and dramatically decreased ascites volume. Moreover, the disorganized peritoneal vasculature became normalized and sera from GW2580-treated ascites protected against endothelial permeability. Therefore, our findings suggest that macrophage-targeted treatment may be a promising strategy toward a safe and effective means to control malignant ascites of EOC. PMID:26471360

  13. Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer

    PubMed Central

    Moughon, Diana L.; He, Huanhuan; Schokrpur, Shiruyeh; Jiang, Ziyue Karen; Yaqoob, Madeeha; David, John; Lin, Crystal; Iruela-Arispe, M. Luisa; Dorigo, Oliver; Wu, Lily

    2015-01-01

    Malignant ascites is a common complication in the late stages of epithelial ovarian cancer (EOC) that greatly diminishes the quality of life of patients. Malignant ascites is a known consequence of vascular dysfunction, but current approved treatments are not effective in preventing fluid accumulation. In this study, we investigated an alternative strategy of targeting macrophage functions to reverse the vascular pathology of malignant ascites using fluid from human patients and an immunocompetent murine model (ID8) of EOC that mirrors human disease by developing progressive vascular disorganization and leakiness culminating in massive ascites. We demonstrate that the macrophage content in ascites fluid from human patients and the ID8 model directly correlates with vascular permeability. To further substantiate macrophages’ role in the pathogenesis of malignant ascites, we blocked macrophage function in ID8 mice using a colony-stimulating factor 1 receptor kinase inhibitor (GW2580). Administration of GW2580 in the late stages of disease resulted in reduced infiltration of protumorigenic (M2) macrophages and dramatically decreased ascites volume. Moreover, the disorganized peritoneal vasculature became normalized and sera from GW2580-treated ascites protected against endothelial permeability. Therefore, our findings suggest that macrophage-targeted treatment may be a promising strategy toward a safe and effective means to control malignant ascites of EOC. PMID:26471360

  14. Manganese-catalyzed late-stage aliphatic C-H azidation.

    PubMed

    Huang, Xiongyi; Bergsten, Tova M; Groves, John T

    2015-04-29

    We report a manganese-catalyzed aliphatic C-H azidation reaction that can efficiently convert secondary, tertiary, and benzylic C-H bonds to the corresponding azides. The method utilizes aqueous sodium azide solution as the azide source and can be performed under air. Besides its operational simplicity, the potential of this method for late-stage functionalization has been demonstrated by successful azidation of various bioactive molecules with yields up to 74%, including the important drugs pregabalin, memantine, and the antimalarial artemisinin. Azidation of celestolide with a chiral manganese salen catalyst afforded the azide product in 70% ee, representing a Mn-catalyzed enantioselective aliphatic C-H azidation reaction. Considering the versatile roles of organic azides in modern chemistry and the ubiquity of aliphatic C-H bonds in organic molecules, we envision that this Mn-azidation method will find wide application in organic synthesis, drug discovery, and chemical biology. PMID:25871027

  15. Effects of feeding on the sustained swimming abilities of late-stage larval Amphiprion melanopus

    NASA Astrophysics Data System (ADS)

    Fisher, R.; Bellwood, D.

    2001-09-01

    To date, all sustained swimming experiments on tropical reef fish larvae have been conducted using unfed larvae. Such studies may produce unrealistic estimates of sustained swimming abilities. We examined the effect of food on the sustained swimming ability of late-stage Amphiprion melanopus. Larvae were swum in a six-channel swimming flume at 7 cm s-1, with "unfed" and "fed" channels. Fed channels had Artemia nauplii added four times per day for 10 min. Feeding larvae during swimming experiments significantly increased their average swimming distance from around 6.9 to 12.2 km, and the maximum swimming distance from around 11.8 to 28.7 km. Existing flume-based estimates of sustained swimming may be underestimating field abilities. With access to food, many larvae may have the potential to swim considerably greater distances than previously suggested.

  16. A Strategic Framework for Utilizing Late-Stage (T4) Translation Research to Address Health Inequities.

    PubMed

    Lopez-Class, Maria; Peprah, Emmanuel; Zhang, Xinzhi; Kaufmann, Peter G; Engelgau, Michael M

    2016-01-01

    Achieving health equity requires that every person has the opportunity to attain their full health potential and no one is disadvantaged from achieving this potential because of social position or other socially determined circumstances. Inequity experienced by populations of lower socioeconomic status is reflected in differences in health status and mortality rates, as well as in the distribution of disease, disability and illness across these population groups. This article gives an overview of the health inequities literature associated with heart, lung, blood and sleep (HLBS) disorders. We present an ecological framework that provides a theoretical foundation to study late-stage T4 translation research that studies implementation strategies for proven effective interventions to address health inequities. PMID:27440979

  17. Upregulation of fibroblast growth factor 1 in the synovial membranes of patients with late stage osteoarthritis.

    PubMed

    Li, R; Wang, B; He, C Q; Yang, Y Q; Guo, H; Chen, Y; Du, T H

    2015-01-01

    Osteoarthritis (OA) is a degenerative disease of the systemic joint that involves multiple cytokines and growth factors. Fibroblast growth factor 1 (FGF-1) is increased in patients with rheumatic arthritis. The aim of this study was to determine whether the expression and secretion of FGF-1 differed in synovial tissue from patients with late stage OA from that in normal tissues. We selected eight patients with late stage OA and eight healthy donors for this study. An enzyme-linked immunosorbent assay was used to determine the amount of FGF-1 in the synovial fluid and in the culture medium of synovial fibroblasts. Real time quantitative polymerase chain reaction (qPCR) analysis was performed to examine the expression levels of FGF-1 and FGF receptor 2 (FGFR2) in synovial and cartilage tissues. We detected FGF-1 in the synovial fluid from all eight donors, as well as in the culture medium of synovial fibroblasts. Synovial fluid from patients with OA and culture medium of OA synovial fibroblasts contained significantly more FGF-1 than those from controls. FGF-1 expression was also lower in the synovial membranes of normal donors than in those of OA patients. FGFR2 expression was also higher in OA cartilage than in normal cartilage. Overall, these results demonstrated that FGF-1 synthesis and secretion by synovial fibroblasts were significantly increased in OA. FGFR2 expression was also shown to be upregulated in patients with OA. These findings suggest that increased FGF-1 signaling correlates with an OA pathological condition. PMID:26400350

  18. Expression profiling of the intermediate and late stages of poxvirus replication.

    PubMed

    Yang, Zhilong; Reynolds, Sara E; Martens, Craig A; Bruno, Daniel P; Porcella, Stephen F; Moss, Bernard

    2011-10-01

    The double-stranded DNA genome of vaccinia virus (VACV), the prototype poxvirus, contains approximately 200 open reading frames (ORFs) that are transcribed at early, intermediate, and late stages of infection. Previous high-throughput deep RNA sequencing allowed us to map 118 VACV early genes that are expressed before viral DNA replication and 93 postreplicative genes. However, the intermediate- and late-stage postreplicative genes could not be differentiated. Here, we synchronized infections with a reversible inhibitor of DNA replication and used a VACV mutant that conditionally transcribes late genes to sequence the two classes of mRNAs. In addition, each postreplicative ORF was individually expressed under conditions that distinguished intermediate and late classes. We identified 38 VACV genes that belong to the late class and 53 that belong to the intermediate class, with some of the latter continuing to be expressed late. These data allowed us to prepare a genome-wide early, intermediate, and late transcription map. Inspection of sequences upstream of these ORFs revealed distinctive characteristics of intermediate and late promoters and suggested that some promoters have intermediate and late elements. The intermediate genes encoded many DNA binding/packaging and core-associated proteins in addition to late transcription factors; the late genes encoded many morphogenesis and mature virion membrane proteins, including those involved in entry, in addition to early transcription factors. The top-ranked antigens for CD4(+) T cells and B cells were mainly intermediate rather than late gene products. The differentiation of intermediate and late genes may enhance understanding of poxvirus replication and lead to improvements in expression vectors and recombinant vaccines. PMID:21795349

  19. Neurotherapeutic Effects of Pueraria mirifica Extract in Early- and Late-Stage Cognitive Impaired Rats.

    PubMed

    Anukulthanakorn, Kanya; Parhar, Ishwar S; Jaroenporn, Sukanya; Kitahashi, Takashi; Watanbe, Gen; Malaivijitnond, Suchinda

    2016-06-01

    We determined the neurotherapeutic effects of Pueraria mirifica extract (PME) and pure puerarin (PU) in comparison with 17β-estradiol (E2 ) in early- and late-stage cognitive impaired rats. Rats were ovariectomized (OVX), kept for 2 and 4 months to induce early- and late-stage cognitive impairment, respectively, and divided into four groups that were treated daily with (i) distilled water, (ii) 100 mg/kg of PME, (iii) 7 mg/kg of PU, and (iv) 80 µg/kg of E2 for 4 months. The estrogen deficiency symptoms of OVX rats were abrogated by treatment with E2 or PME, but not by treatment with PU. The mRNA level of genes associated with amyloid production (App and Bace1) and hyperphosphorylated Tau (Tau4) were upregulated together with the level of impaired cognition in the 2- and 4-month OVX rats. Treatment with E2 reduced the level of cognitive impairment more than that with PME and PU, and 2-month OVX rats were more responsive than 4-month OVX rats. All treatments down-regulated the Bace1 mRNA level in 2-month OVX rats, while PU and PME also decreased the App mRNA level in 2- and 4-month OVX rats, respectively. Only PU suppressed Tau4 expression in 2-month OVX rats. Thus, PME and PU elicit neurotherapeutic effects in different pathways, and earlier treatment is optimal. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26915634

  20. Management of postural sensory conflict and dynamic balance control in late-stage Parkinson's disease.

    PubMed

    Colnat-Coulbois, S; Gauchard, G C; Maillard, L; Barroche, G; Vespignani, H; Auque, J; Perrin, P P

    2011-10-13

    Parkinson's disease (PD) is known to affect postural control, especially in situations needing a change in balance strategy or when a concurrent task is simultaneously performed. However, few studies assessing postural control in patients with PD included homogeneous population in late stage of the disease. Thus, this study aimed to analyse postural control and strategies in a homogeneous population of patients with idiopathic advanced (late-stage) PD, and to determine the contribution of peripheral inputs in simple and more complex postural tasks, such as sensory conflicting and dynamic tasks. Twenty-four subjects with advanced PD (duration: median (M)=11.0 years, interquartile range (IQR)=4.3 years; Unified Parkinson's Disease Rating Scale (UPDRS): M "on-dopa"=13.5, IQR=7.8; UPDRS: M "off-dopa"=48.5, IQR=16.8; Hoehn and Yahr stage IV in all patients) and 48 age-matched healthy controls underwent static (SPT) and dynamic posturographic (DPT) tests and a sensory organization test (SOT). In SPT, patients with PD showed reduced postural control precision with increased oscillations in both anterior-posterior and medial-lateral planes. In SOT, patients with PD displayed reduced postural performances especially in situations in which visual and vestibular cues became predominant to organize balance control, as was the ability to manage balance in situations for which visual or proprioceptive inputs are disrupted. In DPT, postural restabilization strategies were often inefficient to maintain equilibrium resulting in falls. Postural strategies were often precarious, postural regulation involving more hip joint than ankle joint in patients with advanced PD than in controls. Difficulties in managing complex postural situations, such as sensory conflicting and dynamic situations might reflect an inadequate sensory organization suggesting impairment in central information processing. PMID:21627979

  1. Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of the Congo.

    PubMed Central

    Balasegaram, Manica; Harris, Steve; Checchi, Francesco; Ghorashian, Sara; Hamel, Catherine; Karunakara, Unni

    2006-01-01

    OBJECTIVE: To compare the effectiveness of melarsoprol and eflornithine in treating late-stage Gambian trypanosomiasis in the Republic of the Congo. METHODS: We analysed the outcomes of death during treatment and relapse within 1 year of discharge for 288 patients treated with eflornithine, 311 patients treated with the standard melarsoprol regimen and 62 patients treated with a short-course (10-day) melarsoprol regimen between April 2001 and April 2005. FINDINGS: A total of 1.7% (5/288) of patients treated with eflornithine died compared with 4.8% (15/311) of those treated with standard melarsoprol and 6.5% (4/62) of those treated with short-course melarsoprol. Patients treated with eflornithine tended to be younger and were more likely to have trypanosomes or higher white blood cell counts in their cerebrospinal fluid. The cumulated incidence of relapse among patients who attended at least one follow-up visit 1 year after discharge was 8.1% (11/136) for those treated with eflornithine, 14% (36/258) for those treated with standard melarsoprol and 15.5% (9/58) for those treated with shortcourse melarsoprol. In a multivariate analysis, when compared with eflornithine, standard melarsoprol was found to be a risk factor for both death (odds ratio (OR) = 2.87; 95% confidence interval (CI) = 1.03-8.00) and relapse (hazard ratio (HR) = 2.47; 95% CI = 1.22-5.03); when compared with eflornithine, short-course melarsoprol was also found to be a risk factor for death (OR = 3.90; 95% CI = 1.02-14.98) and relapse (HR = 6.65; 95% CI = 2.61-16.94). CONCLUSION: The effectiveness of melarsoprol treatment appears to have diminished. Eflornithine seems to be a better first-line therapy for treating late-stage Gambian trypanosomiasis in the Republic of the Congo. PMID:17128358

  2. Notch Signaling Regulates Late-Stage Epidermal Differentiation and Maintains Postnatal Hair Cycle Homeostasis

    PubMed Central

    Lin, Hsien-Yi; Kao, Cheng-Heng; Lin, Kurt Ming-Chao; Kaartinen, Vesa; Yang, Liang-Tung

    2011-01-01

    Background Notch signaling involves ligand-receptor interactions through direct cell-cell contact. Multiple Notch receptors and ligands are expressed in the epidermis and hair follicles during embryonic development and the adult stage. Although Notch signaling plays an important role in regulating differentiation of the epidermis and hair follicles, it remains unclear how Notch signaling participates in late-stage epidermal differentiation and postnatal hair cycle homeostasis. Methodology and Principal Findings We applied Cre/loxP system to generate conditional gene targeted mice that allow inactivation of critical components of Notch signaling pathway in the skin. Rbpj, the core component of all four Notch receptors, and Pofut1, an essential factor for ligand-receptor interactions, were inactivated in hair follicle lineages and suprabasal layer of the epidermis using the Tgfb3-Cre mouse line. Rbpj conditional inactivation resulted in granular parakeratosis and reactive epidermal hyperplasia. Pofut1 conditional inactivation led to ultrastructural abnormalities in the granular layer and altered filaggrin processing in the epidermis, suggesting a perturbation of the granular layer differentiation. Disruption of Pofut1 in hair follicle lineages resulted in aberrant telogen morphology, a decrease of bulge stem cell markers, and a concomitant increase of K14-positive keratinocytes in the isthmus of mutant hair follicles. Pofut1-deficent hair follicles displayed a delay in anagen re-entry and dysregulation of proliferation and apoptosis during the hair cycle transition. Moreover, increased DNA double stand breaks were detected in Pofut1-deficent hair follicles, and real time PCR analyses on bulge keratinocytes isolated by FACS revealed an induction of DNA damage response and a paucity of DNA repair machinery in mutant bulge keratinocytes. Significance our data reveal a role for Notch signaling in regulating late-stage epidermal differentiation. Notch signaling is

  3. A new method for isolating Trypanosoma brucei gambiense from sleeping sickness patients.

    PubMed

    Dukes, P; Kaukas, A; Hudson, K M; Asonganyi, T; Gashumba, J K

    1989-01-01

    Low infectivity to laboratory mammals and low virulence make Trypanosoma brucei gambiense difficult to isolate and grow in amounts sufficient for biochemical characterization. We report the isolation of T.b. gambiense by feeding cryopreserved primary isolates to laboratory-reared Glossina morsitans morsitans, followed by rapid cultivation in vitro of procyclic forms dissected from infected tsetse fly midguts. This technique allows the characterization of hitherto unsampled populations and avoids selection due to long-term subpassage. Of 16 primary isolates from trypanosomiasis patients of the Fontem focus in Cameroon, 12 (75%) produced infections in tsetse whereas only 4 (25%) infected rats. Ten isolates were subsequently cultivated as procyclic forms in vitro; 2 failed to grow owing to bacterial contamination. In addition, 2 primary isolates from Côte d'Ivoire patients and a stock of low virulence from the Congo Republic were similarly grown. Only one primary isolate produced tsetse salivary gland infections, an observation consistent with the hypothesis that some populations of T.b. gambiense are intrinsically incompatible with G.m. morsitans. PMID:2617625

  4. DETECTION OF CIRCULATING TUMOR DNA IN EARLY AND LATE STAGE HUMAN MALIGNANCIES

    PubMed Central

    Bettegowda, Chetan; Sausen, Mark; Leary, Rebecca; Kinde, Isaac; Agrawal, Nishant; Bartlett, Bjarne; Wang, Hao; Luber, Brandon; Kinzler, Kenneth; Vogelstein, Bert; Papadopoulos, Nickolas

    2014-01-01

    BACKGROUND: The development of minimally-invasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital PCR-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. In particular we studied the plasma of 14 medulloblastoma, 13 WHO grade 2-3 glioma and 14 WHO grade IV astrocytoma cases for levels of ctDNA. METHODS: The basis of our approach is to differentiate DNA shed by normal cells from DNA derived from tumor cells. In order to distinguish the two populations of cell-free DNA, we first identify a tumor-specific alteration. We then query for that exact mutation in matching plasma from the same patient to generate a personalized tumor biomarker. Only DNA derived from the tumor will harbor the genetic alteration. We initially use targeted, exomic, or whole genome sequencing to identify sequence or structural alterations in tumor tissues of 410 individuals. DNA was extracted from less than 5 ml of plasma in each case. The majority of plasma samples were queried for levels of ctDNA using a high fidelity next-generation sequencing approach coined Safe-SeqS. RESULTS: We found that at least one tumor-specific mutant molecule could be identified in <5 mL of plasma in >75% of patients with advanced ovarian, colorectal, bladder, gastroesophoageal, pancreatic, breast, melanoma, hepatocellular and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. Approximately 40% of medulloblastoma and 10% of low or high grade glioma cases had detectable levels of ctDNA. In patients with localized non-CNS tumors, ctDNA was detected in 73%, 57%, 48% and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor (EGFR) blockade in 24 colorectal cancer patients who objectively responded to therapy but who subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase (MAPK) pathway. CONCLUSIONS: Taken together, these data suggest that ctDNA is a sensitive, specific and robust biomarker that can be used for a variety of clinical and research purposes in patients with several multiple different types of cancer. For individuals with CNS neoplasms, alternate strategies may need to be developed in order to detect cell-free tumor derived DNA at levels that are clinically meaningful. ABSTRACT CATEGORY: Neuropathology & Tumor Biomarkers.

  5. Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies

    PubMed Central

    Bettegowda, Chetan; Sausen, Mark; Leary, Rebecca J.; Kinde, Isaac; Wang, Yuxuan; Agrawal, Nishant; Bartlett, Bjarne R.; Wang, Hao; Luber, Brandon; Alani, Rhoda M.; Antonarakis, Emmanuel S.; Azad, Nilofer S.; Bardelli, Alberto; Brem, Henry; Cameron, John L.; Lee, Clarence C.; Fecher, Leslie A.; Gallia, Gary L.; Gibbs, Peter; Le, Dung; Giuntoli, Robert L.; Goggins, Michael; Hogarty, Michael D.; Holdhoff, Matthias; Hong, Seung-Mo; Jiao, Yuchen; Juhl, Hartmut H.; Kim, Jenny J.; Siravegna, Giulia; Laheru, Daniel A.; Lauricella, Calogero; Lim, Michael; Lipson, Evan J.; Marie, Suely Kazue Nagahashi; Netto, George J.; Oliner, Kelly S.; Olivi, Alessandro; Olsson, Louise; Riggins, Gregory J.; Sartore-Bianchi, Andrea; Schmidt, Kerstin; Shih, le-Ming; Oba-Shinjo, Sueli Mieko; Siena, Salvatore; Theodorescu, Dan; Tie, Jeanne; Harkins, Timothy T.; Veronese, Silvio; Wang, Tian-Li; Weingart, Jon D.; Wolfgang, Christopher L.; Wood, Laura D.; Xing, Dongmei; Hruban, Ralph H.; Wu, Jian; Allen, Peter J.; Schmidt, C. Max; Choti, Michael A.; Velculescu, Victor E.; Kinzler, Kenneth W.; Vogelstein, Bert; Papadopoulos, Nickolas; Diaz, Luis A.

    2014-01-01

    The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction–based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer. PMID:24553385

  6. Gas and Dustin Debris Disks: Clues to the Late Stages of Planet Formation

    NASA Technical Reports Server (NTRS)

    Roberge, Aki

    2010-01-01

    The basic character of debris disks was established soon after their discovery in the mid- 1980's. These disks around nearby main sequence stars are composed of material (mostly dust) produced by collisions and/or evaporation of extrasolar asteroids and comets. However, fundamental observational questions about debris disks remain unanswered. How much material do debris disks typically contain and how does it evolve with time? What is the composition of their dust and gas? Are planets present or forming in the disks? Answers to these questions will provide insights into the late-stages of planetary system formation and the origins of terrestrial planet atmospheres. In this talk, I will explain our current understanding of the place of debris disks in the planet formation process. Progress toward addressing the questions given above will be discussed, with emphasis on recent studies of the small but important gas component. Finally, I will outline the implications of debris dust for future efforts to directly image and characterize extrasolar terrestrial planets.

  7. Curcumin: A multi-target disease-modifying agent for late-stage transthyretin amyloidosis

    PubMed Central

    Ferreira, Nelson; Gonçalves, Nádia P.; Saraiva, Maria J.; Almeida, Maria R.

    2016-01-01

    Transthyretin amyloidoses encompass a variety of acquired and hereditary diseases triggered by systemic extracellular accumulation of toxic transthyretin aggregates and fibrils, particularly in the peripheral nervous system. Since transthyretin amyloidoses are typically complex progressive disorders, therapeutic approaches aiming multiple molecular targets simultaneously, might improve therapy efficacy and treatment outcome. In this study, we evaluate the protective effect of physiologically achievable doses of curcumin on the cytotoxicity induced by transthyretin oligomers in vitro by showing reduction of caspase-3 activity and the levels of endoplasmic reticulum-resident chaperone binding immunoglobulin protein. When given to an aged Familial Amyloidotic Polyneuropathy mouse model, curcumin not only reduced transthyretin aggregates deposition and toxicity in both gastrointestinal tract and dorsal root ganglia but also remodeled congophilic amyloid material in tissues. In addition, curcumin enhanced internalization, intracellular transport and degradation of transthyretin oligomers by primary macrophages from aged Familial Amyloidotic Polyneuropathy transgenic mice, suggesting an impaired activation of naïve phagocytic cells exposed to transthyretin toxic intermediate species. Overall, our results clearly support curcumin or optimized derivatives as promising multi-target disease-modifying agent for late-stage transthyretin amyloidosis. PMID:27197872

  8. Narratives of continuity among older people with late stage chronic kidney disease who decline dialysis.

    PubMed

    Llewellyn, Henry; Low, Joe; Smith, Glenn; Hopkins, Katherine; Burns, Aine; Jones, Louise

    2014-08-01

    Chronic and life-threatening conditions are widely thought to shatter the lives of those affected. In this article, we examine the accounts of 19 older people diagnosed with late stage chronic kidney disease who declined dialysis. Accounts were collected through in-depth interview in the United Kingdom (March-November, 2010). Drawing on a phenomenological approach, we focus particularly on the embodied and lived experience of the condition and on how participants constructed treatment modalities and approached treatment choice. We look toward contemporary elaborations of the conceptual framework of biographical disruption to illustrate how participants managed to contain the intrusion of illness and maintain continuity in their lives. We argue that three interactive phenomena mitigated the potential for disruption and allowed participants to maintain continuity: (a) the framing of illness as "old age"; (b) the prior experience of serious illness; and (c) the choice of the treatment with the least potential for disruption. We conclude that a diagnosis of chronic illness in late life does not inevitably shatter lives or engender biographical disruption. Instead, people are able to construct continuity owing to complex narrative interpretations of diagnosis, sensation and treatment choices. PMID:24911508

  9. Late Stage 5 Glacio-isostatic Sea in the St. Lawrence Valley, Canada and United States

    USGS Publications Warehouse

    Occhietti, S.; Balescu, S.; Lamothe, M.; Clet, M.; Cronin, T.; Ferland, P.; Pichet, P.

    1996-01-01

    Although post-glacial marine sediments of late Wisconsinan and early Holocene age are common in eastern Canada and the northeastern United States, remnants of older Pleistocene marine sediments are scarce. A fossiliferous marine clay that predates the classical Wisconsinan was recently discovered in the St. Lawrence Valley. A dominantly estuarine environment is inferred from the geochemistry of the shells (??18O = -7.1) and from benthic foraminifer and ostracode assemblages. The clay indicates a marine invasion (Cartier Sea) shallower and probably shorter than that during the upper late Wisconsinan Champlain Sea episode (12,000-9,500 yr B.P.). The pollen content shows that regional vegetation during the marine episode began as open tundra, then became a Betula and Alnus crispa forest, reached a climatic optimum with Quercus, Corylus, and Abies, and concluded as a Pinus/Picea boreal forest. A corrected infrared stimulated luminescence age of 98,000 ?? 9000 yr is compatible with the epimerization ratio of shells. The Cartier Sea resulted from a post-glacial glacio-isostatic marine invasion in the St. Lawrence lowlands. It probably occurred during late stage 5 and is tentatively assigned to the transition of oxygen isotope substages 5b/5a. This marine episode dates to stage 5 of the preceding continental glacier which extended to middle latitudes in NE America. ?? 1996 University of Washington.

  10. Ultrastructural observations of the early and late stages of gorgonian coral (Junceella juncea) oocytes.

    PubMed

    Tsai, Sujune; Jhuang, Yating; Spikings, Emma; Sung, Ping-Jyun; Lin, Chiahsin

    2014-08-01

    The developmental oogenesis of gorgonian coral was investigated at the histological level. The objective of this study was to examine and improve the understanding of Junceella juncea oogenesis using ultrastructural methods, such as histological sectioning and transmission electron microscopy. At least three types of yolk materials were observed in this study: yolk body, lipid granules and cortical alveoli. Some of the complex yolk materials were encompassed by concentric or arched layers of smooth and rough endoplasmic reticulum and the Golgi complex in early stage oocytes. Different types of vesicles were found in both early and late stage oocytes and some granules could be seen inside the empty vesicles. This may be a possible method for elaborating complex yolk materials. Homogeneous yolks from different types of inclusions were abundant and the autosynthesis of yolk may be a major mechanism in J. juncea oocytes. This is the first report of the ultrastructural observation of oogenesis in gorgonian coral species using transmission electron microscopy. Our study obtained relatively detailed information at the ultrastructural level, and it provides an overview of the oocyte ultrastucture of the gorgonian coral J. juncea. PMID:24973261

  11. Gas and Dust in Debris Disks: Clues to the Late Stages of Planet Formation

    NASA Technical Reports Server (NTRS)

    Roberge, Aki

    2012-01-01

    The basic character of debris disks was established soon after their discovery in the mid- 1980's. These disks around nearby main sequence stars are composed of material (mostly dust) produced by collisions and/or evaporation of extrasolar asteroids and comets. However, fundamental observational questions about debris disks remain unanswered. How much material do debris disks typically contain and how does it evolve with time? What is the composition of their dust and gas? Are planets present or forming in the disks? Answers to these questions will provide insights into the late stages of planetary system formation and the origins of terrestrial planet atmospheres. In this talk, I will explain our current understanding of the place of debris disks in the planet formation process. Progress toward addressing the questions given above will be discussed, with emphasis on recent studies of the small but important gas component. Finally, I will outline the implications of debris dust for future efforts to directly image and characterize extrasolar terrestrial planets.

  12. Melting during late-stage rifting in Afar is hot and deep.

    PubMed

    Ferguson, D J; Maclennan, J; Bastow, I D; Pyle, D M; Jones, S M; Keir, D; Blundy, J D; Plank, T; Yirgu, G

    2013-07-01

    Investigations of a variety of continental rifts and margins worldwide have revealed that a considerable volume of melt can intrude into the crust during continental breakup, modifying its composition and thermal structure. However, it is unclear whether the cause of voluminous melt production at volcanic rifts is primarily increased mantle temperature or plate thinning. Also disputed is the extent to which plate stretching or thinning is uniform or varies with depth with the entire continental lithospheric mantle potentially being removed before plate rupture. Here we show that the extensive magmatism during rifting along the southern Red Sea rift in Afar, a unique region of sub-aerial transition from continental to oceanic rifting, is driven by deep melting of hotter-than-normal asthenosphere. Petrogenetic modelling shows that melts are predominantly generated at depths greater than 80 kilometres, implying the existence of a thick upper thermo-mechanical boundary layer in a rift system approaching the point of plate rupture. Numerical modelling of rift development shows that when breakup occurs at the slow extension rates observed in Afar, the survival of a thick plate is an inevitable consequence of conductive cooling of the lithosphere, even when the underlying asthenosphere is hot. Sustained magmatic activity during rifting in Afar thus requires persistently high mantle temperatures, which would allow melting at high pressure beneath the thick plate. If extensive plate thinning does occur during breakup it must do so abruptly at a late stage, immediately before the formation of the new ocean basin. PMID:23823795

  13. A coping and communication support intervention tailored to older patients diagnosed with late-stage cancer

    PubMed Central

    Rose, Julia Hannum; Radziewicz, Rosanne; Bowman, Karen F; O’Toole, Elizabeth E

    2008-01-01

    As our society ages, increasing numbers of older Americans will be diagnosed and eventually will die of cancer. To date, psycho-oncology interventions for advanced cancer patients have been more successful in reaching younger adult age groups and generally have not been designed to respond to the unique needs and preferences of older patients. Theories and research on successful aging (Baltes and Baltes 1990; Baltes 1997), health information processing style (Miller 1995; Miller et al 2001) and non-directive client-centered therapy (Rogers 1951, 1967), have guided the development of a coping and communication support (CCS) intervention. Key components of this age-sensitive and tailored intervention are described, including problem domains addressed, intervention strategies used and the role of the CCS practitioner. Age group comparisons in frequency of contact, problems raised and intervention strategies used during the first six weeks of follow up indicate that older patients were similar to middle-aged patients in their level of engagement, problems faced and intervention strategies used. Middle-aged patients were more likely to have problems communicating with family members at intervention start up and practical problems as well in follow up contacts. This is the first intervention study specifically designed to be age sensitive and to examine age differences in engagement from the early treatment phase for late-stage cancer through end of life. This tailored intervention is expected to positively affect patients’ quality of care and quality of life over time. PMID:18488881

  14. Creb1 regulates late stage mammalian lung development via respiratory epithelial and mesenchymal-independent mechanisms

    PubMed Central

    Antony, N.; McDougall, A. R.; Mantamadiotis, T.; Cole, T. J.; Bird, A. D.

    2016-01-01

    During mammalian lung development, the morphological transition from respiratory tree branching morphogenesis to a predominantly saccular architecture, capable of air-breathing at birth, is dependent on physical forces as well as molecular signaling by a range of transcription factors including the cAMP response element binding protein 1 (Creb1). Creb1−/− mutant mice exhibit complete neonatal lethality consistent with a lack of lung maturation beyond the branching phase. To further define its role in the developing mouse lung, we deleted Creb1 separately in the respiratory epithelium and mesenchyme. Surprisingly, we found no evidence of a morphological lung defect nor compromised neonatal survival in either conditional Creb1 mutant. Interestingly however, loss of mesenchymal Creb1 on a genetic background lacking the related Crem protein showed normal lung development but poor neonatal survival. To investigate the underlying requirement for Creb1 for normal lung development, Creb1−/− mice were re-examined for defects in both respiratory muscles and glucocorticoid hormone signaling, which are also required for late stage lung maturation. However, these systems appeared normal in Creb1−/− mice. Together our results suggest that the requirement of Creb1 for normal mammalian lung morphogenesis is not dependent upon its expression in lung epithelium or mesenchyme, nor its role in musculoskeletal development. PMID:27150575

  15. Clathrin binding by the adaptor Ent5 promotes late stages of clathrin coat maturation

    PubMed Central

    Hung, Chao-Wei; Duncan, Mara C.

    2016-01-01

    Clathrin is a ubiquitous protein that mediates membrane traffic at many locations. To function, clathrin requires clathrin adaptors that link it to transmembrane protein cargo. In addition to this cargo selection function, many adaptors also play mechanistic roles in the formation of the transport carrier. However, the full spectrum of these mechanistic roles is poorly understood. Here we report that Ent5, an endosomal clathrin adaptor in Saccharomyces cerevisiae, regulates the behavior of clathrin coats after the recruitment of clathrin. We show that loss of Ent5 disrupts clathrin-dependent traffic and prolongs the lifespan of endosomal structures that contain clathrin and other adaptors, suggesting a defect in coat maturation at a late stage. We find that the direct binding of Ent5 with clathrin is required for its role in coat behavior and cargo traffic. Surprisingly, the interaction of Ent5 with other adaptors is dispensable for coat behavior but not cargo traffic. These findings support a model in which Ent5 clathrin binding performs a mechanistic role in coat maturation, whereas Ent5 adaptor binding promotes cargo incorporation. PMID:26842894

  16. ALK5-dependent TGF-β signaling is a major determinant of late stage adult neurogenesis

    PubMed Central

    He, Yingbo; Zhang, Hui; Yung, Andrea; Villeda, Saul A; Jaeger, Philipp A; Olayiwola, Oluwatobi; Fainberg, Nina; Wyss-Coray, Tony

    2014-01-01

    The transforming growth factor-β (TGF-β) signaling pathway serves critical functions in central nervous system (CNS) development, but apart from its proposed neuroprotective actions, its physiological role in the adult brain is unclear. We observed a prominent activation of TGF-β signaling in the adult dentate gyrus and expression of downstream Smad proteins in this neurogenic zone. Consistent with a function of TGF-β signaling in adult neurogenesis, genetic deletion of the TGF-β receptor ALK5 reduced the number, migration, and dendritic arborization of newborn neurons. Conversely, constitutive activation of neuronal ALK5 in forebrain caused a striking increase in these aspects of neurogenesis and was associated with higher expression of c-fos in newborn neurons and with stronger memory function. Our findings describe a new and unexpected role for ALK5-dependent TGF-β signaling as a regulator of the late stages of adult hippocampal neurogenesis which may have implications for changes in neurogenesis during aging and disease. PMID:24859199

  17. Creb1 regulates late stage mammalian lung development via respiratory epithelial and mesenchymal-independent mechanisms.

    PubMed

    Antony, N; McDougall, A R; Mantamadiotis, T; Cole, T J; Bird, A D

    2016-01-01

    During mammalian lung development, the morphological transition from respiratory tree branching morphogenesis to a predominantly saccular architecture, capable of air-breathing at birth, is dependent on physical forces as well as molecular signaling by a range of transcription factors including the cAMP response element binding protein 1 (Creb1). Creb1(-/-) mutant mice exhibit complete neonatal lethality consistent with a lack of lung maturation beyond the branching phase. To further define its role in the developing mouse lung, we deleted Creb1 separately in the respiratory epithelium and mesenchyme. Surprisingly, we found no evidence of a morphological lung defect nor compromised neonatal survival in either conditional Creb1 mutant. Interestingly however, loss of mesenchymal Creb1 on a genetic background lacking the related Crem protein showed normal lung development but poor neonatal survival. To investigate the underlying requirement for Creb1 for normal lung development, Creb1(-/-) mice were re-examined for defects in both respiratory muscles and glucocorticoid hormone signaling, which are also required for late stage lung maturation. However, these systems appeared normal in Creb1(-/-) mice. Together our results suggest that the requirement of Creb1 for normal mammalian lung morphogenesis is not dependent upon its expression in lung epithelium or mesenchyme, nor its role in musculoskeletal development. PMID:27150575

  18. Relationship between early and late stages of information processing: an event-related potential study

    PubMed Central

    Portella, Claudio; Machado, Sergio; Arias-Carrión, Oscar; Sack, Alexander T.; Silva, Julio Guilherme; Orsini, Marco; Leite, Marco Antonio Araujo; Silva, Adriana Cardoso; Nardi, Antonio E.; Cagy, Mauricio; Piedade, Roberto; Ribeiro, Pedro

    2012-01-01

    The brain is capable of elaborating and executing different stages of information processing. However, exactly how these stages are processed in the brain remains largely unknown. This study aimed to analyze the possible correlation between early and late stages of information processing by assessing the latency to, and amplitude of, early and late event-related potential (ERP) components, including P200, N200, premotor potential (PMP) and P300, in healthy participants in the context of a visual oddball paradigm. We found a moderate positive correlation among the latency of P200 (electrode O2), N200 (electrode O2), PMP (electrode C3), P300 (electrode PZ) and the reaction time (RT). In addition, moderate negative correlation between the amplitude of P200 and the latencies of N200 (electrode O2), PMP (electrode C3), P300 (electrode PZ) was found. Therefore, we propose that if the secondary processing of visual input (P200 latency) occurs faster, the following will also happen sooner: discrimination and classification process of this input (N200 latency), motor response processing (PMP latency), reorganization of attention and working memory update (P300 latency), and RT. N200, PMP, and P300 latencies are also anticipated when higher activation level of occipital areas involved in the secondary processing of visual input rise (P200 amplitude). PMID:23355929

  19. Effect of Fluorescent Dyes on In Vitro-Differentiated, Late-Stage Plasmodium falciparum Gametocytes

    PubMed Central

    Gebru, Tamirat; Mordmüller, Benjamin

    2014-01-01

    Plasmodium falciparum gametocytes are not associated with clinical symptoms, but they are responsible for transmitting the pathogen to mosquitoes. Therefore, gametocytocidal interventions are important for malaria control and resistance containment. Currently available drugs and vaccines are not well suited for that purpose. Several dyes have potent antimicrobial activity, but their use against gametocytes has not been investigated systematically. The gametocytocidal activity of nine synthetic dyes and four control compounds was tested against stage V gametocytes of the laboratory strain 3D7 and three clinical isolates of P. falciparum with a bioluminescence assay. Five of the fluorescent dyes had submicromolar 50% inhibitory concentration (IC50) values against mature gametocytes. Three mitochondrial dyes, MitoRed, dihexyloxacarbocyanine iodide (DiOC6), and rhodamine B, were highly active (IC50s < 200 nM). MitoRed showed the highest activity against gametocytes, with IC50s of 70 nM against 3D7 and 120 to 210 nM against clinical isolates. All compounds were more active against the laboratory strain 3D7 than against clinical isolates. In particular, the endoperoxides artesunate and dihydroartemisinin showed a 10-fold higher activity against 3D7 than against clinical isolates. In contrast to all clinically used antimalarials, several fluorescent dyes had surprisingly high in vitro activity against late-stage gametocytes. Since they also act against asexual blood stages, they shall be considered starting points for the development of new antimalarial lead compounds. PMID:25267675

  20. Late-stage volatile saturation as a potential trigger for explosive volcanic eruptions

    NASA Astrophysics Data System (ADS)

    Stock, Michael J.; Humphreys, Madeleine C. S.; Smith, Victoria C.; Isaia, Roberto; Pyle, David M.

    2016-03-01

    Magma reservoirs are thought to grow relatively slowly, assembling incrementally under volatile-saturated conditions. Eruptions may be triggered by injections of volatile-rich melt, or generation of over-pressure due to protracted crystallization. Here, we analyse fluorine, chlorine and water in apatite crystals trapped at different stages of magma evolution, and in melt inclusions from clinopyroxene and biotite crystals expelled during an explosive eruption of the Campi Flegrei caldera, Italy, about 4,000 years ago. We combine our geochemical analyses with thermodynamic modelling to reconstruct the evolution of magmatic volatile contents leading up to the explosive eruption. We find that the magma reservoir remained persistently water-undersaturated throughout most of its lifetime. Even crystals in contact with the melt shortly before eruption show that the magma was volatile-undersaturated. Our models suggest that the melt reached volatile saturation at low temperatures, just before eruption. We suggest that late-stage volatile saturation probably triggered the eruption, and conclude that `priming’ of the magma system for eruption may occur on timescales much shorter than the decadal to centennial timescales thought typical for magma reservoir assembly. Thus, surface deformation pulses that record magma assembly at depth beneath Campi Flegrei and other similar magmatic systems may not be immediately followed by an eruption; and explosive eruptions may begin with little warning.

  1. Curcumin: A multi-target disease-modifying agent for late-stage transthyretin amyloidosis.

    PubMed

    Ferreira, Nelson; Gonçalves, Nádia P; Saraiva, Maria J; Almeida, Maria R

    2016-01-01

    Transthyretin amyloidoses encompass a variety of acquired and hereditary diseases triggered by systemic extracellular accumulation of toxic transthyretin aggregates and fibrils, particularly in the peripheral nervous system. Since transthyretin amyloidoses are typically complex progressive disorders, therapeutic approaches aiming multiple molecular targets simultaneously, might improve therapy efficacy and treatment outcome. In this study, we evaluate the protective effect of physiologically achievable doses of curcumin on the cytotoxicity induced by transthyretin oligomers in vitro by showing reduction of caspase-3 activity and the levels of endoplasmic reticulum-resident chaperone binding immunoglobulin protein. When given to an aged Familial Amyloidotic Polyneuropathy mouse model, curcumin not only reduced transthyretin aggregates deposition and toxicity in both gastrointestinal tract and dorsal root ganglia but also remodeled congophilic amyloid material in tissues. In addition, curcumin enhanced internalization, intracellular transport and degradation of transthyretin oligomers by primary macrophages from aged Familial Amyloidotic Polyneuropathy transgenic mice, suggesting an impaired activation of naïve phagocytic cells exposed to transthyretin toxic intermediate species. Overall, our results clearly support curcumin or optimized derivatives as promising multi-target disease-modifying agent for late-stage transthyretin amyloidosis. PMID:27197872

  2. Two phase deglaciation incorporating a late-stage readvance in the Brunswick, Maine area

    SciTech Connect

    Borelli, C.; Smity, P. . Dept. of Geoscience)

    1993-03-01

    Reinterpretation of late Wisconsinan glacial deposits indicate that retreat of the Laurentide ice margin occurred west of the marine limit in the Brunswick area. Marine transgression deposited the overlying Presumpscot Formation which locally contains organic rich, silty sand. A regionally extensive readvance deformed and truncated the uppermost glaciomarine sediments during the oceanic highstand. Striations and other ice flow indicators which are found underlying the Presumpscot Formation consistently trend NW-SE, while those found on exposed outcrops above the Presumpscot Formation dominantly trend NE-SW. These otherwise anomalous directional flow indicators support a late stage readvance of the ice sheet. Areally extensive, stratified, and locally imbricated outwash caps the glaciomarine sediments. Mineral composition of the basal outwash differs from the upper outwash sequences, supporting the readvance model by indicating different source areas. Multi-phase emergence characterized by terraced landforms caused a reworking and redeposition of sediment in a fluvial, tidally influenced environment. Localized eolian deposits record a late phase reworking of sediment.

  3. Diversity-oriented synthesis of analogues of the novel macrocyclic peptide FR-225497 through late stage functionalization

    PubMed Central

    Mukherjee, Jyotiprasad; Sil, Suman

    2015-01-01

    Summary A concise synthetic approach to a class of biologically interesting cyclic tetrapeptides is reported which involves a late-stage functionalization of a macrocyclic scaffold through cross metathesis in an attempt to create diversity. The utility of this protocol is demonstrated through the preparation of three structural analogues of the important naturally occurring histone deacetylase inhibitor FR-225497. PMID:26734096

  4. Applying NGS Data to Find Evolutionary Network Biomarkers from the Early and Late Stages of Hepatocellular Carcinoma

    PubMed Central

    Wong, Yung-Hao; Wu, Chia-Chou; Lin, Chih-Lung; Chen, Ting-Shou; Chang, Tzu-Hao; Chen, Bor-Sen

    2015-01-01

    Hepatocellular carcinoma (HCC) is a major liver tumor (~80%), besides hepatoblastomas, angiosarcomas, and cholangiocarcinomas. In this study, we used a systems biology approach to construct protein-protein interaction networks (PPINs) for early-stage and late-stage liver cancer. By comparing the networks of these two stages, we found that the two networks showed some common mechanisms and some significantly different mechanisms. To obtain differential network structures between cancer and noncancer PPINs, we constructed cancer PPIN and noncancer PPIN network structures for the two stages of liver cancer by systems biology method using NGS data from cancer cells and adjacent noncancer cells. Using carcinogenesis relevance values (CRVs), we identified 43 and 80 significant proteins and their PPINs (network markers) for early-stage and late-stage liver cancer. To investigate the evolution of network biomarkers in the carcinogenesis process, a primary pathway analysis showed that common pathways of the early and late stages were those related to ordinary cancer mechanisms. A pathway specific to the early stage was the mismatch repair pathway, while pathways specific to the late stage were the spliceosome pathway, lysine degradation pathway, and progesterone-mediated oocyte maturation pathway. This study provides a new direction for cancer-targeted therapies at different stages. PMID:26366411

  5. Molecular Chaperone Mediated Late-Stage Neuroprotection in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

    PubMed Central

    Gray, Anna L.; Dick, James R.; Kanuga, Naheed; Kalmar, Bernadett; Greensmith, Linda; Cheetham, Michael E.

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons in the spinal cord, brain stem, and motor cortex. Mutations in superoxide dismutase (SOD1) are associated with familial ALS and lead to SOD1 protein misfolding and aggregation. Here we show that the molecular chaperone, HSJ1 (DNAJB2), mutations in which cause distal hereditary motor neuropathy, can reduce mutant SOD1 aggregation and improve motor neuron survival in mutant SOD1 models of ALS. Overexpression of human HSJ1a (hHSJ1a) in vivo in motor neurons of SOD1G93A transgenic mice ameliorated disease. In particular, there was a significant improvement in muscle force, increased motor unit number and enhanced motor neuron survival. hHSJ1a was present in a complex with SOD1G93A and led to reduced SOD1 aggregation at late stages of disease progression. We also observed altered ubiquitin immunoreactivity in the double transgenic animals, suggesting that ubiquitin modification might be important for the observed improvements. In a cell model of SOD1G93A aggregation, HSJ1a preferentially bound to mutant SOD1, enhanced SOD1 ubiquitylation and reduced SOD1 aggregation in a J-domain and ubiquitin interaction motif (UIM) dependent manner. Collectively, the data suggest that HSJ1a acts on mutant SOD1 through a combination of chaperone, co-chaperone and pro-ubiquitylation activity. These results show that targeting SOD1 protein misfolding and aggregation in vivo can be neuroprotective and suggest that manipulation of DnaJ molecular chaperones might be useful in the treatment of ALS. PMID:24023695

  6. Small cell lung cancer cells express the late stage gBK tumor antigen: a possible immunotarget for the terminal disease

    PubMed Central

    Hoa, Neil T; Ge, Lisheng; Tajhya, Rajeev B; Beeton, Christine; Cornforth, Andrew N; Abolhoda, Amir; Lambrecht, Nils; DaCosta-Iyer, Maria; Ouyang, Yi; Mai, Anthony P; Hong, Erin; Shon, Judy; Hickey, Michelle J; Erickson, Kate L; Kruse, Carol A; Jadus, Martin R

    2014-01-01

    Big Potassium (BK) ion channels have several splice variants. One splice variant initially described within human glioma cells is called the glioma BK channel (gBK). Using a gBK-specific antibody, we detected gBK within three human small cell lung cancer (SCLC) lines. Electrophysiology revealed that functional membrane channels were found on the SCLC cells. Prolonged exposure to BK channel activators caused the SCLC cells to swell within 20 minutes and resulted in their death within five hours. Transduction of BK-negative HEK cells with gBK produced functional gBK channels. Quantitative RT-PCR analysis using primers specific for gBK, but not with a lung-specific marker, Sox11, confirmed that advanced, late-stage human SCLC tissues strongly expressed gBK mRNA. Normal human lung tissue and early, lower stage SCLC resected tissues very weakly expressed this transcript. Immunofluorescence using the anti-gBK antibody confirmed that SCLC cells taken at the time of the autopsy intensely displayed this protein. gBK may represent a late-stage marker for SCLC. HLA-A*0201 restricted human CTL were generated in vitro using gBK peptide pulsed dendritic cells. The exposure of SCLC cells to interferon-γ (IFN-γ) increased the expression of HLA; these treated cells were killed by the CTL better than non-IFN-γ treated cells even though the IFN-γ treated SCLC cells displayed diminished gBK protein expression. Prolonged incubation with recombinant IFN-γ slowed the in vitro growth and prevented transmigration of the SCLC cells, suggesting IFN-γ might inhibit tumor growth in vivo. Immunotherapy targeting gBK might impede advancement to the terminal stage of SCLC via two pathways. PMID:24936214

  7. Late-stage orogenic processes: How to link surface motion with distinct lithospheric processes

    NASA Astrophysics Data System (ADS)

    Neubauer, F.; Heberer, B.

    2009-04-01

    There is still a lack of knowledge of surface expression caused by deep-seated lithospheric processes, and how such processes could be distinguished from other, e.g. climate-induced, surface processes like denudation. Surface expressions of deep-seated lithospheric processes in convergent settings are expected to have been long-lived and to show large wave-length structures creating a dynamic topography (Wortel and Spakman, 2000; Cloetingh and Ziegler, 2007). Resulting continent-continent collisional orogens are bivergent, and the principal vergency of collisional orogens is controlled by the previous subduction of oceanic lithosphere (Beaumont et al., 1996). A number of tectonic processes are shown to be active during late orogenic phases and these processes particularly result in specific patterns of surface uplift and denudation of the evolving orogens as well as subsidence in the associated foreland basin. A number of these processes are not fully understood. Late-stage orogenic processes include, among others, slab break-off, slab delamination respectively of lithospheric roots, back-thrusting, tectonic indentation and consequent orogen-parallel lateral extrusion and formation of Subduction-Transform Edge Propagator (STEP) faults acting on the subducting lithosphere (Molnar and Tapponnier, 1975; Wortel and Spakman, 2000; Ratschbacher et al., 1991; Govers and Wortel, 2005). Here, we discuss these processes mainly in terms of their near-surface geological expressions within the orogen and the associated foreland basins, and how these processes could be distinguished by such geological features. We also show distinct theoretical models applied to the arcuate Alpine-Balkan-Carpathian-Dinaric system, which is driven by the oblique convergence of Africa-Europe. Slab-break-off results in lateral orogen-parallel migration of sharp subsidence in a linear belt in front of the slab window, coupled subsidence and subsequent uplift/basin inversion of peripheral foreland

  8. An Analytical Model of the Large Neutral Regions during the Late Stage of Reionization

    NASA Astrophysics Data System (ADS)

    Xu, Yidong; Yue, Bin; Su, Meng; Fan, Zuhui; Chen, Xuelei

    2014-02-01

    In this paper, we investigate the nature and distribution of large neutral regions during the late epoch of reionization. In the "bubble model" of reionization, the mass distribution of large ionized regions ("bubbles") during the early stage of reionization is obtained by using the excursion set model, where the ionization of a region corresponds to the first up-crossing of a barrier by random trajectories. We generalize this idea and develop a method to predict the distribution of large-scale neutral regions during the late stage of reionization, taking into account the ionizing background after the percolation of H II regions. The large-scale neutral regions, which we call "neutral islands," are not individual galaxies or minihalos, but larger regions where fewer galaxies formed and hence ionized later and they are identified in the excursion set model with the first down-crossings of the island barrier. Assuming that the consumption rate of ionizing background photons is proportional to the surface area of the neutral islands, we obtained the size distribution of the neutral islands. We also take the "bubbles-in-island" effect into account by considering the conditional probability of up-crossing a bubble barrier after down-crossing the island barrier. We find that this effect is very important. An additional barrier is set to avoid islands being percolated through. We find that there is a characteristic scale for the neutral islands, while the small islands are rapidly swallowed up by the ionizing background; this characteristic scale does not change much as the reionization proceeds.

  9. An analytical model of the large neutral regions during the late stage of reionization

    SciTech Connect

    Xu, Yidong; Yue, Bin; Chen, Xuelei; Su, Meng; Fan, Zuhui

    2014-02-01

    In this paper, we investigate the nature and distribution of large neutral regions during the late epoch of reionization. In the 'bubble model' of reionization, the mass distribution of large ionized regions ('bubbles') during the early stage of reionization is obtained by using the excursion set model, where the ionization of a region corresponds to the first up-crossing of a barrier by random trajectories. We generalize this idea and develop a method to predict the distribution of large-scale neutral regions during the late stage of reionization, taking into account the ionizing background after the percolation of H II regions. The large-scale neutral regions, which we call 'neutral islands', are not individual galaxies or minihalos, but larger regions where fewer galaxies formed and hence ionized later and they are identified in the excursion set model with the first down-crossings of the island barrier. Assuming that the consumption rate of ionizing background photons is proportional to the surface area of the neutral islands, we obtained the size distribution of the neutral islands. We also take the 'bubbles-in-island' effect into account by considering the conditional probability of up-crossing a bubble barrier after down-crossing the island barrier. We find that this effect is very important. An additional barrier is set to avoid islands being percolated through. We find that there is a characteristic scale for the neutral islands, while the small islands are rapidly swallowed up by the ionizing background; this characteristic scale does not change much as the reionization proceeds.

  10. The relationship between tectonic evolution and oil-cracking gas accumulation in late stage for marine superimposed basins

    NASA Astrophysics Data System (ADS)

    Zheng, Min; Wu, Xiaozhi

    2015-04-01

    The marine superimposed basins are rich in oil-cracking gas resources. Their hydrocarbon accumulation processes of late stage have experienced early paleo-oil reservoir accumulation period and late oil-cracking gas period, which are apparently controlled by tectonic evolution. Studying the relationship between tectonic evolution and oil-cracking gas accumulation of late stage has great significance to guide the exploration of oil-cracking gas reservoirs. Taking the relationship between tectonic evolution and oil-cracking gas accumulation of late stage for the Shunan area in the Sichuan Basin as example, through the analysis on the respons of structural evolution to deposition, the relationship between hydrocarbon generation process of ancient source rocks, initial hydrocarbon accumulation, oil cracking and gas accumulation of late stage was studied. The source rocks of the Cambrian Qiongzhusi Fm in the Shunan area experienced three periods of hydrocarbon generation and two periods of hydrocarbon generation lag. During the large-scale tectonic uplift and thick erosion event in the periods of the Caledonian and the Hercynian, the source rocks of the Qiongzhusi Fm had experienced two times of hydrocarbon generation and two times of hydrocarbon generation lag. The overlying super-thick strata deposited during the Indosinian and Yanshan periods made the source rocks of the Qiongzhusi Fm continuously generate oil and gas. The crude oil in the paleo-reservoir of the Longwangmiao Fm had experienced one time of oil-cracking gas process. After the Indo-Chinese epoch, the burial depth of the Triassic strata was deep enough to promote the crude oil in the paleo-reservoir of the Longwangmiao Fm to be cracked gas. This process continued to the late Yanshan period, providing sufficient gas source. The following five conclusions are obtained: The tectonic and depositional evolution of the marine superimposed basins controlled the development of the basic hydrocarbon geology

  11. Metal-catalysed azidation of tertiary C-H bonds suitable for late-stage functionalization

    NASA Astrophysics Data System (ADS)

    Sharma, Ankit; Hartwig, John F.

    2015-01-01

    Many enzymes oxidize unactivated aliphatic C-H bonds selectively to form alcohols; however, biological systems do not possess enzymes that catalyse the analogous aminations of C-H bonds. The absence of such enzymes limits the discovery of potential medicinal candidates because nitrogen-containing groups are crucial to the biological activity of therapeutic agents and clinically useful natural products. In one prominent example illustrating the importance of incorporating nitrogen-based functionality, the conversion of the ketone of erythromycin to the -N(Me)CH2- group in azithromycin leads to a compound that can be dosed once daily with a shorter treatment time. For such reasons, synthetic chemists have sought catalysts that directly convert C-H bonds to C-N bonds. Most currently used catalysts for C-H bond amination are ill suited to the intermolecular functionalization of complex molecules because they require excess substrate or directing groups, harsh reaction conditions, weak or acidic C-H bonds, or reagents containing specialized groups on the nitrogen atom. Among C-H bond amination reactions, those forming a C-N bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to form from ketones or alcohols that might be created in a biosynthetic pathway by oxidation. Here we report a mild, selective, iron-catalysed azidation of tertiary C-H bonds that occurs without excess of the valuable substrate. The reaction tolerates aqueous environments and is suitable for the functionalization of complex structures in the late stages of a multistep synthesis. Moreover, this azidation makes it possible to install a range of nitrogen-based functional groups, including those from Huisgen `click' cycloadditions and the Staudinger ligation. We anticipate that these reactions will create opportunities to modify natural products, their precursors and their derivatives to produce analogues that contain different polarity and charge as a

  12. Differential expression of midgut proteins in Trypanosoma brucei gambiense-stimulated vs. non-stimulated Glossina palpalis gambiensis flies

    PubMed Central

    Geiger, Anne; Hamidou Soumana, Illiassou; Tchicaya, Bernadette; Rofidal, Valérie; Decourcelle, Mathilde; Santoni, Véronique; Hem, Sonia

    2015-01-01

    The unicellular pathogenic protozoan Trypanosoma brucei gambiense is responsible for the chronic form of sleeping sickness. This vector-borne disease is transmitted to humans by the tsetse fly of the group Glossina palpalis, including the subspecies G. p. gambiensis, in which the parasite completes its developmental cycle. Sleeping sickness control strategies can therefore target either the human host or the fly vector. Indeed, suppression of one step in the parasite developmental cycle could abolish parasite transmission to humans, with consequences on the spreading of the disease. In order to develop this type of approach, we have identified, at the proteome level, events resulting from the tripartite interaction between the tsetse fly G. p. gambiensis, its microbiome, and the trypanosome. Proteomes were analyzed from four biological replicates of midguts from flies sampled 3 days post-feeding on either a trypanosome-infected (stimulated flies) or a non-infected (non-stimulated flies) bloodmeal. Over 500 proteins were identified in the midguts of flies from both feeding groups, 13 of which were shown to be differentially expressed in trypanosome-stimulated vs. non-stimulated flies. Functional annotation revealed that several of these proteins have important functions that could be involved in modulating the fly infection process by trypanosomes (and thus fly vector competence), including anti-oxidant and anti-apoptotic, cellular detoxifying, trypanosome agglutination, and immune stimulating or depressive effects. The results show a strong potential for diminishing or even disrupting fly vector competence, and their application holds great promise for improving the control of sleeping sickness. PMID:26029185

  13. Rural-Urban Differences in Late-Stage Breast Cancer: Do Associations Differ by Rural-Urban Classification System?

    PubMed Central

    Pruitt, Sandi L; Eberth, Jan M; Morris, E Scott; Grinsfelder, David B; Cuate, Erica L

    2016-01-01

    Introduction Rural residence is associated with later stage of breast cancer diagnosis in some but not all prior studies. The lack of a standardized definition of rural residence may contribute to these mixed findings. We characterize and compare multiple definitions of rural vs. non-rural residence to provide guidance regarding choice of measures and to further elucidate rural disparities in breast cancer stage at diagnosis. Methods We used Texas Cancer Registry data of 120,738 female breast cancer patients ≥50 years old diagnosed between 1995–2009. We defined rural vs. non-rural residence using 7 different measures and examined their agreement using Kappa statistics. Measures were defined at various geographic levels: county, ZIP code, census tract, and census block group. Late-stage was defined as regional or distant disease. For each measure, we tested the association of rural residence and late-stage cancer with unadjusted and adjusted logistic regression. Covariates included: age; patient race/ethnicity; diagnosis year; census block group-level mammography capacity; and census tract-level percent poverty, percent Hispanic, and percent Black. Results We found moderate to high levels of agreement between measures of rural vs. non-rural residence. For 72.9% of all patients, all 7 definitions agreed as to rural vs. non-rural residence. Overall, 6 of 7 definitions demonstrated an adverse association between rural residence and late-stage disease in unadjusted and adjusted models (Adjusted OR Range = 1.09–1.14). Discussion Our results document a clear rural disadvantage in late-stage breast cancer. We contribute to the heterogeneous literature by comparing varied measures of rural residence. We recommend use of the census tract-level Rural Urban Commuting Area Codes in future cancer outcomes research where small area data are available. PMID:27158685

  14. Ultraviolet to Infrared SED (Spectral Energy Distribution) Analysis of Nearby Late-Stage Merging Galaxies Using CIGALE

    NASA Astrophysics Data System (ADS)

    Weiner, Aaron; Ashby, Matthew; Martinez-Galarza, Juan Rafael; Hayward, Christopher C.; Hung, Chao-Ling; Lanz, Lauranne; Rosenthal, Lee; Smith, Howard Alan; Willner, Steven P.; Zezas, Andreas

    2016-01-01

    We present an analysis of the fundamental properties of nearby merging galaxies based on in-depth analysis of their spectral energy distributions. Our new sample, which is based on the catalog of nearby merging galaxies from the SIGS sample (Spitzer Interacting Galaxy Sample; Lanz et al. 2013, 2014), cross-correlates the Revised IRAC-FSC Redshift Catalogue (Wang et al. 2014) with Galaxy Zoo, which builds on and extends the previous investigation by Lanz et al. in two ways. First it enlarges the sample considerably, increasing the statistical power of the analysis significantly. Second, it includes galaxies in the most advanced merger stage, filling a potential gap in the Lanz et al. sample. The cross-correlation gave 453 possible mergers, between 400 and 453 of which are interacting on some level. After more clearly defining the evolutionary stages of the merging process, these galaxies' stages were identified morphologically, and selected according to brightness () and stage (late stages 4-6), more than tripling the total late-stage sample to about 40 or 50 systems, 16 of which have sufficient observational data for a full SED analysis. These, along with the late-stage mergers found in the SIGS sample, have been photometered from the ultraviolet (UV) to the far-infrared (FIR) and subsequently fit and analyzed by the newly revised and updated CIGALE (Code Investigating Galaxy Emission; Burgarella et al. 2005) in order to retrieve key physical properties of the galaxies including star-formation rate (SFR), AGN fraction, and stellar and dust mass, as well as identify any trends in terms of shape and physical properties of spectra within the evolutionary range of late-stage mergers.

  15. Late-stage orogenic processes: How to link surface motion with distinct lithospheric processes

    NASA Astrophysics Data System (ADS)

    Neubauer, F.; Heberer, B.

    2009-04-01

    There is still a lack of knowledge of surface expression caused by deep-seated lithospheric processes, and how such processes could be distinguished from other, e.g. climate-induced, surface processes like denudation. Surface expressions of deep-seated lithospheric processes in convergent settings are expected to have been long-lived and to show large wave-length structures creating a dynamic topography (Wortel and Spakman, 2000; Cloetingh and Ziegler, 2007). Resulting continent-continent collisional orogens are bivergent, and the principal vergency of collisional orogens is controlled by the previous subduction of oceanic lithosphere (Beaumont et al., 1996). A number of tectonic processes are shown to be active during late orogenic phases and these processes particularly result in specific patterns of surface uplift and denudation of the evolving orogens as well as subsidence in the associated foreland basin. A number of these processes are not fully understood. Late-stage orogenic processes include, among others, slab break-off, slab delamination respectively of lithospheric roots, back-thrusting, tectonic indentation and consequent orogen-parallel lateral extrusion and formation of Subduction-Transform Edge Propagator (STEP) faults acting on the subducting lithosphere (Molnar and Tapponnier, 1975; Wortel and Spakman, 2000; Ratschbacher et al., 1991; Govers and Wortel, 2005). Here, we discuss these processes mainly in terms of their near-surface geological expressions within the orogen and the associated foreland basins, and how these processes could be distinguished by such geological features. We also show distinct theoretical models applied to the arcuate Alpine-Balkan-Carpathian-Dinaric system, which is driven by the oblique convergence of Africa-Europe. Slab-break-off results in lateral orogen-parallel migration of sharp subsidence in a linear belt in front of the slab window, coupled subsidence and subsequent uplift/basin inversion of peripheral foreland

  16. Mouse Fetal Liver Culture System to Dissect Target Gene Functions at the Early and Late Stages of Terminal Erythropoiesis

    PubMed Central

    Zhao, Baobing; Mei, Yang; Yang, Jing; Ji, Peng

    2014-01-01

    Erythropoiesis involves a dynamic process that begins with committed erythroid burst forming units (BFU-Es) followed by rapidly dividing erythroid colony forming units (CFU-Es). After CFU-Es, cells are morphologically recognizable and generally termed terminal erythroblasts. One of the challenges for the study of terminal erythropoiesis is the lack of experimental approaches to dissect gene functions in a chronological manner. In this protocol, we describe a unique strategy to determine gene functions in the early and late stages of terminal erythropoiesis. In this system, mouse fetal liver TER119 (mature erythroid cell marker) negative erythroblasts were purified and transduced with exogenous expression of cDNAs or small hairpin RNAs (shRNAs) for the genes of interest. The cells were subsequently cultured in medium containing growth factors other than erythropoietin (Epo) to maintain their progenitor stage for 12 hr while allowing the exogenous cDNAs or shRNAs to express. The cells were changed to Epo medium after 12 hr to induce cell differentiation and proliferation while the exogenous genetic materials were already expressed. This protocol facilitates analysis of gene functions in the early stage of terminal erythropoiesis. To study late stage terminal erythropoiesis, cells were immediately cultured in Epo medium after transduction. In this way, the cells were already differentiated to the late stage of terminal erythropoiesis when the transduced genetic materials were expressed. We recommend a general application of this strategy that would help understand detailed gene functions in different stages of terminal erythropoiesis. PMID:25225899

  17. The Relationship between Neighborhood Immigrant Composition, Limited English Proficiency, and Late-Stage Colorectal Cancer Diagnosis in California

    PubMed Central

    Mojica, Cynthia M.; Glenn, Beth A.; Chang, Cindy; Bastani, Roshan

    2015-01-01

    Despite the availability of effective early detection technologies, more than half (61%) of colorectal cancers in the United States and 55% in California are identified at an advanced stage. Data on colorectal cancer patients (N = 35,030) diagnosed from 2005 to 2007 were obtained from the California Cancer Registry. Multivariate analyses found a relationship among neighborhood concentration of recent immigrants, neighborhood rates of limited English proficiency, and late-stage colorectal cancer diagnosis. Hispanics living in neighborhoods with a greater percentage of recent immigrants (compared to the lowest percentage) had greater odds (OR 1.57, 95% CI 1.22, 2.02) of late-stage diagnosis whereas Hispanics living in neighborhoods with the highest percentage of limited English proficiency (compared to the lowest percentage) had lower odds (OR .71, 95% CI .51, .99) of late-stage diagnosis. These relationships were not observed for other ethnic groups. Results highlight the complex relationship among race/ethnicity, neighborhood characteristics, and colorectal cancer stage at diagnosis. PMID:26504808

  18. An Internet-Based Multimedia Education Prototype to Enhance Late-Stage Dementia Care: Formative Research Results*

    PubMed Central

    Hobday, John V.; Savik, Kay; Gaugler, Joseph E.

    2011-01-01

    The goal of this project was to develop a portable, Internet-based multimedia education program (IBME) to provide a more efficient training resource for direct care workers (DCWs) who care for nursing home residents suffering from late-stage dementia. Thirty-four DCWs from eight nursing homes in eight states completed five post-test open-ended questions and 20 Likert items on the feasibility, strengths, and weaknesses of the IBME prototype. Pre- and post-test surveys also examined whether late-stage dementia care knowledge changed significantly. Over 90% of DCWs “agreed” or “strongly agreed” that the IBME prototype improved DCWs’ feelings of competency and everyday care delivery. Open-ended comments offered several suggestions for improvement, including group-based discussion of the modules. Results also found that DCWs’ late-stage dementia care knowledge significantly increased (p < .001) following completion of the IBME modules. The IBME prototype offers an online, ansychronous training strategy to enhance dementia-pertinent knowledge and skills related to everyday care delivery in nursing homes. PMID:20691503

  19. Numerical simulations of late-stage magma flow in La Gloria pluton, central Chile

    NASA Astrophysics Data System (ADS)

    Gutierrez, F. J.; Payacan, I.; Bachmann, O.; Parada, M.

    2012-12-01

    along solidification fronts. The core of the chamber remains at temperatures above the solidus as a consequence of thermal insulation from the colder host rocks, ultimately surviving up to 20 k.y. This allows enough time for extraction of residual leucogranitic melt and late magmatic reactive processes. The model explains (1) the previously determined compositional and mineralogical zoning pattern in the pluton; (2) late magmatic mineral re-equilibration recorded in samples from the core of the pluton; (3) the late-stage liquid extraction from a crystal mush, producing leucogranite dikes found in several areas around LGP; and (4) the AMS and mineral orientation data. This research has been developed by the FONDECYT N°11100241 and PBCT-PDA07 projects granted by Chilean National Commission for Science and Technology (CONICYT ). FG and OB were supported by U.S. National Science Foundation (NSF) grant EAR-080982 during the completion of this research. Temperature of the magma: (A) maximum and minimum value on time; and (B) cross section of the model at 3.5 kyr of simulation.

  20. Forces from the Portal Govern the Late-Stage DNA Transport in a Viral DNA Packaging Nanomotor.

    PubMed

    Jing, Peng; Burris, Benjamin; Zhang, Rong

    2016-07-12

    In the Phi29 bacteriophage, the DNA packaging nanomotor packs its double-stranded DNA genome into the virus capsid. At the late stage of DNA packaging, the negatively charged genome is increasingly compacted at a higher density in the capsid with a higher internal pressure. During the process, two Donnan effects, osmotic pressure and Donnan equilibrium potentials, are significantly amplified, which, in turn, affect the channel activity of the portal protein, GP10, embedded in the semipermeable capsid shell. In the research, planar lipid bilayer experiments were used to study the channel activities of the viral protein. The Donnan effect on the conformational changes of the viral protein was discovered, indicating GP10 may not be a static channel at the late stage of DNA packaging. Due to the conformational changes, GP10 may generate electrostatic forces that govern the DNA transport. For the section of the genome DNA that remains outside of the connector channel, a strong repulsive force from the viral protein would be generated against the DNA entry; however, for the section of the genome DNA within the channel, the portal protein would become a Brownian motor, which adopts the flash Brownian ratchet mechanism to pump the DNA against the increasingly built-up internal pressure (up to 20 atm) in the capsid. Therefore, the DNA transport in the nanoscale viral channel at the late stage of DNA packaging could be a consequence of Brownian movement of the genomic DNA, which would be rectified and harnessed by the forces from the interior wall of the viral channel under the influence of the Donnan effect. PMID:27410744

  1. Mass spectrometry data for in vitro protein profiles in early and late stages of Douglas-fir xylogenesis.

    PubMed

    Dziedzic, Jowita A; McDonald, Armando G

    2016-06-01

    A Douglas-fir tissue culture system was developed [1] that could be induced to differentiate into tracheary elements (fibers) making it possible to monitor xylogenesis in vitro by a proteomics approach. Two proteomes, one from an early and one from a late stage of fiber differentiation process were analyzed and compared. Obtained mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository [2] with the dataset identifiers PXD001484 and DOI:10.6019/ PXD001484 [3]. PMID:27408915

  2. Midgut expression of immune-related genes in Glossina palpalis gambiensis challenged with Trypanosoma brucei gambiense

    PubMed Central

    Hamidou Soumana, Illiassou; Tchicaya, Bernadette; Chuchana, Paul; Geiger, Anne

    2014-01-01

    Tsetse flies from the subspecies Glossina morsitans morsitans and Glossina palpalis gambiensis, respectively, transmit Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The former causes the acute form of sleeping sickness, and the latter provokes the chronic form. Although several articles have reported G. m. morsitans gene expression following trypanosome infection, no comparable investigation has been performed for G. p. gambiensis. This report presents results on the differential expression of immune-related genes in G. p. gambiensis challenged with T. b. gambiense. The aim was to characterize transcriptomic events occurring in the tsetse gut during the parasite establishment step, which is the crucial first step in the parasite development cycle within its vector. The selected genes were chosen from those previously shown to be highly expressed in G. m. morsitans, to allow further comparison of gene expression in both Glossina species. Using quantitative PCR, genes were amplified from the dissected midguts of trypanosome-stimulated, infected, non-infected, and self-cleared flies at three sampling timepoints (3, 10, and 20 days) after a bloodmeal. At the 3-day sampling point, transferrin transcripts were significantly up-regulated in trypanosome-challenged flies versus flies fed on non-infected mice. In self-cleared flies, serpin-2 and thioredoxin peroxidase-3 transcripts were significantly up-regulated 10 days after trypanosome challenge, whereas nitric oxide synthase and chitin-binding protein transcripts were up-regulated after 20 days. Although the expression levels of the other genes were highly variable, the expression of immune-related genes in G. p. gambiensis appears to be a time-dependent process. The possible biological significance of these findings is discussed, and the results are compared with previous reports for G. m. morsitans. PMID:25426112

  3. Salmonella enterica serovar Enteritidis enterocolitis during late stages of gestation induces an adverse pregnancy outcome in the murine model.

    PubMed

    Noto Llana, Mariángeles; Sarnacki, Sebastián Hernán; Aya Castañeda, María del Rosario; Pustovrh, María Carolina; Gartner, Alejandra Sonia; Buzzola, Fernanda Roxana; Cerquetti, María Cristina; Giacomodonato, Mónica Nancy

    2014-01-01

    Foodborne diseases caused by Salmonella enterica serovar Enteritidis (S. Enteritidis) are a significant health problem. Pregnancy, state of immunological tolerance, is a predisposing condition for the development of infections with intracellular pathogens. Salmonella species can cause pregnancy complications such as chorioamnionitis, transplacental fetal infection, pre term labor, abortions, neonatal and maternal septicemia. However, the specific mechanisms by which Salmonella infections trigger these alterations are not clear. In the present work, using a self-limiting enterocolitis murine model, we show that the ingestion of a low dose of S. Enteritidis at late stages of pregnancy (day 15 of gestation) is sufficient to induce massive maternal infection. We found that Salmonella infection leads to 40% of pre term delivery, 33% of abortion and fetal growth restriction. Placental dysfunction during S. Enteritidis enterocolitis was confirmed through cellular infiltration and hypoxia markers (MPO activity and COX-1 and COX-2 expression, respectively). Apoptosis in placental tissue due to Salmonella infection was also evident at day 18 of gestation when investigated by morphometric procedure, DNA fragmentation and Fas/FasL expression. Also, the expression of IFN-γ, TNF-α, IL-17 and IL-10 was up regulated in response to Salmonella not only in placenta, but also in amniotic fluid and maternal serum. Altogether, our results demonstrate that S. Enteritidis enterocolitis during late stages of gestation causes detrimental effect on pregnancy outcome. PMID:25365504

  4. Long-term effects of laser-imiquimod combination in the treatment of late-stage melanoma patients

    NASA Astrophysics Data System (ADS)

    Naylor, Mark F.; Le, Henry; Li, Xiaosong; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

    2012-03-01

    Topical application of a potent immunological modulator, imiquimod, followed by laser irradiation has been used for the treatment of late-stage melanoma patients. This novel approach, laser-assisted laser immunotherapy (LIT), targets the root course of melanoma, a highly metastatic cancer. We started a phase I clinical trial in 2006 with promising initial outcomes. The laser-imiquimod combination showed significant palliative effects for these patients with multiple treatment cycles. For the returning patients, we found that the recurrent tumors were less aggressive than usually seen in untreated patients. The current protocol uses a light-absorbing dye for selective laser photothermal interaction with a non-invasive treatment mode. It has limitations for patient treatment, particularly for large, deeper tumors, and for patients with dark pigmented skins. This study provides some information on the treated patients (both stage IV and stage IV) during the past several years. We also discuss the future directions of LIT, particularly in the area of photothermal treatment mode with a new approach of interstitial irradiation. The current results in melanoma treatment using LIT indicate that the combination of photothermal therapy and immunological stimulation may hold the key for the treatment of late-stage, metastatic cancers, not only for cutaneous cancers such as melanoma and breast cancer, but also for deep and internal tumors using different operations modes such as interstitial laser irradiation.

  5. Overexpression of feline tripartite motif-containing 25 interferes with the late stage of feline leukemia virus replication.

    PubMed

    Koba, Ryota; Oguma, Keisuke; Sentsui, Hiroshi

    2015-06-01

    Tripartite motif-containing 25 (TRIM25) regulates various cellular processes through E3 ubiquitin ligase activity. Previous studies have revealed that the expression of TRIM25 is induced by type I interferon and that TRIM25 is involved in the host cellular innate immune response against retroviral infection. Although retroviral infection is prevalent in domestic cats, the roles of feline TRIM25 in the immune response against these viral infections are poorly understood. Because feline TRIM25 is expected to modulate the infection of feline leukemia virus (FeLV), we investigated its effects on early- and late-stage FeLV replication. This study revealed that ectopic expression of feline TRIM25 in HEK293T cells reduced viral protein levels leading to the inhibition of FeLV release. Our findings show that feline TRIM25 has a potent antiviral activity and implicate an antiviral mechanism whereby feline TRIM25 interferes with late-stage FeLV replication. PMID:25913257

  6. New insights on the late-stage history of glacial Lake Ojibway: implications for meltwater discharges of the last deglaciation

    NASA Astrophysics Data System (ADS)

    Roy, Martin; Veillette, Jean J.; Godbout, Pierre-Marc

    2016-04-01

    The decay of the Laurentide ice sheet is believed to be responsible for abrupt climate variations during the last deglaciation and early Holocene, notably through massive discharges of meltwater that had accumulated in large ice-dammed lakes such as Lake Agassiz and Lake Ojibway. Indeed, high-resolution North Atlantic marine records indicate that the ocean's circulation was affected by several outbursts of meltwater during the late deglacial interval. Yet, field evidence and geological data supporting multi-step drawdowns of Lake Agassiz-Ojibway are relatively limited, underlying important uncertainties in the late-stage history of these glacial lakes. Furthermore, physical evidence for the drainage of glacial lakes remains relatively rare in depositional records, giving rise to much debate on the location of outlets and discharge pathways, as well as on the climate impact of the attendant meltwater forcing. Recent investigations of geomorphological and sedimentary records in northern Ontario and Quebec (Canada) have revealed new insights on the late-stage evolution of Lake Ojibway. The number of Ojibway lake phases have so far remained poorly documented mainly because of the dominance of fine-grained glaciolacustrine sediments in the lake basin that prevented the formation of extensive sandy/bouldery strandlines. We thus developed an alternative approach based on the study of a complex sequence of relict terraces carved in the Ojibway clay plain. The elevation measurement of 154 raised wave-cut scarps provided evidence for four distinct shorelines, three of which projecting well below the main outlet that controlled the elevation of the lake during the deglaciation. The elevation, uplift gradients, and areal extent of these shorelines indicate that these low-elevation lake levels formed during the late stages of the deglaciation, following abrupt drawdowns of the lake's surface. Insights on the origin of these late-stage phases are provided from sediment sequences

  7. Respiratory viral infections in institutions from late stage of the first and second waves of pandemic influenza A (H1N1) 2009, Ontario, Canada

    PubMed Central

    Asner, Sandra; Peci, Adriana; Marchand‐Austin, Alex; Winter, Anne‐Luise; Olsha, Romy; Kristjanson, Erik; Low, Donald E.; Gubbay, Jonathan B.

    2012-01-01

    Please cite this paper as: Asner et al. (2012) Respiratory viral infections in institutions from late stage of the first and second waves of pandemic A (H1N1) 2009, Ontario, Canada. Influenza and Other Respiratory Viruses 6(3), e11–e15. We report the impact of respiratory viruses on various outbreak settings by using surveillance data from the late first and second wave periods of the 2009 pandemic. A total of 278/345(78·5%) outbreaks tested positive for at least one respiratory virus by multiplex PCR. We detected A(H1N1)pdm09 in 20·6% of all reported outbreaks of which 54·9% were reported by camps, schools, and day cares (CSDs) and 29·6% by long‐term care facilities (LCFTs), whereas enterovirus/human rhinovirus (ENT/HRV) accounted for 62% outbreaks of which 83·7% were reported by long‐term care facilities (LCTFs). ENT/HRV was frequently identified in LTCF outbreaks involving elderly residents, whereas in CSDs, A(H1N1)pdm09 was primarily detected. PMID:22353417

  8. Downregulation of transforming growth factor β (TGFβ) and latent TGFβ binding protein (LTBP)-4 expression in late stage canine mammary tumours.

    PubMed

    Klopfleisch, R; Schütze, M; Gruber, A D

    2010-12-01

    Although canine mammary tumours (CMT) are the most common malignant tumours in bitches the pathogenesis is far from understood. To analyse the role of the transforming growth factor β (TGFβ) family in the carcinogenesis of CMT, relative mRNA and protein expression of TGFβ-1, -2 and -3, TGFβ receptor (TGFβR)-1 and -3, latent TGFβ-binding protein (LTBP)-1, -3 and -4, and oestrogen receptor α in CMT were quantified. mRNA expression concentrations were measured in laser-microdissected tissue samples of mammary adenomas, carcinomas and their lymph node metastases and normalised to the non-neoplastic mammary gland of the same dog. Carcinomas and metastases had significantly decreased expression levels of TGFβ-3, TGFβR-3 and LTBP-4, but increased LTBP-1 expression when compared to non-neoplastic glands or adenomas. Decreased TGFβ and LTBP-4 expression were confirmed immunohistochemically. The data suggested that loss of TGFβ-3 and LTBP-4 may have growth-stimulatory effects in late-stage tumours, and loss of their expression, together with reduced TGFβR-3 expression, may be associated with increased proliferative activity of CMT similar to findings in human breast cancer. PMID:19836277

  9. Synthesis and Late-Stage Functionalization of Complex Molecules through C–H Fluorination and Nucleophilic Aromatic Substitution

    PubMed Central

    2015-01-01

    We report the late-stage functionalization of multisubstituted pyridines and diazines at the position α to nitrogen. By this process, a series of functional groups and substituents bound to the ring through nitrogen, oxygen, sulfur, or carbon are installed. This functionalization is accomplished by a combination of fluorination and nucleophilic aromatic substitution of the installed fluoride. A diverse array of functionalities can be installed because of the mild reaction conditions revealed for nucleophilic aromatic substitutions (SNAr) of the 2-fluoroheteroarenes. An evaluation of the rates for substitution versus the rates for competitive processes provides a framework for planning this functionalization sequence. This process is illustrated by the modification of a series of medicinally important compounds, as well as the increase in efficiency of synthesis of several existing pharmaceuticals. PMID:24918484

  10. FORMING CLOSE-IN EARTH-LIKE PLANETS VIA A COLLISION-MERGER MECHANISM IN LATE-STAGE PLANET FORMATION

    SciTech Connect

    Ji Jianghui; Jin Sheng; Tinney, C. G. E-mail: qingxiaojin@gmail.com

    2011-01-20

    The large number of exoplanets found to orbit their host stars in very close orbits have significantly advanced our understanding of the planetary formation process. It is now widely accepted that such short-period planets cannot have formed in situ, but rather must have migrated to their current orbits from a formation location much farther from their host star. In the late stages of planetary formation, once the gas in the protoplanetary disk has dissipated and migration has halted, gas giants orbiting in the inner disk regions will excite planetesimals and planetary embryos, resulting in an increased rate of orbital crossings and large impacts. We present the results of dynamical simulations for planetesimal evolution in this later stage of planet formation. We find that a mechanism is revealed by which the collision-merger of planetary embryos can kick terrestrial planets directly into orbits extremely close to their parent stars.

  11. SU-E-T-381: Radio-Dynamic Therapy (RDT) for the Treatment of Late-Stage Cancers

    SciTech Connect

    Ma, C; Chen, L; Price, R; Zhang, Q; Zeng, J; Xu, K; Sun, Q

    2014-06-01

    Purpose: Photo-dynamic therapy (PDT) is an effective treatment modality because of the preferential absorption of photosensitizing agent in tumor cells than in surrounding normal tissues. A limitation of PDT for cancer therapy is the finite penetration of laser light to activate the targeting agent in deep-seated tumors. Radio-dynamic therapy (RDT) is designed to overcome this problem by the combination of high-energy (up to 45MV) photon beams and photo/radio-sensitizers. This work investigates the feasibility of PDT for late-stage cancer patients who are no longer respond to conventional therapies available. Methods: The high-energy photon beams are generated using a LA45 RaceTrack Microtron (Top Grade Medical, Beijing, China). The targeting agent investigated is 5- aminolevulinic acid (5-ALA). Both in vitro cell lines and in vivo animal models have been used to investigate the mechanisms of RDT and its therapeutic effects and normal tissue toxicities. Oral 5-ALA (30-60 mg/kg) was administered 4-6 hours before the radiation treatment and the total radiation dose varied between 0.1-4.0Gy in 1-4 fractions. Clinical trials are initiated in China for late-stage cancer patients targeting both primary tumors utilizing localized therapies such as 3DCRT/IMRT and metastases using TBI. Results: There is clear correlation between the cell death and the 5-ALA concentration/radiation dose. The therapeutic effect of RDT is demonstrated using an animal model where the volume of parotid tumors for the RT only group continued to grow after 3Gy irradiation while the RDT group showed a complete response with the same radiation dose. The preliminary clinical results showed encouraging clinical outcome. Conclusion: RDT is a novel treatment technique that may be developed into an effective cancer treatment modality. Further studies on the mechanisms of RDT and its potential clinical applications are warranted.

  12. Effect of chicory seed extract on glucose tolerance test (GTT) and metabolic profile in early and late stage diabetic rats

    PubMed Central

    2012-01-01

    Background and purpose of the study The goal was to evaluate and compare the effects of aqueous extract of the seeds of chicory, Cichorium intybus L., on glucose tolerance test (GTT) and blood biochemical indices of experimentally-induced hyperglycemic rats. Methods Late stage and early stage of Type 2 diabetes mellitus (T2DM) were induced in rats by streptozotocin (STZ) and a combination of STZ and niacinamide (NIA/STZ), respectively. Within each group, one subgroup received daily i. p. injections of chicory extract (125 mg/kg body weight, for 28 days). Body weight and fasting blood sugar (FBS) were measured weekly. Blood was analyzed for glycosylated hemoglobin (HbA1c) and sera for alanine aminotransferase (ALT), aspartate aminotransferase (AST), nitric oxide (NO), triacylglycerol (TG), total cholesterol (TC), total protein, and insulin on days 10 and 28 after treatment. Intraperitoneal glucose tolerance test (IPGTT) along with insulin determination was performed on a different set of rats in which the chicory-treated groups received the extract for 10 days. Results During 4 weeks of treatment, chicory prevented body-weight loss and decreased FBS. ALT activities and levels of TG, TC and HbA1c decreased, and concentration of NO increased in the chicory treated groups (p < 0.05). Unlike late-stage diabetes, fasting serum insulin concentrations were higher and GTT pattern approximated to normal in chicory-treated early-stage diabetic rats. Conclusions Chicory appeared to have short-term (about 2 hours, as far as GTT is concerned) and long-term (28 days, in this study) effects on diabetes. Chicory may be useful as a natural dietary supplement for slowing down the pace of diabetes progress, and delaying the development of its complications. PMID:23352214

  13. Late-stage magmatic processes at Albano Maar, Colli Albani, Italy: insights from FTIR analysis of leucites

    NASA Astrophysics Data System (ADS)

    Cross, J. K.; Roberge, J.; Smith, V.; Giordano, G.; Tomlinson, E.; Menzies, M. A.

    2011-12-01

    The recently erupted Albano Maar, one of the Via dei Laghi phreatomagmatic eruptions of Colli Albani, Italy have eruptive deposits that are K-foiditic (9wt% K2O) and silica under-saturated (48-52wt% SiO2). These compositions suggest the melts are low viscosity [1, 2], but they fuelled very explosive eruptions, namely the widespread large Peperino ignimbrite (phreato-Plinian) deposits. Therefore a question asked by researchers is how could these melts explode and would they, if they had not interacted with groundwater? Experimental work has shown that the melt chemistries at Colli Albani require a volatile saturated system [3]. Consequently the CO2 and H2O content of the melts are critical to understanding the petrogenetic processes at Albano Maar. Since the juvenile tephra clasts exhibit extensive late stage micro-crystallization (mainly leucite), analysis of glass is difficult and not representative as the majority of the volatile components may have exsolved from the melt. Melt inclusions are also commonly recrystallized and often leaky so here we unravel the complex volatile histories of the melts using the abundant leucite crystals, which have been shown to contain magmatic water in recent studies [4]. FTIR analysis of leucite phenocrysts and microcrysts within juvenile tephra clasts (syn-eruptive) of all the erupted units at Albano Maar provide an interesting insight into volatile variations and record a late stage CO2 fluxing event, which would have contributed to the explosive nature of the eruptions. This study has also allowed for an increased understanding of the nominally anhydrous minerals (NAMs) that crucially record volatile speciation and fluxing in high level magmatic systems. [1] Freda et al., 2006, Bul Vol, 68, pp567-591 [2] Cross et al., 2011 IUGG abs [3] Freda et al., 2008, Lithos, pp397-415 [4] Ventura et al., 2008, Am Min, 93, pp1538-1544

  14. Motor neuron pathology and behavioral alterations at late stages in a SMA mouse model.

    PubMed

    Fulceri, Federica; Bartalucci, Alessia; Paparelli, Silvio; Pasquali, Livia; Biagioni, Francesca; Ferrucci, Michela; Ruffoli, Riccardo; Fornai, Francesco

    2012-03-01

    Spinal muscular atrophy (SMA) is a neurogenetic autosomal recessive disorder characterized by degeneration of lower motor neurons. The validation of appropriate animal models is key in fostering SMA research. Recent studies set up an animal model showing long survival and slow disease progression. This model is knocked out for mouse SMN (Smn(-/-)) gene and carries a human mutation of the SMN1 gene (SMN1A2G), along with human SMN2 gene. In the present study we used this knock out double transgenic mouse model (SMN2(+/+); Smn(-/-); SMN1A2G(+/-)) to characterize the spinal cord pathology along with motor deficit at prolonged survival times. In particular, motor neuron loss was established stereologically (44.77%) after motor deficit reached a steady state. At this stage, spared motor neurons showed significant cell body enlargement. Moreover, similar to what was described in patients affected by SMA we found neuronal heterotopy (almost 4% of total motor neurons) in the anterior white matter. The delayed disease progression was likely to maintain fair motor activity despite a dramatic loss of large motor neurons. This provides a wonderful tool to probe novel drugs finely tuning the survival of motor neurons. In fact, small therapeutic effects protracted over considerable time intervals (even more than a year) are expected to be magnified. PMID:22306031

  15. LL-37 as a therapeutic target for late stage prostate cancer

    PubMed Central

    Hensel, Jonathan A.; Chanda, Diptiman; Kumar, Sanjay; Sawant, Anandi; Grizzle, William E.; Siegal, Gene P.; Ponnazhagan, Selvarangan

    2010-01-01

    BACKGROUND The antimicrobial peptide, LL-37 (leucine-leucine-37), stimulates proliferation, angiogenesis and cellular migration, inhibits apoptosis and is associated with inflammation. Since these functional processes are often exaggerated in cancer, the aim of the present study was to investigate the expression and role of LL-37 in prostate cancer (PCa) and establish its value as a therapeutic target. METHODS We evaluated the expression of LL-37 and the murine orthologue, Cathelicidin Related Anti-Microbial Peptide (CRAMP) in human and murine prostate tumors, respectively. Compared to normal/benign prostate tissue, both LL-37 and CRAMP were increasingly over-expressed with advancing grades of primary prostate cancer and its metastasis in human tissues and in the Transgenic Adenocarcinoma Mouse Prostate (TRAMP) model, correspondingly. We subsequently knocked down CRAMP in the highly tumorigenic TRAMP-C1 cell line via a RNA interference (RNAi) strategy to examine the importance of CRAMP on cellular proliferation, angiogenesis, invasion, apoptosis, activation of signaling pathways and tumor kinetics. RESULTS Abrogation of CRAMP expression led to decreased proliferation, invasion, type IV collagenase, and the amount of phosphorylated Erk1/2 and Akt signaling in vitro. These results were paralleled in vivo. Syngenic implantation of TRAMP-C1 cells subjected to CRAMP knock-down resulted in a decreased tumor incidence and size, and the down regulation of pro-tumorigenic mechanisms. CONCLUSIONS CRAMP knockdown in a murine prostate cancer model analogously demonstrated the tumorigenic contributions of LL-37 in PCa and its potential as a novel therapeutic target for the treatment of PCa and potentially, other cancers over-expressing the peptide. PMID:20957672

  16. Trim33/Tif1γ is involved in late stages of granulomonopoiesis in mice.

    PubMed

    Chrétien, Marie-Lorraine; Legouge, Caroline; Martin, Romain Z; Hammann, Arlette; Trad, Malika; Aucagne, Romain; Largeot, Anne; Bastie, Jean-Noël; Delva, Laurent; Quéré, Ronan

    2016-08-01

    Trim33/Tif1γ (Trim33) is a member of the tripartite motif family. Using a conditional hematopoietic-specific Trim33 knock-out (Trim33(Δ/Δ)) mouse, we showed previously that Trim33 deficiency in hematopoietic stem cells leads to severe defects in hematopoiesis, resembling the main features of human chronic myelomonocytic leukemia. We also demonstrated that Trim33 is involved in hematopoietic aging through TGFβ signaling. Nevertheless, how Trim33 contributes to the terminal stages of myeloid differentiation remains to be clarified. We reveal here the crucial role of Trim33 expression in the control of mature granulomonocytic differentiation. An important component of Trim33-deficient mice is the alteration of myeloid differentiation, as characterized by dysplastic features, abnormal granulocyte and monocyte maturation, and the expansion of CD11b(+)Ly6G(high)Ly6C(low) myeloid cells, which share some features with polymorphonuclear-myeloid-derived suppressor cells. Moreover, in Trim33(Δ/Δ) mice, we observed the alteration of CSF-1-mediated macrophage differentiation in association with the lack of Csf-1 receptor. Altogether, these results indicate that Trim33 deficiency leads to the expansion of a subset of myeloid cells characterizing the myelodysplastic/myeloproliferative neoplasm. PMID:27130375

  17. Suppression of aversive memories associates with changes in early and late stages of neurocognitive processing.

    PubMed

    Chen, Chunping; Liu, Chao; Huang, Ruiwang; Cheng, Dazhi; Wu, Haiyan; Xu, Pengfei; Mai, Xiaoqin; Luo, Yue-Jia

    2012-10-01

    Unwanted memories, such as emotionally negative, can be intentionally suppressed through voluntary control in humans. Memory suppression is thought to be mediated by the interplay of a chain of neurocognitive processes. However, empirical data in support of this notion is lacking. Using high-temporal resolution event-related potential (ERP) technique, we investigated the time course of ERPs associated with suppression of negative and neutral memories in a Think/No-Think paradigm in young, healthy participants. Results showed that participants had greater difficulty in suppressing emotionally negative memories than neutral ones. ERPs and source analyses demonstrated that memory suppression processing for negative and neutral memories were generally associated with changes during early components of a time window of 70-260 ms, such as P1 and N2, mainly at the right inferior frontal gyrus and occipital lobe; suppression of aversive memories was associated with two major late ERP components between 380 and 800 ms, with significantly smaller later negativity (LN) but larger late parietal positivity (LPP), primarily at the right medial and superior frontal gyri. These results suggest that differences in early components may reflect early stages of suppression processing including visual awareness, attention reallocation, and executive processing. Differences in late components between suppression of aversive and neutral memories may reflect a process of down-regulating conscious recollection of memory representations supported by prefrontal and parietal networks. A less effective control of this process, as evidenced by smaller LN and larger LPP, may explain the fact that emotionally negative memories were harder to be suppressed. Altogether, these findings suggest that suppression of aversive memories requires down-regulation of late conscious recollection, which can be dissociated from early visual and attention processing in memory suppression. PMID:22917568

  18. RNA-seq de novo Assembly Reveals Differential Gene Expression in Glossina palpalis gambiensis Infected with Trypanosoma brucei gambiense vs. Non-Infected and Self-Cured Flies

    PubMed Central

    Hamidou Soumana, Illiassou; Klopp, Christophe; Ravel, Sophie; Nabihoudine, Ibouniyamine; Tchicaya, Bernadette; Parrinello, Hugues; Abate, Luc; Rialle, Stéphanie; Geiger, Anne

    2015-01-01

    Trypanosoma brucei gambiense (Tbg), causing the sleeping sickness chronic form, completes its developmental cycle within the tsetse fly vector Glossina palpalis gambiensis (Gpg) before its transmission to humans. Within the framework of an anti-vector disease control strategy, a global gene expression profiling of trypanosome infected (susceptible), non-infected, and self-cured (refractory) tsetse flies was performed, on their midguts, to determine differential genes expression resulting from in vivo trypanosomes, tsetse flies (and their microbiome) interactions. An RNAseq de novo assembly was achieved. The assembled transcripts were mapped to reference sequences for functional annotation. Twenty-four percent of the 16,936 contigs could not be annotated, possibly representing untranslated mRNA regions, or Gpg- or Tbg-specific ORFs. The remaining contigs were classified into 65 functional groups. Only a few transposable elements were present in the Gpg midgut transcriptome, which may represent active transpositions and play regulatory roles. One thousand three hundred and seventy three genes differentially expressed (DEGs) between stimulated and non-stimulated flies were identified at day-3 post-feeding; 52 and 1025 between infected and self-cured flies at 10 and 20 days post-feeding, respectively. The possible roles of several DEGs regarding fly susceptibility and refractoriness are discussed. The results provide new means to decipher fly infection mechanisms, crucial to develop anti-vector control strategies. PMID:26617594

  19. The transcriptional signatures of Sodalis glossinidius in the Glossina palpalis gambiensis flies negative for Trypanosoma brucei gambiense contrast with those of this symbiont in tsetse flies positive for the parasite: possible involvement of a Sodalis-hosted prophage in fly Trypanosoma refractoriness?

    PubMed

    Hamidou Soumana, Illiassou; Loriod, Béatrice; Ravel, Sophie; Tchicaya, Bernadette; Simo, Gustave; Rihet, Pascal; Geiger, Anne

    2014-06-01

    Tsetse flies, such as Glossina palpalis gambiensis, are blood-feeding insects that could be subverted as hosts of the parasite Trypanosoma brucei gambiense: initiated in the tsetse fly mid gut, the developmental program of this parasite further proceeds in the salivary glands. The flies act as vectors of this human-invasive parasite when their salivary glands sustain the generation of metacyclic trypomastigotes, the exclusive morphotypes pre-programmed to further develop in the human individuals. Briefly, once the metacyclic trypomastigotes have been deposited in the skin of humans from whom the parasite-hosting tsetse flies are taking their blood meals, the complex developmental program of this Trypanosoma brucei subspecies can result in a severe disease named sleeping sickness. Unveiling the processes that could prevent, in tsetse flies, the developmental program of T. b. gambiense could contribute reducing the prevalence of the disease. Using a global approach, we were curious to extract transcriptional signatures of Sodalis glossinidius, a symbiont hosted by three distinct groups of tsetse flies. To meet this objective, the transcriptome of S. glossinidius from susceptible and refractory tsetse flies was analyzed at 3, 10 and 20 days after flies blood feed on T. b. gambiense-hosting mice. Within this temporal window, 176 trypanosome responsive genes were shown to interact in well-defined patterns making it possible to distinguish flies susceptible to the parasite infection from refractory flies. Among the modulated transcripts in the symbiont population of flies refractory to trypanosome infection many were shown to cluster within the following networks: "lysozyme activity, bacteriolytic enzyme, bacterial cytolysis, cell wall macromolecule catabolic process". These novel data are further delineated in the following questions: could the activation of prophage hosted by S. glossinidius lead to the release of bacterial agonists that trigger the tsetse fly immune

  20. Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014

    PubMed Central

    Schneider, Lon S.; Mangialasche, Francesca; Andreasen, Niels; Feldman, Howard; Giacobini, Ezio; Jones, Roy; Mantua, Valentina; Mecocci, Patrizia; Pani, Luca; Winblad, Bengt; Kivipelto, Miia

    2014-01-01

    The modern era of drug development for Alzheimer’s disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer’s disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here we review the development of treatments for Alzheimer’s disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer’s disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild to moderate Alzheimer’s disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer’s disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6 to 12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities

  1. Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014.

    PubMed

    Schneider, L S; Mangialasche, F; Andreasen, N; Feldman, H; Giacobini, E; Jones, R; Mantua, V; Mecocci, P; Pani, L; Winblad, B; Kivipelto, M

    2014-03-01

    The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or 'mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living

  2. Human African Trypanosomiasis Transmission, Kinshasa, Democratic Republic of Congo

    PubMed Central

    Diabakana, Philemon Mansinsa; Mesu, Victor Kande Betu Ku; Manzambi, Emile Zola; Ollivier, Gaelle; Asonganyi, Tazoacha; Cuny, Gerard; Grébaut, Pascal

    2006-01-01

    To investigate the epidemiology of human African trypanosomiasis (sleeping sickness) in Kinshasa, Democratic Republic of Congo, 2 entomologic surveys were conducted in 2005. Trypanosoma brucei gambiense and human-blood meals were found in tsetse fly midguts, which suggested active disease transmission. Vector control should be used to improve human African trypanosomiasis control efforts. PMID:17326955

  3. Late-Stage Caregiving

    MedlinePlus

    ... Daily Life Daily Plan Activities Communication Food & Eating Music & Art Personal Care Incontinence Bathing Dressing & Grooming Dental ... For example, try: Playing his or her favorite music Reading portions of books that have meaning for ...

  4. Magma mixing in late-stage granitoids of the Pioneer intrusive complex, south central Idaho and tectonic implications

    SciTech Connect

    Woods, A.J.; Geist, D. . Dept. of Geology)

    1993-04-01

    Eocene granitoids that intrude the Pioneer Mountain core complex, located approximately twenty miles northeast of Sun Valley, Idaho, grad west to east from mafic granodiorite to porphyritic quartz monzonite. The two main phases, porphyritic coarse-grained quartz monzonite and fine-grained granodiorite, exhibit field evidence suggestive of magma mixing as indicated by gradational contacts with swirling textures on scales from centimeters to tens of meters, and both phases are found as inclusion within each other. Generally, granodiorite intrudes quartz monzonite and may represent a late stage injection into the center of the semi-consolidated monzonitic magma. Petrological modeling indicates the hybrids are mixtures of the monzonite and granodiorite. Field and petrographic evidence suggest emplacement of the granitoids occurred before latest faulting, as demonstrated by a lack of contact metamorphic effects on the surrounding Paleozoic sediments. Moreover, the development of gneissic fabric, cataclastic and mylonitic fabrics, development of cross-cutting chlorite, epidote, and quartz veinlets, and brecciated fault contacts within the granitoids provide further support for Eocene emplacement prior to or contemporaneous with faulting. These observations provide additional constraints on the cessation of extensional tectonics in south central Idaho.

  5. The role of the temporal lobe semantic system in number knowledge: evidence from late-stage semantic dementia.

    PubMed

    Jefferies, Elizabeth; Bateman, David; Lambon Ralph, Matthew A

    2005-01-01

    Previous reports have demonstrated that many aspects of number knowledge remain unimpaired in semantic dementia, despite severe comprehension problems in other domains. It is argued that this advantage for numbers arises because the disease spares the parietal lobe magnitude system thought to be critical for number processing. Models of numerical cognition that favour a separation between verbal and magnitude representations of number might, however, predict a restricted impairment of the verbal number code in this condition. We obtained support for this hypothesis in a patient with late-stage semantic dementia. She was impaired at a variety of tasks tapping the verbal number code; for example, reading and writing Arabic numerals, naming and word-picture matching with dot pictures, reading aloud number words, digit span and magnitude comparison/serial ordering tasks with number words. In contrast, she demonstrated good understanding of the magnitude and serial order of numbers when tested with Arabic numerals and non-symbolic representations. These findings suggest that although the magnitude meaning of numbers is isolated from the temporal lobe semantic system, the anterior infero-temporal lobe may play a critical role in binding English number words to their non-symbolic magnitude meaning. PMID:15716160

  6. Plasmodium falciparum cysteine protease falcipain-2 cleaves erythrocyte membrane skeletal proteins at late stages of parasite development.

    PubMed

    Hanspal, Manjit; Dua, Meenakshi; Takakuwa, Yuichi; Chishti, Athar H; Mizuno, Akiko

    2002-08-01

    Plasmodium falciparum-derived cysteine protease falcipain-2 cleaves host erythrocyte hemoglobin at acidic pH and specific components of the membrane skeleton at neutral pH. Analysis of stage-specific expression of these 2 proteolytic activities of falcipain-2 shows that hemoglobin-hydrolyzing activity is maximum in early trophozoites and declines rapidly at late stages, whereas the membrane skeletal protein hydrolyzing activity is markedly increased at the late trophozoite and schizont stages. Among the erythrocyte membrane skeletal proteins, ankyrin and protein 4.1 are cleaved by native and recombinant falcipain-2 near their C-termini. To identify the precise peptide sequence at the hydrolysis site of protein 4.1, we used a recombinant construct of protein 4.1 as substrate followed by MALDI-MS analysis of the cleaved product. We show that falcipain-2-mediated cleavage of protein 4.1 occurs immediately after lysine 437, which lies within a region of the spectrin-actin-binding domain critical for erythrocyte membrane stability. A 16-mer peptide containing the cleavage site completely inhibited the enzyme activity and blocked falcipain-2-induced fragmentation of erythrocyte ghosts. Based on these results, we propose that falcipain-2 cleaves hemoglobin in the acidic food vacuole at the early trophozoite stage, whereas it cleaves specific components of the red cell skeleton at the late trophozoite and schizont stages. It is the proteolysis of skeletal proteins that causes membrane instability, which, in turn, facilitates parasite release in vivo. PMID:12130521

  7. Effects of laser immunotherapy on late-stage, metastatic breast cancer patients in a Phase II clinical trial

    NASA Astrophysics Data System (ADS)

    Ferrel, Gabriela L.; Zhou, Feifan; Li, Xiaosong; Hode, Tomas; Nordquist, Robert E.; Alleruzzo, Luciano; Chen, Wei R.

    2014-03-01

    Laser immunotherapy (LIT), a novel technique with a local intervention to induce systemic antitumor effects, was developed to treat metastatic cancers. The pre-clinical studies of LIT have shown its unique characteristics in generating a specific antitumor immunity in treating metastatic tumors in rats and mice. For late-stage, metastatic breast cancer patients, who were considered to be out of other available treatment options, we conducted a small Phase II clinical trial using LIT starting in 2009 in Lima, Peru. This Phase II study was closed in December of 2012, as acknowldged by the Ministry of Health (MOH) of Peur letter 438-2014-OGITT/INS dated March 5th, 2014. Ten patients were enrolled and received LIT in one or multiple 4-week treatment cycles. At the study closing date, four patients were alive and two of them remained cancer free. Here, following the successful conclusion of our Phase II study, we report the clinical effects of LIT on metastatic breast cancer patients. Specifically, we present the overall status of all the patients three years after the treatment and also the outcomes of two long-term surviving patients.

  8. Differential responses of individuals with late-stage dementia to two novel environments: a multimedia room and an interior garden.

    PubMed

    Goto, Seiko; Kamal, Naveed; Puzio, Helene; Kobylarz, Fred; Herrup, Karl

    2014-01-01

    The purpose of this study was to determine the responses of individuals with advanced dementia to two novel sensory environments in a nursing home facility. The first was a multisensory Snoezelen room; the second was a temporary Japanese garden. Subjects viewed each environment twice a week for 15 minutes during the study. Stress was measured using heart rate and informant-based behavioral changes. By these criteria, the garden-viewing group showed positive behavioral changes while the responses of the subjects in the Snoezelen group were more negative. The response of the subjects' pulse rate was most dramatic. During the 15 minutes in the garden, the average rate (all subjects/all visits) was significantly less than in their residential room. In the Snoezelen room, we detected little or no change. The impact of the garden could also be seen in the negative behavioral signs elicited upon returning the subjects to the garden room after the installation had been replaced with plants and furniture arranged with no formal design. We propose that exposure to a small interior Japanese garden could be an effective intervention for individuals suffering from late stage Alzheimer's disease. PMID:25024307

  9. Extreme chemical conditions of crystallisation of Umbrian Melilitolites and wealth of rare, late stage/hydrothermal minerals

    NASA Astrophysics Data System (ADS)

    Stoppa, F.; Schiazza, M.

    2014-12-01

    Melilitolites of the Umbria Latium Ultra-alkaline District display a complete crystallisation sequence of peculiar, late-stage mineral phases and hydrothermal/cement minerals, analogous to fractionated mineral associations from the Kola Peninsula. This paper summarises 20 years of research which has resulted in the identification of a large number of mineral species, some very rare or completely new and some not yet classified. The progressive increasing alkalinity of the residual liquid allowed the formation of Zr-Ti phases and further delhayelitemacdonaldite mineral crystallisation in the groundmass. The presence of leucite and kalsilite in the igneous assemblage is unusual and gives a kamafugitic nature to the rocks. Passage to non-igneous temperatures (T<600 °C) is marked by the metastable reaction and formation of a rare and complex zeolite association (T<300 °C). Circulation of low-temperature (T<100 °C) K-Ca-Ba-CO2-SO2-fluids led to the precipitation of sulphates and hydrated and/or hydroxylated silicate-sulphate-carbonates. As a whole, this mineral assemblage can be considered typical of ultra-alkaline carbonatitic rocks.

  10. Characterization of mesostasis regions in lunar basalts: Understanding late-stage melt evolution and its influence on apatite formation

    NASA Astrophysics Data System (ADS)

    Potts, Nicola J.; TartèSe, Romain; Anand, Mahesh; Westrenen, Wim; Griffiths, Alexandra A.; Barrett, Thomas J.; Franchi, Ian A.

    2016-07-01

    Recent studies geared toward understanding the volatile abundances of the lunar interior have focused on the volatile-bearing accessory mineral apatite. Translating measurements of volatile abundances in lunar apatite into the volatile inventory of the silicate melts from which they crystallized, and ultimately of the mantle source regions of lunar magmas, however, has proved more difficult than initially thought. In this contribution, we report a detailed characterization of mesostasis regions in four Apollo mare basalts (10044, 12064, 15058, and 70035) in order to ascertain the compositions of the melts from which apatite crystallized. The texture, modal mineralogy, and reconstructed bulk composition of these mesostasis regions vary greatly within and between samples. There is no clear relationship between bulk-rock basaltic composition and that of bulk-mesostasis regions, indicating that bulk-rock composition may have little influence on mesostasis compositions. The development of individual melt pockets, combined with the occurrence of silicate liquid immiscibility, exerts greater control on the composition and texture of mesostasis regions. In general, the reconstructed late-stage lunar melts have roughly andesitic to dacitic compositions with low alkali contents, displaying much higher SiO2 abundances than the bulk compositions of their host magmatic rocks. Relevant partition coefficients for apatite-melt volatile partitioning under lunar conditions should, therefore, be derived from experiments conducted using intermediate compositions instead of compositions representing mare basalts.

  11. Serine protease P-IIc is responsible for the digestion of yolk proteins at the late stage of silkworm embryogenesis.

    PubMed

    Wang, Dandan; Zhang, Yan; Dong, Zhaoming; Guo, Pengchao; Ma, Sanyuan; Guo, Kaiyu; Xia, Qingyou; Zhao, Ping

    2016-07-01

    In silkworms, yolk proteins comprise vitellin, egg-specific protein and 30K proteins, which are sequentially degraded by endogenous proteases strictly regulated during embryogenesis. Although the process has been extensively investigated, there is still a gap in the knowledge about the degradation of silkworm yolk proteins on the last two days of embryonic development. In the present study, we isolated and purified a gut serine protease P-IIc, which demonstrated optimal activity at 25 °C and pH 11. Semi-quantitative RT-PCR combined with western blotting showed that P-IIc was actively expressed and significantly accumulated in the gut on the last two days of embryogenesis. When natural yolk proteins were incubated with P-IIc in vitro, vitellin and ESP were selectively degraded. P-IIc also demonstrated activity towards 30K proteins as evidenced by rapid and complete digestion of BmLP1 and partial digestion of BmLP2 and BmLP3. Furthermore, RNAi knockdown of P-IIc in silkworm embryos significantly reduced the degradation rate of residual yolk proteins on embryonic day 10. Taken together, our results indicate that P-IIc represents an embryonic gut protease with a relatively broad substrate specificity, which plays an important role in the degradation of yolk proteins at the late stage of silkworm embryogenesis. PMID:27137459

  12. X-Ray Computed Tomography: Semiautomated Volumetric Analysis of Late-Stage Lung Tumors as a Basis for Response Assessments

    PubMed Central

    Bendtsen, C.; Kietzmann, M.; Korn, R.; Mozley, P. D.; Schmidt, G.; Binnig, G.

    2011-01-01

    Background. This study presents a semiautomated approach for volumetric analysis of lung tumors and evaluates the feasibility of using volumes as an alternative to line lengths as a basis for response evaluation criteria in solid tumors (RECIST). The overall goal for the implementation was to accurately, precisely, and efficiently enable the analyses of lesions in the lung under the guidance of an operator. Methods. An anthropomorphic phantom with embedded model masses and 71 time points in 10 clinical cases with advanced lung cancer was analyzed using a semi-automated workflow. The implementation was done using the Cognition Network Technology. Results. Analysis of the phantom showed an average accuracy of 97%. The analyses of the clinical cases showed both intra- and interreader variabilities of approximately 5% on average with an upper 95% confidence interval of 14% and 19%, respectively. Compared to line lengths, the use of volumes clearly shows enhanced sensitivity with respect to determining response to therapy. Conclusions. It is feasible to perform volumetric analysis efficiently with high accuracy and low variability, even in patients with late-stage cancer who have complex lesions. PMID:21747819

  13. Characterization of mesostasis regions in lunar basalts: Understanding late-stage melt evolution and its influence on apatite formation

    NASA Astrophysics Data System (ADS)

    Potts, Nicola J.; TartèSe, Romain; Anand, Mahesh; Westrenen, Wim; Griffiths, Alexandra A.; Barrett, Thomas J.; Franchi, Ian A.

    2016-09-01

    Recent studies geared toward understanding the volatile abundances of the lunar interior have focused on the volatile-bearing accessory mineral apatite. Translating measurements of volatile abundances in lunar apatite into the volatile inventory of the silicate melts from which they crystallized, and ultimately of the mantle source regions of lunar magmas, however, has proved more difficult than initially thought. In this contribution, we report a detailed characterization of mesostasis regions in four Apollo mare basalts (10044, 12064, 15058, and 70035) in order to ascertain the compositions of the melts from which apatite crystallized. The texture, modal mineralogy, and reconstructed bulk composition of these mesostasis regions vary greatly within and between samples. There is no clear relationship between bulk-rock basaltic composition and that of bulk-mesostasis regions, indicating that bulk-rock composition may have little influence on mesostasis compositions. The development of individual melt pockets, combined with the occurrence of silicate liquid immiscibility, exerts greater control on the composition and texture of mesostasis regions. In general, the reconstructed late-stage lunar melts have roughly andesitic to dacitic compositions with low alkali contents, displaying much higher SiO2 abundances than the bulk compositions of their host magmatic rocks. Relevant partition coefficients for apatite-melt volatile partitioning under lunar conditions should, therefore, be derived from experiments conducted using intermediate compositions instead of compositions representing mare basalts.

  14. Acylated Cholesteryl Galactosides Are Specific Antigens of Borrelia Causing Lyme Disease and Frequently Induce Antibodies in Late Stages of Disease

    PubMed Central

    Stübs, Gunthard; Fingerle, Volker; Wilske, Bettina; Göbel, Ulf B.; Zähringer, Ulrich; Schumann, Ralf R.; Schröder, Nicolas W. J.

    2009-01-01

    Borrelia burgdorferi sensu lato is the causative agent of Lyme disease (LD), an infectious disease occurring in North America, Europe, and Asia in different clinical stages. B. burgdorferi sensu lato encompasses at least 12 species, with B. burgdorferi sensu stricto, B. garinii, and B. afzelii being of highest clinical importance. Immunologic testing for LD as well as recent vaccination strategies exclusively refer to proteinaceous antigens. However, B. burgdorferi sensu stricto exhibits glycolipid antigens, including 6-O-acylated cholesteryl β-d-galactopyranoside (ACGal), and first the data indicated that this compound may act as an immunogen. Here we investigated whether B. garinii and B. afzelii also possess this antigen, and whether antibodies directed against these compounds are abundant among patients suffering from different stages of LD. Gas-liquid chromatography/mass spectroscopy and NMR spectroscopy showed that both B. garinii and B. afzelii exhibit ACGal in high quantities. In contrast, B. hermsii causing relapsing fever features 6-O-acylated cholesteryl β-d-glucopyranoside (ACGlc). Sera derived from patients diagnosed for LD contained antibodies against ACGal, with 80% of patients suffering from late stage disease exhibiting this feature. Antibodies reacted with ACGal from all three B. burgdorferi species tested, but not with ACGlc from B. hermsii. These data show that ACGal is present in all clinically important B. burgdorferi species, and that specific antibodies against this compound are frequently found during LD. ACGal may thus be an interesting tool for improving diagnostics as well as for novel vaccination strategies. PMID:19307181

  15. C-H bond activation enables the rapid construction and late-stage diversification of functional molecules

    NASA Astrophysics Data System (ADS)

    Wencel-Delord, Joanna; Glorius, Frank

    2013-05-01

    The beginning of the twenty-first century has witnessed significant advances in the field of C-H bond activation, and this transformation is now an established piece in the synthetic chemists' toolbox. This methodology has the potential to be used in many different areas of chemistry, for example it provides a perfect opportunity for the late-stage diversification of various kinds of organic scaffolds, ranging from relatively small molecules like drug candidates, to complex polydisperse organic compounds such as polymers. In this way, C-H activation approaches enable relatively straightforward access to a plethora of analogues or can help to streamline the lead-optimization phase. Furthermore, synthetic pathways for the construction of complex organic materials can now be designed that are more atom- and step-economical than previous methods and, in some cases, can be based on synthetic disconnections that are just not possible without C-H activation. This Perspective highlights the potential of metal-catalysed C-H bond activation reactions, which now extend beyond the field of traditional synthetic organic chemistry.

  16. Total synthesis of gracilioether F. Development and application of Lewis acid promoted ketene–alkene [2+2] cycloadditions and late-stage C—H oxidation

    SciTech Connect

    Rasik, Christopher M.; Brown, M. Kevin

    2014-12-22

    The first synthesis of gracilioether F, a polyketide natural product with an unusual tricyclic core and five contiguous stereocenters, is described. Key steps of the synthesis include a Lewis acid promoted ketene–alkene [2+2] cycloaddition and a late-stage carboxylic acid directed C(sp³)—H oxidation. The synthesis requires only eight steps from norbornadiene.

  17. Differences in Late-Stage Diagnosis, Treatment, and Colorectal Cancer-Related Death between Rural and Urban African Americans and Whites in Georgia

    ERIC Educational Resources Information Center

    Hines, Robert B.; Markossian, Talar W.

    2012-01-01

    Purpose: Disparities in health outcomes due to a diagnosis of colorectal cancer (CRC) have been reported for a number of demographic groups. This study was conducted to examine the outcomes of late-stage diagnosis, treatment, and cancer-related death according to race and geographic residency status (rural vs urban). Methods: This study utilized…

  18. Origin of rhythmic anorthositic-pyroxenitic layering in the Damiao anorthosite complex, China: Implications for late-stage fractional crystallization and genesis of Fe-Ti oxide ores

    NASA Astrophysics Data System (ADS)

    Li, Li-Xing; Li, Hou-Min; Li, Yong-Zhan; Yao, Tong; Yang, Xiu-Qing; Chen, Jing

    2015-12-01

    The ∼1.7 Ga Damiao anorthosite complex (DAC) in the North China Craton contains abundant Ti-magnetite-dominated ore deposits. Both the Fe-Ti-P-rich silicate rocks and massive Fe-Ti-(P) ores occur as discordant late-stage dikes cross-cutting early-stage anorthosites with irregular but sharp boundaries. Field and petrographic observations indicate that some late-stage dikes are composed of unique oxide-apatite gabbronorites (OAGNs), whereas others comprise well-developed alternating late-stage anorthosites and Fe-Ti-P-rich pyroxenites defining rhythmic layers. Massive Fe-Ti-(P) ores are closely related to the Fe-Ti-P-rich pyroxenites. Plagioclase and whole-rock compositions of different rock types were analyzed to constrain the late-stage magma evolution and genesis of the Fe-Ti oxide ores. The similar mineralogical assemblages, REE and HFSE patterns suggest that the different rock types formed by differentiation from a common parental magma. Early-stage anorthosites are characterized by positive Eu anomalies and low REE contents, whereas the late-stage dike-like rocks display no significant Eu anomalies and high REE contents. Plagioclase compositions in the late-stage rocks show a decrease of An contents when compared to that of the early-stage rocks. Based on field relations, petrography and well-defined linear compositional trends, the sequence of crystallization is inferred as: early-stage anorthosites + leuconorites + norites, OAGNs, late-stage anorthosites + Fe-Ti-P-rich pyroxenites + massive Fe-Ti-(P) ores, and massive Fe-Ti-(P) ores. The OAGNs which underwent relatively rapid crystallization represent an early phase during the residual magma evolution after anorthosite separation, whereas the rhythmic layers formed by slow but extensive fractional crystallization of interstitial melt. High solubility of phosphorous played an important role in the formation of rhythmic layering. Massive Fe-Ti-(P) ores crystallized and segregated directly from the magma of Fe

  19. Diagenesis and late-stage porosity development in the pennsylvanian strawn formation, val verde basin, Texas, U.S.A

    USGS Publications Warehouse

    David, Newell K.; Goldstein, R.H.; Burdick, C.J.

    2005-01-01

    The Middle Pennsylvanian (Desmoinesian) Strawn Formation in the Trans-Pecos area of Texas was deposited during relative tectonic quiescence that prevailed before rapid infilling of the Val Verde Basin. It represents one of a series of backstepping carbonate ramps formed on the craton side of this foreland basin. Strawn Formation carbonate rocks in three cores - Conoco Anna McClung #3-1, Alex Mitchell S2-1R, and Creek Ranch #10-1 - show several shallowing-up ward sequences, each a few meters thick. The Creek Ranch core displays the deepest-water characteristics of the three cores; the lower part of this core is dominated by graded bedding. The Mitchell and McClung cores contain skeletal-rich carbonates. Both of these cores display characteristics of shallow-water bank or lagoonal environments. All three cores have approximately the same diagenetic history. Primary fluid inclusions indicate early porosity-occluding interparticle and mold-filling calcite precipitated from water with a narrow range of salinities. Modal salinities are that of seawater, but slightly lesser salinities (indicating mixing of seawater and meteoric water) and slightly greater salinities (indicating evaporative concentration of seawater) are also indicated. The influence of meteoric groundwater can be detected by stable-isotope analyses of the early cements at stratigraphic levels that correlate to the tops of the major shallowing-upward depositional sequences. However, subaerial exposure surfaces are not demonstrated in these cores but were likely to be present updip. Most porosity is cement-reduced vugs, dissolution-enlarged (and cement-reduced) molds (> 1/16 mm, < 4 mm), and fractures. Minor intraparticle, intercrystalline, and shelter porosity is also present. Reservoir porosity is caused by fracturing and a late-stage dissolution event. Dissolution in the Creek Ranch core is not as pronounced as in the other cores because of a dearth of skeletal material. Porous zones in the McClung and

  20. Necropsy findings in American alligator late-stage embryos and hatchlings from northcentral Florida lakes contaminated with organochlorine pesticides

    USGS Publications Warehouse

    Sepulveda, M.S.; Del, Piero F.; Wiebe, J.J.; Rauschenberger, H.R.; Gross, T.S.

    2006-01-01

    Increased American alligator (Alligator mississippiensis) embryo and neonatal mortality has been reported from several northcentral Florida lakes contaminated with old-use organochlorine pesticides (OCPs). However, a clear relationship among these contaminants and egg viability has not been established, suggesting the involvement of additional factors in these mortalities. Thus, the main objective of this study was to determine the ultimate cause of mortality of American alligator late-stage embryos and hatchlings through the conduction of detailed pathological examinations, and to evaluate better the role of OCPs in these mortalities. Between 2000 and 2001, 236 dead alligators were necropsied at or near hatching (after ???65 days of artificial incubation and up to 1 mo of age posthatch). Dead animals were collected from 18 clutches ranging in viability from 0% to 95%. Total OCP concentrations in yolk ranged from ???100 to 52,000 ??g/kg, wet weight. The most common gross findings were generalized edema (34%) and organ hyperemia (29%), followed by severe emaciation (14%) and gross deformities (3%). Histopathologic examination revealed lesions in 35% of the animals, with over half of the cases being pneumonia, pulmonary edema, and atelectasis. Within and across clutches, dead embryos and hatchlings compared with their live cohorts were significantly smaller and lighter. Although alterations in growth and development were not related to yolk OCPs, there was an increase in prevalence of histologic lesions in clutches with high OCPs. Overall, these results indicate that general growth retardation and respiratory abnormalities were a major contributing factor in observed mortalities and that contaminants may increase the susceptibility of animals to developing certain pathologic conditions. ?? Wildlife Disease Association 2006.

  1. Testing personalized medicine: patient and physician expectations of next-generation genomic sequencing in late-stage cancer care

    PubMed Central

    Miller, Fiona A; Hayeems, Robin Z; Bytautas, Jessica P; Bedard, Philippe L; Ernst, Scott; Hirte, Hal; Hotte, Sebastien; Oza, Amit; Razak, Albiruni; Welch, Stephen; Winquist, Eric; Dancey, Janet; Siu, Lillian L

    2014-01-01

    Developments in genomics, including next-generation sequencing technologies, are expected to enable a more personalized approach to clinical care, with improved risk stratification and treatment selection. In oncology, personalized medicine is particularly advanced and increasingly used to identify oncogenic variants in tumor tissue that predict responsiveness to specific drugs. Yet, the translational research needed to validate these technologies will be conducted in patients with late-stage cancer and is expected to produce results of variable clinical significance and incidentally identify genetic risks. To explore the experiential context in which much of personalized cancer care will be developed and evaluated, we conducted a qualitative interview study alongside a pilot feasibility study of targeted DNA sequencing of metastatic tumor biopsies in adult patients with advanced solid malignancies. We recruited 29/73 patients and 14/17 physicians; transcripts from semi-structured interviews were analyzed for thematic patterns using an interpretive descriptive approach. Patient hopes of benefit from research participation were enhanced by the promise of novel and targeted treatment but challenged by non-findings or by limited access to relevant trials. Family obligations informed a willingness to receive genetic information, which was perceived as burdensome given disease stage or as inconsequential given faced challenges. Physicians were optimistic about long-term potential but conservative about immediate benefits and mindful of elevated patient expectations; consent and counseling processes were expected to mitigate challenges from incidental findings. These findings suggest the need for information and decision tools to support physicians in communicating realistic prospects of benefit, and for cautious approaches to the generation of incidental genetic information. PMID:23860039

  2. Testing personalized medicine: patient and physician expectations of next-generation genomic sequencing in late-stage cancer care.

    PubMed

    Miller, Fiona A; Hayeems, Robin Z; Bytautas, Jessica P; Bedard, Philippe L; Ernst, Scott; Hirte, Hal; Hotte, Sebastien; Oza, Amit; Razak, Albiruni; Welch, Stephen; Winquist, Eric; Dancey, Janet; Siu, Lillian L

    2014-03-01

    Developments in genomics, including next-generation sequencing technologies, are expected to enable a more personalized approach to clinical care, with improved risk stratification and treatment selection. In oncology, personalized medicine is particularly advanced and increasingly used to identify oncogenic variants in tumor tissue that predict responsiveness to specific drugs. Yet, the translational research needed to validate these technologies will be conducted in patients with late-stage cancer and is expected to produce results of variable clinical significance and incidentally identify genetic risks. To explore the experiential context in which much of personalized cancer care will be developed and evaluated, we conducted a qualitative interview study alongside a pilot feasibility study of targeted DNA sequencing of metastatic tumor biopsies in adult patients with advanced solid malignancies. We recruited 29/73 patients and 14/17 physicians; transcripts from semi-structured interviews were analyzed for thematic patterns using an interpretive descriptive approach. Patient hopes of benefit from research participation were enhanced by the promise of novel and targeted treatment but challenged by non-findings or by limited access to relevant trials. Family obligations informed a willingness to receive genetic information, which was perceived as burdensome given disease stage or as inconsequential given faced challenges. Physicians were optimistic about long-term potential but conservative about immediate benefits and mindful of elevated patient expectations; consent and counseling processes were expected to mitigate challenges from incidental findings. These findings suggest the need for information and decision tools to support physicians in communicating realistic prospects of benefit, and for cautious approaches to the generation of incidental genetic information. PMID:23860039

  3. Late-stage cooling history of the Eastern and Southern Alps and its linkage to Adria indentation

    NASA Astrophysics Data System (ADS)

    Heberer, Bianca; Reverman, Rebecca; Fellin, Maria; Neubauer, Franz; Dunkl, István; Zattin, Massimiliano; Seward, Diane; Brack, Peter; Genser, Johann

    2016-04-01

    Late-orogenic indentation by rigid lithospheric plates and microplates into softer orogenic wedges leads to post-collisional shortening, lithospheric thickening and vertical and lateral extrusion. The European Eastern and Southern Alps represent a prime example of indenter tectonics. Their Late Neogene geodynamic framework is influenced primarily by the ca. NW-ward motion and counterclockwise rotation of the Adriatic microplate with respect to Europe, which resulted in an oblique, dextral transpressional setting. In this study we refine the late-stage exhumation pattern related to indentation of the eastern Adriatic indenter, i.e. the still northward pushing triangular northeastern part of the Southalpine block that indented the Eastern Alps. New apatite (U-Th)/He and apatite fission track thermochronometry data come from (1) the Karawanken Mountains adjacent to the eastern Periadriatic fault along the northeastern edge of the indenter and from (2) the central-eastern Southern Alps from within the indenter and from its western edge. We find apatite (U-Th)/He ages from the Karawanken Mountains ranging between 11 and 6 Ma, which indicate an episode of fault-related exhumation leading to the formation of a positive flower structure and an associated peripheral foreland basin as well as lateral activity along the Periadriatic fault system. Apatite (U/Th)/He and fission-track data combined with previous data from the Southern Alps indicate that exhumation largely occurred during the Late Miocene, too, and was maximized along thrust systems, with highly differential amounts of vertical displacement along individual structures. Our new data contribute to mounting evidence for widespread Late Miocene tectonic activity in the Eastern and Southern Alps. They demonstrate a shift from deformation and exhumation concentrated within the Tauern Window at the beginning of the indentation process, to less pronounced, but more widespread exhumation along the edges as well as the

  4. [Standing crop and spatial distribution of meiofauna in Yellow Sea at late stage of Enteromorpha prolifera bloom in 2008].

    PubMed

    Wu, Xiu-Qin; Xu, Kui-Dong; Yu, Zi-Shan; Yu, Ting-Ting; Meng, Zhao-Cui; Dai, Ren-Hai; Lei, Yan-Li

    2010-08-01

    An investigation was made on the standing crop, spatial distribution, sediment environment of meiofauna at 33 stations (including 22 stations in cold water mass area and 9 stations in Enteromorpha prolifera bloom area) in the Yellow Sea at the late stage of E. prolifera bloom in summer 2008. In this southern Yellow Sea area which was seriously impacted by the green algal bloom, the silt and clay contents in the sediments in 2008 had an obvious increase, compared with those in 2007, and the sediment chlorophyll-a and phaeophytin a contents in 2008 did not show obvious changes in cold water mass area but distinctly decreased in southern Jiangsu inshore area and Yangtze River estuary. Within the total 16 meiofaunal groups sorted, no marked variation was observed in their vertical distribution and in the contribution of each group to the total meiofauna. In 2008, the average abundance of meiofauna was (1375 +/- 793) ind x 10 cm(-2), and the biomass was (1203 +/- 707) micro x 10 cm(-2), both of which were decreased by about 1/3, compared with those in 2007. The meiofaunal standing crop was decreased more obviously in the stations heavily affected by the E. prolifera bloom, while that in the Yellow Sea cold water mass area was slightly increased, resulting in an unusual trend of meiofaunal standing crop decreasing from the central area of cold water mass to the inshore area in the southern Yellow Sea. By contrast, and as usual, the meiofaunal standing crop was increased from the cold water mass area to the inshore area in the northern Yellow Sea. Statistical analyses suggested that only the meiofaunal abundance had positive correlation with the salinity in the stations heavily affected by the green algal bloom. Our study indicated that macroalgal bloom obviously inhibited the standing crop of meiofauna in the inshore area. The decrease was not due to the deficiency of food concentration, but likely caused by the deposition and degradation of the E. prolifera bloom. PMID

  5. Physicians' experiences of caring for late-stage HIV patients in the post-HAART era: challenges and adaptations.

    PubMed

    Karasz, Alison; Dyche, Larry; Selwyn, Peter

    2003-11-01

    As medical treatment for AIDS has become more complex, the need for good palliative and end-of-life care has also increased for patients with advanced disease. Such care is often inadequate, especially among low-income, ethnic minority patients. The current study investigated physicians' experiences with caring for dying HIV patients in an underserved, inner city community in the Bronx, NY. The goals of the study included: (1) to investigate the barriers to effective end-of-life care for HIV patients; and (2) to examine physicians' experiences of role hindrance and frustration in caring for dying patients in the era of HAART. Qualitative, open-ended interviews were conducted with 16 physicians. Physicians identified two core, prescriptive myths shaping their care for patients with HIV. The 'Good Doctor Myth' equates good medical care with the delivery of efficacious biomedical care. The role of the physician is defined as technical curer, while the patient's role is limited to consultation and compliance. The 'Good Death Myth' envisions an ideal death which is acknowledged, organized, and pain free: the role of the physician is defined as that of comforter and supporter in the dying process. Role expectations associated with these myths were often disappointed. First, late-stage patients refused to adhere to treatment and were thus dying "unnecessarily." Second, patients often refused to acknowledge, accept, or plan for the end of life and as a result died painful, chaotic deaths. These realities presented intense psychological and practical challenges for providers. Adaptive coping included both behavioral and cognitive strategies. Successful adaptation resulted in "positive engagement," experienced by participants as a continuing sense of fascination, gratification, and joy. Less successful adaptation could result in detachment or anger. Participants believed that engagement had a powerful impact on patient care. Working with dying HIV patients in the post

  6. Nativity disparities in late-stage diagnosis and cause-specific survival among Hispanic women with invasive cervical cancer: An analysis of Surveillance, Epidemiology, and End Results data

    PubMed Central

    Montealegre, Jane R.; Zhou, Renke; Amirian, E. Susan; Follen, Michele; Scheurer, Michael E.

    2014-01-01

    Purpose While cervical cancer screening and risk behaviors have been found to vary among U.S.- and foreign-born Hispanic women, many cancer epidemiology studies have conceptualized Hispanics as a homogenous group. Here we examine differences in cervical cancer stage at diagnosis and survival among Hispanic women by nativity. Methods We use data from the Surveillance, Epidemiology, and End Results (SEER) program, 1998–2008. Nativity was based on place of birth and was categorized as U.S.- versus foreign-born. Distant and regional tumors were classified as late-stage, while local tumors were classified as early-stage. Results Forty seven percent of cases of invasive cervical cancer among Hispanics were diagnosed at a late stage and over half of invasive cervical cancer cases were among foreign-born women. Foreign-born Hispanic women were significantly more likely than U.S.-born Hispanics to have late-stage diagnosis, after adjusting for age at diagnosis and tumor histology (adjusted odds ration= 1.09, p-value = 0.003). There was heterogeneity in the association between nativity and survival by stage at diagnosis. Among cases with early-stage diagnosis, survival was poorer among foreign-born versus U.S.-born Hispanics after adjusting for age at diagnosis, histology, and cancer-directed therapy (adjusted HR = 1.31, p-value = 0.030). However, among cases with late-stage diagnosis, survival was better among foreign--born Hispanics (adjusted HR = 0.81, p-value < 0.001). Conclusions We hypothesize that nativity differences in survival may be indicative of diverse risk, screening, and treatment profiles. Given such differences, it may be inappropriate to aggregate Hispanics as a single group for cervical cancer research. PMID:23934001

  7. Correlation between Ultrasound Reflection Intensity and Tumor Ablation Ratio of Late-Stage Pancreatic Carcinoma in HIFU Therapy: Dynamic Observation on Ultrasound Reflection Intensity

    PubMed Central

    Ge, Hui-Yu; Miao, Li-Ying; Wang, Jin-Rui; Xiong, Liu-Lin; Yan, Fang; Zheng, Cui-Shan; Jia, Jian-Wen; Cui, Li-Gang; Chen, Wen

    2013-01-01

    The minimally invasive high-intensity focused ultrasound (HIFU) therapy is thermal ablation treatment for late-stage pancreatic carcinoma with widely recognized safety and effectiveness, but there are currently no instant assessment methods for its ablation effect. It is vital to find a real-time high-sensitive assessment method. This research aims to dynamically observe the variation rules of ultrasound reflection intensity, analyze the correlation between ultrasound reflection intensity and tumor ablation ratio, and find out the value of ultrasound reflection intensity in prognosis of HIFU ablation effect. HIFU intermittent therapies were retrospectively analyzed for 31 subjects with late-stage pancreatic carcinoma from March 2007 to December 2009 in the study. The variation rules of the ultrasound reflection intensity during HIFU therapy were summarized and the correlation between ultrasound reflection intensity and tumor ablation ratio was analyzed based on the tumor ablation ratio indicated by CT scanning. The conclusion is that variation of ultrasound reflection intensity can be used for initial assessment of tumor ablation in HIFU therapy and early prognosis of overall HIFU ablation, providing important clinical basis for improving safety and effectiveness of HIFU therapy. Ultrasound can work as a real-time imaging instrument for observation of HIFU ablation effect in treating late-stage pancreatic carcinoma. PMID:24453916

  8. Increased tumor necrosis factor alpha (TNF-alpha) and natural killer cell (NK) function using an integrative approach in late stage cancers.

    PubMed

    See, Darryl; Mason, Stephanie; Roshan, Ramesh

    2002-05-01

    Natural products may increase cytotoxic activity of Natural Killer Cells (NK) Tumor Necrosis Factor alpha (TNF-alpha) while decreasing DNA damage in patients with late-stage cancer. Pilot studies have suggested that a combination of Nutraceuticals can raise NK cell function and TNF-alpha alpha activity and result in improved clinical outcomes in patients with late stage cancer. The objective of the study is to determine if Nutraceuticals can significantly raise NK function and TNF levels in patients with late stage cancer. After informed consent was obtained, 20 patients with stage IV, end-stage cancer were evaluated (one bladder, five breast, two prostate, one neuroblastoma, two non-small cell lung, three colon, 1 mesothelioma, two lymphoma, one ovarian, one gastric, one osteosarcoma). Transfer Factor Plus (TFP+, 3 tablets 3 times per day), IMUPlus (non denatured milk whey protein, 40 gm/day); Intravenous (50 to 100 gm/day) and oral (1-2 gm/day) ascorbic acid; Agaricus Blazeii Murill teas (10 gm/day); Immune Modulator Mix (a combination of vitamin, minerals, antioxidants and immune-enhancing natural products); nitrogenated soy extract (high levels of genistein and dadzein) and Andrographis Paniculata (500 mg twice, daily) were used. Baseline NK function by standard 4 h 51Cr release assay and TNF alpha and receptor levels were measured by ELISA from resting and phytohemagglutinin (PHA) stimulated adherent and non-adherent Peripheral Blood Mononuclear Cell (PBMC). Total mercaptans and glutathione in plasma were taken and compared to levels measured 6 months later. Complete blood counts and chemistry panels were routinely monitored. As of a mean of 6 months, 16/20 patients were still alive. The 16 survivors had significantly higher NK function than baseline (p < .01 for each) and TNF-alpha levels in all four cell populations studied (p < .01 for each). Total mercaptans (p < .01) and TNF-alpha receptor levels were significantly reduced (p < .01). It was also observed

  9. Single Phase 40Ar/39Ar Dating of Rajahmundry Trap Basalts Contemporaneous With Late Stage Deccan Trap Volcanism

    NASA Astrophysics Data System (ADS)

    Knight, K. B.; Knight, K. B.; Renne, P. R.; Renne, P. R.; Halkett, A.; White, N.

    2001-12-01

    The Rajahmundry Traps of eastern peninsular India, often considered to be outliers of the Deccan Traps, occupy ~35 km2 centered on the Krishna-Godavari Basin and extending offshore in the sub-surface. Onshore exposures average 60m in thickness, including a laterally continuous sedimentary interlayer of laterite, limestone and shale ( ~2m thick, total) separating `upper' flows from `lower' flows. 40Ar/39Ar CO2 laser incremental heating analysis of twelve plagioclase separates from Rajahmundry Trap basalts reveal an age of ~64.6 Ma for the entire sequence based on the FCs standard at 28.02 Ma. Flows chosen for dating include 8 sites spanning both the `upper' and `lower' flow sequences. Paleontological studies of sediments adjacent to the basalt at depth in Krishna-Godavari Basin, e.g. Jaiprakash et al. (1993), suggest that the period of time covered by the two flows and intertrappean sediments is up to ca. 6 myr. Dates obtained for this study, however, show that ages for both upper and lower flows are indistinguishable within 2σ error from one another, and span ~2 Ma at most, pointing to a substantial hiatus in the sedimentary record at the top of the upper basalt flows. Extremely high Ca/K ratios (up to ~400) in several samples limits precision due to error propagation attending the large correction necessary for reactor produced 36Ar from Ca. However, plateau ages as precise as 64.8 +/- 0.4 and 65.5 +/- 0.8 from above and below (respectively, 2σ errors) the sedimentary interlayer have been obtained. Samples with both high and low Ca/K ratios confirm rapid eruption of the entire Rajahmundry Trap sequence. A petrogenetic link between these basalts and the Deccan Trap basalts (the remains of which lie over 300 km from the nearest exposure of Rajahmundry Trap) has been suggested but has yet to be substantiated. These new data clearly place the eruption of the Rajahmundry Traps temporally close to the K-T boundary, coincident with late stage Deccan volcanism and

  10. Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates.

    PubMed

    Graf, Fabrice E; Baker, Nicola; Munday, Jane C; de Koning, Harry P; Horn, David; Mäser, Pascal

    2015-08-01

    Aquaglyceroporin-2 is a known determinant of melarsoprol-pentamidine cross-resistance in Trypanosoma brucei brucei laboratory strains. Recently, chimerization at the AQP2-AQP3 tandem locus was described from melarsoprol-pentamidine cross-resistant Trypanosoma brucei gambiense isolates from sleeping sickness patients in the Democratic Republic of the Congo. Here, we demonstrate that reintroduction of wild-type AQP2 into one of these isolates fully restores drug susceptibility while expression of the chimeric AQP2/3 gene in aqp2-aqp3 null T. b. brucei does not. This proves that AQP2-AQP3 chimerization is the cause of melarsoprol-pentamidine cross-resistance in the T. b. gambiense isolates. PMID:26042196

  11. The significance of late-stage processes in lava flow emplacement: squeeze-ups in the 2001 Etna flow field

    NASA Astrophysics Data System (ADS)

    Applegarth, L. J.; Pinkerton, H.; James, M. R.

    2009-04-01

    The general processes associated with the formation and activity of ephemeral boccas in lava flow fields are well documented (e.g. Pinkerton & Sparks 1976; Polacci & Papale 1997). The importance of studying such behaviour is illustrated by observations of the emplacement of a basaltic andesite flow at Parícutin during the 1940s. Following a pause in advance of one month, this 8 km long flow was reactivated by the resumption of supply from the vent, which forced the rapid drainage of stagnant material in the flow front region. The material extruded during drainage was in a highly plastic state (Krauskopf 1948), and its displacement allowed hot fluid lava from the vent to be transported in a tube to the original flow front, from where it covered an area of 350,000 m2 in one night (Luhr & Simkin 1993). Determining when a flow has stopped advancing, and cannot be drained in such a manner, is therefore highly important in hazard assessment and flow modelling, and our ability to do this may be improved through the examination of relatively small-scale secondary extrusions and boccas. The 2001 flank eruption of Mt. Etna, Sicily, resulted in the emplacement of a 7 km long compound `a`ā flow field over a period of 23 days. During emplacement, many ephemeral boccas were observed in the flow field, which were active for between two and at least nine days. The longer-lived examples initially fed well-established flows that channelled fresh material from the main vent. With time, as activity waned, the nature of the extruded material changed. The latest stages of development of all boccas involved the very slow extrusion of material that was either draining from higher parts of the flow or being forced out of the flow interior as changing local flow conditions pressurised parts of the flow that had been stagnant for some time. Here we describe this late-stage activity of the ephemeral boccas, which resulted in the formation of ‘squeeze-ups' of lava with a markedly different

  12. Genotoxic effect of a binary mixture of dicamba- and glyphosate-based commercial herbicide formulations on Rhinella arenarum (Hensel, 1867) (Anura, Bufonidae) late-stage larvae.

    PubMed

    Soloneski, Sonia; Ruiz de Arcaute, Celeste; Larramendy, Marcelo L

    2016-09-01

    The acute toxicity of two herbicide formulations, namely, the 57.71 % dicamba (DIC)-based Banvel(®) and the 48 % glyphosate (GLY)-based Credit(®), alone as well as the binary mixture of these herbicides was evaluated on late-stage Rhinella arenarum larvae (stage 36) exposed under laboratory conditions. Mortality was used as an endpoint for determining acute lethal effects, whereas the single-cell gel electrophoresis (SCGE) assay was employed as genotoxic endpoint to study sublethal effects. Lethality studies revealed LC5096 h values of 358.44 and 78.18 mg L(-1) DIC and GLY for Banvel(®) and Credit(®), respectively. SCGE assay revealed, after exposure for 96 h to either 5 and 10 % of the Banvel(®) LC5096 h concentration or 5 and 10 % of the Credit(®) LC5096 h concentration, an equal significant increase of the genetic damage index (GDI) regardless of the concentration of the herbicide assayed. The binary mixtures of 5 % Banvel(®) plus 5 % Credit(®) LC5096 h concentrations and 10 % Banvel(®) plus 10 % Credit(®) LC5096 h concentrations induced equivalent significant increases in the GDI in regard to GDI values from late-stage larvae exposed only to Banvel(®) or Credit(®). This study represents the first experimental evidence of acute lethal and sublethal effects exerted by DIC on the species, as well as the induction of primary DNA breaks by this herbicide in amphibians. Finally, a synergistic effect of the mixture of GLY and DIC on the induction of primary DNA breaks on circulating blood cells of R. arenarum late-stage larvae could be demonstrated. PMID:27250090

  13. Unravelling Human Trypanotolerance: IL8 is Associated with Infection Control whereas IL10 and TNFα Are Associated with Subsequent Disease Development

    PubMed Central

    Ilboudo, Hamidou; Bras-Gonçalves, Rachel; Camara, Mamadou; Flori, Laurence; Camara, Oumou; Sakande, Hassane; Leno, Mamadou; Petitdidier, Elodie; Jamonneau, Vincent; Bucheton, Bruno

    2014-01-01

    In West Africa, Trypanosoma brucei gambiense, causing human African trypanosomiasis (HAT), is associated with a great diversity of infection outcomes. In addition to patients who can be diagnosed in the early hemolymphatic phase (stage 1) or meningoencephalitic phase (stage 2), a number of individuals can mount long-lasting specific serological responses while the results of microscopic investigations are negative (SERO TL+). Evidence is now increasing to indicate that these are asymptomatic subjects with low-grade parasitemia. The goal of our study was to investigate the type of immune response occurring in these “trypanotolerant” subjects. Cytokines levels were measured in healthy endemic controls (n = 40), stage 1 (n = 10), early stage 2 (n = 19), and late stage 2 patients (n = 23) and in a cohort of SERO TL+ individuals (n = 60) who were followed up for two years to assess the evolution of their parasitological and serological status. In contrast to HAT patients which T-cell responses appeared to be activated with increased levels of IL2, IL4, and IL10, SERO TL+ exhibited high levels of proinflammatory cytokines (IL6, IL8 and TNFα) and an almost absence of IL12p70. In SERO TL+, high levels of IL10 and low levels of TNFα were associated with an increased risk of developing HAT whereas high levels of IL8 predicted that serology would become negative. Further studies using high throughput technologies, hopefully will provide a more detailed view of the critical molecules or pathways underlying the trypanotolerant phenotype. PMID:25375156

  14. Increasing late stage colorectal cancer and rectal cancer mortality demonstrates the need for screening: a population based study in Ireland, 1994-2010

    PubMed Central

    2014-01-01

    Background This paper describes trends in colorectal cancer incidence, survival and mortality from 1994 to 2010 in Ireland prior to the introduction of population-based screening. Methods We examined incidence (National Cancer Registry Ireland (NCRI) and mortality (Central Statistics Office) from 1994 to 2010. Age standardised rates (ASR) for incidence and mortality have been calculated, weighted by the European standard population. Annual percentage change was calculated in addition to testing for linear trends in treatment and case fraction of early and late stage disease. Relative survival was calculated considering deaths from all causes. Results The colorectal cancer ASR was 63.7 per 100,000 in males and 38.7 per 100,000 in females in 2010. There was little change in the ASR over time in either sex, or when colon and rectal cancers were considered separately; however the number of incident cancers increased significantly during 1994-2010 (1752 to 2298). The case fractions of late stage (III/IV) colon and rectal cancers rose significantly over time. One and 5 year relative survival improved for both sexes between the periods 1994-2008. Colorectal cancer mortality ASRs decreased annually from 1994-2009 by 1.8% (95% CI -2.2, -1.4). Rectal cancer mortality ASRs rose annually by 2.4% (95% CI 1.1, 3.6) and 2.8% (95% CI 1.2, 4.4) in males and females respectively. Conclusions Increases in late-stage disease and rectal cancer mortality demonstrate an urgent need for colorectal cancer screening. However, the narrow age range at which screening is initially being rolled-out in Ireland means that the full potential for reductions in late-stage cancers and incidence and mortality are unlikely to be achieved. While it is possible that the observed increase in rectal cancer mortality may be partly an artefact of cause of death misclassification, it could also be explained by variations in treatment and adherence to best practice guidelines; further investigation is

  15. TrypTect CIATT--a card indirect agglutination trypanosomiasis test for diagnosis of Trypanosoma brucei gambiense and T. b. rhodesiense infections.

    PubMed

    Nantulya, V M

    1997-01-01

    A simple and rapid test, the card indirect agglutination trypanosomiasis test (TrypTect CIATT) is described, for detecting circulating antigens in persons suffering from Trypanosoma brucei gambiense and T. b. rhodesiense infection by latex agglutination. The sensitivity of the test (95.8% for T. b. gambiense and 97.7% for T. b. rhodesiense) was significantly higher than that of lymph node puncture, microhaematocrit centrifugation and cerebrospinal fluid examination after single and double centrifugation. The specificity of the test was also high: 106 blood donor sera as well as sera from 37 patients with malaria, 25 with visceral leishmaniasis, 10 with schistosomiasis, 5 with filariasis and 10 with hydatid disease, from trypanosomiasis-free areas, gave negative results. Eighteen clinical suspects from active disease transmission foci, without microscopically detectable parasitaemia but with a positive test result, were further examined by lumbar puncture and inoculation of blood into mice; 11 (61%) were found to be infected, suggesting that the test had a high positive predictive value. This study showed that TrypTect CIATT is a useful test for rapid diagnosis of both patent and non-patent T. b. gambiense and T. b. rhodesiense infections. PMID:9463665

  16. AtMYB2 Regulates Whole Plant Senescence by Inhibiting Cytokinin-Mediated Branching at Late Stages of Development in Arabidopsis1[C][W][OA

    PubMed Central

    Guo, Yongfeng; Gan, Susheng

    2011-01-01

    Whole plant senescence of monocarpic plants consists of three major processes: arrest of shoot apical meristem, organ senescence, and permanent suppression of axillary buds. At early stages of development, axillary buds are inhibited by shoot apex-produced auxin, a mechanism known as apical dominance. How the buds are suppressed as an essential part of whole plant senescence, especially when the shoot apexes are senescent, is not clear. Here, we report an AtMYB2-regulated post apical dominance mechanism by which Arabidopsis (Arabidopsis thaliana) inhibits the outgrowth of axillary buds as part of the whole plant senescence program. AtMYB2 is expressed in the compressed basal internode region of Arabidopsis at late stages of development to suppress the production of cytokinins, the group of hormones that are required for axillary bud outgrowth. atmyb2 T-DNA insertion lines have enhanced expression of cytokinin-synthesizing isopentenyltransferases genes, contain higher levels of cytokinins, and display a bushy phenotype at late stages of development. As a result of the continuous generation of new shoots, atmyb2 plants have a prolonged life span. The AtMYB2 promoter-directed cytokinin oxidase 1 gene in the T-DNA insertion lines reduces the endogenous cytokinin levels and restores the bushy phenotype to the wild type. PMID:21543729

  17. Evidence for throttling as a control over localized late-stage Au/Ag mineralization in the Mineral Hill breccia pipe, Golden Sunlight mine, Jefferson County, Montana

    SciTech Connect

    Coppinger, W.W.; Porter, E.

    1985-01-01

    A restricted zone of anomalous gold and silver mineralization, coupled with localized intense alteration and textural variations, documents the existence of a natural throttle which controlled Au/Ag emplacement during late-stage mineralization of the Mineral Hill breccia pipe. The zone is roughly funnel-shaped with a maximum width of 10m and a length of 30m. Mineralization and alteration are developed along the trend of a steep-dipping to vertical fracture zone and apparently pinch out at depth. Small displacement post-mineralization cross-faults offset contacts and influence grade distribution within the feature. Breccia texture, nature and intensity of alteration, and ore grade very systematically from the margin to the interior of the zone. The breccia becomes rubbly and friable, with frothy, cellular quartz comprising the matrix and as much as 50 percent of the rock in some locations. Au/Ag grades vary directly with the development of the cellular quartz and are highest in the interior, grading to local background levels in the wallrock. Barite and minor white opaline quartz occur in the matrix adjacent to contacts, diminishing in volume toward the interior. Minor primary hematite occurs in some clasts in the interior. Iron-oxides after sulfides are common throughout the zone. The feature is interpreted as late-stage localized zone of venting and pressure-release developed above a constriction in the Mineral Hill hydrothermal mineralizing system.

  18. Sensitivity and Specificity of a Prototype Rapid Diagnostic Test for the Detection of Trypanosoma brucei gambiense Infection: A Multi-centric Prospective Study

    PubMed Central

    Bisser, Sylvie; Lumbala, Crispin; Nguertoum, Etienne; Kande, Victor; Flevaud, Laurence; Vatunga, Gedeao; Boelaert, Marleen; Büscher, Philippe; Josenando, Theophile; Bessell, Paul R.; Biéler, Sylvain; Ndung’u, Joseph M.

    2016-01-01

    Background A major challenge in the control of human African trypanosomiasis (HAT) is lack of reliable diagnostic tests that are rapid and easy to use in remote areas where the disease occurs. In Trypanosoma brucei gambiense HAT, the Card Agglutination Test for Trypanosomiasis (CATT) has been the reference screening test since 1978, usually on whole blood, but also in a 1/8 dilution (CATT 1/8) to enhance specificity. However, the CATT is not available in a single format, requires a cold chain for storage, and uses equipment that requires electricity. A solution to these challenges has been provided by rapid diagnostic tests (RDT), which have recently become available. A prototype immunochromatographic test, the SD BIOLINE HAT, based on two native trypanosomal antigens (VSG LiTat 1.3 and VSG LiTat 1.5) has been developed. We carried out a non-inferiority study comparing this prototype to the CATT 1/8 in field settings. Methodology/Principal Findings The prototype SD BIOLINE HAT, the CATT Whole Blood and CATT 1/8 were systematically applied on fresh blood samples obtained from 14,818 subjects, who were prospectively enrolled through active and passive screening in clinical studies in three endemic countries of central Africa: Angola, the Democratic Republic of the Congo and the Central African Republic. One hundred and forty nine HAT cases were confirmed by parasitology. The sensitivity and specificity of the prototype SD BIOLINE HAT was 89.26% (95% confidence interval (CI) = 83.27–93.28) and 94.58% (95% CI = 94.20–94.94) respectively. The sensitivity and specificity of the CATT on whole blood were 93.96% (95% CI = 88.92–96.79) and 95.91% (95% CI = 95.58–96.22), and of the CATT 1/8 were 89.26% (95% CI = 83.27–93.28) and 98.88% (95% CI = 98.70–99.04) respectively. Conclusion/Significance After further optimization, the prototype SD BIOLINE HAT could become an alternative to current screening methods in primary healthcare settings in remote, resource

  19. The 11,600-MW protein encoded by region E3 of adenovirus is expressed early but is greatly amplified at late stages of infection.

    PubMed Central

    Tollefson, A E; Scaria, A; Saha, S K; Wold, W S

    1992-01-01

    We have reported that an 11,600-MW (11.6K) protein is coded by region E3 of adenovirus. We have now prepared two new antipeptide antisera that have allowed us to characterize this protein further. The 11.6K protein migrates as multiple diffuse bands having apparent Mws of about 14,000, 21,000, and 31,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Immunoblotting as well as virus mutants with deletions in the 11.6K gene were used to show that the various gel bands represent forms of 11.6K. The 11.6K protein was synthesized in very low amounts during early stages of infection, from the scarce E3 mRNAs d and e which initiate from the E3 promoter. However, 11.6K was synthesized very abundantly at late stages of infection, approximately 400 times the rate at early stages, from new mRNAs termed d' and e'. Reverse transcriptase-polymerase chain reaction and RNA blot experiments indicated that mRNAs d' and e' had the same body (the coding portion) and the same middle exon (the y leader) as early E3 mRNAs d and e, but mRNAs d' and e' were spliced at their 5' termini to the major late tripartite leader which is found in all mRNAs in the major late transcription unit. mRNAs d' and e' and the 11.6K protein were the only E3 mRNAs and protein that were scarce early and were greatly amplified at late stages of infection. This suggests that specific cis- or trans-acting sequences may function to enhance the splicing of mRNAs d' and e' at late stages of infection and perhaps to suppress the splicing of mRNAs d and e at early stages of infection. We propose that the 11.6K gene be considered not only a member of region E3 but also a member of the major late transcription unit. Images PMID:1316473

  20. Aliphatic Halogenase Enables Late-Stage C-H Functionalization: Selective Synthesis of a Brominated Fischerindole Alkaloid with Enhanced Antibacterial Activity.

    PubMed

    Zhu, Qin; Hillwig, Matthew L; Doi, Yohei; Liu, Xinyu

    2016-03-15

    The anion promiscuity of a newly discovered standalone aliphatic halogenase WelO5 was probed and enabled the selective synthesis of 13R-bromo-12-epi-fischerindole U via late-stage enzymatic functionalization of an unactivated sp(3) C-H bond. Pre-saturating the WelO5 active site with a non-native bromide anion was found to be critical to the highly selective in vitro transfer of bromine, instead of chlorine, to the target carbon center and also allowed the relative binding affinity of bromide and chloride towards the WelO5 enzyme to be assessed. This study further revealed the critical importance of halogen substitution on modulating the antibiotic activity of fischerindole alkaloids and highlights the promise of WelO5-type aliphatic halogenases as enzymatic tools to fine-tune the bioactivity of complex natural products. PMID:26749394

  1. Disparities in late stage diagnosis, treatment, and breast cancer-related death by race, age, and rural residence among women in Georgia.

    PubMed

    Markossian, Talar W; Hines, Robert B

    2012-01-01

    The objectives of this study were to examine the outcomes of late stage breast cancer diagnosis, receiving first course treatment, and breast cancer-related death by race, age, and rural/urban residence in Georgia. The authors used cross-sectional and follow-up data (1992-2007) for Atlanta and Rural Georgia cancer registries that are part of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (N = 23,500 incident breast cancer cases in non-Hispanic whites or non-Hispanic African Americans). Multilevel modeling and Cox proportional hazard models revealed that compared to whites, African American women had significantly increased odds of late stage diagnosis (odds ratio [OR] = 2.08, p = 0.0001) and unknown tumor stage (OR = 1.27, p = 0.0001), decreased odds of receiving radiation (OR = 0.93, p = 0.041) or surgery (OR = 0.50, p = 0.0001), and increased risk of death following breast cancer diagnosis (hazard rate ratio [HR] = 1.50, p = 0.0001). Increased age was significantly associated with the odds of late/unknown stage at diagnosis, worse treatment, and survival. Women residing in rural areas had significantly decreased odds of receiving radiation and surgery with radiation (OR = 0.59, p = 0.0001), and for receiving breast-conserving surgery compared to mastectomy (OR = 0.73, p = 0.005). Factors affecting each level of the breast cancer continuum are distinct and should be examined separately. Efforts are needed to alleviate disparities in breast cancer outcomes in hard-to-reach populations. PMID:22591230

  2. Lazaroid compounds prevent early but not late stages of oxidant-induced cell injury: potential explanation for the lack of efficacy of lazaroids in clinical trials.

    PubMed

    Huang, H; Patel, P B; Salahudeen, A K

    2001-01-01

    Earlier in vitro studies demonstrated the remarkable potency of the lazaroid compounds to prevent oxidant-induced early cell injury. However, the ability of lazaroid compounds to limit oxidative injury in vivo(including renal ischemia-reperfusion) has been less certain, and the early clinical trials using lazaroids to limit CNS injury or organ injury in the setting of transplantation have not been promising. Lazaroid compounds are potent inhibitors of lipid peroxidation, and their inability to influence other key injury processes, particularly during the late stages of cell injury, might partly explain the limited clinical efficacy. To test this, renal tubular (LLC-PK1) cells were incubated with 250 micromH(2)O(2)for 135 min, in the presence or absence of 2-methyl aminochroman (2-MAC, U-83836E), a lazaroid with potent ability to inhibit lipid peroxidation, or desferrioxamine, (DFO) an iron chelator with broader antioxidant efficacy. Cell injury, lipid peroxidation, DNA damage and ATP depletion were measured in the early (immediately after H(2)O(2)incubation) and late (24 h after H(2)O(2)incubation) stages of cell injury. In the early stage, 2-MAC suppressed H(2)O(2)-induced lipid peroxidation and LDH release, but not the DNA damage, ATP depletion or loss of cell replication. In contrast, DFO suppressed all of the measurements. In the late stages, despite continued suppression of lipid peroxidation, only DFO maintained significant cytoprotection against H(2)O(2), and this was accompanied by reduced DNA damage, higher ATP levels and preservation of cell proliferation. Thus, the inability of the lazaroid compound 2-MAC to sustain cytoprotection in the later stages of cell injury might provide at least a partial explanation for the inefficiency of lazaroids to limit tissue injury in clinical and certain in vivo settings. PMID:11207066

  3. Distribution of calcifying and silicifying phytoplankton in relation to environmental and biogeochemical parameters during the late stages of the 2005 North East Atlantic Spring Bloom

    NASA Astrophysics Data System (ADS)

    Leblanc, K.; Hare, C. E.; Feng, Y.; Berg, G. M.; Ditullio, G. R.; Neeley, A.; Benner, I.; Sprengel, C.; Beck, A.; Sanudo-Wilhelmy, S. A.; Passow, U.; Klinck, K.; Rowe, J. M.; Wilhelm, S. W.; Brown, C. W.; Hutchins, D. A.

    2009-06-01

    The late stage of the North East Atlantic (NEA) spring bloom was investigated during June 2005 along a transect section from 45 to 66° N between 15 and 20° W in order to characterize the contribution of siliceous and calcareous phytoplankton groups and describe their distribution in relation to environmental factors. We measured several biogeochemical parameters such as nutrients, surface trace metals, algal pigments, biogenic silica (BSi), particulate inorganic carbon (PIC) or calcium carbonate, particulate organic carbon, nitrogen and phosphorus (POC, PON and POP, respectively), as well as transparent exopolymer particles (TEP). Results were compared with other studies undertaken in this area since the JGOFS NABE program. Characteristics of the spring bloom generally agreed well with the accepted scenario for the development of the autotrophic community. The NEA seasonal diatom bloom was in the late stages when we sampled the area and diatoms were constrained to the northern part of our transect, over the Icelandic Basin (IB) and Icelandic Shelf (IS). Coccolithophores dominated the phytoplankton community, with a large distribution over the Rockall-Hatton Plateau (RHP) and IB. The Porcupine Abyssal Plain (PAP) region at the southern end of our transect was the region with the lowest biomass, as demonstrated by very low chl-a concentrations and a community dominated by picophytoplankton. Early depletion of dissolved silicic acid (DSi) and increased stratification of the surface layer most likely triggered the end of the diatom bloom, leading to coccolithophore dominance. The chronic Si deficiency observed in the NEA could be linked to moderate Fe limitation, which increases the efficiency of the Si pump. TEP closely mirrored the distribution of both biogenic silica at depth and prymnesiophytes in the surface layer suggesting the sedimentation of the diatom bloom in the form of aggregates, but the relative contribution of diatoms and coccolithophores to carbon

  4. Distribution of calcifying and silicifying phytoplankton in relation to environmental and biogeochemical parameters during the late stages of the 2005 North East Atlantic Spring Bloom

    NASA Astrophysics Data System (ADS)

    Leblanc, K.; Hare, C. E.; Feng, Y.; Berg, G. M.; Ditullio, G. R.; Neeley, A.; Benner, I.; Sprengel, C.; Beck, A.; Sanudo-Wilhelmy, S. A.; Passow, U.; Klinck, K.; Rowe, J. M.; Wilhelm, S. W.; Brown, C. W.; Hutchins, D. A.

    2009-10-01

    The late stage of the North East Atlantic (NEA) spring bloom was investigated during June 2005 along a transect section from 45 to 66° N between 15 and 20° W in order to characterize the contribution of siliceous and calcareous phytoplankton groups and describe their distribution in relation to environmental factors. We measured several biogeochemical parameters such as nutrients, surface trace metals, algal pigments, biogenic silica (BSi), particulate inorganic carbon (PIC) or calcium carbonate, particulate organic carbon, nitrogen and phosphorus (POC, PON and POP, respectively), as well as transparent exopolymer particles (TEP). Results were compared with other studies undertaken in this area since the JGOFS NABE program. Characteristics of the spring bloom generally agreed well with the accepted scenario for the development of the autotrophic community. The NEA seasonal diatom bloom was in the late stages when we sampled the area and diatoms were constrained to the northern part of our transect, over the Icelandic Basin (IB) and Icelandic Shelf (IS). Coccolithophores dominated the phytoplankton community, with a large distribution over the Rockall-Hatton Plateau (RHP) and IB. The Porcupine Abyssal Plain (PAP) region at the southern end of our transect was the region with the lowest biomass, as demonstrated by very low Chla concentrations and a community dominated by picophytoplankton. Early depletion of dissolved silicic acid (DSi) and increased stratification of the surface layer most likely triggered the end of the diatom bloom, leading to coccolithophore dominance. The chronic Si deficiency observed in the NEA could be linked to moderate Fe limitation, which increases the efficiency of the Si pump. TEP closely mirrored the distribution of both biogenic silica at depth and prymnesiophytes in the surface layer suggesting the sedimentation of the diatom bloom in the form of aggregates, but the relative contribution of diatoms and coccolithophores to carbon

  5. Changes in Thalamic Connectivity in the Early and Late Stages of Amnestic Mild Cognitive Impairment: A Resting-State Functional Magnetic Resonance Study from ADNI

    PubMed Central

    Cai, Suping; Huang, Liyu; Zou, Jia; Jing, Longlong; Zhai, Buzhong; Ji, Gongjun; von Deneen, Karen M.; Ren, Junchan; Ren, Aifeng

    2015-01-01

    We used resting-state functional magnetic resonance imaging (fMRI) to investigate changes in the thalamus functional connectivity in early and late stages of amnestic mild cognitive impairment. Data of 25 late stages of amnestic mild cognitive impairment (LMCI) patients, 30 early stages of amnestic mild cognitive impairment (EMCI) patients and 30 well-matched healthy controls (HC) were analyzed from the Alzheimer’s disease Neuroimaging Initiative (ADNI). We focused on the correlation between low frequency fMRI signal fluctuations in the thalamus and those in all other brain regions. Compared to healthy controls, we found functional connectivity between the left/right thalamus and a set of brain areas was decreased in LMCI and/or EMCI including right fusiform gyrus (FG), left and right superior temporal gyrus, left medial frontal gyrus extending into supplementary motor area, right insula, left middle temporal gyrus (MTG) extending into middle occipital gyrus (MOG). We also observed increased functional connectivity between the left/right thalamus and several regions in LMCI and/or EMCI including left FG, right MOG, left and right precuneus, right MTG and left inferior temporal gyrus. In the direct comparison between the LMCI and EMCI groups, we obtained several brain regions showed thalamus-seeded functional connectivity differences such as the precentral gyrus, hippocampus, FG and MTG. Briefly, these brain regions mentioned above were mainly located in the thalamo-related networks including thalamo-hippocampus, thalamo-temporal, thalamo-visual, and thalamo-default mode network. The decreased functional connectivity of the thalamus might suggest reduced functional integrity of thalamo-related networks and increased functional connectivity indicated that aMCI patients could use additional brain resources to compensate for the loss of cognitive function. Our study provided a new sight to understand the two important states of aMCI and revealed resting-state fMRI is

  6. The Ste20-like kinase SvkA of Dictyostelium discoideum is essential for late stages of cytokinesis.

    PubMed

    Rohlfs, Meino; Arasada, Rajesh; Batsios, Petros; Janzen, Julia; Schleicher, Michael

    2007-12-15

    The genome of the social amoeba Dictyostelium discoideum encodes approximately 285 kinases, which represents approximately 2.6% of the total genome and suggests a signaling complexity similar to that of yeasts and humans. The behavior of D. discoideum as an amoeba and during development relies heavily on fast rearrangements of the actin cytoskeleton. Here, we describe the knockout phenotype of the svkA gene encoding severin kinase, a homolog of the human MST3, MST4 and YSK1 kinases. SvkA-knockout cells show drastic defects in cytokinesis, development and directed slug movement. The defect in cytokinesis is most prominent, leading to multinucleated cells sometimes with >30 nuclei. The defect arises from the frequent inability of svkA-knockout cells to maintain symmetry during formation of the cleavage furrow and to sever the last cytosolic connection. We demonstrate that GFP-SvkA is enriched at the centrosome and localizes to the midzone during the final stage of cell division. This distribution is mediated by the C-terminal half of the kinase, whereas a rescue of the phenotypic changes requires the active N-terminal kinase domain as well. The data suggest that SvkA is part of a regulatory pathway from the centrosome to the midzone, thus regulating the completion of cell division. PMID:18042625

  7. Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression.

    PubMed

    da Silva-Diz, Victoria; Simón-Extremera, Pilar; Bernat-Peguera, Adrià; de Sostoa, Jana; Urpí, Maria; Penín, Rosa M; Sidelnikova, Diana Pérez; Bermejo, Oriol; Viñals, Joan Maria; Rodolosse, Annie; González-Suárez, Eva; Moruno, Antonio Gómez; Pujana, Miguel Ángel; Esteller, Manel; Villanueva, Alberto; Viñals, Francesc; Muñoz, Purificación

    2016-03-01

    Cancer stem-like cells (CSC) play key roles in long-term tumor propagation and metastasis, but their dynamics during disease progression are not understood. Tumor relapse in patients with initially excised skin squamous cell carcinomas (SCC) is characterized by increased metastatic potential, and SCC progression is associated with an expansion of CSC. Here, we used genetically and chemically-induced mouse models of skin SCC to investigate the signaling pathways contributing to CSC function during disease progression. We found that CSC regulatory mechanisms change in advanced SCC, correlating with aggressive tumor growth and enhanced metastasis. β-Catenin and EGFR signaling, induced in early SCC CSC, were downregulated in advanced SCC. Instead, autocrine FGFR1 and PDGFRα signaling, which have not been previously associated with skin SCC CSC, were upregulated in late CSC and promoted tumor growth and metastasis, respectively. Finally, high-grade and recurrent human skin SCC recapitulated the signaling changes observed in advanced mouse SCC. Collectively, our findings suggest a stage-specific switch in CSC regulation during disease progression that could be therapeutically exploited by targeting the PDGFR and FGFR1 pathways to block relapse and metastasis of advanced human skin SCC. PMID:26719534

  8. Role of the long cytoplasmic domain of the SIV Env glycoprotein in early and late stages of infection

    PubMed Central

    Vzorov, Andrei N; Weidmann, Armin; Kozyr, Natalia L; Khaoustov, Vladimir; Yoffe, Boris; Compans, Richard W

    2007-01-01

    Background The Env glycoproteins of retroviruses play an important role in the initial steps of infection involving the binding to cell surface receptors and entry by membrane fusion. The Env glycoprotein also plays an important role in viral assembly at a late step of infection. Although the Env glycoprotein interacts with viral matrix proteins and cellular proteins associated with lipid rafts, its possible role during the early replication events remains unclear. Truncation of the cytoplasmic tail (CT) of the Env glycoprotein is acquired by SIV in the course of adaptation to human cells, and is known to be a determinant of SIV pathogenicity. Results We compared SIV viruses with full length or truncated (T) Env glycoproteins to analyze possible differences in entry and post-entry events, and assembly of virions. We observed that early steps in replication of SIV with full length or T Env were similar in dividing and non-dividing cells. However, the proviral DNA of the pathogenic virus clone SIVmac239 with full length Env was imported to the nucleus about 20-fold more efficiently than proviral DNA of SIVmac239T with T Env, and 100-fold more efficiently than an SIVmac18T variant with a single mutation A239T in the SU subunit and with a truncated cytoplasmic tail (CT). In contrast, proviral DNA of SIVmac18 with a full length CT and with a single mutation A239T in the SU subunit was imported to the nucleus about 50-fold more efficiently than SIVmac18T. SIV particles with full length Env were released from rhesus monkey PBMC, whereas a restriction of release of virus particles was observed from human 293T, CEMx174, HUT78 or macrophages. In contrast, SIV with T Envs were able to overcome the inhibition of release in human HUT78, CEMx174, 293T or growth-arrested CEMx174 cells and macrophages resulting in production of infectious particles. We found that the long CT of the Env glycoprotein was required for association of Env with lipid rafts. An Env mutant C787S which

  9. Pitavastatin Reduces Inflammation in Atherosclerotic Plaques in Apolipoprotein E-Deficient Mice with Late Stage Renal Disease

    PubMed Central

    Figueiredo, Jose-Luiz; New, Sophie E. P.; Quillard, Thibaut; Goettsch, Claudia; Koga, Jun-ichiro; Sonoki, Hiroyuki; Matsumoto, Jiro; Aikawa, Masanori; Aikawa, Elena

    2015-01-01

    Objectives Chronic renal disease (CRD) accelerates atherosclerosis and cardiovascular calcification. Statins reduce low-density lipoprotein-cholesterol levels in patients with CRD, however, the benefits of statins on cardiovascular disease in CRD remain unclear. This study has determined the effects of pitavastatin, the newest statin, on arterial inflammation and calcification in atherogenic mice with CRD. Methods and Results CRD was induced by 5/6 nephrectomy in cholesterol-fed apolipoprotein E-deficient mice. Mice were randomized into three groups: control mice, CRD mice, and CRD mice treated with pitavastatin. Ultrasonography showed that pitavastatin treatment significantly attenuated luminal stenosis in brachiocephalic arteries of CRD mice. Near-infrared molecular imaging and correlative Mac3 immunostaining demonstrated a significant reduction in macrophage accumulation in pitavastatin-treated CRD mice. Pitavastatin treatment reduced levels of osteopontin in plasma and atherosclerotic lesions in CRD mice, but did not produce a significant reduction in calcification in atherosclerotic plaques as assesses by histology. CRD mice had significantly higher levels of phosphate in plasma than did control mice, which did not change by pitavastatin. In vitro, pitavastatin suppressed the expression of osteopontin in peritoneal macrophages stimulated with phosphate or calcium/phosphate in concentrations similar to those found in human patients with CRD. Conclusion Our study provides in vivo evidence that pitavastatin reduces inflammation within atherosclerotic lesions in CRD mice. PMID:26367531

  10. Highly Aggregated Antibody Therapeutics Can Enhance the in Vitro Innate and Late-stage T-cell Immune Responses

    PubMed Central

    Joubert, Marisa K.; Hokom, Martha; Eakin, Catherine; Zhou, Lei; Deshpande, Meghana; Baker, Matthew P.; Goletz, Theresa J.; Kerwin, Bruce A.; Chirmule, Naren; Narhi, Linda O.; Jawa, Vibha

    2012-01-01

    Aggregation of biotherapeutics has the potential to induce an immunogenic response. Here, we show that aggregated therapeutic antibodies, previously generated and determined to contain a variety of attributes (Joubert, M. K., Luo, Q., Nashed-Samuel, Y., Wypych, J., and Narhi, L. O. (2011) J. Biol. Chem. 286, 25118–25133), can enhance the in vitro innate immune response of a population of naive human peripheral blood mononuclear cells. This response depended on the aggregate type, inherent immunogenicity of the monomer, and donor responsiveness, and required a high number of particles, well above that detected in marketed drug products, at least in this in vitro system. We propose a cytokine signature as a potential biomarker of the in vitro peripheral blood mononuclear cell response to aggregates. The cytokines include IL-1β, IL-6, IL-10, MCP-1, MIP-1α, MIP-1β, MMP-2, and TNF-α. IL-6 and IL-10 might have an immunosuppressive effect on the long term immune response. Aggregates made by stirring induced the highest response compared with aggregates made by other methods. Particle size in the 2–10 μm range and the retention of some folded structure were associated with an increased response. The mechanism of aggregate activation at the innate phase was found to occur through specific cell surface receptors (the toll-like receptors TLR-2 and TLR-4, FcγRs, and the complement system). The innate signal was shown to progress to an adaptive T-cell response characterized by T-cell proliferation and secretion of T-cell cytokines. Investigating the ability of aggregates to induce cytokine signatures as biomarkers of immune responses is essential for determining their risk of immunogenicity. PMID:22584577

  11. Behavioral Characterization of A53T Mice Reveals Early and Late Stage Deficits Related to Parkinson’s Disease

    PubMed Central

    Paumier, Katrina L.; Sukoff Rizzo, Stacey J.; Berger, Zdenek; Chen, Yi; Gonzales, Cathleen; Kaftan, Edward; Li, Li; Lotarski, Susan; Monaghan, Michael; Shen, Wei; Stolyar, Polina; Vasilyev, Dmytro; Zaleska, Margaret; D. Hirst, Warren; Dunlop, John

    2013-01-01

    Parkinson's disease (PD) pathology is characterized by the formation of intra-neuronal inclusions called Lewy bodies, which are comprised of alpha-synuclein (α-syn). Duplication, triplication or genetic mutations in α-syn (A53T, A30P and E46K) are linked to autosomal dominant PD; thus implicating its role in the pathogenesis of PD. In both PD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of protein aggregates (i.e., α-syn) and neurodegeneration. Characterization of the timing and nature of symptomatic dysfunction is important for understanding the impact of α-syn on disease progression. Furthermore, this knowledge is essential for identifying pathways and molecular targets for therapeutic intervention. To this end, we examined various functional and morphological endpoints in the transgenic mouse model expressing the human A53T α-syn variant directed by the mouse prion promoter at specific ages relating to disease progression (2, 6 and 12 months of age). Our findings indicate A53T mice develop fine, sensorimotor, and synaptic deficits before the onset of age-related gross motor and cognitive dysfunction. Results from open field and rotarod tests show A53T mice develop age-dependent changes in locomotor activity and reduced anxiety-like behavior. Additionally, digigait analysis shows these mice develop an abnormal gait by 12 months of age. A53T mice also exhibit spatial memory deficits at 6 and 12 months, as demonstrated by Y-maze performance. In contrast to gross motor and cognitive changes, A53T mice display significant impairments in fine- and sensorimotor tasks such as grooming, nest building and acoustic startle as early as 1–2 months of age. These mice also show significant abnormalities in basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD). Combined, these data indicate the A53T model exhibits early- and late-onset behavioral and synaptic impairments

  12. Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease.

    PubMed

    Paumier, Katrina L; Sukoff Rizzo, Stacey J; Berger, Zdenek; Chen, Yi; Gonzales, Cathleen; Kaftan, Edward; Li, Li; Lotarski, Susan; Monaghan, Michael; Shen, Wei; Stolyar, Polina; Vasilyev, Dmytro; Zaleska, Margaret; D Hirst, Warren; Dunlop, John

    2013-01-01

    Parkinson's disease (PD) pathology is characterized by the formation of intra-neuronal inclusions called Lewy bodies, which are comprised of alpha-synuclein (α-syn). Duplication, triplication or genetic mutations in α-syn (A53T, A30P and E46K) are linked to autosomal dominant PD; thus implicating its role in the pathogenesis of PD. In both PD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of protein aggregates (i.e., α-syn) and neurodegeneration. Characterization of the timing and nature of symptomatic dysfunction is important for understanding the impact of α-syn on disease progression. Furthermore, this knowledge is essential for identifying pathways and molecular targets for therapeutic intervention. To this end, we examined various functional and morphological endpoints in the transgenic mouse model expressing the human A53T α-syn variant directed by the mouse prion promoter at specific ages relating to disease progression (2, 6 and 12 months of age). Our findings indicate A53T mice develop fine, sensorimotor, and synaptic deficits before the onset of age-related gross motor and cognitive dysfunction. Results from open field and rotarod tests show A53T mice develop age-dependent changes in locomotor activity and reduced anxiety-like behavior. Additionally, digigait analysis shows these mice develop an abnormal gait by 12 months of age. A53T mice also exhibit spatial memory deficits at 6 and 12 months, as demonstrated by Y-maze performance. In contrast to gross motor and cognitive changes, A53T mice display significant impairments in fine- and sensorimotor tasks such as grooming, nest building and acoustic startle as early as 1-2 months of age. These mice also show significant abnormalities in basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD). Combined, these data indicate the A53T model exhibits early- and late-onset behavioral and synaptic impairments

  13. Epidemiology of human African trypanosomiasis

    PubMed Central

    Franco, Jose R; Simarro, Pere P; Diarra, Abdoulaye; Jannin, Jean G

    2014-01-01

    Human African trypanosomiasis (HAT), or sleeping sickness, is caused by Trypanosoma brucei gambiense, which is a chronic form of the disease present in western and central Africa, and by Trypanosoma brucei rhodesiense, which is an acute disease located in eastern and southern Africa. The rhodesiense form is a zoonosis, with the occasional infection of humans, but in the gambiense form, the human being is regarded as the main reservoir that plays a key role in the transmission cycle of the disease. The gambiense form currently assumes that 98% of the cases are declared; the Democratic Republic of the Congo is the most affected country, with more than 75% of the gambiense cases declared. The epidemiology of the disease is mediated by the interaction of the parasite (trypanosome) with the vectors (tsetse flies), as well as with the human and animal hosts within a particular environment. Related to these interactions, the disease is confined in spatially limited areas called “foci”, which are located in Sub-Saharan Africa, mainly in remote rural areas. The risk of contracting HAT is, therefore, determined by the possibility of contact of a human being with an infected tsetse fly. Epidemics of HAT were described at the beginning of the 20th century; intensive activities have been set up to confront the disease, and it was under control in the 1960s, with fewer than 5,000 cases reported in the whole continent. The disease resurged at the end of the 1990s, but renewed efforts from endemic countries, cooperation agencies, and nongovernmental organizations led by the World Health Organization succeeded to raise awareness and resources, while reinforcing national programs, reversing the trend of the cases reported, and bringing the disease under control again. In this context, sustainable elimination of the gambiense HAT, defined as the interruption of the transmission of the disease, was considered as a feasible target for 2030. Since rhodesiense HAT is a zoonosis

  14. Epidemiology of human African trypanosomiasis.

    PubMed

    Franco, Jose R; Simarro, Pere P; Diarra, Abdoulaye; Jannin, Jean G

    2014-01-01

    Human African trypanosomiasis (HAT), or sleeping sickness, is caused by Trypanosoma brucei gambiense, which is a chronic form of the disease present in western and central Africa, and by Trypanosoma brucei rhodesiense, which is an acute disease located in eastern and southern Africa. The rhodesiense form is a zoonosis, with the occasional infection of humans, but in the gambiense form, the human being is regarded as the main reservoir that plays a key role in the transmission cycle of the disease. The gambiense form currently assumes that 98% of the cases are declared; the Democratic Republic of the Congo is the most affected country, with more than 75% of the gambiense cases declared. The epidemiology of the disease is mediated by the interaction of the parasite (trypanosome) with the vectors (tsetse flies), as well as with the human and animal hosts within a particular environment. Related to these interactions, the disease is confined in spatially limited areas called "foci", which are located in Sub-Saharan Africa, mainly in remote rural areas. The risk of contracting HAT is, therefore, determined by the possibility of contact of a human being with an infected tsetse fly. Epidemics of HAT were described at the beginning of the 20th century; intensive activities have been set up to confront the disease, and it was under control in the 1960s, with fewer than 5,000 cases reported in the whole continent. The disease resurged at the end of the 1990s, but renewed efforts from endemic countries, cooperation agencies, and nongovernmental organizations led by the World Health Organization succeeded to raise awareness and resources, while reinforcing national programs, reversing the trend of the cases reported, and bringing the disease under control again. In this context, sustainable elimination of the gambiense HAT, defined as the interruption of the transmission of the disease, was considered as a feasible target for 2030. Since rhodesiense HAT is a zoonosis, where

  15. Petrology and geochemistry of late-stage intrusions of the A-type, mid-Proterozoic Pikes Peak batholith (Central Colorado, USA): Implications for petrogenetic models

    USGS Publications Warehouse

    Smith, D.R.; Noblett, J.; Wobus, R.A.; Unruh, D.; Douglass, J.; Beane, R.; Davis, C.; Goldman, S.; Kay, G.; Gustavson, B.; Saltoun, B.; Stewart, J.

    1999-01-01

    The ~1.08 Ga anorogenic, A-type Pikes Peak batholith (Front Range, central Colorado) is dominated by coarse-grained, biotite ?? amphibole syenogranites and minor monzogranites, collectively referred to as Pikes Peak granite (PPG). The batholith is also host to numerous small, late-stage plutons that have been subdivided into two groups (e.g. Wobus, 1976. Studies in Colorado Field Geology, Colorado School of Mines Professional Contributions, Colorado): (1) a sodic series (SiO2= ~44-78 wt%; K/Na=0.32-1.36) composed of gabbro, diabase, syenite/quartz syenite and fayalite and sodic amphibole granite; and (2) a potassic series (SiO2= ~ 70-77 wt%; K/Na=0.95-2.05), composed of biotite granite and minor quartz monzonite. Differences in major and trace element and Nd isotopic characteristics for the two series indicate different petrogenetic histories. Potassic granites of the late-stage intrusions appear to represent crustal anatectic melts derived from tonalite sources, based on comparison of their major element compositions with experimental melt products. In addition, Nd isotopic characteristics of the potassic granites [??(Nd)(1.08 Ga) = -0.2 to -2.7] overlap with those for tonalites/granodiorites [ca 1.7 Ga Boulder Creek intrusions; ??(Nd)(1.08 Ga) = -2.4 to -3.6] exposed in the region. Some of the partial melts evolved by fractionation dominated by feldspar. The late-stage potassic granites share geochemical characteristics with most of the PPG, which is also interpreted to have an anatectic origin involving tonalitic crust. The origin of monzogranites associated with the PPG remains unclear, but mixing between granitic and mafic or intermediate magmas is a possibility. Syenites and granites of the sodic series cannot be explained as crustal melts, but are interpreted as fractionation products of mantle-derived mafic magmas with minor crustal input. High temperature and low oxygen fugacity estimates (e.g. Frost et al., 1988. American Mineralogist 73, 727-740) support

  16. Fluid biopsy for Circulating Tumor Cell identification in Patients with early and late stage Non-Small Cell Lung Cancer; a glimpse into lung cancer biology

    PubMed Central

    Wendel, Marco; Bazhenova, Lyudmila; Boshuizen, Rogier; Kolatkar, Anand; Honnatti, Meghana; Cho, Edward H.; Marrinucci, Dena; Sandhu, Ajay; Perricone, Anthony; Thistlethwaite, Patricia; Bethel, Kelly; Nieva, Jorge; van den Heuvel, Michel; Kuhn, Peter

    2012-01-01

    Circulating tumor cell (CTC) counts are an established prognostic marker in metastatic prostate, breast, and colorectal cancer, and recent data suggests a similar role in late stage non-small cell lung cancer (NSCLC). However, due to sensitivity constraints in current enrichment-based CTC detection technologies, there is little published data about CTC prevalence rates and morphologic heterogeneity in early stage NSCLC, or the correlation of CTCs with disease progression and their usability for clinical staging. We investigated CTC counts, morphology, and aggregation in early stage, locally advanced, and metastatic NSCLC patients by using a fluid phase biopsy approach that identifies CTCs without relying on surface receptor-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. HD-CTCs were analyzed in blood samples from 78 chemotherapy-naïve NSCLC patients. 73% of the total population had a positive HD-CTC count (> 0 CTC in 1 mL of blood) with a median of 4.4 HD-CTCs/mL (range 0–515.6) and a mean of 44.7 (±95.2) HD-CTCs/mL. No significant difference in the medians of HD-CTC counts was detected between stage IV (n=31, range 0–178.2), stage III (n=34, range 0–515.6) and stages I/II (n=13, range 0–442.3). Furthermore, HD-CTCs exhibited a uniformity in terms of molecular and physical characteristics such as fluorescent cytokeratin intensity, nuclear size, frequency of apoptosis and aggregate formation across the spectrum of staging. Our results demonstrate that, despite stringent morphologic inclusion criteria for the definition of HD-CTCs, the HD-CTC assay shows high sensitivity in the detection and characterization of both early and late stage lung cancer CTCs. Larger studies are warranted to investigate the prognostic value of CTC profiling in early stage lung cancer. This finding has implications for the design of larger studies examining screening, therapy, and surveillance in

  17. Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology

    NASA Astrophysics Data System (ADS)

    Wendel, Marco; Bazhenova, Lyudmila; Boshuizen, Rogier; Kolatkar, Anand; Honnatti, Meghana; Cho, Edward H.; Marrinucci, Dena; Sandhu, Ajay; Perricone, Anthony; Thistlethwaite, Patricia; Bethel, Kelly; Nieva, Jorge; van den Heuvel, Michel; Kuhn, Peter

    2012-02-01

    Circulating tumor cell (CTC) counts are an established prognostic marker in metastatic prostate, breast and colorectal cancer, and recent data suggest a similar role in late stage non-small cell lung cancer (NSCLC). However, due to sensitivity constraints in current enrichment-based CTC detection technologies, there are few published data about CTC prevalence rates and morphologic heterogeneity in early-stage NSCLC, or the correlation of CTCs with disease progression and their usability for clinical staging. We investigated CTC counts, morphology and aggregation in early stage, locally advanced and metastatic NSCLC patients by using a fluid-phase biopsy approach that identifies CTCs without relying on surface-receptor-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. HD-CTCs were analyzed in blood samples from 78 chemotherapy-naïve NSCLC patients. 73% of the total population had a positive HD-CTC count (>0 CTC in 1 mL of blood) with a median of 4.4 HD-CTCs mL-1 (range 0-515.6) and a mean of 44.7 (±95.2) HD-CTCs mL-1. No significant difference in the medians of HD-CTC counts was detected between stage IV (n = 31, range 0-178.2), stage III (n = 34, range 0-515.6) and stages I/II (n = 13, range 0-442.3). Furthermore, HD-CTCs exhibited a uniformity in terms of molecular and physical characteristics such as fluorescent cytokeratin intensity, nuclear size, frequency of apoptosis and aggregate formation across the spectrum of staging. Our results demonstrate that despite stringent morphologic inclusion criteria for the definition of HD-CTCs, the HD-CTC assay shows high sensitivity in the detection and characterization of both early- and late-stage lung cancer CTCs. Extensive studies are warranted to investigate the prognostic value of CTC profiling in early-stage lung cancer. This finding has implications for the design of extensive studies examining screening, therapy and surveillance in

  18. Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study

    SciTech Connect

    Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka; Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi; Yoshida, Toshinori; Shibutani, Makoto

    2015-09-15

    Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600 mg/kg body weight/day for 28 days. In the subgranular zone (SGZ), 600 mg/kg CPZ increased the number of cleaved caspase-3{sup +} apoptotic cells. At ≥ 120 mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥ 120 mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥ 120 mg/kg decreased phosphorylated TRKB{sup +} interneurons, although the number of reelin{sup +} interneurons was unchanged. At 600 mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells. - Highlights: • Effect of 28-day CPZ exposure on hippocampal neurogenesis was examined in rats. • CPZ suppressed intermediate neurogenesis and late-stage neurogenesis in the dentate gyrus. • CPZ suppressed BDNF signals to interneurons by decrease of

  19. Three-dimensional Fe speciation of an inclusion cloud within an ultradeep diamond by confocal μ-X-ray absorption near edge structure: evidence for late stage overprint.

    PubMed

    Silversmit, Geert; Vekemans, Bart; Appel, Karen; Schmitz, Sylvia; Schoonjans, Tom; Brenker, Frank E; Kaminsky, Felix; Vincze, Laszlo

    2011-08-15

    A stream of 1-20 μm sized mineral inclusions having the negative crystal shape of its host within an "ultra-deep" diamond from Rio Soriso (Juina area, Mato Grosso State, Brazil) has been studied with confocal μ-X-ray absorption near edge structure (μXANES) at the Fe K and Mn K edges. This technique allows the three-dimensional nondestructive speciation of the Fe and Mn containing minerals within the inclusion cloud. The observed Fe-rich inclusions were identified to be ferropericlase (Fe,Mg)O, hematite and a mixture of these two minerals. Confocal μ-X-ray fluorescence (μXRF) further showed that Ca-rich inclusions were present as well, which are spatially separated from or in close contact with the Fe-rich inclusions. The inclusions are aligned along a plane, which most likely represents a primary growth zone. In the close vicinity of the inclusions, carbon coated planar features are visible. The three-dimensional distribution indicates a likely fluid overprint along an open crack. Our results imply that an imposed negative diamond shape of an inclusion alone does not exclude epigenetic formation or intense late stage overprint. PMID:21707095

  20. Three-dimensional Geometry of a Current Sheet in the High Solar Corona: Evidence for Reconnection in the Late Stage of the Coronal Mass Ejections

    NASA Astrophysics Data System (ADS)

    Kwon, Ryun-Young; Vourlidas, Angelos; Webb, David

    2016-07-01

    Motivated by the standard flare model, ray-like structures in the wake of coronal mass ejections (CMEs) have been often interpreted as proxies of the reconnecting current sheet connecting the CME with the postflare arcade. We present the three-dimensional properties of a post-CME ray derived from white light images taken from three different viewing perspectives on 2013 September 21. By using a forward modeling method, the direction, cross section, and electron density are determined within the heliocentric distance range of 5–9 R ⊙. The width and depth of the ray are 0.42 ± 0.08 R ⊙ and 1.24 ± 0.35 R ⊙, respectively, and the electron density is (2.0 ± 0.5) × 104 cm‑3, which seems to be constant with height. Successive blobs moving outward along the ray are observed around 13 hr after the parent CME onset. We model the three-dimensional geometry of the parent CME with the Gradual Cylindrical Shell model and find that the CME and ray are coaxial. We suggest that coaxial post-CME rays, seen in coronagraph images, with successive formation of blobs could be associated with current sheets undergoing magnetic reconnection in the late stage of CMEs.

  1. Fibroblast growth factor 18 increases the trophic effects of bone marrow mesenchymal stem cells on chondrocytes isolated from late stage osteoarthritic patients.

    PubMed

    Zhang, Zhenyu; Wang, Yan; Li, Mingchao; Li, Jiaping; Wu, Jian

    2014-01-01

    Coculture of mesenchymal stem cells with chondrocytes increases production of cartilaginous matrix. Chondrocytes isolated from late stage osteoarthritic patients usually lost their phenotype of producing cartilaginous matrix. Fibroblast growth factor 18 is believed to redifferentiate OA chondrocyte into functionally active chondrocytes. The aim of this study is to investigate the supportive effects of MSCs on OA chondrocytes and test if FGF18 could enhance the responsiveness of OA chondrocytes to the support of MSCs in a coculture system. Both pellet and transwell co-cultures were used. GAG quantification, hydroxyproline assay, and qPCR were performed. An ectopic models of cartilage formation was also applied. Our data indicated that, in pellets coculture of MSCs and OA chondrocytes, matrix production was increased in the presence of FGF18, comparing to the monoculture of chondrocytes. Results from transwell coculture study showed that expression of matrix producing genes in OA chondrocytes increased when cocultured with MSCs with FGF18 in culture medium, while hypertrophic genes were not changed by coculture. Finally, coimplantation of MSCs with OA chondrocytes produces more matrix than chondrocytes only. In conclusion, FGF18 can restore the responsiveness of OA chondrocytes to the trophic effects of MSCs. Coimplantation of MSCs and OA chondrocytes treated with FGF18 may be a good alternative cell source for regenerating cartilage tissue that is degraded during OA pathological changes. PMID:25544847

  2. Immune checkpoint blockade reveals the stimulatory capacity of tumor-associated CD103(+) dendritic cells in late-stage ovarian cancer.

    PubMed

    Flies, Dallas B; Higuchi, Tomoe; Harris, Jaryse C; Jha, Vibha; Gimotty, Phyllis A; Adams, Sarah F

    2016-08-01

    Although immune infiltrates in ovarian cancer are associated with improved survival, the ovarian tumor environment has been characterized as immunosuppressive, due in part to functional shifts among dendritic cells with disease progression. We hypothesized that flux in dendritic cell subpopulations with cancer progression were responsible for observed differences in antitumor immune responses in early and late-stage disease. Here we identify three dendritic cell subsets with disparate functions in the ovarian tumor environment. CD11c+CD11b(-)CD103(+) dendritic cells are absent in the peritoneal cavity of healthy mice but comprise up to 40% of dendritic cells in tumor-bearing mice and retain T cell stimulatory capacity in advanced disease. Among CD11c+CD11b+ cells, Lair-1 expression distinguishes stimulatory and immunoregulatory DC subsets, which are also enriched in the tumor environment. Notably, PD-L1 is expressed by Lair-1(hi) immunoregulatory dendritic cells, and may contribute to local tumor antigen-specific T cell dysfunction. Using an adoptive transfer model, we find that PD-1 blockade enables tumor-associated CD103(+) dendritic cells to promote disease clearance. These data demonstrate that antitumor immune capacity is maintained among local dendritic cell subpopulations in the tumor environment with cancer progression. Similar dendritic cell subsets are present in malignant ascites from women with ovarian cancer, supporting the translational relevance of these results. PMID:27622059

  3. Plasma Neurofilament Heavy Chain Levels Correlate to Markers of Late Stage Disease Progression and Treatment Response in SOD1G93A Mice that Model ALS

    PubMed Central

    Lu, Ching-Hua; Petzold, Axel; Kalmar, Bernadett; Dick, James; Malaspina, Andrea; Greensmith, Linda

    2012-01-01

    Background Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder characterised by progressive degeneration of motor neurons leading to death, typically within 3–5 years of symptom onset. The diagnosis of ALS is largely reliant on clinical assessment and electrophysiological findings. Neither specific investigative tools nor reliable biomarkers are currently available to enable an early diagnosis or monitoring of disease progression, hindering the design of treatment trials. Methodology/Principal Findings In this study, using the well-established SOD1G93A mouse model of ALS and a new in-house ELISA method, we have validated that plasma neurofilament heavy chain protein (NfH) levels correlate with both functional markers of late stage disease progression and treatment response. We detected a significant increase in plasma levels of phosphorylated NfH during disease progression in SOD1G93A mice from 105 days onwards. Moreover, increased plasma NfH levels correlated with the decline in muscle force, motor unit survival and, more significantly, with the loss of spinal motor neurons in SOD1 mice during this critical period of decline. Importantly, mice treated with the disease modifying compound arimoclomol had lower plasma NfH levels, suggesting plasma NfH levels could be validated as an outcome measure for treatment trials. Conclusions/Significance These results show that plasma NfH levels closely reflect later stages of disease progression and therapeutic response in the SOD1G93A mouse model of ALS and may potentially be a valuable biomarker of later disease progression in ALS. PMID:22815892

  4. Formation of the Short-lived Radionuclide 36Cl in the Protoplanetary Disk During Late-stage Irradiation of a Volatile-rich Reservoir

    NASA Astrophysics Data System (ADS)

    Jacobsen, Benjamin; Matzel, Jennifer; Hutcheon, Ian D.; Krot, Alexander N.; Yin, Qing-Zhu; Nagashima, Kazuhide; Ramon, Erick C.; Weber, Peter K.; Ishii, Hope A.; Ciesla, Fred J.

    2011-04-01

    Short-lived radionuclides (SLRs) in the early solar system provide fundamental insight into protoplanetary disk evolution. We measured the 36Cl-36S-isotope abundance in wadalite (<15 μm), a secondary chlorine-bearing mineral found in calcium-aluminum-rich inclusions (CAIs) in the Allende CV chondrite, to decipher the origin of the SLR 36Cl (τ 1/2 ~ 3 × 105 yr) in the early solar system. Its presence, initial abundance, and the noticeable decoupling from 26Al raise serious questions about the origin of SLRs. The inferred initial 36Cl abundance for wadalite, corresponding to a 36Cl/35Cl ratio of (1.81 ± 0.13) × 10-5, is the highest 36Cl abundance ever reported in any early solar system material. The high level of 36Cl in wadalite and the absence of 26Al (26Al/27Al <= 3.9 × 10-6) in co-existing grossular (1) unequivocally support the production of 36Cl by late-stage solar energetic particle irradiation in the protoplanetary disk and (2) indicates that the production of 36Cl, recorded by wadalite, is unrelated to the origin of 26Al and other SLRs (10Be, 53Mn) recorded by primary minerals of CAIs and chondrules. We infer that 36Cl was largely produced by irradiation of a volatile-rich reservoir in an optically thin protoplanetary disk adjacent to the region in which the CV chondrite parent asteroid accreted while the Sun was a weak T Tauri star. Subsequently, 36Cl accreted into the Allende CV chondrite together with condensed water ices.

  5. Long-Term Effects of Safinamide on Dyskinesia in Mid- to Late-Stage Parkinson’s Disease: A Post-Hoc Analysis

    PubMed Central

    Cattaneo, Carlo; Ferla, R. La; Bonizzoni, Erminio; Sardina, Marco

    2015-01-01

    Abstract Background: Safinamide is a novel α-aminoamide with dopaminergic and non-dopaminergic properties developed as adjunctive therapy for patients with PD. Results from a 24-month double-blind controlled study suggested that as add-on to levodopa (and other PD medications) the benefits of safinamide on dyskinesia may be related to severity of dyskinesia at baseline. Objective: This post-hoc analysis further characterized the effects of safinamide on dyskinesia in mid- to late-stage PD patients. Methods: Patients were stratified by the presence or absence of dyskinesia at baseline, and by whether or not the dose of levodopa had been changed during the 24-month treatment period. Differences between safinamide and placebo were evaluated using the Wilcoxon rank-sum test. Results: For the overall treated population (with or without baseline dyskinesia), safinamide 100 mg/day significantly improved the dyskinesia rating scale score, compared with placebo, in the subgroup of patients with no change in levodopa dose (p = 0.0488). For patients with baseline dyskinesia, improvements over placebo were also significant (p = 0.0153) in patients with or without changes in levodopa dose, and nearly significant (p = 0.0546) in patients with no change in levodopa dose, suggesting that these improvements were not due to levodopa dose reductions. Conclusions: While no statistically significant difference in mean DRS scores was seen between safinamide and placebo in the original study population, the present post-hoc analysis helps to provide a meaningful interpretation of the long-term effects of safinamide on dyskinesia. These results may be related to safinamide state- and use-dependent inhibition of sodium channels and stimulated glutamate release, and are unlikely due to reduced dopaminergic stimulation. PMID:26406127

  6. Expression of CP4 EPSPS in microspores and tapetum cells of cotton (Gossypium hirsutum) is critical for male reproductive development in response to late-stage glyphosate applications.

    PubMed

    Chen, Yun-Chia Sophia; Hubmeier, Christopher; Tran, Minhtien; Martens, Amy; Cerny, R Eric; Sammons, R Doug; CaJacob, Claire

    2006-09-01

    Plants expressing Agrobacterium sp. strain CP4 5-enolpyruvylshikimate-3-phosphate synthase (CP4 EPSPS) are known to be resistant to glyphosate, a potent herbicide that inhibits the activity of the endogenous plant EPSPS. The RR1445 transgenic cotton line (current commercial line for Roundup Ready Cotton) was generated using the figwort mosaic virus (FMV) 35S promoter to drive the expression of the CP4 EPSPS gene, and has excellent vegetative tolerance to glyphosate. However, with high glyphosate application rates at developmental stages later than the four-leaf stage (late-stage applications: applications that are inconsistent with the Roundup labels), RR1445 shows male sterility. Another transgenic cotton line, RR60, was generated using the FMV 35S promoter and the Arabidopsis elongation factor-1alpha promoter (AtEF1alpha) for the expression of CP4 EPSPS. RR60 has excellent vegetative and reproductive tolerance to applications of glyphosate at all developmental stages. Histochemical analyses were conducted to examine the male reproductive development at the cellular level of these cotton lines in response to glyphosate applications, and to investigate the correlation between glyphosate injury and the expression of CP4 EPSPS in male reproductive tissues. The expression of CP4 EPSPS in RR60 was found to be strong in all male reproductive cell types. Conversely, CP4 EPSPS expression in RR1445 was low in pollen mother cells, male gametophytes and tapetum, three crucial male reproductive cell types. Our results indicate that the FMV 35S promoter, although expressing strongly in most vegetative tissues in plants, has extremely low activity in these cell types. PMID:17309724

  7. Highly siderophile elements and 187Re-187Os isotopic systematics of the Allende meteorite: Evidence for primary nebular processes and late-stage alteration

    NASA Astrophysics Data System (ADS)

    Archer, G. J.; Ash, R. D.; Bullock, E. S.; Walker, R. J.

    2014-04-01

    The abundances of highly siderophile elements (HSE) Re, Os, Ir, Ru, Pt, and Pd, as well as 187Re-187Os isotopic systematics were determined for calcium-aluminum-rich inclusions (CAIs), chondrules, and matrix, separated from the CV3 carbonaceous chondrite Allende. Consistent with prior studies, CAIs are characterized by significant depletions in Pd relative to the other HSE, while the other HSE are in generally bulk chondritic relative abundances. The depletions in Pd can be linked with initial formation of CAIs via condensation, or subsequent processing by evaporative processes. Chondrules generally have relative HSE patterns similar to CAIs, although they have lower absolute abundances. Palladium depletions in chondrules may reflect solid metal-liquid metal fractionation at the time of formation, or alternatively, be the result of processes that acted on precursor materials. Matrix samples have nearly chondritic absolute abundances of all HSE measured. Consequently, matrix is the only major chondritic component examined here that shows no relative depletion in Pd. Mass balance suggests the existence of an unidentified Pd-rich carrier, although it is possible that the dataset presented here is too limited to represent typical HSE abundances of some chondritic components (e.g., chondrules). The 187Re-187Os isotopic systematics of only six out of twenty-four Allende chondritic components analyzed plot within uncertainties of a 4568 Ma primordial reference isochron. The deviations from the expected isochron most likely reflect late-stage, open-system behavior within the last 2 billion years, and, in some cases, could even have resulted from terrestrial alteration. The open-system behavior is most readily observed in small, millimeter-size sub-samples of Allende, consistent with Re and/or Os mobility on that scale.

  8. Swimming abilities of wild-caught, late-stage larvae of Diplodus capensis and Sarpa salpa (Pisces: Sparidae) from temperate South Africa

    NASA Astrophysics Data System (ADS)

    Pattrick, Paula; Strydom, Nadine A.

    2009-12-01

    Understanding the movement of marine fish larvae in coastal habitats requires an assessment of active swimming abilities. The critical speed ( U-crit) and endurance swimming of late-stage larvae of Diplodus capensis and Sarpa salpa (Family Sparidae), common inshore recreational linefish species, were measured in a laboratory swimming chamber. Postflexion and settlement-stage larvae were collected from the wild in a small bay on the warm temperate coast of South Africa. Larvae were allowed to acclimate in captivity and were tested soon after capture. For the endurance tests a speed of 18 cm s -1 was selected, as this approximated the mean current speed observed in the coastal environment of the area. The mean U-crit value (maximum swimming speed) for D. capensis (19 cm s -1) was similar to that of S. salpa (18 cm s -1), and similarly mean endurance (km swum) for S. salpa (8 km) was similar to that of D. capensis (6 km). The increase in critical speed and endurance swimming abilities with standard length was best described by a linear relationship. At lengths between 12 and 15 mm BL, D. capensis was the better swimmer, whereas S. salpa was the better swimmer between 15 and 16 mm BL. Of all the larvae that swam at critical speed, 90% were in an inertial environment. These swimming speeds exceed the modal current velocities observed in the shallow nearshore of the study region where these larvae occur abundantly. These swimming abilities provide larvae with the potential to influence their dispersal trajectories and ultimately influence their distribution in their nearshore nursery areas.

  9. FORMATION OF THE SHORT-LIVED RADIONUCLIDE {sup 36}Cl IN THE PROTOPLANETARY DISK DURING LATE-STAGE IRRADIATION OF A VOLATILE-RICH RESERVOIR

    SciTech Connect

    Jacobsen, Benjamin; Yin Qingzhu; Matzel, Jennifer; Hutcheon, Ian D.; Ramon, Erick C.; Weber, Peter K.; Krot, Alexander N.; Nagashima, Kazuhide; Ishii, Hope A.; Ciesla, Fred J.

    2011-04-20

    Short-lived radionuclides (SLRs) in the early solar system provide fundamental insight into protoplanetary disk evolution. We measured the {sup 36}Cl-{sup 36}S-isotope abundance in wadalite (<15 {mu}m), a secondary chlorine-bearing mineral found in calcium-aluminum-rich inclusions (CAIs) in the Allende CV chondrite, to decipher the origin of the SLR {sup 36}Cl ({tau}{sub 1/2} {approx} 3 x 10{sup 5} yr) in the early solar system. Its presence, initial abundance, and the noticeable decoupling from {sup 26}Al raise serious questions about the origin of SLRs. The inferred initial {sup 36}Cl abundance for wadalite, corresponding to a {sup 36}Cl/{sup 35}Cl ratio of (1.81 {+-} 0.13) x 10{sup -5}, is the highest {sup 36}Cl abundance ever reported in any early solar system material. The high level of {sup 36}Cl in wadalite and the absence of {sup 26}Al ({sup 26}Al/{sup 27}Al {<=} 3.9 x 10{sup -6}) in co-existing grossular (1) unequivocally support the production of {sup 36}Cl by late-stage solar energetic particle irradiation in the protoplanetary disk and (2) indicates that the production of {sup 36}Cl, recorded by wadalite, is unrelated to the origin of {sup 26}Al and other SLRs ({sup 10}Be, {sup 53}Mn) recorded by primary minerals of CAIs and chondrules. We infer that {sup 36}Cl was largely produced by irradiation of a volatile-rich reservoir in an optically thin protoplanetary disk adjacent to the region in which the CV chondrite parent asteroid accreted while the Sun was a weak T Tauri star. Subsequently, {sup 36}Cl accreted into the Allende CV chondrite together with condensed water ices.

  10. Mineral thermobarometry and fluid inclusion studies on the Closepet granite, Eastern Dharwar Craton, south India: Implications to emplacement and evolution of late-stage fluid

    NASA Astrophysics Data System (ADS)

    Bhattacharya, Sourabh; Panigrahi, Mruganka K.; Jayananda, M.

    2014-09-01

    The Closepet granite (CPG), a spectacularly exposed magmatic body along with other intrusive bodies (to the east of it) typifies the late Archean granitic activity in the Eastern Dharwar Craton (EDC), south India. In the present study, the P-T-fO2 conditions of emplacement and physico-chemical environment of the associated magmatic-hydrothermal regime of CPG have been retrieved on the basis of mineral chemical and fluid inclusion studies. Amphibole-plagioclase Ti-in-amphibole and Ti-in-biotite geothermometers along with Al-in-amphibole geobarometer have been used to reconstruct the emplacement temperature and pressure conditions in the majority of the pluton. Estimated temperatures of emplacement of CPG vary from to 740 to 540 °C. A variation of pressure from 4.8 to 4.1 kilo bars corresponding to this temperature range was obtained. While there is a faint south to north negative gradient in temperature, the variation of pressure does not seem to follow this trend and indicates more or less same crustal level of emplacement for the body between Ramanagaram-Kalyandurga segment extending for about 230 km. Mineral chemistry of biotite indicates crystallization of CPG under high oxygen fugacity conditions (mostly above QFM buffer) with no clear spatial variation in the fugacity of halogen species in the late-stage magmatic fluid. It may be surmised that barring the southernmost part of CPG, there is no perceptible variation in the physicochemical environment of emplacement. Fluid Inclusion studies in the granitic matrix quartz and pegmatite/vein quartz show dominance of H2O and H2O-CO2 fluids respectively in them. The difference in the fluid characteristics is interpreted in terms of the initial loss of CO2 rich fluid from granitic magma and aqueous-rich nature during the later stages of crystallization of quartz. The exsolved CO2-rich fluid was responsible in formation of the later quartz and pegmatitic veins at different crustal levels and also possibly was

  11. Safinamide as Add-On Therapy to Levodopa in Mid- to Late-Stage Parkinson’s Disease Fluctuating Patients: Post hoc Analysesof Studies 016 and SETTLE

    PubMed Central

    Cattaneo, Carlo; Sardina, Marco; Bonizzoni, Ermino

    2016-01-01

    Background: Studies 016 and SETTLE showed that safinamide was safe and effective as adjunct therapy in patients with advanced Parkinson’s disease (PD) and motor fluctuations. The addition of safinamide to a stable dose of levodopa alone or with other antiparkinsonian medications significantly increased ON time with no/non-troublesome dyskinesia, decreased OFF time and improved Parkinson’s symptoms. Objective: To evaluate the clinical effects of safinamide 100 mg/day on motor fluctuations and cardinal Parkinson’s symptoms in specific patient subgroups using pooled data from Studies 016 and SETTLE. Methods: Both studies were double blind, placebo-controlled, randomized, phase 3 trials which enrolled patients with mid- to late-stage PD experiencing motor fluctuations while receiving optimized and stable doses of levodopa, alone or with other dopaminergic treatments. The present post-hoc analyses assessed the change from baseline in ON time (with no or non-troublesome dyskinesia) and OFF time in subgroups of patients who were receiving only levodopa at baseline, who were classified as “mild fluctuators” (daily OFF time ≤4 h), and who were receiving concomitant dopaminergic therapy, with or without amantadine, and the effects of safinamide versus placebo on individual cardinal PD symptoms during ON time. Results: Safinamide significantly increased mean ON time (with no or non-troublesome dyskinesia) and reduced mean OFF time when used as first adjunct therapy in levodopa-treated patients and patients with mild motor fluctuations. Mean daily ON time (with no or non-troublesome dyskinesia) and OFF time were favorably changed, compared with placebo, to similar extents regardless of whether patients were receiving concomitant dopamine agonists, catechol-O-methyltransferase inhibitors and amantadine. Additionally, safinamide improved bradykinesia, rigidity, tremor and gait. Conclusions: Safinamide was a safe and effective first adjunct therapy in levodopa

  12. Continuous evaluation of changes in the serum proteome from early to late stages of sepsis caused by Klebsiella pneumoniae.

    PubMed

    Raju M, Swathi; V, Jahnavi; Kamaraju, Ratnakar S; Sritharan, Venkataraman; Rajkumar, Karthik; Natarajan, Sumathi; Kumar, Anil D; Burgula, Sandeepta

    2016-06-01

    Serum protein profiles of patients with bacterial sepsis from the day of diagnosis until recovery/mortality were compared from early to late stages in response to severe sepsis using two dimensional electrophoresis. The proteins exhibiting changes during the course of sepsis (20‑28 day mortality) were selected and identified by matrix‑assisted laser desorption ionization‑time of flight‑tandem mass spectrometry. Among the proteins identified, haptoglobin (Hp), transthyretin (TTR), orosomucoid 1/α1 acid glycoprotein (ORM1), α1 antitrypsin (A1AT), serum amyloid A (SAA) and S100A9 exhibited differential expression patterns between survivors (S; n=6) and non‑survivors (NS; n=6), particularly during the early stages of sepsis. Expression factors (EFs), taken as the ratio between the NS and S during early stages, showed ratios of Hp, 0.39 (P≤0.012); TTR, 3.96 (P≤0.03); ORM1, 0.69 (P≤0.79); A1AT, 0.92 (P≤0.87) and SAA, 0.69 (P≤0.01). S100A9, an acute phase protein, exhibited an EF ratio of 1.68 (P≤0.004) during the end stages of sepsis. A delayed rise in levels was observed in Hp, A1AT, ORM1, S100A9 and SAA, whereas TTR levels increased during the early stages of sepsis in NS. Analysis of inflammatory responses in the early stages of sepsis revealed increased mRNA expression in leukocytes of interleukin (IL)‑6 (EF, 2.50), IL‑10 (EF, 1.70) and prepronociceptin (EF, 1.6), which is a precursor for nociceptin in NS compared with S, and higher Toll‑like receptor‑4 (EF, 0.30) levels in S compared with NS. Therefore, a weaker acute phase response in the early stages of sepsis in NS, combined with an inefficient inflammatory response, may contribute to sepsis mortality. PMID:27082932

  13. Formation of short-lived radionuclides in the protoplanetary disk during late-stage irradiation of a volatile-rich reservoir

    SciTech Connect

    Jacobsen, B; Matzel, J; Hutcheon, I D; Krot, A N; Yin, Q -; Nagashima, K; Ramon, E; Weber, P; Ishii, H; Ciesla, F

    2010-11-30

    The origin of short-lived (t{sub 1/2} < 5 Myr) and now extinct radionuclides ({sup 10}Be, {sup 26}Al, {sup 36}Cl, {sup 41}Ca, {sup 53}Mn, {sup 60}Fe; hereafter SLRs) is fundamental to understanding the formation of the early solar system. Two distinct classes of models have been proposed to explain the origin of SLRs: (1) injection from a nearby stellar source (e.g., supernova, asymptotic giant branch star or Wolf-Rayet star) and (2) solar energetic particle irradiation of dust and gas near the proto-Sun. Recent studies have demonstrated that {sup 36}Cl was extant in the early solar system. However, its presence, initial abundance and the noticeable decoupling from {sup 26}Al raise serious questions about the origin of SLRs. Here we report {sup 36}Cl-{sup 36}S and {sup 26}Al-{sup 26}Mg systematics for wadalite and grossular, secondary minerals in a calcium-aluminum-rich inclusion (CAI) from the CV chondrite Allende that allow us to reassess the origin of SLRs. The inferred abundance of {sup 36}Cl in wadalite, corresponding to a {sup 36}Cl/{sup 35}Cl ratio of (1.81 {+-} 0.13) x 10{sup -5}, is the highest {sup 36}Cl abundance reported in any early solar system material. The high level of {sup 36}Cl in wadalite and the absence of {sup 26}Al ({sup 26}Al/{sup 27}Al {le} 3.9 x 10{sup -6}) in co-existing grossular indicates that (1) {sup 36}Cl formed by late-stage solar energetic particle irradiation and (2) the production of {sup 36}Cl, recorded by secondary minerals, is unrelated to the origin of {sup 26}Al and other SLRs ({sup 10}Be, {sup 53}Mn) recorded by primary minerals of CAIs and chondrules. We conclude that 36Cl was produced by solar energetic particle irradiation of a volatile-rich reservoir in an optically thin protoplanetary disk adjacent to the accretion region of the CV chondrite parent asteroid.

  14. Synthesis of highly functionalized oligobenzamide proteomimetic foldamers by late stage introduction of sensitive groups† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ob00078a Click here for additional data file.

    PubMed Central

    Burslem, George M.; Kyle, Hannah F.; Prabhakaran, Panchami; Breeze, Alexander L.; Edwards, Thomas A.; Warriner, Stuart L.; Nelson, Adam

    2016-01-01

    α-Helix proteomimetics represent an emerging class of ligands that can be used to inhibit an array of helix mediated protein–protein interactions. Within this class of inhibitor, aromatic oligobenzamide foldamers have been widely and successfully used. This manuscript describes alternative syntheses of these compounds that can be used to access mimetics that are challenging to synthesize using previously described methodologies, permitting access to compounds functionalized with multiple sensitive side chains and accelerated library assembly through late stage derivatisation. PMID:27005701

  15. Dosimetric difference amongst 3 techniques: TomoTherapy, sliding-window intensity-modulated radiotherapy (IMRT), and RapidArc radiotherapy in the treatment of late-stage nasopharyngeal carcinoma (NPC)

    SciTech Connect

    Lee, Francis Kar-ho Yip, Celia Wai-yi; Cheung, Frankie Chun-hung; Leung, Alex Kwok-cheung; Chau, Ricky Ming-chun; Ngan, Roger Kai-cheong

    2014-04-01

    To investigate the dosimetric difference amongst TomoTherapy, sliding-window intensity-modulated radiotherapy (IMRT), and RapidArc radiotherapy in the treatment of late-stage nasopharyngeal carcinoma (NPC). Ten patients with late-stage (Stage III or IV) NPC treated with TomoTherapy or IMRT were selected for the study. Treatment plans with these 3 techniques were devised according to departmental protocol. Dosimetric parameters for organ at risk and treatment targets were compared between TomoTherapy and IMRT, TomoTherapy and RapidArc, and IMRT and RapidArc. Comparison amongst the techniques was done by statistical tests on the dosimetric parameters, total monitor unit (MU), and expected delivery time. All 3 techniques achieved similar target dose coverage. TomoTherapy achieved significantly lower doses in lens and mandible amongst the techniques. It also achieved significantly better dose conformity to the treatment targets. RapidArc achieved significantly lower dose to the eye and normal tissue, lower total MU, and less delivery time. The dosimetric advantages of the 3 techniques were identified in the treatment of late-stage NPC. This may serve as a guideline for selection of the proper technique for different clinical cases.

  16. Population genomics reveals the origin and asexual evolution of human infective trypanosomes.

    PubMed

    Weir, William; Capewell, Paul; Foth, Bernardo; Clucas, Caroline; Pountain, Andrew; Steketee, Pieter; Veitch, Nicola; Koffi, Mathurin; De Meeûs, Thierry; Kaboré, Jacques; Camara, Mamadou; Cooper, Anneli; Tait, Andy; Jamonneau, Vincent; Bucheton, Bruno; Berriman, Matt; MacLeod, Annette

    2016-01-01

    Evolutionary theory predicts that the lack of recombination and chromosomal re-assortment in strictly asexual organisms results in homologous chromosomes irreversibly accumulating mutations and thus evolving independently of each other, a phenomenon termed the Meselson effect. We apply a population genomics approach to examine this effect in an important human pathogen, Trypanosoma brucei gambiense. We determine that T.b. gambiense is evolving strictly asexually and is derived from a single progenitor, which emerged within the last 10,000 years. We demonstrate the Meselson effect for the first time at the genome-wide level in any organism and show large regions of loss of heterozygosity, which we hypothesise to be a short-term compensatory mechanism for counteracting deleterious mutations. Our study sheds new light on the genomic and evolutionary consequences of strict asexuality, which this pathogen uses as it exploits a new biological niche, the human population. PMID:26809473

  17. Options for Field Diagnosis of Human African Trypanosomiasis

    PubMed Central

    Chappuis, François; Loutan, Louis; Simarro, Pere; Lejon, Veerle; Büscher, Philippe

    2005-01-01

    Human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense or T. b. rhodesiense remains highly prevalent in several rural areas of sub-Saharan Africa and is lethal if left untreated. Therefore, accurate tools are absolutely required for field diagnosis. For T. b. gambiense HAT, highly sensitive tests are available for serological screening but the sensitivity of parasitological confirmatory tests remains insufficient and needs to be improved. Screening for T. b. rhodesiense infection still relies on clinical features in the absence of serological tests available for field use. Ongoing research is opening perspectives for a new generation of field diagnostics. Also essential for both forms of HAT is accurate determination of the disease stage because of the high toxicity of melarsoprol, the drug most widely used during the neurological stage of the illness. Recent studies have confirmed the high accuracy of raised immunoglobulin M levels in the cerebrospinal fluid for the staging of T. b. gambiense HAT, and a promising simple assay (LATEX/IgM) is being tested in the field. Apart from the urgent need for better tools for the field diagnosis of this neglected disease, improved access to diagnosis and treatment for the population at risk remains the greatest challenge for the coming years. PMID:15653823

  18. Negishi Cross-Coupling Is Compatible with a Reactive B–Cl Bond: Development of a Versatile Late-Stage Functionalization of 1,2-Azaborines and Its Application to the Synthesis of New BN Isosteres of Naphthalene and Indenyl

    PubMed Central

    Brown, Alec N.; Li, Bo; Liu, Shih-Yuan

    2016-01-01

    The compatibility of the Negishi cross-coupling reaction with the versatile B–Cl functionality has been demonstrated in the context of late-stage functionalization of 1,2-azaborines. Alkyl-, aryl-, and alkenylzinc reagents have been utilized for the functionalization of the triply orthogonal precursor 3-bromo-1-(tert-butyldimethylsilyl)-2-chloro-1,2-dihydro-1,2-azaborine (2) to furnish new 2,3-substituted monocyclic 1,2-azaborines. This methodology has enabled the synthesis of previously elusive BN-naphthalene and BN-indenyl structures from a common intermediate. PMID:26148959

  19. Discovery of a Promiscuous Non-Heme Iron Halogenase in Ambiguine Alkaloid Biogenesis: Implication for an Evolvable Enzyme Family for Late-Stage Halogenation of Aliphatic Carbons in Small Molecules.

    PubMed

    Hillwig, Matthew L; Zhu, Qin; Ittiamornkul, Kuljira; Liu, Xinyu

    2016-05-01

    The elucidation of enigmatic enzymatic chlorination timing in ambiguine indole alkaloid biogenesis led to the discovery and characterization of AmbO5 protein as a promiscuous non-heme iron aliphatic halogenase. AmbO5 was shown capable of selectively modifying seven structurally distinct ambiguine, fischerindole and hapalindole alkaloids with chlorine via late-stage aliphatic C-H group functionalization. Cross-comparison of AmbO5 with a previously characterized aliphatic halogenase homolog WelO5 that has a restricted substrate scope led to the identification of a C-terminal sequence motif important for substrate tolerance and specificity. Mutagenesis of 18 residues of WelO5 within the identified sequence motif led to a functional mutant with an expanded substrate scope identical to AmbO5, but an altered substrate specificity from the wild-type enzymes. These observations collectively provide evidence on the evolvable nature of AmbO5/WelO5 enzyme duo in the context of hapalindole-type alkaloid biogenesis and implicate their promise for the future development of designer biocatalysis for the selective late-stage modification of unactivated aliphatic carbon centers in small molecules with halogens. PMID:27027281

  20. Development of multiplex serological assay for the detection of human African trypanosomiasis.

    PubMed

    Nzou, Samson Muuo; Fujii, Yoshito; Miura, Masashi; Mwau, Matilu; Mwangi, Anne Wanjiru; Itoh, Makoto; Salam, Md Abdus; Hamano, Shinjiro; Hirayama, Kenji; Kaneko, Satoshi

    2016-04-01

    Human African trypanosomiasis (HAT) is a disease caused by Kinetoplastid infection. Serological tests are useful for epidemiological surveillance. The aim of this study was to develop a multiplex serological assay for HAT to assess the diagnostic value of selected HAT antigens for sero-epidemiological surveillance. We cloned loci encoding eight antigens from Trypanosoma brucei gambiense, expressed the genes in bacterial systems, and purified the resulting proteins. Antigens were subjected to Luminex multiplex assays using sera from HAT and VL patients to assess the antigens' immunodiagnostic potential. Among T. b. gambiense antigens, the 64-kDa and 65-kDa invariant surface glycoproteins (ISGs) and flagellar calcium binding protein (FCaBP) had high sensitivity for sera from T. b. gambiense patients, yielding AUC values of 0.871, 0.737 and 0.858 respectively in receiver operating characteristics (ROC) analysis. The ISG64, ISG65, and FCaBP antigens were partially cross-reactive to sera from Trypanosoma brucei rhodesiense patients. The GM6 antigen was cross-reactive to sera from T. b. rhodesiense patients as well as to sera from VL patients. Furthermore, heterogeneous antibody responses to each individual HAT antigen were observed. Testing for multiple HAT antigens in the same panel allowed specific and sensitive detection. Our results demonstrate the utility of applying multiplex assays for development and evaluation of HAT antigens for use in sero-epidemiological surveillance. PMID:26519611

  1. A New Nonpolar N-Hydroxy Imidazoline Lead Compound with Improved Activity in a Murine Model of Late-Stage Trypanosoma brucei brucei Infection Is Not Cross-Resistant with Diamidines

    PubMed Central

    Ríos Martínez, Carlos H.; Miller, Florence; Ganeshamoorthy, Kayathiri; Glacial, Fabienne; Kaiser, Marcel; de Koning, Harry P.; Eze, Anthonius A.; Lagartera, Laura; Herraiz, Tomás

    2014-01-01

    Treatment of late-stage sleeping sickness requires drugs that can cross the blood-brain barrier (BBB) to reach the parasites located in the brain. We report here the synthesis and evaluation of four new N-hydroxy and 12 new N-alkoxy derivatives of bisimidazoline leads as potential agents for the treatment of late-stage sleeping sickness. These compounds, which have reduced basicity compared to the parent leads (i.e., are less ionized at physiological pH), were evaluated in vitro against Trypanosoma brucei rhodesiense and in vivo in murine models of first- and second-stage sleeping sickness. Resistance profile, physicochemical parameters, in vitro BBB permeability, and microsomal stability also were determined. The N-hydroxy imidazoline analogues were the most effective in vivo, with 4-((1-hydroxy-4,5-dihydro-1H-imidazol-2-yl)amino)-N-(4-((1-hydroxy-4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)benzamide (14d) showing 100% cures in the first-stage disease, while 15d, 16d, and 17d appeared to slightly improve survival. In addition, 14d showed weak activity in the chronic model of central nervous system infection in mice. No evidence of reduction of this compound with hepatic microsomes and mitochondria was found in vitro, suggesting that N-hydroxy imidazolines are metabolically stable and have intrinsic activity against T. brucei. In contrast to its unsubstituted parent compound, the uptake of 14d in T. brucei was independent of known drug transporters (i.e., T. brucei AT1/P2 and HAPT), indicating a lower predisposition to cross-resistance with other diamidines and arsenical drugs. Hence, the N-hydroxy bisimidazolines (14d in particular) represent a new class of promising antitrypanosomal agents. PMID:25421467

  2. Respiratory viral infections in institutions from late stage of the first and second waves of pandemic influenza A (H1N1) 2009, Ontario, Canada.

    PubMed

    Asner, Sandra; Peci, Adriana; Marchand-Austin, Alex; Winter, Anne-Luise; Olsha, Romy; Kristjanson, Erik; Low, Donald E; Gubbay, Jonathan B

    2012-05-01

    We report the impact of respiratory viruses on various outbreak settings by using surveillance data from the late first and second wave periods of the 2009 pandemic. A total of 278/345(78·5%) outbreaks tested positive for at least one respiratory virus by multiplex PCR. We detected A(H1N1)pdm09 in 20·6% of all reported outbreaks of which 54·9% were reported by camps, schools, and day cares (CSDs) and 29·6% by long-term care facilities (LCFTs), whereas enterovirus/human rhinovirus (ENT/HRV) accounted for 62% outbreaks of which 83·7% were reported by long-term care facilities (LCTFs). ENT/HRV was frequently identified in LTCF outbreaks involving elderly residents, whereas in CSDs, A(H1N1)pdm09 was primarily detected. PMID:22353417

  3. Tacrolimus (FK506) Suppresses TREM-1 Expression at an Early but Not at a Late Stage in a Murine Model of Fungal Keratitis

    PubMed Central

    Jia, Xiuhua; Lin, Binwu; Huang, Xi; Zhong, Jing; Li, Weihua; Lin, Xiaolei; Sun, Yifang; Yuan, Jin

    2014-01-01

    Purpose To investigate the efficacy and mechanism of tacrolimus(FK506), which is a novel macrolide immunosuppressant, in inhibiting triggering receptor expressed on myeloid cells-1 (TREM-1) expression in a murine keratitis model induced by Aspergillus fumigatus. Method TREM-1 was detected in 11 fungus-infected human corneas by quantitative real-time PCR (qRT-PCR). RAW264.7 macrophages were divided into four groups, which received treatment with zymosan (100 µg/ml), zymosan (100 µg/ml) + mTREM-1/Fc protein (1 µg/ml), or zymosan (100 µg/ml) + FK506 (20 µM) or negative-control treatment. After this treatment, the expression of TREM-1, interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) was assayed using qRT-PCR and ELISA. The mouse model of fungal keratitis was created by intrastromal injection with Aspergillus fumigatus, and the mice were divided into 2 groups: group A received vehicle eye drops 4 times each day, and group B received 4 doses of FK506 eye drops each day. Corneal damage was evaluated by clinical scoring and histologic examination,and myeloperoxidase (MPO) protein levels were also detected by ELISA. The expression of TREM-1, IL-1β and TNFα was then determined at different time points using qRT-PCR and ELISA. Results TREM-1 expression dramatically increased in the human corneas with fungal keratitis. In contrast, FK506 reduced the expression of TREM-1, IL-1β and TNFα in RAW264.7 macrophages stimulated with zymosan. In the mouse model, at day 1 post-infection, the corneal score of the FK506-treated group was lower than that of the control, and polymorphonuclear neutrophil (PMN) infiltration was diminished. TREM-1, IL-1β and TNFα expression was significantly reduced at the same time point. However, the statistically significant differences in cytokine expression, clinical scores and infiltration disappeared at 5 days post-infection. Conclusions FK506 may inhibit the inflammation induced by fungi and alleviate the severity of corneal

  4. Spontaneous CNV in a Novel Mutant Mouse Is Associated With Early VEGF-A–Driven Angiogenesis and Late-Stage Focal Edema, Neural Cell Loss, and Dysfunction

    PubMed Central

    Nagai, Norihiro; Lundh von Leithner, Pete; Izumi-Nagai, Kanako; Hosking, Brett; Chang, Bo; Hurd, Ron; Adamson, Peter; Adamis, Anthony P.; Foxton, Richard H.; Ng, Yin Shan; Shima, David T.

    2014-01-01

    Purpose. Characterization of a mouse model of spontaneous choroidal neovascularization (sCNV) and its effect on retinal architecture and function. Methods. The sCNV mouse phenotype was characterized by using fundus photography, fluorescein angiography, confocal scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), ERG, immunostaining, biochemistry, and electron microscopy. A role for VEGF-A signaling in sCNV was investigated by using neutralizing antibodies and a role for macrophages explored by cell-depletion studies. Results. The sCNV starts between postnatal day 10 and 15 (P10–P15), increasing in number and severity causing RPE disruption and dysfunction. Various morphological methods confirmed the choroidal origin and subretinal position of the angiogenic vessels. At approximately P25, vessels were present in the outer retina with instances of anastomosis of some sCNV lesions with the retinal vasculature. The number of CNV lesions was significantly decreased by systemic blockade of the VEGF-A pathway. Choroidal neovascularization size also was significantly modulated by reducing the number of lesion-associated macrophages. Later stages of sCNV were associated with edema, neuronal loss, and dysfunction. Conclusions. The sCNV mouse is a new model for the study of both early and late events associated with choroidal neovascularization. Pharmacological reduction in sCNV with VEGF-A antagonists and an anti-inflammatory strategy suggests the model may be useful for investigating novel targets for treating human ocular neovascular disease. PMID:24845632

  5. Late-stage sulfides and sulfarsenides in Lower Cambrian black shale (stone coal) from the Huangjiawan mine, Guizhou Province, People's Republic of China

    USGS Publications Warehouse

    Belkin, H.E.; Luo, K.

    2008-01-01

    The Ni-Mo Huangjiawan mine, Guizhou Province, People's Republic of China, occurs in Lower Cambrian black shale (stone coal) in an area where other mines have recently extracted ore from the same horizon. Detailed electron microprobe (EMPA) and scanning electron microscope (SEM) analyses of representative thin sections have revealed a complex assemblage of sulfides and sulfarsenides. Early sulfidic and phosphatic nodules and host matrix have been lithified, somewhat fractured, and then mineralized with later-stage sulfides and sulfarsenides. Gersdorffite, millerite, polydymite, pyrite, sphalerite, chalcopyrite, galena, and clausthalite have been recognized. EMPA data are given for the major phases. Pyrite trace-element distributions and coeval Ni-, As-sulfides indicate that in the main ore layer, the last sulfide deposition was Ni-As-Co-rich. Mo and V deposition were early in the petrogenesis of these rocks. The assemblages gersdorffite-millerite-polydymite (pyrite) and millerite-gersdorffite (pyrite) and the composition of gersdorffite indicate a formation temperature of between 200?? and 300??C suggesting that the last solutions to infiltrate and mineralize the samples were related to hydrothermal processes. Environmentally sensitive elements such as As, Cd, and Se are hosted by sulfides and sulfarsenides and are the main source of these elements to residual soil. Crops grown on them are enriched in these elements, and they may be hazardous for animal and human consumption. ?? Springer-Verlag 2007.

  6. Dietary Vitamin D3 Suppresses Pulmonary Immunopathology Associated with Late-Stage Tuberculosis in C3HeB/FeJ Mice.

    PubMed

    Reeme, Allison E; Robinson, Richard T

    2016-02-01

    Tuberculosis (TB) is a significant human disease caused by inhalation of Mycobacterium tuberculosis. Left untreated, TB mortality is associated with a failure to resolve pulmonary immunopathology. There is currently widespread interest in using vitamin D3 (VitD3) as an adjunct therapy for TB because numerous in vitro studies have shown that VitD3 has direct and indirect mycobactericidal activities. However, to date, there have been no in vivo studies addressing whether VitD3 affects experimental TB outcome. In this study, we used C3HeB/FeJ mice to determine whether dietary VitD3 influences the outcome of experimental TB. We observed that although M. tuberculosis burdens did not differ between mice on a VitD3-replete diet (VitD(HI) mice) and mice on a VitD3-deficient diet (VitD(LO) mice), the inflammatory response in VitD(HI) mice was significantly attenuated relative to VitD(LO) controls. Specifically, the expression of multiple inflammatory pathways was reduced in the lungs at later disease stages as were splenocyte IL12/23p40 and IFN-γ levels following ex vivo restimulation. Dietary VitD3 also suppressed the accumulation of T cells in the mediastinal lymph nodes and lung granulomatous regions while concomitantly accelerating the accumulation of F4/80(+) and Ly6C/Ly6G(+) lineages. The altered inflammatory profile of VitD(HI) mice also associated with reductions in pulmonary immunopathology. VitD receptor-deficient (vdr(-/-)) radiation bone marrow chimeras demonstrate that reductions in pulmonary TB immunopathology are dependent on hematopoietic VitD responsiveness. Collectively, our data support a model wherein the in vivo role of VitD3 during TB is not to promote M. tuberculosis killing but rather to function through hematopoietic cells to reduce M. tuberculosis-elicited immunopathology. PMID:26729807

  7. Coping with Late-Stage Alzheimer's Disease

    MedlinePlus

    ... bed or in a chair. Also, a physical therapist can show you how to move the person's body joints using range-of-motion exercises. During ... Ask the home health aide, nurse, or physical therapist how to use the equipment. Move the person to a different position at least every 2 ...

  8. Silver-catalyzed late-stage fluorination.

    PubMed

    Tang, Pingping; Furuya, Takeru; Ritter, Tobias

    2010-09-01

    Carbon-fluorine bond formation by transition metal catalysis is difficult, and only a few methods for the synthesis of aryl fluorides have been developed. All reported transition-metal-catalyzed fluorination reactions for the synthesis of functionalized arenes are based on palladium. Here we present silver catalysis for carbon-fluorine bond formation. Our report is the first example of the use of the transition metal silver to form carbon-heteroatom bonds by cross-coupling catalysis. The functional group tolerance and substrate scope presented here have not been demonstrated for any other fluorination reaction to date. PMID:20695434

  9. The effect of expressive and instrumental touch on the behavior states of older adults with late-stage dementia of the Alzheimer's type and on music therapist's perceived rapport.

    PubMed

    Belgrave, Melita

    2009-01-01

    The purpose of this study was to examine the effect of music therapy interventions utilizing two types of touch, expressive touch and instrumental touch, on the behavior states of older adults who have late-stage dementia of the Alzheimer's type. A secondary purpose of this study was to examine the perceived effectiveness of the music therapist when expressive and instrumental touch was employed during music therapy sessions. A within-subject design was used with 9 participants receiving 3 sessions in each of the experimental conditions: no touch, expressive touch, and instrumental touch. Results of a one-way ANOVA revealed that expressive touch was significantly more effective during the initial session in eliciting and maintaining alert behavior states than the instrumental and control conditions; however, there were no significant differences between the experimental and control conditions during the first and second session repetitions. Rapport ratings revealed that the therapist's client rapport was perceived to be significantly higher during both the expressive touch and instrumental touch conditions than during the control condition. These findings have important implications for music therapy practice and the effective use of nonverbal communication. PMID:19463031

  10. Determinants of Human African Trypanosomiasis Elimination via Paratransgenesis.

    PubMed

    Gilbert, Jennifer A; Medlock, Jan; Townsend, Jeffrey P; Aksoy, Serap; Ndeffo Mbah, Martial; Galvani, Alison P

    2016-03-01

    Human African trypanosomiasis (HAT), transmitted by tsetse flies, has historically infected hundreds of thousands of individuals annually in sub-Saharan Africa. Over the last decade, concerted control efforts have reduced reported cases to below 10,000 annually, bringing complete elimination within reach. A potential technology to eliminate HAT involves rendering the flies resistant to trypanosome infection. This approach can be achieved through the introduction of transgenic Sodalis symbiotic bacteria that have been modified to produce a trypanocide, and propagated via Wolbachia symbionts, which confer a reproductive advantage to the paratransgenic tsetse. However, the population dynamics of these symbionts within tsetse flies have not yet been evaluated. Specifically, the key factors that determine the effectiveness of paratransgenesis have yet to be quantified. To identify the impact of these determinants on T.b. gambiense and T.b. rhodesiense transmission, we developed a mathematical model of trypanosome transmission that incorporates tsetse and symbiont population dynamics. We found that fecundity and mortality penalties associated with Wolbachia or recombinant Sodalis colonization, probabilities of vertical transmission, and tsetse migration rates are fundamental to the feasibility of HAT elimination. For example, we determined that HAT elimination could be sustained over 25 years when Wolbachia colonization minimally impacted fecundity or mortality, and when the probability of recombinant Sodalis vertical transmission exceeded 99.9%. We also found that for a narrow range of recombinant Sodalis vertical transmission probability (99.9-90.6% for T.b. gambiense and 99.9-85.8% for T.b. rhodesiense), cumulative HAT incidence was reduced between 30% and 1% for T.b. gambiense and between 21% and 3% for T.b. rhodesiense, although elimination was not predicted. Our findings indicate that fitness and mortality penalties associated with paratransgenic symbionts, as well

  11. Determinants of Human African Trypanosomiasis Elimination via Paratransgenesis

    PubMed Central

    Gilbert, Jennifer A.; Medlock, Jan; Townsend, Jeffrey P.; Aksoy, Serap

    2016-01-01

    Human African trypanosomiasis (HAT), transmitted by tsetse flies, has historically infected hundreds of thousands of individuals annually in sub-Saharan Africa. Over the last decade, concerted control efforts have reduced reported cases to below 10,000 annually, bringing complete elimination within reach. A potential technology to eliminate HAT involves rendering the flies resistant to trypanosome infection. This approach can be achieved through the introduction of transgenic Sodalis symbiotic bacteria that have been modified to produce a trypanocide, and propagated via Wolbachia symbionts, which confer a reproductive advantage to the paratransgenic tsetse. However, the population dynamics of these symbionts within tsetse flies have not yet been evaluated. Specifically, the key factors that determine the effectiveness of paratransgenesis have yet to be quantified. To identify the impact of these determinants on T.b. gambiense and T.b. rhodesiense transmission, we developed a mathematical model of trypanosome transmission that incorporates tsetse and symbiont population dynamics. We found that fecundity and mortality penalties associated with Wolbachia or recombinant Sodalis colonization, probabilities of vertical transmission, and tsetse migration rates are fundamental to the feasibility of HAT elimination. For example, we determined that HAT elimination could be sustained over 25 years when Wolbachia colonization minimally impacted fecundity or mortality, and when the probability of recombinant Sodalis vertical transmission exceeded 99.9%. We also found that for a narrow range of recombinant Sodalis vertical transmission probability (99.9–90.6% for T.b. gambiense and 99.9–85.8% for T.b. rhodesiense), cumulative HAT incidence was reduced between 30% and 1% for T.b. gambiense and between 21% and 3% for T.b. rhodesiense, although elimination was not predicted. Our findings indicate that fitness and mortality penalties associated with paratransgenic symbionts, as

  12. Proteomic, Microarray, and Signature-Tagged Mutagenesis Analyses of Anaerobic Pseudomonas aeruginosa at pH 6.5, Likely Representing Chronic, Late-Stage Cystic Fibrosis Airway Conditions▿ †

    PubMed Central

    Platt, Mark D.; Schurr, Michael J.; Sauer, Karin; Vazquez, Gustavo; Kukavica-Ibrulj, Irena; Potvin, Eric; Levesque, Roger C.; Fedynak, Amber; Brinkman, Fiona S. L.; Schurr, Jill; Hwang, Sung-Hei; Lau, Gee W.; Limbach, Patrick A.; Rowe, John J.; Lieberman, Michael A.; Barraud, Nicolas; Webb, Jeremy; Kjelleberg, Staffan; Hunt, Donald F.; Hassett, Daniel J.

    2008-01-01

    Patients suffering from cystic fibrosis (CF) commonly harbor the important pathogen Pseudomonas aeruginosa in their airways. During chronic late-stage CF, P. aeruginosa is known to grow under reduced oxygen tension and is even capable of respiring anaerobically within the thickened airway mucus, at a pH of ∼6.5. Therefore, proteins involved in anaerobic metabolism represent potentially important targets for therapeutic intervention. In this study, the clinically relevant “anaerobiome” or “proteogenome” of P. aeruginosa was assessed. First, two different proteomic approaches were used to identify proteins differentially expressed under anaerobic versus aerobic conditions. Microarray studies were also performed, and in general, the anaerobic transcriptome was in agreement with the proteomic results. However, we found that a major portion of the most upregulated genes in the presence of NO3− and NO2− are those encoding Pf1 bacteriophage. With anaerobic NO2−, the most downregulated genes are those involved postglycolytically and include many tricarboxylic acid cycle genes and those involved in the electron transport chain, especially those encoding the NADH dehydrogenase I complex. Finally, a signature-tagged mutagenesis library of P. aeruginosa was constructed to further screen genes required for both NO3− and NO2− respiration. In addition to genes anticipated to play important roles in the anaerobiome (anr, dnr, nar, nir, and nuo), the cysG and dksA genes were found to be required for both anaerobic NO3− and NO2− respiration. This study represents a major step in unraveling the molecular machinery involved in anaerobic NO3− and NO2− respiration and offers clues as to how we might disrupt such pathways in P. aeruginosa to limit the growth of this important CF pathogen when it is either limited or completely restricted in its oxygen supply. PMID:18203836

  13. Proteomic, microarray, and signature-tagged mutagenesis analyses of anaerobic Pseudomonas aeruginosa at pH 6.5, likely representing chronic, late-stage cystic fibrosis airway conditions.

    PubMed

    Platt, Mark D; Schurr, Michael J; Sauer, Karin; Vazquez, Gustavo; Kukavica-Ibrulj, Irena; Potvin, Eric; Levesque, Roger C; Fedynak, Amber; Brinkman, Fiona S L; Schurr, Jill; Hwang, Sung-Hei; Lau, Gee W; Limbach, Patrick A; Rowe, John J; Lieberman, Michael A; Barraud, Nicolas; Webb, Jeremy; Kjelleberg, Staffan; Hunt, Donald F; Hassett, Daniel J

    2008-04-01

    Patients suffering from cystic fibrosis (CF) commonly harbor the important pathogen Pseudomonas aeruginosa in their airways. During chronic late-stage CF, P. aeruginosa is known to grow under reduced oxygen tension and is even capable of respiring anaerobically within the thickened airway mucus, at a pH of approximately 6.5. Therefore, proteins involved in anaerobic metabolism represent potentially important targets for therapeutic intervention. In this study, the clinically relevant "anaerobiome" or "proteogenome" of P. aeruginosa was assessed. First, two different proteomic approaches were used to identify proteins differentially expressed under anaerobic versus aerobic conditions. Microarray studies were also performed, and in general, the anaerobic transcriptome was in agreement with the proteomic results. However, we found that a major portion of the most upregulated genes in the presence of NO(3)(-) and NO(2)(-) are those encoding Pf1 bacteriophage. With anaerobic NO(2)(-), the most downregulated genes are those involved postglycolytically and include many tricarboxylic acid cycle genes and those involved in the electron transport chain, especially those encoding the NADH dehydrogenase I complex. Finally, a signature-tagged mutagenesis library of P. aeruginosa was constructed to further screen genes required for both NO(3)(-) and NO(2)(-) respiration. In addition to genes anticipated to play important roles in the anaerobiome (anr, dnr, nar, nir, and nuo), the cysG and dksA genes were found to be required for both anaerobic NO(3)(-) and NO(2)(-) respiration. This study represents a major step in unraveling the molecular machinery involved in anaerobic NO(3)(-) and NO(2)(-) respiration and offers clues as to how we might disrupt such pathways in P. aeruginosa to limit the growth of this important CF pathogen when it is either limited or completely restricted in its oxygen supply. PMID:18203836

  14. Tsetse Flies (Glossina) as Vectors of Human African Trypanosomiasis: A Review

    PubMed Central

    Changasi, Robert Emojong

    2016-01-01

    Human African Trypanosomiasis (HAT) transmitted by the tsetse fly continues to be a public health issue, despite more than a century of research. There are two types of the disease, the chronic gambiense and the acute rhodesiense-HAT. Fly abundance and distribution have been affected by changes in land-use patterns and climate. However, disease transmission still continues. Here, we review some aspects of HAT ecoepidemiology in the context of altered infestation patterns and maintenance of the transmission cycle as well as emerging options in disease and vector control. PMID:27034944

  15. Role of expression site switching in the development of resistance to human Trypanosome Lytic Factor-1 in Trypanosoma brucei brucei

    PubMed Central

    Kieft, Rudo; Stephens, Natalie A.; Capewell, Paul; MacLeod, Annette; Hajduk, Stephen L.

    2012-01-01

    Human high-density lipoproteins (HDLs) play an important role in human innate immunity to infection by African trypanosomes with a minor subclass, Trypanosome Lytic Factor-1 (TLF-1), displaying highly selective cytotoxicity to the veterinary pathogen Trypanosoma brucei brucei but not against the human sleeping sickness pathogens Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense. T. b. rhodesiense has evolved the serum resistance associated protein (SRA) that binds and confers resistance to TLF-1 while T. b. gambiense lacks the gene for SRA indicating that these parasites have diverse mechanisms of resistance to TLF-1. Recently, we have shown that T. b. gambiense (group 1) resistance to TLF-1 correlated with the loss of the haptoglobin/hemoglobin receptor (HpHbR) expression, the protein responsible for high affinity binding and uptake of TLF-1. In the course of these studies we also examined TLF-1 resistant T. b. brucei cell lines, generated by long-term in vitro selection. We found that changes in TLF-1 susceptibility in T. b. brucei correlated with changes in variant surface glycoprotein (VSG) expression in addition to reduced TLF-1 binding and uptake. To determine whether the expressed VSG or expression site associated genes (ESAGs) contribute to TLF-1 resistance we prepared a TLF-1 resistant T. b. brucei with a selectable marker in a silent bloodstream expression site (BES). Drug treatment allowed rapid selection of trypanosomes that activated the tagged BES. These studies show that TLF-1 resistance in T. b. brucei is largely independent of the expressed VSG or ESAGs further supporting the central role of HpHbR expression in TLF-1 susceptibility in these cells. PMID:22226682

  16. Role of expression site switching in the development of resistance to human Trypanosome Lytic Factor-1 in Trypanosoma brucei brucei.

    PubMed

    Kieft, Rudo; Stephens, Natalie A; Capewell, Paul; MacLeod, Annette; Hajduk, Stephen L

    2012-05-01

    Human high-density lipoproteins (HDLs) play an important role in human innate immunity to infection by African trypanosomes with a minor subclass, Trypanosome Lytic Factor-1 (TLF-1), displaying highly selective cytotoxicity to the veterinary pathogen Trypanosoma brucei brucei but not against the human sleeping sickness pathogens Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense. T. b. rhodesiense has evolved the serum resistance associated protein (SRA) that binds and confers resistance to TLF-1 while T. b. gambiense lacks the gene for SRA indicating that these parasites have diverse mechanisms of resistance to TLF-1. Recently, we have shown that T. b. gambiense (group 1) resistance to TLF-1 correlated with the loss of the haptoglobin/hemoglobin receptor (HpHbR) expression, the protein responsible for high affinity binding and uptake of TLF-1. In the course of these studies we also examined TLF-1 resistant T. b. brucei cell lines, generated by long-term in vitro selection. We found that changes in TLF-1 susceptibility in T. b. brucei correlated with changes in variant surface glycoprotein (VSG) expression in addition to reduced TLF-1 binding and uptake. To determine whether the expressed VSG or expression site associated genes (ESAGs) contribute to TLF-1 resistance we prepared a TLF-1 resistant T. b. brucei with a selectable marker in a silent bloodstream expression site (BES). Drug treatment allowed rapid selection of trypanosomes that activated the tagged BES. These studies show that TLF-1 resistance in T. b. brucei is largely independent of the expressed VSG or ESAGs further supporting the central role of HpHbR expression in TLF-1 susceptibility in these cells. PMID:22226682

  17. Population genomics reveals the origin and asexual evolution of human infective trypanosomes

    PubMed Central

    Weir, William; Capewell, Paul; Foth, Bernardo; Clucas, Caroline; Pountain, Andrew; Steketee, Pieter; Veitch, Nicola; Koffi, Mathurin; De Meeûs, Thierry; Kaboré, Jacques; Camara, Mamadou; Cooper, Anneli; Tait, Andy; Jamonneau, Vincent; Bucheton, Bruno; Berriman, Matt; MacLeod, Annette

    2016-01-01

    Evolutionary theory predicts that the lack of recombination and chromosomal re-assortment in strictly asexual organisms results in homologous chromosomes irreversibly accumulating mutations and thus evolving independently of each other, a phenomenon termed the Meselson effect. We apply a population genomics approach to examine this effect in an important human pathogen, Trypanosoma brucei gambiense. We determine that T.b. gambiense is evolving strictly asexually and is derived from a single progenitor, which emerged within the last 10,000 years. We demonstrate the Meselson effect for the first time at the genome-wide level in any organism and show large regions of loss of heterozygosity, which we hypothesise to be a short-term compensatory mechanism for counteracting deleterious mutations. Our study sheds new light on the genomic and evolutionary consequences of strict asexuality, which this pathogen uses as it exploits a new biological niche, the human population. DOI: http://dx.doi.org/10.7554/eLife.11473.001 PMID:26809473

  18. Trypanosome resistance to human innate immunity: targeting Achilles' heel.

    PubMed

    Stephens, Natalie A; Kieft, Rudo; Macleod, Annette; Hajduk, Stephen L

    2012-12-01

    Trypanosome lytic factors (TLFs) are powerful, naturally occurring toxins in humans that provide sterile protection against infection by several African trypanosomes. These trypanocidal complexes predominantly enter the parasite by binding to the trypanosome haptoglobin/hemoglobin receptor (HpHbR), trafficking to the lysosome, causing membrane damage and, ultimately, cell lysis. Despite TLF-mediated immunity, the parasites that cause human African Trypanosomiasis (HAT), Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, have developed independent mechanisms of resistance to TLF killing. In this review we describe the parasite defenses that allow trypanosome infections of humans and discuss how targeting these apparent strengths of the parasite may reveal their Achilles' heel, leading to new approaches in the treatment of HAT. PMID:23059119

  19. Trypanosome resistance to human innate immunity: targeting Achilles’ heel

    PubMed Central

    Stephens, Natalie A.; Kieft, Rudo; MacLeod, Annette; Hajduk, Stephen L.

    2015-01-01

    Trypanosome lytic factors (TLFs) are powerful, naturally-occurring toxins in humans that provide sterile protection against infection by several African trypanosomes. These trypanocidal complexes predominantly enter the parasite by binding to the trypanosome haptoglobin/hemoglobin receptor (HpHbR), trafficking to the lysosome, causing membrane damage and ultimately, cell lysis. Despite TLF-mediated immunity, the parasites that cause human African Trypanosomiasis (HAT), Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, have developed independent mechanisms of resistance to TLF killing. Here we describe the parasite defenses that allow trypanosome infections of humans and discuss how targeting these apparent strengths of the parasite may reveal their Achilles’ heel, leading to new approaches in the treatment of HAT. PMID:23059119

  20. Haptoglobin-hemoglobin receptor independent killing of African trypanosomes by human serum and trypanosome lytic factors

    PubMed Central

    Bullard, Whitney; Kieft, Rudo; Capewell, Paul; Veitch, Nicola J.; Macleod, Annette; Hajduk, Stephen L.

    2012-01-01

    The haptoglobin-hemoglobin receptor (HpHbR) of African trypanosomes plays a critical role in human innate immunity against these parasites. Localized to the flagellar pocket of the veterinary pathogen Trypanosoma brucei brucei this receptor binds Trypanosome Lytic Factor-1 (TLF-1), a subclass of human high-density lipoprotein (HDL) facilitating endocytosis, lysosomal trafficking and subsequent killing. Recently, we found that group 1 Trypanosoma brucei gambiense does not express a functional HpHbR. We now show that loss of the TbbHpHbR reduces the susceptibility of T. b. brucei to human serum and TLF-1 by 100- and 10,000-fold, respectively. The relatively high concentrations of human serum and TLF-1 needed to kill trypanosomes lacking the HpHbR indicates that high affinity TbbHpHbR binding enhances the cytotoxicity; however, in the absence of TbbHpHbR, other receptors or fluid phase endocytosis are sufficient to provide some level of susceptibility. Human serum contains a second innate immune factor, TLF-2, that has been suggested to kill trypanosomes independently of the TbbHpHbR. We found that T. b. brucei killing by TLF-2 was reduced in TbbHpHbR-deficient cells but to a lesser extent than TLF-1. This suggests that both TLF-1 and TLF-2 can be taken up via the TbbHpHbR but that alternative pathways exist for the uptake of these toxins. Together the findings reported here extend our previously published studies and suggest that group 1 T. b. gambiense has evolved multiple mechanisms to avoid killing by trypanolytic human serum factors. PMID:22286709

  1. Haptoglobin-hemoglobin receptor independent killing of African trypanosomes by human serum and trypanosome lytic factors.

    PubMed

    Bullard, Whitney; Kieft, Rudo; Capewell, Paul; Veitch, Nicola J; Macleod, Annette; Hajduk, Stephen L

    2012-01-01

    The haptoglobin-hemoglobin receptor (HpHbR) of African trypanosomes plays a critical role in human innate immunity against these parasites. Localized to the flagellar pocket of the veterinary pathogen Trypanosoma brucei brucei this receptor binds Trypanosome Lytic Factor-1 (TLF-1), a subclass of human high-density lipoprotein (HDL) facilitating endocytosis, lysosomal trafficking and subsequent killing. Recently, we found that group 1 Trypanosoma brucei gambiense does not express a functional HpHbR. We now show that loss of the TbbHpHbR reduces the susceptibility of T. b. brucei to human serum and TLF-1 by 100- and 10,000-fold, respectively. The relatively high concentrations of human serum and TLF-1 needed to kill trypanosomes lacking the HpHbR indicates that high affinity TbbHpHbR binding enhances the cytotoxicity; however, in the absence of TbbHpHbR, other receptors or fluid phase endocytosis are sufficient to provide some level of susceptibility. Human serum contains a second innate immune factor, TLF-2, that has been suggested to kill trypanosomes independently of the TbbHpHbR. We found that T. b. brucei killing by TLF-2 was reduced in TbbHpHbR-deficient cells but to a lesser extent than TLF-1. This suggests that both TLF-1 and TLF-2 can be taken up via the TbbHpHbR but that alternative pathways exist for the uptake of these toxins. Together the findings reported here extend our previously published studies and suggest that group 1 T. b. gambiense has evolved multiple mechanisms to avoid killing by trypanolytic human serum factors. PMID:22286709

  2. Role of estrogen receptor alpha in human cervical cancer-associated fibroblasts: a transcriptomic study.

    PubMed

    Kumar, Mahesh M; Davuluri, Sravanthi; Poojar, Sridhar; Mukherjee, Geetashree; Bajpai, Akhilesh Kumar; Bafna, Uttam Dungarmal; Devi, Uma K; Kallur, Pramod P R; Kshitish, Acharya K; Jayshree, R S

    2016-04-01

    Cancer-Associated Fibroblasts (CAFs) are crucial in genesis and progression of tumors; however, cervical CAFs (C-CAFs) are not well characterized. Estradiol (E2) has been implicated as a cofactor in human papillomavirus (HPV)-mediated cervical cancer (CxCa), both in animal models and in women using oral contraceptives; however, the exact role of the hormone is unclear. Human C-CAFs have recently been shown to express estrogen receptor alpha (ER-α). We investigated gene expression patterns in ex vivo cultured early and late stage C-CAFs in the context of E2. CAFs were isolated from four patients with early and two patients with late stage CxCa. ER-α expression in CxCa tissues was localized to stromal fibroblast-like cells and confirmed in ex vivo cultured C-CAFs. Two ER antagonists (ICI 182,780 and Methyl Piperidino Pyrazole) were used to unravel ER signaling in CAFs. Microarray technology was used for expression profiling and validated by quantitative reverse transcription PCR. The transcriptomes of C-CAFs across stages indicated their activated state. C-CAFs had gene expression patterns associated with both pro-tumorigenic and pro-inflammatory signaling. Late-stage C-CAFs compared to those of early stage appeared to be more actively metabolizing and cycling but expressed fewer genes related to immune function. We report differential expression profiles between C-CAFs: early vs. late stage and in the presence of ER antagonists. Both ER antagonists seemed to modulate C-CAF function by down regulating genes associated with cell cycle and metabolism, affecting angiogenesis and cancer progression. This study characterized C-CAFs from early and late stage disease, and experiments with ER inhibitors emphasized the probable importance of canonical ER-α signaling. Interfering with paracrine signaling through fibroblast ER-α is worth exploiting as a targeted therapy in CxCa management. PMID:26499945

  3. Human African trypanosomiasis of the CNS: current issues and challenges

    PubMed Central

    Kennedy, Peter G.E.

    2004-01-01

    Human African trypanosomiasis (HAT), also known as sleeping sickness, is a major cause of mortality and morbidity in sub-Saharan Africa. Current therapy with melarsoprol for CNS HAT has unacceptable side-effects with an overall mortality of 5%. This review discusses the issues of diagnosis and staging of CNS disease, its neuropathogenesis, and the possibility of new therapies for treating late-stage disease. PMID:14966556

  4. Beyond Tsetse--Implications for Research and Control of Human African Trypanosomiasis Epidemics.

    PubMed

    Welburn, Susan C; Molyneux, David H; Maudlin, Ian

    2016-03-01

    Epidemics of both forms of human African trypanosomiasis (HAT) are confined to spatially stable foci in Sub-Saharan Africa while tsetse distribution is widespread. Infection rates of Trypanosoma brucei gambiense in tsetse are extremely low and cannot account for the catastrophic epidemics of Gambian HAT (gHAT) seen over the past century. Here we examine the origins of gHAT epidemics and evidence implicating human genetics in HAT epidemiology. We discuss the role of stress causing breakdown of heritable tolerance in silent disease carriers generating gHAT outbreaks and see how peculiarities in the epidemiologies of gHAT and Rhodesian HAT (rHAT) impact on strategies for disease control. PMID:26826783

  5. Costs Of Using “Tiny Targets” to Control Glossina fuscipes fuscipes, a Vector of Gambiense Sleeping Sickness in Arua District of Uganda

    PubMed Central

    Shaw, Alexandra P. M.; Tirados, Inaki; Mangwiro, Clement T. N.; Esterhuizen, Johan; Lehane, Michael J.; Torr, Stephen J.; Kovacic, Vanja

    2015-01-01

    Introduction To evaluate the relative effectiveness of tsetse control methods, their costs need to be analysed alongside their impact on tsetse populations. Very little has been published on the costs of methods specifically targeting human African trypanosomiasis Methodology/Principal Findings In northern Uganda, a 250 km2 field trial was undertaken using small (0.5 X 0.25 m) insecticide-treated targets (“tiny targets”). Detailed cost recording accompanied every phase of the work. Costs were calculated for this operation as if managed by the Ugandan vector control services: removing purely research components of the work and applying local salaries. This calculation assumed that all resources are fully used, with no spare capacity. The full cost of the operation was assessed at USD 85.4 per km2, of which USD 55.7 or 65.2% were field costs, made up of three component activities (target deployment: 34.5%, trap monitoring: 10.6% and target maintenance: 20.1%). The remaining USD 29.7 or 34.8% of the costs were for preliminary studies and administration (tsetse surveys: 6.0%, sensitisation of local populations: 18.6% and office support: 10.2%). Targets accounted for only 12.9% of the total cost, other important cost components were labour (24.1%) and transport (34.6%). Discussion Comparison with the updated cost of historical HAT vector control projects and recent estimates indicates that this work represents a major reduction in cost levels. This is attributed not just to the low unit cost of tiny targets but also to the organisation of delivery, using local labour with bicycles or motorcycles. Sensitivity analyses were undertaken, investigating key prices and assumptions. It is believed that these costs are generalizable to other HAT foci, although in more remote areas, with denser vegetation and fewer people, costs would increase, as would be the case for other tsetse control techniques. PMID:25811956

  6. Late-stage flood lavas in the Elysium region, Mars

    NASA Technical Reports Server (NTRS)

    Plescia, J. B.

    1987-01-01

    In the southeastern part of the Elysium region is a unit that exhibits little texture and a generally low albedo and that has a very low crater frequency. This unit has been mapped as smooth plains material and previously interpreted as an eolian deposit on the basis of Mariner 9 images. More recently, the unit was mapped as material deposited during a channeling episode. The author interprets the smooth plains unit as being a volcanic deposit composed of low viscosity lava flows: both flood lavas and individual flows. The reasons for these conclusions are given and briefly discussed.

  7. Late-stage accretion and habitability of terrestrial planets

    NASA Astrophysics Data System (ADS)

    Raymond, Sean Neylon

    The final stage in the formation of terrestrial planets consists of the accumulation of ~1000 km "planetary embryos" and ~1 km planetesimals via collisional accretion., under the mutual gravity of other solid bodies and the gas giant planets (if any). Water is delivered to planets via collisions with volatile-rich bodies that condensed past the snow line, beyond about 2.5 AU. We present results of a large number of relatively low-resolution simulations, designed to assess the predictability of systems of terrestrial planets as a function of "observables" such as the orbit of gas giant planets. These show that a variety of terrestrial planets can form, from small, dry, Mars-like worlds to planets with similar properties to Earth, to >3 Earth mass "water worlds" with >=30 times as much water as the Earth. The terrestrial planets are largely shaped by the influence of the giant planets and the surface density of material. We have uncovered trends between the terrestrial planets and (i) the mass, (ii) the orbital distance and (iii) the orbital eccentricity of a giant planet, (iv) the surface density of the disk, and (v) the disk's density profile. Five simulations with 1000-2000 particles reveal new aspects of the accretion process Water is delivered to the terrestrial planets as a few large planetesimals in a "hit or miss" process, and as billions of planetesimals in a robust way. The water delivery process is therefore more robust than previously thought, implying that the range of water contents of extra-solar Earths is less stochastic than indicated in previous studies; most planets accrete water- rich bodies. We simulate terrestrial accretion in the presence of close-in giant planets (e.g., "hot jupiters"), assuming these form and migrate quickly. Potentially habitable planets can form in these systems, but are likely to be iron-poor. Asteroid belts may exist between the terrestrial planets and hot jupiters in these systems. We have also tested the accretion process in four known extra- solar planetary systems. In 55 Cancri, terrestrial planets form relatively easily, and may have orbits in the habitable zone and significant water contents.

  8. Late stages of massive star evolution and nucleosynthesis

    SciTech Connect

    Nomoto, Ken'ichi; Hashimoto, Masa-aki

    1986-01-01

    The evolution of massive stars in the mass range of 8 to 25 M solar mass is reviewed. The effect of electron degeneracy on the gravothermal nature of stars is discussed. Depending on the stellar mass, the stars form three types of cores, namely, non-degenerate, semi-degenerate, and strongly degenerate cores. The evolution for these cases is quite distinct from each other and leads to the three different types of final fate. It is suggested that our helium star model, which is equivalent to a 25 M solar mass star, will form a relatively small mass iron core despite the faster /sup 12/C(..cap alpha..,..gamma..)/sup 16/O reaction. 50 refs., 21 figs.

  9. Vortex Ring Structure at Late Stages of Formation

    NASA Astrophysics Data System (ADS)

    Fabris, Drazen; Liepmann, Dorian

    1996-11-01

    The development of a vortex ring as it moves several diameters from the generating nozzle is studied experimentally with DPIV. For longer piston strokes (L/D = 2) and for moderate Reynolds numbers (Γ / ν of several thousand) the vorticity distribution includes a region of rotational fluid near the front stagnation point of the ring. This region of fluid is a remnant of the shear layer rolling up to form the core of the ring and is a consequence of the stopping condition of the formation. This structure persists for at least several diameters of the ring advection.

  10. Late Stages of Accretion of Uranus and Neptune

    NASA Technical Reports Server (NTRS)

    Stewart, Glen R.

    2002-01-01

    A series of N-body simulations were done to try and form Uranus and Neptune from a swarm of a hundred sub-Earth-sized planetary embryos initially on low-inclination, nearly circular orbits beyond Saturn. These calculations were designed to test published Monte Carlo simulations and N-body simulations. Whereas these studies reported successful formation of Uranus and Neptune sized planets, we found very little accretion at all. This occurs because the embryos are dynamically excited by each other and the gravitational effects of Jupiter and Saturn on a time scale that is short compared to the collision time scale. This process produces large orbital eccentricities and inclinations which significantly reduce the collisional cross-section of the embryos because it reduces the effect of gravitational focusing.

  11. Failed magmatic eruptions: Late-stage cessation of magma ascent

    USGS Publications Warehouse

    Moran, S.C.; Newhall, C.; Roman, D.C.

    2011-01-01

    When a volcano becomes restless, a primary question is whether the unrest will lead to an eruption. Here we recognize four possible outcomes of a magmatic intrusion: "deep intrusion", "shallow intrusion", "sluggish/viscous magmatic eruption", and "rapid, often explosive magmatic eruption". We define "failed eruptions" as instances in which magma reaches but does not pass the "shallow intrusion" stage, i. e., when magma gets close to, but does not reach, the surface. Competing factors act to promote or hinder the eventual eruption of a magma intrusion. Fresh intrusion from depth, high magma gas content, rapid ascent rates that leave little time for enroute degassing, opening of pathways, and sudden decompression near the surface all act to promote eruption, whereas decreased magma supply from depth, slow ascent, significant enroute degassing and associated increases in viscosity, and impingement on structural barriers all act to hinder eruption. All of these factors interact in complex ways with variable results, but often cause magma to stall at some depth before reaching the surface. Although certain precursory phenomena, such as rapidly escalating seismic swarms or rates of degassing or deformation, are good indicators that an eruption is likely, such phenomena have also been observed in association with intrusions that have ultimately failed to erupt. A perpetual difficulty with quantifying the probability of eruption is a lack of data, particularly on instances of failed eruptions. This difficulty is being addressed in part through the WOVOdat database. Papers in this volume will be an additional resource for scientists grappling with the issue of whether or not an episode of unrest will lead to a magmatic eruption.

  12. Late stages of accumulation and early evolution of the planets

    NASA Technical Reports Server (NTRS)

    Vityazev, Andrey V.; Perchernikova, G. V.

    1991-01-01

    Recently developed solutions of problems are discussed that were traditionally considered fundamental in classical solar system cosmogony: determination of planetary orbit distribution patterns, values for mean eccentricity and orbital inclinations of the planets, and rotation periods and rotation axis inclinations of the planets. Two important cosmochemical aspects of accumulation are examined: the time scale for gas loss from the terrestrial planet zone, and the composition of the planets in terms of isotope data. It was concluded that the early beginning of planet differentiation is a function of the heating of protoplanets during collisions with large (thousands of kilometers) bodies. Energetics, heat mass transfer processes, and characteristic time scales of these processes at the early stages of planet evolution are considered.

  13. Recent Simulations of the Late Stages Growth of Jupiter

    NASA Technical Reports Server (NTRS)

    Lissauer, Jack J.; D'Angelo, Gennaro; Hubickyj, Olenka

    2012-01-01

    Presented by Lissauer et al. (2009, Icarus 199, 338) are used to test the model of capture of Jupiter's irregular satellites within proto-Jupiter's distended and thermally-supported envelope. We find such capture highly unlikely, since the envelope shrinks too slowly for a large number of moons to be retained, and many of those that would be retained would orbit closer to the planet than do the observed Jovian irregulars. Our calculations do not address (and therefore do not exclude) the possibility that the irregular satellites were captured as a result of gas drag within a circumjovian disk. Support for this research from NASA Outer Planets Research Program is gratefully acknowledged.

  14. The Economics of Late-Stage Chronic Kidney Disease.

    PubMed

    Provenzano, Robert

    2016-07-01

    Health care reimbursement is undergoing a fundamental change from volume-driven to value-driven care. The Patient Protection and Affordable Care Act is marshaling this change and empowering hospitals through Accountable Care Organizations to accept risk. ESRD care/nephrology was awarded the only disease-specific Accountable Care Organization, ESRD Seamless Care Organizations. Dialysis providers in partnership with nephrologists will be exploring how ESRD Seamless Care Organizations will drive improvement in care. CKD care and economics will no longer be isolated from ESRD but possibly more closely linked to global patient outcomes. Preparation for these changes will require unique co-operation and collaboration between nephrologists, dialysis providers, payers, and hospitals/health care systems. Early pilot trials, demonstration projects, and special need programs have suggested value care can be delivered. Whether these results are scalable needs to be determined. PMID:27324674

  15. Late stages in the evolution of classical novae

    NASA Technical Reports Server (NTRS)

    Starrfield, S.; Krautter, J.; Sonneborn, G.; Shore, S. N.; Wagner, R. M.; Austin, S.; Saizar, P.; Ferland, G.; Wade, R.; Gehrz, R. D.

    1990-01-01

    We have begun a study of the long term evolution of novae in outburst in order to determine the means by which they return in quiescence when nuclear burning has ended. This project involves both IUE and optical observations and theoretical predictions. Recently, in the initial observational part of this project, we have obtained IUE Short Wavelength Prime (SWP) spectra of GQ Mus 1983 and QU Vul 1984. Each spectrum was a 16 hour exposure using a combined US1 plus Vilspa shift. No novae have been studied in the UV for as long as QU Vul and GQ Mus and observations of their spectral evolution are providing unique data on the turn-off time scale. We have also obtained the spectra of old novae from the IUE archives in order to compare and contrast the existing spectra with those of GQ Mus and Qu Vul. The theoretical prediction is that a nova should be very hot just before turnoff but x ray observations from EXOSAT do not confirm this prediction.

  16. Late-stage summit activity of Martian shield volcanoes

    NASA Technical Reports Server (NTRS)

    Mouginis-Mark, P. J.

    1982-01-01

    The preservation of morphologically fresh lava flows which pre-date the most recent episodes of caldera collapse at the summits of Ascraeus, Arsia and Olympus Montes indicates that explosive eruptions were not associated with this stage of Tharsis shield volcanism. The existence of resurfaced floor segments, complex wrinkle ridges, and lava terraces within the summit craters suggests that lava lakes comprised the dominant form of the intra-caldera activity. Multiple collapse episodes on Ascraeus and Olympus Montes are indicated by the nested summit craters. The most plausible cause of caldera collapse appears to be large-scale sub-terminal effusive activity, which is corroborated by the previously recognized existence of large lava flows on the flanks of these volcanoes. Due to the implied sequence of large-scale explosive (silicic) volcanism followed by effusive (basaltic) activity, it appears highly unlikely that ignimbrites or other forms of pyroclastic flows (previously proposed as possible deposits within the Olympus Mons aureole material) were ever erupted from the Tharsis Montes.

  17. Glossina fuscipes populations provide insights for Human African Trypanosomiasis transmission in Uganda

    PubMed Central

    Aksoy, Serap; Caccone, Adalgisa; Galvani, Alison P.; Okedi, Loyce M.

    2013-01-01

    Uganda has both forms of human African trypanosomiasis (HAT): the chronic gambiense disease in the northwest and the acute rhodesiense disease in the south. The recent spread of rhodesiense into central Uganda has raised concerns given the different control strategies the two diseases require. We present knowledge on the population genetics of the major vector species Glossina fuscipes fuscipes in Uganda with a focus on population structure, measures of gene flow between populations, and the occurrence of polyandry. The microbiome composition and diversity is discussed, focusing on their potential role on trypanosome infection outcomes. We discuss the implications of these findings for large-scale tsetse control programs, including suppression or eradication, being undertaken in Uganda and potential future genetic applications. PMID:23845311

  18. Ameliorating replicative senescence of human bone marrow stromal cells by PSMB5 overexpression

    SciTech Connect

    Lu, Li; Song, Hui-Fang; Wei, Jiao-Long; Liu, Xue-Qin; Song, Wen-Hui; Yan, Ba-Yi; Yang, Gui-Jiao; Li, Ang; Yang, Wu-Lin

    2014-01-24

    Highlights: • PSMB5 overexpression restores the differentiation potential of aged hBMSCs. • PSMB5 overexpression enhances the proteasomal activity of late-stage hBMSCs. • PSMB5 overexpression inhibits replicative senescence and improved cell viability. • PSMB5 overexpression promotes cell growth by upregulating the Cyclin D1/CDK4 complex. - Abstract: Multipotent human bone marrow stromal cells (hBMSCs) potentially serve as a source for cell-based therapy in regenerative medicine. However, in vitro expansion was inescapably accompanied with cell senescence, characterized by inhibited proliferation and compromised pluripotency. We have previously demonstrated that this aging process is closely associated with reduced 20S proteasomal activity, with down-regulation of rate-limiting catalytic β-subunits particularly evident. In the present study, we confirmed that proteasomal activity directly contributes to senescence of hBMSCs, which could be reversed by overexpression of the β5-subunit (PSMB5). Knocking down PSMB5 led to decreased proteasomal activity concurrent with reduced cell proliferation in early-stage hBMSCs, which is similar to the senescent phenotype observed in late-stage cells. In contrast, overexpressing PSMB5 in late-stage cells efficiently restored the normal activity of 20S proteasomes and promoted cell growth, possibly via upregulating the Cyclin D1/CDK4 complex. Additionally, PSMB5 could enhance cell resistance to oxidative stress, as evidenced by the increased cell survival upon exposing senescent hBMSCs to hydrogen peroxide. Furthermore, PSMB5 overexpression retained the pluripotency of late-stage hBMSCs by facilitating their neural differentiation both in vitro and in vivo. Collectively, our work reveals a critical role of PSMB5 in 20S proteasome-mediated protection against replicative senescence, pointing to a possible strategy for maintaining the integrity of culture-expanded hBMSCs by manipulating the expression of PSMB5.

  19. Reducing Human-Tsetse Contact Significantly Enhances the Efficacy of Sleeping Sickness Active Screening Campaigns: A Promising Result in the Context of Elimination

    PubMed Central

    Courtin, Fabrice; Camara, Mamadou; Rayaisse, Jean-Baptiste; Kagbadouno, Moise; Dama, Emilie; Camara, Oumou; Traoré, Ibrahima S.; Rouamba, Jérémi; Peylhard, Moana; Somda, Martin B.; Leno, Mamadou; Lehane, Mike J.; Torr, Steve J.; Solano, Philippe; Jamonneau, Vincent; Bucheton, Bruno

    2015-01-01

    Background Control of gambiense sleeping sickness, a neglected tropical disease targeted for elimination by 2020, relies mainly on mass screening of populations at risk and treatment of cases. This strategy is however challenged by the existence of undetected reservoirs of parasites that contribute to the maintenance of transmission. In this study, performed in the Boffa disease focus of Guinea, we evaluated the value of adding vector control to medical surveys and measured its impact on disease burden. Methods The focus was divided into two parts (screen and treat in the western part; screen and treat plus vector control in the eastern part) separated by the Rio Pongo river. Population census and baseline entomological data were collected from the entire focus at the beginning of the study and insecticide impregnated targets were deployed on the eastern bank only. Medical surveys were performed in both areas in 2012 and 2013. Findings In the vector control area, there was an 80% decrease in tsetse density, resulting in a significant decrease of human tsetse contacts, and a decrease of disease prevalence (from 0.3% to 0.1%; p=0.01), and an almost nil incidence of new infections (<0.1%). In contrast, incidence was 10 times higher in the area without vector control (>1%, p<0.0001) with a disease prevalence increasing slightly (from 0.5 to 0.7%, p=0.34). Interpretation Combining medical and vector control was decisive in reducing T. b. gambiense transmission and in speeding up progress towards elimination. Similar strategies could be applied in other foci. PMID:26267667

  20. Pulmonary toxoplasmosis in human immunodeficiency virus-infected patients in the era of antiretroviral therapy.

    PubMed

    Velásquez, Jorge N; Ledesma, Bibiana A; Nigro, Monica G; Vittar, Natalia; Rueda, Nestor; De Carolis, Luis; Figueiras, Olga; Carnevale, Silvana; Corti, Marcelo

    2016-01-01

    Toxoplasmosis is a severe opportunistic infection in patients infected with the human immunodeficiency virus (HIV). The lung is a major site of infection after the central nervous system. In this report we described two cases of pneumonia due to Toxoplasma gondii infection in HIV patients with antiretroviral therapy. Clinical and radiological abnormalities are not specific. Pulmonary toxoplasmosis should be considered in HIV-infected patients with late stage of HIV, CD4 count less than 100 cells/µl and a poor adherence to HAART. PMID:26933317

  1. Pulmonary toxoplasmosis in human immunodeficiency virus-infected patients in the era of antiretroviral therapy

    PubMed Central

    Velásquez, Jorge N; Ledesma, Bibiana A; Nigro, Monica G; Vittar, Natalia; Rueda, Nestor; De Carolis, Luis; Figueiras, Olga; Carnevale, Silvana; Corti, Marcelo

    2016-01-01

    Toxoplasmosis is a severe opportunistic infection in patients infected with the human immunodeficiency virus (HIV). The lung is a major site of infection after the central nervous system. In this report we described two cases of pneumonia due to Toxoplasma gondii infection in HIV patients with antiretroviral therapy. Clinical and radiological abnormalities are not specific. Pulmonary toxoplasmosis should be considered in HIV-infected patients with late stage of HIV, CD4 count less than 100 cells/µl and a poor adherence to HAART. PMID:26933317

  2. Three-dimensional analysis of inner ear development in human embryos.

    PubMed

    Yasuda, Megumi; Yamada, Shigehito; Uwabe, Chigako; Shiota, Kohei; Yasuda, Yoshiko

    2007-09-01

    The development of the inner ear is difficult to understand morphologically, because it proceeds in a complicated manner. Chronological 3-D reconstructed models of the inner ear primordium in human embryos (Carnegie stage 16-22) were created from the histological serial sections in the Kyoto Collection of Human Embryos using 3-D-reconstruction software on a personal computer. The endolymphatic duct begins to extend at stage 18 and continues to extend. The formation of the anterior and posterior semicircular ducts begins at stage 17. The upper lateral region of the otic pouch starts to sink inward at stage 17 and then the epithelia of both sides face and fuse with each other. The fusion disappears and the mesenchyme appears in the primordium, which looks like a hole in the otic pouch at stage 18. The mesenchyme begins to enlarge in the otic pouch at late stage 18, and continues to enlarge until the formation of the loop of semicircular ducts at stage 19. The lateral semicircular duct is formed similarly at stages 18 and 19. In the mesenchyme of the lateral semicircular duct, we found apoptotic death near the epithelium of the otic pouch at late stage 19. The cochlear duct already begins to extend at stage 16. First it extends to the opposite direction of the future cochlear rotation at stage 16 and 17, and then turns to the future rotating direction at stage 18. The cochlear duct initiates rotation at late stage 19. The cochlear duct continues to rotate and forms approximately one winding at stage 22. PMID:17867342

  3. Challenges towards the elimination of Human African Trypanosomiasis in the sleeping sickness focus of Campo in southern Cameroon.

    PubMed

    Simo, Gustave; Mbida Mbida, Jean Arthur; Ebo'o Eyenga, Vincent; Asonganyi, Tazoacha; Njiokou, Flobert; Grébaut, Pascal

    2014-01-01

    The sleeping sickness focus of Campo lies along the Atlantic coast and extends along the Ntem River, which constitutes the Cameroonian and Equatorial Guinean border. It is a hypo-endemic focus with the disease prevalence varying from 0.3 to 0.86% during the last few decades. Investigations on animal reservoirs revealed a prevalence of Trypanosoma brucei gambiense of 0.6% in wild animals and 4.83% in domestic animals of this focus. From 2001 to 2012, about 19 931 tsetse were collected in this focus and five tsetse species including Glossina palpalis palpalis, G. pallicera, G. nigrofusca, G. tabaniformis and G. caliginea were identified. The analysis of blood meals of these flies showed that they feed on human, pig, goat, sheep, and wild animals such as antelope, duiker, wild pig, turtle and snake. The percentage of blood meals taken on these hosts varies according to sampling periods. For instance, 6.8% of blood meals from pig were reported in 2004 and 22% in 2008. This variation is subjected to considerable evolutions because the Campo HAT focus is submitted to socio-economic mutations including the reopening of a new wood company, the construction of autonomous port at "Kribi" as well as the dam at "Memve ele". These activities will bring more that 3000 inhabitants around Campo and induce the deforestation for the implementation of farmlands as well as breeding of domestic animals. Such mutations have impacts on the transmission and the epidemiology of sleeping sickness due to the modification of the fauna composition, the nutritional behavior of tsetse, the zoophilic/anthropophilic index. To achieve the elimination goal in the sleeping sickness focus of Campo, we report in this paper the current epidemiological situation of the disease, the research findings of the last decades notably on the population genetics of trypanosomes, the modifications of nutritional behavior of tsetse, the prevalence of T. b. gambiense in humans, domestic and wild animals. An overview

  4. Functional Characterization of Human Stem Cell-Derived Cardiomyocytes

    PubMed Central

    Kirsch, Authors Glenn E.; Obejero-Paz, Carlos A.; Bruening-Wright, Andrew

    2014-01-01

    Cardiac toxicity is a leading contributor to late-stage attrition in the drug discovery process and to withdrawal of approved from the market. In vitro assays that enable earlier and more accurate testing for cardiac risk provide early stage predictive indicators that aid in mitigating risk. Human cardiomyocytes, the most relevant subjects for early stage testing, are severely limited in supply. But human stem cell-derived cardiomyocytes (SC-hCM) are readily available from commercial sources and are increasingly used in academic research, drug discovery and safety pharmacology. As a result, SC-hCM electrophysiology has become a valuable tool to assess cardiac risk associated with drugs. This unit describes techniques for recording individual currents carried by sodium, calcium and potassium ions, as well as single cell action potentials, and impedance recordings from contracting syncytia of thousands of interconnected cells. PMID:25152802

  5. [Impact of the dynamics of human settlement on tsetse and trypanosomosis distribution in the Mouhoun river basin (Burkina Faso)].

    PubMed

    Rouamba, J; Jamonneau, V; Sidibé, I; Solano, P; Courtin, F

    2009-03-01

    In Burkina Faso, the Mouhoun river basin (formerly "Black Volta") constitutes a historical focus of Human (HAT) and Animal (AAT) African Trypanosomoses, both transmitted by tsetse flies. Nowadays, HAT seems to have disappeared from this area, while AAT still causes severe economic losses. In order to explain these different epidemiological situations, we undertook a geographical study based on the analysis of aerial pictures between 1952 and 2007, and field surveys to collect medical, entomological, and veterinary data on trypanosomoses. Our results suggest that in this area, landscapes have been dramatically modified as a consequence of population growth, and in turn have had an impact on the number and distribution of tsetse flies. Combined with the historical medical action on HAT which probably led to the disappearance of T. b. gambiense, this environmental degradation and the development of hydrological structures provide explanations for the local disappearance of HAT, and for the maintenance of AAT. It appears necessary to extrapolate these studies to other areas in order to identify the factors explaining the presence/absence of trypanosomoses in the context of human population growth and climatic changes, in order to help to target priority areas for the control of these diseases. PMID:19353947

  6. GnRH receptors in human granulosa cells: Anatomical localization and characterization by autoradiographic study

    SciTech Connect

    Latouche, J.; Crumeyrolle-Arias, M.; Jordan, D.; Kopp, N.; Augendre-Ferrante, B.; Cedard, L.; Haour, F. )

    1989-09-01

    The presence of receptors for GnRH in human ovary has been investigated by quantitative autoradiography. Simultaneous visualization and characterization of specific receptors on frozen sections were obtained on six pairs of human ovaries. Among them only one exhibited a large preovulatory follicle. This dominant follicle exhibited a specific and high affinity binding capacity for {sup 125}I-GnRHa exclusively localized on the granulosa cell layer. Analysis of saturation curve indicates a Kd value of 0.22 nM and Bmax of 9.6 fmol/mg protein. In contrast LH-hCG binding sites were present in all antral follicles. These data demonstrate for the first time the presence of high affinity GnRH receptors in human granulosa cells at a late stage of follicular maturation.

  7. Myxoma and vaccinia viruses exploit different mechanisms to enter and infect human cancer cells

    SciTech Connect

    Villa, Nancy Y.; Bartee, Eric; Mohamed, Mohamed R.; Rahman, Masmudur M.; Barrett, John W.; McFadden, Grant

    2010-06-05

    Myxoma (MYXV) and vaccinia (VACV) viruses have recently emerged as potential oncolytic agents that can infect and kill different human cancer cells. Although both are structurally similar, it is unknown whether the pathway(s) used by these poxviruses to enter and cause oncolysis in cancer cells are mechanistically similar. Here, we compared the entry of MYXV and VACV-WR into various human cancer cells and observed significant differences: 1 - low-pH treatment accelerates fusion-mediated entry of VACV but not MYXV, 2 - the tyrosine kinase inhibitor genistein inhibits entry of VACV, but not MYXV, 3 - knockdown of PAK1 revealed that it is required for a late stage event downstream of MYXV entry into cancer cells, whereas PAK1 is required for VACV entry into the same target cells. These results suggest that VACV and MYXV exploit different mechanisms to enter into human cancer cells, thus providing some rationale for their divergent cancer cell tropisms.

  8. Effects of cytochalasin B on the intrcellular bactericidal activity of human neutrophils.

    PubMed

    Okuda, K

    1975-06-01

    Cytochalasin B (CB) is known to have some inhibitory effects on cytokinesis, single-cell movement, bacterial uptake by phagocytes, and many other processes. The effects of CB on intraleukocytic bactericidal activities in human leukocytes were studied, and the results were summarized as follows. (i) CB inhibited the early stage of the intracellular bactericidal activity of human leukocytes against Streptococcus pyogenes D58 (group A). The effect was rapidly eliminated by rinsing the CB solution. (ii) In the late stage of the intracellular bactericidal process, however, CB possessed no effect against S. pyogenes D58 (group A) and Staphylococcus aureus 209P. (iii) CB also inhibited the translocation of myeloperoxidase granules to the phagosomes of human neutrophils. PMID:1155917

  9. Ginsenosides may enhance the functionality of human embryonic stem cell-derived cardiomyocytes in vitro.

    PubMed

    Kim, Yoon Young; Ku, Jun Beom; Liu, Hung Ching; Ku, Seung-Yup; Kim, Seok Hyun; Choi, Young Min

    2014-10-01

    Various chemicals have been reported to induce the differentiation of human embryonic stem cells (hESCs) into cardiomyocytes (CMs), however, their contributions to the functionality of hESC-derived CMs are still limited. In this study, we evaluated the effects of red ginseng extract (RGE), ginsenoside-Rb1 (gRb1, panaxadiol), and ginsenoside-Re (gRe, panaxatriol) on the differentiation of hESCs and the functionality of derived CMs. Undifferentiated hESCs were treated with 0.25 mg/mL RGE, 10 μmol/L gRb1, or 10 μmol/L gRe for 48 hours at the differentiation induction (early stage) or maturation (late stage) period. The expression of mesodermal and cardiac transcription factor genes was upregulated in the ginsenoside-treated groups from early stage. The expression of cardiac sarcomeric genes was significantly upregulated at the late stage. The gRb1- and gRe-treated groups upregulated the expression of potassium voltage-gated channel subfamily E member 1 (KCNE1) and the gRe-treated group showed a longer beating duration compared to the control. Taken together, ginsenosides may enhance the functionality of hESC-derived CMs in vitro. PMID:24615935

  10. Lysis of Trypanosoma brucei by a toxic subspecies of human high density lipoprotein.

    PubMed

    Hajduk, S L; Moore, D R; Vasudevacharya, J; Siqueira, H; Torri, A F; Tytler, E M; Esko, J D

    1989-03-25

    Trypanosoma brucei brucei is an important pathogen of domestic cattle in sub-Saharan Africa and is closely related to the human sleeping sickness parasites, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. However, T. b. brucei is non-infectious to humans. The restriction of the host range of T. b. brucei results from the sensitivity of the parasite to lysis by toxic human high density lipoproteins (HDL) (Rifkin, M. R. (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 3450-3454). We show in this report that trypanosome lytic activity is not a universal feature of all human HDL particles but rather that it is associated with a minor subclass of HDL. We have purified the lytic activity about 8,000-fold and have identified and characterized the subspecies of HDL responsible for trypanosome lysis. This class of HDL has a relative molecular weight of 490,000, a buoyant density of 1.21-1.24 g/ml, and a particle diameter of 150-210 A. It contains apolipoproteins AI, AII, CI, CII, and CIII, and monoclonal antibodies against apo-AI and apo-AII inhibit trypanocidal activity. In addition to these common apolipoproteins, the particles also contain at least three unique proteins, as measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under nonreducing conditions. Treatment of the particles with dithiothreitol resulted in the disappearance of two of the proteins and abolished trypanocidal activity. Two-dimensional gel electrophoresis showed that these proteins were a disulfide-linked trimer of 45,000, 36,000, and 13,500-Da polypeptides and dimers of the 36,000- and 13,500-Da polypeptides or of 65,000- and 8,500-Da polypeptides. Studies on the lysis of T. b. brucei by the purified particle suggest that the lytic pathway may involve the uptake of the trypanocidal subspecies of HDL by endocytosis. PMID:2494183

  11. Physics and chemistry of the late stages of stellar evolution — an introduction

    NASA Astrophysics Data System (ADS)

    Kwok, Sun

    2016-07-01

    The stellar evolution from the asymptotic giant branch (AGB) to planetary nebulae (PN) contains some of the most interesting physical and chemical processes in the Universe. Within a time period of one million years starting from the nucleosynthesis of carbon in the core, we witness the chemical synthesis of molecules in the atmosphere, followed by the condensation of minerals and organics in the stellar outflow. Different phases of supersonic stellar winds, both spherical symmetric and highly collimated, and their interactions lead to a series of dynamical processes and morphological transformation of the stellar ejecta. Most interestingly, PN are now known to be major sources of complex organics in the Galaxy. Organic compounds of mixed aromatic and aliphatic structures have been observed to form in the post-AGB evolution over time scales as short as hundreds of years. There is likely that these stellar organics journeyed through the Galaxy and were embedded in early Solar System.

  12. Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection.

    PubMed

    Lee, Chia Min; Weight, Alisha K; Haldar, Jayanta; Wang, Ling; Klibanov, Alexander M; Chen, Jianzhu

    2012-12-11

    Covalently conjugating multiple copies of the drug zanamivir (ZA; the active ingredient in Relenza) via a flexible linker to poly-l-glutamine (PGN) enhances the anti-influenza virus activity by orders of magnitude. In this study, we investigated the mechanisms of this phenomenon. Like ZA itself, the PGN-attached drug (PGN-ZA) binds specifically to viral neuraminidase and inhibits both its enzymatic activity and the release of newly synthesized virions from infected cells. Unlike monomeric ZA, however, PGN-ZA also synergistically inhibits early stages of influenza virus infection, thus contributing to the markedly increased antiviral potency. This inhibition is not caused by a direct virucidal effect, aggregation of viruses, or inhibition of viral attachment to target cells and the subsequent endocytosis; rather, it is a result of interference with intracellular trafficking of the endocytosed viruses and the subsequent virus-endosome fusion. These findings both rationalize the great anti-influenza potency of PGN-ZA and reveal that attaching ZA to a polymeric chain confers a unique mechanism of antiviral action potentially useful for minimizing drug resistance. PMID:23185023

  13. Large planetary nebulae and their significance to the late stages of stellar evolution

    NASA Technical Reports Server (NTRS)

    Kaler, James B.; Shaw, Richard A.; Kwitter, Karen B.

    1990-01-01

    Spectrophotometry of 75 large PNe with Shklovsky radii greater than 0.15 pc is presented and used to calculate nebular parameters and compositions, stellar Zanstra temperatures and luminosities, and core masses. Nine new Peimbert type I nebulae are identified. About 40 percent of the stars that are on cooling tracks are above 0.7 solar mass, and over 15 percent are above 0.8 solar mass. The large planetaries demonstrate a clear positive correlation between nitrogen enrichment and core mass. N/O is anticorrelated with O/H. The radii of the nebulae whose stars lie along specific cooling tracks increase monotonically with decreasing central star temperature. For a given central temperature, the nebular radii also increase with increasing core mass, showing that in this part of the log L-log T plane the higher mass cores evolve more slowly in agreement with theoretical prediction. However, theoretical evolutionary rates for the large nebulae stars appear to be much too slow.

  14. Molecular analysis of late-stage fiber development in upland cotton

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cotton is the world's most important textile and the number one value-added crop. It plays a crucial role in the economy of Texas – supporting close to 50,000 jobs and supplying $2 billion to the state economy. Its role is even more evident in the South Plains of Texas, which supplies approximately...

  15. Patterns of seeking medical care among Egyptian breast cancer patients: relationship to late-stage presentation.

    PubMed

    Mousa, Shimaa M; Seifeldin, Ibrahim A; Hablas, Ahmed; Elbana, Eman S; Soliman, Amr S

    2011-12-01

    Breast cancer is the most common cancer among Egyptian women, accounting for 37.6% of female tumors, and is often diagnosed at later stages. The objective of this study was to investigate breast cancer patient navigation through the health care system in the Nile Delta. Interviews were conducted with 163 newly diagnosed breast cancer patients at the Tanta Cancer Center (TCC), the major cancer center of the region. Patients described their medical care pathway from the initial symptom experienced until their arrival at TCC. Patients whose initial contact was with a general surgeon (OR: 7.6, 95% CI: 2.1, 27.6), primary care provider (OR: 12.2, 95% CI: 2.9, 51.0), or gynecologist (OR: 8.6, 95% CI: 1.4, 53.4) were significantly more likely to experience a delay in reaching the TCC as compared to those visiting a surgical oncologist. Overcoming health care system and patient navigation barriers in developing countries may reduce the time for breast cancer patients to reach a cancer center for early management. PMID:21807518

  16. Perceptions of Burden in Patients With Late-Stage Cancer and Their Caregivers

    ClinicalTrials.gov

    2015-05-27

    Brain and Central Nervous System Tumors; Chronic Myeloproliferative Disorders; Depression; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Psychosocial Effects of Cancer and Its Treatment; Unspecified Adult Solid Tumor, Protocol Specific

  17. TAp63gamma is required for the late stages of myogenesis

    PubMed Central

    Cefalù, S; Lena, AM; Vojtesek, B; Musarò, A; Rossi, A; Melino, G; Candi, E

    2015-01-01

    p53 family members, p63 and p73, play a role in controlling early stage of myogenic differentiation. We demonstrated that TAp63gamma, unlike the other p53 family members, is markedly up-regulated during myogenic differentiation in murine C2C7 cell line. We also found that myotubes formation was inhibited upon TAp63gamma knock-down, as also indicated by atrophyic myotubes and reduction of myoblasts fusion index. Analysis of TAp63gamma-dependend transcripts identified several target genes involved in skeletal muscle contractility energy metabolism, myogenesis and skeletal muscle autocrine signaling. These results indicate that TAp63gamma is a late marker of myogenic differentiation and, by controlling different sub-sets of target genes, it possibly contributes to muscle growth, remodeling, functional differentiation and tissue homeostasis. PMID:25790093

  18. The estimated prevalence and incidence of late stage age related macular degeneration in the UK

    PubMed Central

    Jarrar, Zakariya; Wormald, Richard; Cook, Derek G; Fletcher, Astrid E; Rudnicka, Alicja R

    2012-01-01

    Background UK estimates of age related macular degeneration (AMD) occurrence vary. Aims To estimate prevalence, number and incidence of AMD by type in the UK population aged ≥50 years. Methods Age-specific prevalence rates of AMD obtained from a Bayesian meta-analysis of AMD prevalence were applied to UK 2007–2009 population data. Incidence was estimated from modelled age-specific prevalence. Results Overall prevalence of late AMD was 2.4% (95% credible interval (CrI) 1.7% to 3.3%), equivalent to 513 000 cases (95% CrI 363 000 to 699 000); estimated to increase to 679 000 cases by 2020. Prevalences were 4.8% aged ≥65 years, 12.2% aged ≥80 years. Geographical atrophy (GA) prevalence rates were 1.3% (95% CrI 0.9% to 1.9%), 2.6% (95% CrI 1.8% to 3.7%) and 6.7% (95% CrI 4.6% to 9.6%); neovascular AMD (NVAMD) 1.2% (95% CrI 0.9% to 1.7%), 2.5% (95% CrI 1.8% to 3.4%) and 6.3% (95% CrI 4.5% to 8.6%), respectively. The estimated number of prevalent cases of late AMD were 60% higher in women versus men (314 000 cases in women, 192 000 men). Annual incidence of late AMD, GA and NVAMD per 1000 women was 4.1 (95% CrI 2.4% to 6.8%), 2.4 (95% CrI 1.5% to 3.9%) and 2.3 (95% CrI 1.4% to 4.0%); in men 2.6 (95% CrI 1.5% to 4.4%), 1.7 (95% CrI 1.0% to 2.8%) and 1.4 (95% CrI 0.8% to 2.4%), respectively. 71 000 new cases of late AMD were estimated per year. Conclusions These estimates will guide health and social service provision for those with late AMD and enable estimation of the cost of introducing new treatments. PMID:22329913

  19. Crevasse-squeeze ridge corridors: Diagnostic features of late-stage palaeo-ice stream activity

    NASA Astrophysics Data System (ADS)

    Evans, David J. A.; Storrar, Robert D.; Rea, Brice R.

    2016-04-01

    A 200-km-long and 10-km-wide linear assemblage of till-filled geometrical ridges on the bed of the Maskwa palaeo-ice stream of the late Wisconsinan southwest Laurentide Ice Sheet are interpreted as crevasse-squeeze ridges (CSR) developed during internal flow unit reorganization, immediately prior to ice stream shutdown. Ridge orientations are predominantly orientated WNW-ESE, with a subordinate WSW-ENE alignment, both indicative of ice fracture development transverse to former ice stream flow, as indicated by NNE-SSW aligned MSGL. Subglacial till injection into basal and/or full depth, mode I and II crevasses occurred at the approximate centreline of the ice stream, in response to extension and fracturing. Landform preservation indicates that this took place during the final stages of ice streaming, immediately prior to ice stream shutdown. This linear zone of ice fracturing therefore likely represents the narrowing of the fast-flowing trunk, similar to the plug flow identified in some surging valley glaciers. Lateral drag between the final active flow unit and the slower moving ice on either side is likely recorded by the up-ice bending of the CSR limbs. The resulting CSR corridor, here related to an individual ice stream flow unit, constitutes a previously unreported style of crevasse infilling and contrasts with two existing CSR patterns: (1) wide arcuate zones of CSRs related to widespread fracturing within glacier surge lobes; and (2) narrow concentric arcs of CSRs and recessional push moraines related to submarginal till deformation at active temperate glacier lobes.

  20. Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits

    PubMed Central

    Ramanathan, Dhakshin S.; Conner, James M.; Anilkumar, Arjun A.

    2014-01-01

    Previous studies reported that early postnatal cholinergic lesions severely perturb early cortical development, impairing neuronal cortical migration and the formation of cortical dendrites and synapses. These severe effects of early postnatal cholinergic lesions preclude our ability to understand the contribution of cholinergic systems to the later-stage maturation of topographic cortical representations. To study cholinergic mechanisms contributing to the later maturation of motor cortical circuits, we first characterized the temporal course of cortical motor map development and maturation in rats. In this study, we focused our attention on the maturation of cortical motor representations after postnatal day 25 (PND 25), a time after neuronal migration has been accomplished and cortical volume has reached adult size. We found significant maturation of cortical motor representations after this time, including both an expansion of forelimb representations in motor cortex and a shift from proximal to distal forelimb representations to an extent unexplainable by simple volume enlargement of the neocortex. Specific cholinergic lesions placed at PND 24 impaired enlargement of distal forelimb representations in particular and markedly reduced the ability to learn skilled motor tasks as adults. These results identify a novel and essential role for cholinergic systems in the late refinement and maturation of cortical circuits. Dysfunctions in this system may constitute a mechanism of late-onset neurodevelopmental disorders such as Rett syndrome and schizophrenia. PMID:25505106

  1. Neuroprotective effects of electroacupuncture on early- and late-stage spinal cord injury

    PubMed Central

    Wu, Min-fei; Zhang, Shu-quan; Liu, Jia-bei; Li, Ye; Zhu, Qing-san; Gu, Rui

    2015-01-01

    Previous studies have shown that the neurite growth inhibitor Nogo-A can cause secondary neural damage by activating RhoA. In the present study, we hypothesized that electroacupuncture promotes neurological functional recovery after spinal cord injury by inhibiting RhoA expression. We established a rat model of acute spinal cord injury using a modification of Allen's method. The rats were given electroacupuncture treatment at Dazhui (Du14), Mingmen (Du4), Sanyinjiao (SP6), Huantiao (GB30), Zusanli (ST36) and Kunlun (BL60) acupoints with a sparse-dense wave at a frequency of 4 Hz for 30 minutes, once a day, for a total of 7 days. Seven days after injury, the Basso, Beattie and Bresnahan (BBB) locomotor scale and inclined plane test scores were significantly increased, the number of apoptotic cells in the spinal cord tissue was significantly reduced, and RhoA and Nogo-A mRNA and protein expression levels were decreased in rats given electroacupuncture compared with rats not given electroacupuncture. Four weeks after injury, pathological tissue damage in the spinal cord at the site of injury was alleviated, the numbers of glial fibrillary acidic protein- and neurofilament 200-positive fibers were increased, the latencies of somatosensory-evoked and motor-evoked potentials were shortened, and their amplitudes were increased in rats given electroacupuncture. These findings suggest that electroacupuncture treatment reduces neuronal apoptosis and decreases RhoA and Nogo-A mRNA and protein expression at the site of spinal cord injury, thereby promoting tissue repair and neurological functional recovery. PMID:26692861

  2. Blockade of Nerve Sprouting and Neuroma Formation Markedly Attenuates the Development of Late Stage Cancer Pain

    PubMed Central

    Mantyh, William G.; Jimenez-Andrade, Juan M.; Stake, James I.; Bloom, Aaron P.; Kaczmarska, Magdalena J.; Taylor, Reid N.; Freeman, Katie T.; Ghilardi, Joseph R.; Kuskowski, Michael A.; Mantyh, Patrick W.

    2010-01-01

    For many patients, pain is the first sign of cancer and, while pain can be present at any time, the frequency and intensity of pain tend to increase with advancing stages of the disease. Thus, between 75 and 90% of patients with metastatic or advanced-stage cancer will experience significant cancer-induced pain. One major unanswered question is why cancer pain increases and frequently becomes more difficult to fully control with disease progression. To gain insight into this question we used a mouse model of bone cancer pain to demonstrate that as tumor growth progresses within bone, Tropomyosin receptor kinase A (TrkA)-expressing sensory and sympathetic nerve fibers undergo profuse sprouting and form neuroma-like structures. To address what is driving the pathological nerve reorganization we administered an antibody to nerve growth factor (anti-NGF). Early sustained administration of anti-NGF, whose cognate receptor is TrkA, blocks the pathological sprouting of sensory and sympathetic nerve fibers, the formation of neuroma-like structures, and inhibits the development of cancer pain. These results suggest that cancer cells and their associated stromal cells release NGF, which induces a pathological remodeling of sensory and sympathetic nerve fibers. This pathological remodeling of the peripheral nervous system then participates in driving cancer pain. Similar to therapies that target the cancer itself, the data presented here suggest that the earlier that therapies blocking this pathological nerve remodeling are initiated, the more effective the control of cancer pain. PMID:20851743

  3. Autophagy Inhibition Delays Early but Not Late-Stage Metastatic Disease.

    PubMed

    Barnard, Rebecca A; Regan, Daniel P; Hansen, Ryan J; Maycotte, Paola; Thorburn, Andrew; Gustafson, Daniel L

    2016-08-01

    The autophagy pathway has been recognized as a mechanism of survival and therapy resistance in cancer, yet the extent of autophagy's function in metastatic progression is still unclear. Therefore, we used murine models of metastatic cancer to investigate the effect of autophagy modulation on metastasis development. Pharmacologic and genetic autophagy inhibition were able to impede cell proliferation in culture, but did not impact the development of experimentally induced 4T1 and B16-F10 metastases. Similarly, autophagy inhibition by adjuvant chloroquine (CQ) treatment did not delay metastasis in an orthotopic 4T1, tumor-resection model. However, neoadjuvant CQ treatment or genetic autophagy inhibition resulted in delayed metastasis development, whereas stimulation of autophagy by trehalose hastened development. Cisplatin was also administered either as a single agent or in combination with CQ. The combination of cisplatin and CQ was antagonistic. The effects of autophagy modulation on metastasis did not appear to be due to alterations in the intrinsic metastatic capability of the cells, as modulating autophagy had no impact on migration, invasion, or anchorage-independent growth in vitro. To explore the possibility of autophagy's influence on the metastatic microenvironment, bone marrow-derived cells (BMDCs), which mediate the establishment of the premetastatic niche, were measured in the lung and in circulation. Trehalose-treated mice had significantly more BMDCs than either vehicle- or CQ-treated mice. Autophagy inhibition may be most useful as a treatment to impede early metastatic development. However, modulating autophagy may also alter the efficacy of platinum-based therapies, requiring caution when considering combination therapies. PMID:27231155

  4. Mechanical and structural changes of the rat cervix in late-stage pregnancy.

    PubMed

    Poellmann, Michael J; Chien, Edward K; McFarlin, Barbara L; Wagoner Johnson, Amy J

    2013-01-01

    Dysregulated remodeling of the cervix precedes preterm birth, a major cause of infant mortality and morbidity. The goal of this work was to identify changes in the mechanical properties of the cervix in late gestation. The tensile and load relaxation properties of cervices from rats 15-21 days (full term) post-conception were measured. Stiffness and load at 25% circumferential strain decreased with gestational age and correlated with the initial circumference of the cervix. Load-relaxation curves were accurately described by a seven parameter quasi-linear viscoelastic model, where three parameters associated with stiffness and load capacity decrease with gestational age and correlate with initial circumference. Time-dependent parameters did not depend on age or structure. Mechanical properties correlated with water content, but unexpectedly not with measures of collagen content, solubility, or organization. Quantitative measurements of cervical stiffness and structure will lead to a more accurate description of cervical remodeling and prediction of preterm birth. PMID:23127627

  5. Mechanical and structural changes of the rat cervix in late-stage pregnancy

    PubMed Central

    Poellmann, Michael J.; Chien, Edward K.; McFarlin, Barbara L.

    2012-01-01

    Dysregulated remodeling of the cervix precedes preterm birth, a major cause of infant mortality and morbidity. The goal of this work was to identify changes in the mechanical properties of the cervix in late gestation. The tensile and load relaxation properties of cervices from rats 15 days to 21 days (full term) post-conception were measured. Stiffness and load at 25% circumferential strain decreased with gestational age and correlated with the initial circumference of the cervix. Load-relaxation curves were accurately described by a seven parameter quasi-linear viscoelastic model, where three parameters associated with stiffness and load capacity decrease with gestational age and correlate with initial circumference. Time-dependent parameters did not depend on age or structure. Mechanical properties correlated with water content, but unexpectedly not with measures of collagen content, solubility, or organization. Quantitative measurements of cervical stiffness and structure will lead to a more accurate description of cervical remodeling and prediction of preterm birth. PMID:23127627

  6. Use of ultrasonography to identify late-stage maturity in rainbow trout Oncorhynchus mykiss

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Morphometric measurements by ultrasonography has been used to determine gonad and follicle size in many species of fish for purposes of identifying sex and estimating stage of maturation. We have been using a portable ultrasound system (SonoSite MicroMaxx, L25e/13-6 MHz transducer) to identify fem...

  7. A Late Stage Strategy for the Functionalization of Triazolium-based NHC catalysts

    PubMed Central

    Ozboya, Kerem E.

    2015-01-01

    A strategy for the diversification of triazolium-based catalysts is presented. This method is based on the reduction to the triazoline, which serves as a suitable and stable substrate for Pd-mediated cross-coupling, followed by trityl cation mediated reoxidation to the triazolium. PMID:25954060

  8. Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits.

    PubMed

    Ramanathan, Dhakshin S; Conner, James M; Anilkumar, Arjun A; Tuszynski, Mark H

    2015-03-01

    Previous studies reported that early postnatal cholinergic lesions severely perturb early cortical development, impairing neuronal cortical migration and the formation of cortical dendrites and synapses. These severe effects of early postnatal cholinergic lesions preclude our ability to understand the contribution of cholinergic systems to the later-stage maturation of topographic cortical representations. To study cholinergic mechanisms contributing to the later maturation of motor cortical circuits, we first characterized the temporal course of cortical motor map development and maturation in rats. In this study, we focused our attention on the maturation of cortical motor representations after postnatal day 25 (PND 25), a time after neuronal migration has been accomplished and cortical volume has reached adult size. We found significant maturation of cortical motor representations after this time, including both an expansion of forelimb representations in motor cortex and a shift from proximal to distal forelimb representations to an extent unexplainable by simple volume enlargement of the neocortex. Specific cholinergic lesions placed at PND 24 impaired enlargement of distal forelimb representations in particular and markedly reduced the ability to learn skilled motor tasks as adults. These results identify a novel and essential role for cholinergic systems in the late refinement and maturation of cortical circuits. Dysfunctions in this system may constitute a mechanism of late-onset neurodevelopmental disorders such as Rett syndrome and schizophrenia. PMID:25505106

  9. Neuroprotective effects of electroacupuncture on early- and late-stage spinal cord injury.

    PubMed

    Wu, Min-Fei; Zhang, Shu-Quan; Liu, Jia-Bei; Li, Ye; Zhu, Qing-San; Gu, Rui

    2015-10-01

    Previous studies have shown that the neurite growth inhibitor Nogo-A can cause secondary neural damage by activating RhoA. In the present study, we hypothesized that electroacupuncture promotes neurological functional recovery after spinal cord injury by inhibiting RhoA expression. We established a rat model of acute spinal cord injury using a modification of Allen's method. The rats were given electroacupuncture treatment at Dazhui (Du14), Mingmen (Du4), Sanyinjiao (SP6), Huantiao (GB30), Zusanli (ST36) and Kunlun (BL60) acupoints with a sparse-dense wave at a frequency of 4 Hz for 30 minutes, once a day, for a total of 7 days. Seven days after injury, the Basso, Beattie and Bresnahan (BBB) locomotor scale and inclined plane test scores were significantly increased, the number of apoptotic cells in the spinal cord tissue was significantly reduced, and RhoA and Nogo-A mRNA and protein expression levels were decreased in rats given electroacupuncture compared with rats not given electroacupuncture. Four weeks after injury, pathological tissue damage in the spinal cord at the site of injury was alleviated, the numbers of glial fibrillary acidic protein- and neurofilament 200-positive fibers were increased, the latencies of somatosensory-evoked and motor-evoked potentials were shortened, and their amplitudes were increased in rats given electroacupuncture. These findings suggest that electroacupuncture treatment reduces neuronal apoptosis and decreases RhoA and Nogo-A mRNA and protein expression at the site of spinal cord injury, thereby promoting tissue repair and neurological functional recovery. PMID:26692861

  10. Expression of defense-related genes in maize developing kernels in late stages

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We analyzed temporal patterns of gene expression profiles in developing kernels of Tex6, reported to have reduced aflatoxin contamination, at 25, 30, 35, 40 and 45 days after pollination (DAP) using maize oligonuleotide microarray. There was a total of 57,452 70-mer oligonucleotides on the array. Th...

  11. Spontaneous locomotor activity in late-stage chicken embryos is modified by stretch of leg muscles.

    PubMed

    Bradley, Nina S; Ryu, Young U; Yeseta, Marie C

    2014-03-15

    Chicks initiate bilateral alternating steps several days before hatching and adaptively walk within hours of hatching, but emergence of precocious walking skills is not well understood. One of our aims was to determine whether interactions between environment and movement experience prior to hatching are instrumental in establishing precocious motor skills. However, physiological evidence of proprioceptor development in the chick has yet to be established; thus, one goal of this study was to determine when in embryogenesis proprioception circuits can code changes in muscle length. A second goal was to determine whether proprioception circuits can modulate leg muscle activity during repetitive limb movements for stepping (RLMs). We hypothesized that proprioception circuits code changes in muscle length and/or tension, and modulate locomotor circuits producing RLMs in anticipation of adaptive locomotion at hatching. To this end, leg muscle activity and kinematics were recorded in embryos during normal posture and after fitting one ankle with a restraint that supported the limb in an atypical posture. We tested the hypotheses by comparing leg muscle activity during spontaneous RLMs in control posture and ankle extension restraint. The results indicated that proprioceptors detect changes in muscle length and/or muscle tension 3 days before hatching. Ankle extension restraint produced autogenic excitation of the ankle flexor and reciprocal inhibition of the ankle extensor. Restraint also modified knee extensor activity during RLMs 1 day before hatching. We consider the strengths and limitations of these results and propose that proprioception contributes to precocious locomotor development during the final 3 days before hatching. PMID:24265423

  12. Facial affect recognition in early and late-stage schizophrenia patients.

    PubMed

    Romero-Ferreiro, María Verónica; Aguado, Luis; Rodriguez-Torresano, Javier; Palomo, Tomás; Rodriguez-Jimenez, Roberto; Pedreira-Massa, José Luis

    2016-04-01

    Prior studies have shown deficits in social cognition and emotion perception in first-episode psychosis (FEP) and multi-episode schizophrenia (MES) patients. These studies compared patients at different stages of the illness with only a single control group which differed in age from at least one clinical group. The present study provides new evidence of a differential pattern of deficit in facial affect recognition in FEP and MES patients using a double age-matched control design. Compared to their controls, FEP patients only showed impaired recognition of fearful faces (p=.007). In contrast to this, the MES patients showed a more generalized deficit compared to their age-matched controls, with impaired recognition of angry, sad and fearful faces (ps<.01) and an increased misattribution of emotional meaning to neutral faces. PANSS scores of FEP patients on Depressed factor correlated positively with the accuracy to recognize fearful expressions (r=.473). For the MES group fear recognition correlated positively with negative PANSS factor (r=.498) and recognition of sad and neutral expressions was inversely correlated with disorganized PANSS factor (r=-.461 and r=-.541, respectively). These results provide evidence that a generalized impairment of affect recognition is observed in advanced-stage patients and is not characteristic of the early stages of schizophrenia. Moreover, the finding that anomalous attribution of emotional meaning to neutral faces is observed only in MES patients suggests that an increased attribution of salience to social stimuli is a characteristic of social cognition in advanced stages of the disorder. PMID:26874869

  13. Evolution of late stage differentiates in the Palisades Sill, New York and New Jersey

    NASA Astrophysics Data System (ADS)

    Block, Karin A.; Steiner, Jeffrey C.; Puffer, John H.; Jones, Kevin M.; Goldstein, Steven L.

    2015-08-01

    The Palisades Sill at Upper Nyack, NY contains evolved rocks that crystallized as ferrodiabase and ferrogranophyre and occupy 50% to 60% of the local thickness. 143Nd/144Nd isotope values for rocks representing Palisades diversity range between 0.512320 and 0.512331, and indicate a homogeneous source for the Palisades and little or no contamination from shallow crustal sediments. Petrographic analysis of ferrodiabase suggests that strong iron enrichment was the result of prolonged quiescence in cycles of magmatic input. Ferrogranophyres in the updip northern Palisades at Upper Nyack are members of a suite of cogenetic rocks with similar composition to 'sandwich horizon' rocks of the southern Palisades at Fort Lee, NJ, but display distinct mineralogical and textural features. Differences in textural and mineralogical features are attributed to a) updip (lateral) migration of residual liquid as the sill propagated closer to the surface; b) deformation caused by tectonic shifts; and c) crystallization in the presence of deuteric hydrothermal fluids resulting in varying degrees of alteration. A model connecting multiple magmatic pulses, compaction and mobilization of residual liquid by compositional convection, closed-system differentiation, synchronous with tapping of the sill for extrusion of coeval basaltic subaerial flows is presented. The persistence of a low-temperature mushy layer, represented by ferrogranophyres, supports the possibility of a long-lived conduit subject to reopening after periods of quiescence in magmatic input, leading to the extrusion of the multiple flows of the Orange Mountain Basalt and perhaps even subsequent Preakness Basalt flows, depending on solidification conditions. A sub-Newark Basin network of sills subjected to similar protracted input of pulses as hypothesized for the Palisades was likely responsible for 600 ka of magmatic activity required to emplace a third set of Watchung flood basalts, the Hook Mountain Basalt.

  14. Curative effect of photodynamic therapy for 42 cases of moderate or late stage in esophagus cancer

    NASA Astrophysics Data System (ADS)

    Bai, Xiao-Min; Shen, Guang-Rong; Chen, Weng-Ge; Guo, Tao

    1998-11-01

    34 patients with advanced esophagus cancer and 8 cases of cancer of gastric cardia were treated by photodynamic therapy. The therapeutic effectiveness of the treatment was evaluated according the criteria used in China. CR 63.2 percent SR 11.3 percent, MR 2 percent. The total effective rate was 76.5 percent. There was no significant side effect in this group except mild skin photosensitization and pigmentation and exacerbation of pain in a few cases.

  15. Synthesis and dephosphorylation of MARCKS in the late stages of megakaryocyte maturation drive proplatelet formation.

    PubMed

    Machlus, Kellie R; Wu, Stephen K; Stumpo, Deborah J; Soussou, Thomas S; Paul, David S; Campbell, Robert A; Kalwa, Hermann; Michel, Thomas; Bergmeier, Wolfgang; Weyrich, Andrew S; Blackshear, Perry J; Hartwig, John H; Italiano, Joseph E

    2016-03-17

    Platelets are essential for hemostasis, and thrombocytopenia is a major clinical problem. Megakaryocytes (MKs) generate platelets by extending long processes, proplatelets, into sinusoidal blood vessels. However, very little is known about what regulates proplatelet formation. To uncover which proteins were dynamically changing during this process, we compared the proteome and transcriptome of round vs proplatelet-producing MKs by 2D difference gel electrophoresis (DIGE) and polysome profiling, respectively. Our data revealed a significant increase in a poorly-characterized MK protein, myristoylated alanine-rich C-kinase substrate (MARCKS), which was upregulated 3.4- and 5.7-fold in proplatelet-producing MKs in 2D DIGE and polysome profiling analyses, respectively. MARCKS is a protein kinase C (PKC) substrate that binds PIP2. In MKs, it localized to both the plasma and demarcation membranes. MARCKS inhibition by peptide significantly decreased proplatelet formation 53%. To examine the role of MARCKS in the PKC pathway, we treated MKs with polymethacrylate (PMA), which markedly increased MARCKS phosphorylation while significantly inhibiting proplatelet formation 84%, suggesting that MARCKS phosphorylation reduces proplatelet formation. We hypothesized that MARCKS phosphorylation promotes Arp2/3 phosphorylation, which subsequently downregulates proplatelet formation; both MARCKS and Arp2 were dephosphorylated in MKs making proplatelets, and Arp2 inhibition enhanced proplatelet formation. Finally, we used MARCKS knockout (KO) mice to probe the direct role of MARCKS in proplatelet formation; MARCKS KO MKs displayed significantly decreased proplatelet levels. MARCKS expression and signaling in primary MKs is a novel finding. We propose that MARCKS acts as a "molecular switch," binding to and regulating PIP2 signaling to regulate processes like proplatelet extension (microtubule-driven) vs proplatelet branching (Arp2/3 and actin polymerization-driven). PMID:26744461

  16. Gold deposition caused by carbonation of biotite during late-stage fluid flow

    NASA Astrophysics Data System (ADS)

    Pearce, Mark A.; White, Alistair J. R.; Fisher, Louise A.; Hough, Robert M.; Cleverley, James S.

    2015-12-01

    Alteration reactions associated with gold mineralisation can be used to elucidate the nature of the fluid that transported gold into a deposit. At the Junction gold deposit, Kambalda, Western Australia, gold is hosted in a metamorphosed and hydrothermally altered dolerite. Mineralisation at the deposit scale is associated with zones of K, CO2 and S metasomatism, as is common in many greenstone hosted gold deposits. However, at the thin-section scale gold is not closely associated with sulphide minerals but within zones of carbonate metasomatism and K-loss where pre-existing biotite has reacted to produce chlorite, muscovite and Fe-Mg carbonates. Gold precipitation is intimately associated with biotite breakdown where calcite is locally absent. Quantified mineral modes from detailed microstructural mapping are used to balance reactions describing the breakdown of biotite in the presence and absence of calcite. Using the basic assumption that Al is immobile during metasomatism the reactions are successfully balanced, even in a manifestly open system. Modelling of fluid-rock reactions using HCh constrains the fluid composition (0.11 < X(CO2) < 0.13) and fluid-rock ratios (< 12:1) that can produce the observed mineral assemblage. Additional modelling of solid solution mineral phases using THERMOCALC estimates alteration conditions of 390 °C, 4 kbar and also suggests a fluid X(CO2) ~ 0.1. Both these models show that the observed muscovite and chlorite compositions can be produced primarily through the removal of K from the measured precursor biotite. We show that it is not possible to transport and deposit all the gold observed in the alteration zone with the low fluid-rock ratios obtained from modelling of silicate alteration and inferred gold concentrations in these fluids. We suggest that this is typical of greenstone hosted gold deposits and that mechanisms other than aqueous solution, which can transport higher gold concentrations, must be considered.

  17. Metal-Catalyzed Azidation of Tertiary C–H Bonds Suitable for Late-Stage Functionalization

    PubMed Central

    Sharma, Ankit

    2014-01-01

    Some enzymes are able to selectively oxidize unactivated aliphatic C-H bonds to form alcohols; however biological systems do not possess enzymes that are able to catalyze the analogous amination of a C-H bond.1,2 The absence of such chemistry is limiting because nitrogen-containing groups are found in therapeutic agents and clinically useful natural products. In one prominent example, the conversion of the ketone of erythromycin to the –N(Me)CH2– group in azithromycin leads to a compound that can be dosed once daily with a shorter length of treatment.3,4 For such reasons, synthetic chemists are very interested in identifying catalysts that can directly convert C-H bonds to C-N bonds. Most currently used catalysts for C-H bond amination are ill suited for the functionalization of complex molecules, because they require excess substrate or directing groups, harsh reaction conditions, weak or acidic C-H bonds, or reagents containing specialized groups on the nitrogen atom.5-14 Among C-H bond amination reactions, those forming a carbon-nitrogen bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to generate enzymatically from ketone or alcohol precursors.15 In this manuscript, we report a mild, selective, iron-catalyzed azidation of tertiary C-H bonds with substrate as limiting reagent. The reaction tolerates aqueous environments and is suitable for “late-stage” functionalization of complex structures. Moreover, this azidation creates the ability to install a range of nitrogen functional groups, including those from bio-orthogonal Huisgen “click” cycloadditions and the Staudinger ligation.16-19 For these reasons, we anticipate this methodology will create opportunities to easily modify natural products, their precursors, and their derivatives to analogs that contain distinct polarity and charge from nitrogen-containing groups. It could also be used to help identify targets of biologically active molecules by creating a point of attachment, for example to fluorescent tags or ‘handles’ for affinity chromatography, directly onto complex molecular structures. PMID:25631448

  18. Art Therapy for an Individual with Late Stage Dementia: A Clinical Case Description

    ERIC Educational Resources Information Center

    Tucknott-Cohen, Tisah; Ehresman, Crystal

    2016-01-01

    This article describes the healing benefits of art therapy for an individual with dementia of the Alzheimer's type. In this clinical case description, a woman diagnosed with Alzheimer's disease received individual art therapy for 17 weeks. The treatment concerns that arose, altered view of reality, agitation, and retrogenesis provide insight on…

  19. LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions

    PubMed Central

    2013-01-01

    Background LEDGINs are novel allosteric HIV integrase (IN) inhibitors that target the lens epithelium-derived growth factor (LEDGF)/p75 binding pocket of IN. They block HIV-1 integration by abrogating the interaction between LEDGF/p75 and IN as well as by allosterically inhibiting the catalytic activity of IN. Results Here we demonstrate that LEDGINs reduce the replication capacity of HIV particles produced in their presence. We systematically studied the molecular basis of this late effect of LEDGINs and demonstrate that HIV virions produced in their presence display a severe replication defect. Both the late effect and the previously described, early effect on integration contribute to LEDGIN antiviral activity as shown by time-of-addition, qPCR and infectivity assays. The late effect phenotype requires binding of LEDGINs to integrase without influencing proteolytic cleavage or production of viral particles. LEDGINs augment IN multimerization during virion assembly or in the released viral particles and severely hamper the infectivity of progeny virions. About 70% of the particles produced in LEDGIN-treated cells do not form a core or display aberrant empty cores with a mislocalized electron-dense ribonucleoprotein. The LEDGIN-treated virus displays defective reverse transcription and nuclear import steps in the target cells. The LEDGIN effect is possibly exerted at the level of the Pol precursor polyprotein. Conclusion Our results suggest that LEDGINs modulate IN multimerization in progeny virions and impair the formation of regular cores during the maturation step, resulting in a decreased infectivity of the viral particles in the target cells. LEDGINs thus profile as unique antivirals with combined early (integration) and late (IN assembly) effects on the HIV replication cycle. PMID:23721378

  20. Complex care needs of patients with late-stage HIV disease: A retrospective study

    PubMed Central

    Halman, Mark; Carusone, Soo Chan; Stranks, Sarah; Schaefer-McDaniel, Nicole; Stewart, Ann

    2013-01-01

    This retrospective chart review provides a profile of an emerging population of vulnerable HIV patients with complex comorbidities. Data were abstracted from all 87 patients admitted in 2008 to Casey House, a community-based hospital dedicated to supportive and palliative care for persons with HIV in Toronto, Canada. We describe patient characteristics, including medical and psychiatric conditions, and use a Venn diagram and case study to illustrate the frequency and reality of co-occurring conditions that contribute to the complexity of patients’ health and health care needs. The mean age at admission was 48.9 years (SD = 10.5). Eighty percent were male. Patients experienced a mean of 5.8 medical comorbidities (SD = 2.3) and 1.9 psychiatric disorders (lifetime axis I diagnoses). Forty-one patients (47%) experienced cognitive impairment including HIV-associated dementia. Patients were on a mean of 11.8 (SD = 5.3) medications at admission; 74% were on antiretroviral medications with 55% reporting full adherence. Current alcohol and drug use was common with 54% reporting active use at admission. Our Venn diagram illustrates the breadth of complexity in the clients with 9% of clients living in unstable housing with three or more medical comorbidites and two or more psychiatric diagnoses. Comprehensive HIV program planning should include interventions that can flexibly adapt to meet the multidimensional and complex needs of this segment of patients. Researchers, policymakers and clinicians need to have greater awareness of overlapping medical, psychiatric and psychosocial comorbidities. Inclusion of the needs of these most vulnerable patients in the development of evidence based guidelines is an important step for effectively treating, preventing and planning for the future of HIV/AIDS care.

  1. Cold, warm, and hot gas in the late-stage merger NGC 7252

    NASA Technical Reports Server (NTRS)

    Hibbard, J. E.; Guhathakurta, Puragra; Van Gorkom, J. H.; Schweizer, Francois

    1994-01-01

    We present the first observations of the neutral hydrogen distribution and x-ray emission in the prototypical merger remnant NGC 7252, the 'Atoms-for-Peace' galaxy. These data are supplemented by accurate B and R surface photometry, reaching a limit of mu(sub B) = 26.5 mag/sq arcsec, and images taken through a narrow-band H alpha filter. We find all of the 2 x 10(exp 9)/sq h solar mass of atomic gas to be restricted to the outer, tidal regions of this system (H(sub zero) = 100 h km/s/Mpc). By contrast, the molecular gas traced by the (12)CO(1 approaches zero) map of Wang et al. (1992) is confined to an inner rotating disk of radius 7 seconds and has an H alpha counterpart. The gap between the atomic and molecular gas distributions is filled in by diffuse H alpha emission and perhaps by x-ray emission. The velocity field of the atomic gas in the tidal tails indicates that they are swinging through space in the same sense as the rotation of the inner gas disk. The H I at the apparent base of the northwestern tail seems to be falling back toward the main body of the galaxy, yet there is no H I associated with this main stellar body: This suggests ongoing efficient conversion of the atomic gas into other phases in this region. The H alpha velocity anomalies previously found in the remnant body may be produced in part by the combination of tail-related, noncircular motions and the inner gas-disk rotation. Both tidal tails have bluer B-R colors than the main body of the remnant, with the bluest regions coinciding with peaks in the gas column density. Each tail contains one giant H II region near the end of its optical light distribution. These H II regions are associated with large concentrations of gas and stars that approach the sizes and gas contents of dwarf galaxies. The H I extends beyond the end of the optical tails and reaches projected distances of 62/h kpc east and 120/h kpc northwest from the center. We discuss the possible relevance of these data to : (1) the transformation of merged spirals into ellipticls; (2) the generation of ripples by returning tidal material; and (3) the formation of bound stellar systems from tidally torn material.

  2. Cold, warm, and hot gas in the late-stage merger NGC 7252

    NASA Astrophysics Data System (ADS)

    Hibbard, J. E.; Guhathakurta, Puragra; van Gorkom, J. H.; Schweizer, Francois

    1994-01-01

    We present the first observations of the neutral hydrogen distribution and x-ray emission in the prototypical merger remnant NGC 7252, the 'Atoms-for-Peace' galaxy. These data are supplemented by accurate B and R surface photometry, reaching a limit of muB = 26.5 mag/sq arcsec, and images taken through a narrow-band H alpha filter. We find all of the 2 x 109/sq h solar mass of atomic gas to be restricted to the outer, tidal regions of this system (Hzero = 100 h km/s/Mpc). By contrast, the molecular gas traced by the (12)CO(1 approaches zero) map of Wang et al. (1992) is confined to an inner rotating disk of radius 7 seconds and has an H alpha counterpart. The gap between the atomic and molecular gas distributions is filled in by diffuse H alpha emission and perhaps by x-ray emission. The velocity field of the atomic gas in the tidal tails indicates that they are swinging through space in the same sense as the rotation of the inner gas disk. The H I at the apparent base of the northwestern tail seems to be falling back toward the main body of the galaxy, yet there is no H I associated with this main stellar body: This suggests ongoing efficient conversion of the atomic gas into other phases in this region. The H alpha velocity anomalies previously found in the remnant body may be produced in part by the combination of tail-related, noncircular motions and the inner gas-disk rotation. Both tidal tails have bluer B-R colors than the main body of the remnant, with the bluest regions coinciding with peaks in the gas column density. Each tail contains one giant H II region near the end of its optical light distribution. These H II regions are associated with large concentrations of gas and stars that approach the sizes and gas contents of dwarf galaxies. The H I extends beyond the end of the optical tails and reaches projected distances of 62/h kpc east and 120/h kpc northwest from the center. We discuss the possible relevance of these data to : (1) the transformation of merged spirals into ellipticls; (2) the generation of ripples by returning tidal material; and (3) the formation of bound stellar systems from tidally torn material.

  3. ECO fill: automated fill modification to support late-stage design changes

    NASA Astrophysics Data System (ADS)

    Davis, Greg; Wilson, Jeff; Yu, J. J.; Chiu, Anderson; Chuang, Yao-Jen; Yang, Ricky

    2014-03-01

    One of the most critical factors in achieving a positive return for a design is ensuring the design not only meets performance specifications, but also produces sufficient yield to meet the market demand. The goal of design for manufacturability (DFM) technology is to enable designers to address manufacturing requirements during the design process. While new cell-based, DP-aware, and net-aware fill technologies have emerged to provide the designer with automated fill engines that support these new fill requirements, design changes that arrive late in the tapeout process (as engineering change orders, or ECOs) can have a disproportionate effect on tapeout schedules, due to the complexity of replacing fill. If not handled effectively, the impacts on file size, run time, and timing closure can significantly extend the tapeout process. In this paper, the authors examine changes to design flow methodology, supported by new fill technology, that enable efficient, fast, and accurate adjustments to metal fill late in the design process. We present an ECO fill methodology coupled with the support of advanced fill tools that can quickly locate the portion of the design affected by the change, remove and replace only the fill in that area, while maintaining the fill hierarchy. This new fill approach effectively reduces run time, contains fill file size, minimizes timing impact, and minimizes mask costs due to ECO-driven fill changes, all of which are critical factors to ensuring time-to-market schedules are maintained.

  4. Impingement syndrome. A review of late stage II and early stage III lesions.

    PubMed

    Post, M; Cohen, J

    1986-06-01

    From 1980 to 1984, 72 patients with impingement syndrome were treated by anterior acromioplasty before they developed rotator cuff tears. Follow-up evaluations averaged 23 months (range, five to 48 months). The average age was 42 years (range, 23-61 years). Preoperatively, 80% of the patients had pain at rest; the other 20% complained of pain during moderate activity. At the time of follow-up examination, 89% showed significant improvement, while 11% remained unchanged. Thirty-seven percent of the patients had varying degrees of muscle weakness preoperatively; of these, 71% were improved, 21% were unchanged, and 8% had a further decrease in the range of motion postoperatively. The results indicate that anterior acromioplasty is an excellent procedure for relief of pain due to impingement. Additionally, beneficial results were obtained in range of motion and muscle strength. In only a few select cases was lateral clavicle excision or tenodesis of the long head of the biceps necessary. Caution is advised in allowing return to strenuous activity unless the patient has recovered adequate strength in the cuff musculature. PMID:3720075

  5. Proteomic analysis of middle and late stages of bread wheat (Triticum aestivum L.) grain development

    PubMed Central

    Zhang, Ning; Chen, Feng; Huo, Wang; Cui, Dangqun

    2015-01-01

    Proteomic approaches were applied in four grain developmental stages of the Chinese bread wheat Yunong 201 and its ethyl methanesulfonate (EMS) mutant line Yunong 3114. 2-DE and tandem MALDI-TOF/TOF-MS analyzed proteome characteristics during middle and late grain development of the Chinese bread wheat Yunong 201 and its EMS mutant line Yunong 3114 with larger grain sizes. We identified 130 differentially accumulated protein spots representing 88 unique proteins, and four main expression patterns displayed a dynamic description of middle and late grain formation. Those identified protein species participated in eight biochemical processes: stress/defense, carbohydrate metabolism, protein synthesis/assembly/degradation, storage proteins, energy production and transportation, photosynthesis, transcription/translation, signal transduction. Comparative proteomic characterization demonstrated 12 protein spots that co-accumulated in the two wheat cultivars with different expression patterns, and six cultivar-specific protein spots including serpin, small heat shock protein, β-amylase, α-amylase inhibitor, dimeric α-amylase inhibitor precursor, and cold regulated protein. These cultivar-specific protein spots possibly resulted in differential yield-related traits of the two wheat cultivars. Our results provide valuable information for dissection of molecular and genetics basis of yield-related traits in bread wheat and the proteomic characterization in this study could also provide insights in the biology of middle and late grain development. PMID:26442048

  6. The I/S-to-illite reaction in the late stage diagenesis

    USGS Publications Warehouse

    Lanson, B.; Champion, D.

    1991-01-01

    XRF analyses of individual grains show that the I/S minerals become more illitic (near mica composition) with depth, but they always contain a portion of a smectite component, that is, silica-rich, low layer charge component. Both lath I/S and hexagonal illite minerals appear to grow by adding illite layers of the same composition (0.9 potassium atoms and a slight celadonite, phengite component) onto original crystallites. -from Authors

  7. Estimating canopy leaf area index in the late stages of wheat growth using continuous wavelet transform

    NASA Astrophysics Data System (ADS)

    Huang, Yan; Tian, Qingjiu; Wang, Lei; Geng, Jun; Lyu, Chunguang

    2014-01-01

    The existing hyperspectral vegetation indices used for estimating the canopy leaf area index (LAI) of winter wheat (Triticum aestivum L.) performed well, but the use of such indices at late growth stages can lead to inaccurate results. To improve the performance of LAI models for wheat in late growth stages, the continuous wavelet transform (CWT) method was applied in this study and used to decompose the canopy reflectance and its first derivative into wavelet coefficients. The correlation scalograms of wavelet coefficients and the LAI were then constructed and used to extract the top 1% correlated region as the wavelet feature. The canopy LAI estimation model for late growth wheat was established at last and compared with models based on 12 different types of hyperspectral vegetation indices. The results showed that, compared with the estimation models using the hyperspectral vegetation indices (for which the R2 values were all less than 0.15 and the root-mean-square errors (RMSEs) were greater than 1), the CWT-based canopy LAI estimation model for late growth wheat had obvious improvements in accuracy (maximum R2 of 0.53 and minimum of RMSE of 0.78). Hence, this new method shows promise for use in agricultural and ecological applications.

  8. Ferumoxytol-Enhanced Magnetic Resonance Imaging in Late-Stage CKD.

    PubMed

    Mukundan, Srinivasan; Steigner, Michael L; Hsiao, Li-Li; Malek, Sayeed K; Tullius, Stefan G; Chin, Matthew S; Siedlecki, Andrew M

    2016-06-01

    Ferumoxytol is a superparamagnetic iron oxide particle encapsulated by a semisynthetic carbohydrate with properties that can be used by the nephrologist for diagnosis and therapy. Ferumoxytol is approved by the US Food and Drug Administration for treating iron deficiency anemia in the setting of chronic kidney disease, but not for clinical diagnostic imaging. It has gained appeal as a magnetic resonance imaging contrast agent in patients with estimated glomerular filtration rates < 30mL/min/1.73m(2) in whom gadolinium-based contrast magnetic resonance imaging agents are relatively contraindicated because of the association with gadolinium deposition and nephrogenic systemic fibrosis. Ferumoxytol metabolism is not dependent on kidney function, but rather is removed from the circulation by the reticuloendothelial system of the liver, spleen, and bone marrow. Additionally, the prolonged intravascular half-life (>14 hours) of ferumoxytol allows for longer image acquisition and repeat imaging, if necessary. In patients with contraindications for gadolinium contrast agents, ferumoxytol is an alternative agent for vascular assessment, including patency and course. PMID:26786296

  9. Successes and Failures for Drugs in Late-Stage Development for Alzheimer's Disease

    PubMed Central

    Berk, Camryn; Sabbagh, Marwan

    2014-01-01

    To date, symptomatic medications prevail as the mainstay of treatment options for Alzheimer's disease (AD). There have been tremendous investments made to increase the numbers of drugs approved and the targets engaged, in an effort to alter the disease course or pathophysiology of AD. Unfortunately, almost all studies have not met expectations and no new drug (beyond medical foods) has been approved for the treatment of AD in the last decade. This review is a comparison of novel AD therapies in the late phases of clinical testing with recent high-profile clinical failures and agents in development with relatively unexplored mechanisms of action, with a focus on their potential as therapeutic agents and their proposed advantages over the treatments currently in use. PMID:23943247

  10. Successes and failures for drugs in late-stage development for Alzheimer's disease.

    PubMed

    Berk, Camryn; Sabbagh, Marwan N

    2013-10-01

    To date, symptomatic medications prevail as the mainstay of treatment options for Alzheimer's disease (AD). There have been tremendous investments made to increase the numbers of drugs approved and the targets engaged, in an effort to alter the disease course or pathophysiology of AD. Unfortunately, almost all studies have not met expectations and no new drug (beyond medical foods) has been approved for the treatment of AD in the last decade. This review is a comparison of novel AD therapies in the late phases of clinical testing, including recent high-profile clinical failures, and agents in development with relatively unexplored mechanisms of action, with a focus on their potential as therapeutic agents and their proposed advantages over the treatments currently in use. PMID:23943247

  11. Approaching a flat boundary with a block copolymer coated emulsion drop: late stage drainage dynamics

    NASA Astrophysics Data System (ADS)

    Rozairo, Damith; Croll, Andrew

    Understanding the dynamics of the formation and drainage of the thin fluid film that becomes trapped by a deformable droplet as it approaches another object is crucial to the advancement of many industrial and biomedical applications. Adding amphiphilic diblock copolymers, which are becoming more commonly used in drug delivery and oil recovery, only add to the complexity. Despite their increased use, little is known about how long polymer chains fill an emulsion drop's interface or how the molecules influence hydrodynamic processes. We study the drainage dynamics of a thin water film trapped between mica and a diblock copolymer saturated oil droplet. Specifically, we examine several different polystyrene-b-poly(ethylene oxide) (PS-PEO) molecules self-assembled at a toluene-water interface using laser scanning confocal microscopy. Our experiments reveal that the molecular details of the polymer chains deeply influence the drainage times, indicating that they are not acting as a 'simple' surfactant. The presence of the chains creates a much slower dynamic as fluid is forced to drain through an effective polymer brush, the brush itself determined by chain packing at the interface. We present a simple model which accounts for the basic physics of the interface.

  12. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells.

    PubMed

    Lee, John K; Phillips, John W; Smith, Bryan A; Park, Jung Wook; Stoyanova, Tanya; McCaffrey, Erin F; Baertsch, Robert; Sokolov, Artem; Meyerowitz, Justin G; Mathis, Colleen; Cheng, Donghui; Stuart, Joshua M; Shokat, Kevan M; Gustafson, W Clay; Huang, Jiaoti; Witte, Owen N

    2016-04-11

    MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention. PMID:27050099

  13. Ex Vivo Expansion of Human Mesenchymal Stem Cells in Defined Serum-Free Media

    PubMed Central

    Jung, Sunghoon; Panchalingam, Krishna M.; Rosenberg, Lawrence; Behie, Leo A.

    2012-01-01

    Human mesenchymal stem cells (hMSCs) are presently being evaluated for their therapeutic potential in clinical studies to treat various diseases, disorders, and injuries. To date, early-phase studies have indicated that the use of both autologous and allogeneic hMSCs appear to be safe; however, efficacy has not been demonstrated in recent late-stage clinical trials. Optimized cell bioprocessing protocols may enhance the efficacy as well as safety of hMSC therapeutics. Classical media used for generating hMSCs are typically supplemented with ill-defined supplements such as fetal bovine serum (FBS) or human-sourced alternatives. Ideally, culture media are desired to have well-defined serum-free formulations that support the efficient production of hMSCs while maintaining their therapeutic and differentiation capacity. Towards this objective, we review here current cell culture media for hMSCs and discuss medium development strategies. PMID:22645619

  14. A literature review of economic evaluations for a neglected tropical disease: human African trypanosomiasis ("sleeping sickness").

    PubMed

    Sutherland, C Simone; Yukich, Joshua; Goeree, Ron; Tediosi, Fabrizio

    2015-02-01

    Human African trypanosomiasis (HAT) is a disease caused by infection with the parasite Trypanosoma brucei gambiense or T. b. rhodesiense. It is transmitted to humans via the tsetse fly. Approximately 70 million people worldwide were at risk of infection in 1995, and approximately 20,000 people across Africa are infected with HAT. The objective of this review was to identify existing economic evaluations in order to summarise cost-effective interventions to reduce, control, or eliminate the burden of HAT. The studies included in the review were compared and critically appraised in order to determine if there were existing standardised methods that could be used for economic evaluation of HAT interventions or if innovative methodological approaches are warranted. A search strategy was developed using keywords and was implemented in January 2014 in several databases. The search returned a total of 2,283 articles. After two levels of screening, a total of seven economic evaluations were included and underwent critical appraisal using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist 6: Economic Evaluations. Results from the existing studies focused on the cost-effectiveness of interventions for the control and reduction of disease transmission. Modelling was a common method to forecast long-term results, and publications focused on interventions by category, such as case detection, diagnostics, drug treatments, and vector control. Most interventions were considered cost-effective based on the thresholds described; however, the current treatment, nifurtomix-eflornithine combination therapy (NECT), has not been evaluated for cost-effectiveness, and considerations for cost-effective strategies for elimination have yet to be completed. Overall, the current evidence highlights the main components that play a role in control; however, economic evaluations of HAT elimination strategies are needed to assist national decision makers, stakeholders, and

  15. Control of human African trypanosomiasis in the Quiçama focus, Angola.

    PubMed Central

    Ruiz, José Antonio; Simarro, Pere P.; Josenando, Teofilo

    2002-01-01

    OBJECTIVE: To update the epidemiological status of human African trypanosomiasis (HAT), also known as sleeping sickness, in the Quiçama focus, province of Bengo, Angola, and to establish a HAT control programme. METHODS: In 1997, 8796 people (the population of 31 villages) were serologically screened for Trypanosoma brucei gambiense, the causative agent of HAT. In 1998 and 1999, surveys were carried out in villages where HAT cases had been identified in 1997. Individuals were screened using the card agglutination trypanosomiasis test (CATT), and then examined for the presence of the parasite. CATT- positive individuals in whom the presence of the parasite could not be confirmed were further tested with the CATT using serum dilutions, and those with a positive antibody end titre of 1-in-4 or above were followed-up. Patients with < or =10 white cells/micro l and no trypanosomes in their cerebrospinal fluid (CSF) were classified as being in the first stage of the disease. Vector control was not considered necessary or feasible. FINDINGS: The main transmission areas were on the Kwanza riverbanks, where 5042 inhabitants live. In 1997, the HAT prevalence was 1.97%, but this decreased to 0.55% in 1998 and to 0.33% in 1999. The relapse rate was 3% in patients treated with pentamidine and 3.5% in patients treated with melarsoprol. In patients treated with pentamidine, there was no difference in the relapse rate for patients with initial CSF white cell counts of 0-5 cells/ micro l or 6-10 cells/micro l. The overall mortality rate was 0.6% and the rate of reactive arsenical encephalopathy among the melarsoprol-treated patients was 1.7%. CONCLUSION: The epidemiological status of the disease was updated and the transmission areas were defined. The control methods implemented allowed the disease prevalence to be reduced. PMID:12378293

  16. Bacillus anthracis Lethal Toxin Reduces Human Alveolar Epithelial Barrier Function

    PubMed Central

    Langer, Marybeth; Duggan, Elizabeth Stewart; Booth, John Leland; Patel, Vineet Indrajit; Zander, Ryan A.; Silasi-Mansat, Robert; Ramani, Vijay; Veres, Tibor Zoltan; Prenzler, Frauke; Sewald, Katherina; Williams, Daniel M.; Coggeshall, Kenneth Mark; Awasthi, Shanjana; Lupu, Florea; Burian, Dennis; Ballard, Jimmy Dale; Braun, Armin

    2012-01-01

    The lung is the site of entry for Bacillus anthracis in inhalation anthrax, the deadliest form of the disease. Bacillus anthracis produces virulence toxins required for disease. Alveolar macrophages were considered the primary target of the Bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target of Bacillus anthracis lethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination of Bacillus anthracis from the lung in early disease and promoting edema in late stages of the illness. PMID:23027535

  17. A Literature Review of Economic Evaluations for a Neglected Tropical Disease: Human African Trypanosomiasis (“Sleeping Sickness”)

    PubMed Central

    Sutherland, C. Simone; Yukich, Joshua; Goeree, Ron; Tediosi, Fabrizio

    2015-01-01

    Human African trypanosomiasis (HAT) is a disease caused by infection with the parasite Trypanosoma brucei gambiense or T. b. rhodesiense. It is transmitted to humans via the tsetse fly. Approximately 70 million people worldwide were at risk of infection in 1995, and approximately 20,000 people across Africa are infected with HAT. The objective of this review was to identify existing economic evaluations in order to summarise cost-effective interventions to reduce, control, or eliminate the burden of HAT. The studies included in the review were compared and critically appraised in order to determine if there were existing standardised methods that could be used for economic evaluation of HAT interventions or if innovative methodological approaches are warranted. A search strategy was developed using keywords and was implemented in January 2014 in several databases. The search returned a total of 2,283 articles. After two levels of screening, a total of seven economic evaluations were included and underwent critical appraisal using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist 6: Economic Evaluations. Results from the existing studies focused on the cost-effectiveness of interventions for the control and reduction of disease transmission. Modelling was a common method to forecast long-term results, and publications focused on interventions by category, such as case detection, diagnostics, drug treatments, and vector control. Most interventions were considered cost-effective based on the thresholds described; however, the current treatment, nifurtomix-eflornithine combination therapy (NECT), has not been evaluated for cost-effectiveness, and considerations for cost-effective strategies for elimination have yet to be completed. Overall, the current evidence highlights the main components that play a role in control; however, economic evaluations of HAT elimination strategies are needed to assist national decision makers, stakeholders, and

  18. Domestic Animal Hosts Strongly Influence Human-Feeding Rates of the Chagas Disease Vector Triatoma infestans in Argentina

    PubMed Central

    Gürtler, Ricardo E.; Cecere, María C.; Vázquez-Prokopec, Gonzalo M.; Ceballos, Leonardo A.; Gurevitz, Juan M.; Fernández, María del Pilar; Kitron, Uriel; Cohen, Joel E.

    2014-01-01

    Background The host species composition in a household and their relative availability affect the host-feeding choices of blood-sucking insects and parasite transmission risks. We investigated four hypotheses regarding factors that affect blood-feeding rates, proportion of human-fed bugs (human blood index), and daily human-feeding rates of Triatoma infestans, the main vector of Chagas disease. Methods A cross-sectional survey collected triatomines in human sleeping quarters (domiciles) of 49 of 270 rural houses in northwestern Argentina. We developed an improved way of estimating the human-feeding rate of domestic T. infestans populations. We fitted generalized linear mixed-effects models to a global model with six explanatory variables (chicken blood index, dog blood index, bug stage, numbers of human residents, bug abundance, and maximum temperature during the night preceding bug catch) and three response variables (daily blood-feeding rate, human blood index, and daily human-feeding rate). Coefficients were estimated via multimodel inference with model averaging. Findings Median blood-feeding intervals per late-stage bug were 4.1 days, with large variations among households. The main bloodmeal sources were humans (68%), chickens (22%), and dogs (9%). Blood-feeding rates decreased with increases in the chicken blood index. Both the human blood index and daily human-feeding rate decreased substantially with increasing proportions of chicken- or dog-fed bugs, or the presence of chickens indoors. Improved calculations estimated the mean daily human-feeding rate per late-stage bug at 0.231 (95% confidence interval, 0.157–0.305). Conclusions and Significance Based on the changing availability of chickens in domiciles during spring-summer and the much larger infectivity of dogs compared with humans, we infer that the net effects of chickens in the presence of transmission-competent hosts may be more adequately described by zoopotentiation than by zooprophylaxis

  19. Intrinsic functional brain architecture derived from graph theoretical analysis in the human fetus.

    PubMed

    Thomason, Moriah E; Brown, Jesse A; Dassanayake, Maya T; Shastri, Rupal; Marusak, Hilary A; Hernandez-Andrade, Edgar; Yeo, Lami; Mody, Swati; Berman, Susan; Hassan, Sonia S; Romero, Roberto

    2014-01-01

    The human brain undergoes dramatic maturational changes during late stages of fetal and early postnatal life. The importance of this period to the establishment of healthy neural connectivity is apparent in the high incidence of neural injury in preterm infants, in whom untimely exposure to ex-uterine factors interrupts neural connectivity. Though the relevance of this period to human neuroscience is apparent, little is known about functional neural networks in human fetal life. Here, we apply graph theoretical analysis to examine human fetal brain connectivity. Utilizing resting state functional magnetic resonance imaging (fMRI) data from 33 healthy human fetuses, 19 to 39 weeks gestational age (GA), our analyses reveal that the human fetal brain has modular organization and modules overlap functional systems observed postnatally. Age-related differences between younger (GA <31 weeks) and older (GA≥31 weeks) fetuses demonstrate that brain modularity decreases, and connectivity of the posterior cingulate to other brain networks becomes more negative, with advancing GA. By mimicking functional principles observed postnatally, these results support early emerging capacity for information processing in the human fetal brain. Current technical limitations, as well as the potential for fetal fMRI to one day produce major discoveries about fetal origins or antecedents of neural injury or disease are discussed. PMID:24788455

  20. Hedyotis diffusa water extract diminished the cytotoxic effects of chemotherapy drugs against human breast cancer MCF7 cells.

    PubMed

    Dong, Qiulin; Ling, Binbing; Gao, Bosong; Maley, Jason; Sammynaiken, Ramaswami; Yang, Jian

    2014-05-01

    Hedyotis diffusa is a Chinese herbal medicine widely used in combination with other herbal medicines such as Scutellaria barbata to treat various types of cancer. Late-stage and recurrent cancer patients usually use H. diffusa during chemotherapy in expecting to achieve additive or synergistic therapeutic effects. Several classes of active ingredients, including anthraquinones, iridoid glucosides and stigmasterols. have been isolated and characterized from H. diffusa. In the current study, we isolated alkaloid/flavonoid from H diffusa and showed that the crude alkaloid/flavonoid extract rather than its three major components possessed antitumor activity against human breast cancer cell line MCF7. Co-administration of H. diffusa water extract diminished the cytotoxicities of chemotherapy drugs doxorubicin, cyclophosphamide and docetaxel towards the MCF7 cells, implicating that H. diffusa should not be used during breast cancer chemotherapy. PMID:25026725

  1. In Silico Identification of a Candidate Synthetic Peptide (Tsgf118–43) to Monitor Human Exposure to Tsetse Flies in West Africa

    PubMed Central

    Dama, Emilie; Cornelie, Sylvie; Camara, Mamadou; Somda, Martin Bienvenu; Poinsignon, Anne; Ilboudo, Hamidou; Elanga Ndille, Emmanuel; Jamonneau, Vincent; Solano, Philippe; Remoue, Franck; Bengaly, Zakaria; Belem, Adrien Marie Gaston; Bucheton, Bruno

    2013-01-01

    Background The analysis of humoral responses directed against the saliva of blood-sucking arthropods was shown to provide epidemiological biomarkers of human exposure to vector-borne diseases. However, the use of whole saliva as antigen presents several limitations such as problems of mass production, reproducibility and specificity. The aim of this study was to design a specific biomarker of exposure to tsetse flies based on the in silico analysis of three Glossina salivary proteins (Ada, Ag5 and Tsgf1) previously shown to be specifically recognized by plasma from exposed individuals. Methodology/Principal Findings Synthetic peptides were designed by combining several linear epitope prediction methods and Blast analysis. The most specific peptides were then tested by indirect ELISA on a bank of 160 plasma samples from tsetse infested areas and tsetse free areas. Anti-Tsgf118–43 specific IgG levels were low in all three control populations (from rural Africa, urban Africa and Europe) and were significantly higher (p<0.0001) in the two populations exposed to tsetse flies (Guinean HAT foci, and South West Burkina Faso). A positive correlation was also found between Anti-Tsgf118–43 IgG levels and the risk of being infected by Trypanosoma brucei gambiense in the sleeping sickness foci of Guinea. Conclusion/Significance The Tsgf118–43 peptide is a suitable and promising candidate to develop a standardize immunoassay allowing large scale monitoring of human exposure to tsetse flies in West Africa. This could provide a new surveillance indicator for tsetse control interventions by HAT control programs. PMID:24086785

  2. FGF21 and the late adaptive response to starvation in humans

    PubMed Central

    Fazeli, Pouneh K.; Lun, Mingyue; Kim, Soo M.; Bredella, Miriam A.; Wright, Spenser; Zhang, Yang; Lee, Hang; Catana, Ciprian; Klibanski, Anne; Patwari, Parth; Steinhauser, Matthew L.

    2015-01-01

    In mice, FGF21 is rapidly induced by fasting, mediates critical aspects of the adaptive starvation response, and displays a number of positive metabolic properties when administered pharmacologically. In humans, however, fasting does not consistently increase FGF21, suggesting a possible evolutionary divergence in FGF21 function. Moreover, many key aspects of FGF21 function in mice have been identified in the context of transgenic overexpression or administration of supraphysiologic doses, rather than in a physiologic setting. Here, we explored the dynamics and function of FGF21 in human volunteers during a 10-day fast. Unlike mice, which show an increase in circulating FGF21 after only 6 hours, human subjects did not have a notable surge in FGF21 until 7 to 10 days of fasting. Moreover, we determined that FGF21 induction was associated with decreased thermogenesis and adiponectin, an observation that directly contrasts with previous reports based on supraphysiologic dosing. Additionally, FGF21 levels increased after ketone induction, demonstrating that endogenous FGF21 does not drive starvation-mediated ketogenesis in humans. Instead, a longitudinal analysis of biologically relevant variables identified serum transaminases — markers of tissue breakdown — as predictors of FGF21. These data establish FGF21 as a fasting-induced hormone in humans and indicate that FGF21 contributes to the late stages of adaptive starvation, when it may regulate the utilization of fuel derived from tissue breakdown. PMID:26529252

  3. Data in support of transcriptional regulation and function of Fas-antisense long noncoding RNA during human erythropoiesis

    PubMed Central

    Villamizar, Olga; Chambers, Christopher B.; Mo, Yin-Yuan; Torry, Donald S.; Hofstrand, Reese; Riberdy, Janice M.; Persons, Derek A.; Wilber, Andrew

    2016-01-01

    This paper describes data related to a research article titled, “Fas-antisense long noncoding RNA is differentially expressed during maturation of human erythrocytes and confers resistance to Fas-mediated cell death” [1]. Long noncoding RNAs (lncRNAs) are increasingly appreciated for their capacity to regulate many steps of gene expression. While recent studies suggest that many lncRNAs are functional, the scope of their actions throughout human biology is largely undefined including human red blood cell development (erythropoiesis). Here we include expression data for 82 lncRNAs during early, intermediate and late stages of human erythropoiesis using a commercial qPCR Array. From these data, we identified lncRNA Fas-antisense 1 (Fas-AS1 or Saf) described in the research article. Also included are 5′ untranslated sequences (UTR) for lncRNA Saf with transcription factor target sequences identified. Quantitative RT-PCR data demonstrate relative levels of critical erythroid transcription factors, GATA-1 and KLF1, in K562 human erythroleukemia cells and maturing erythroblasts derived from human CD34+ cells. End point and quantitative RT-PCR data for cDNA prepared using random hexamers versus oligo(dT)18 revealed that lncRNA Saf is not effectively polyadenylated. Finally, we include flow cytometry histograms demonstrating Fas levels on maturing erythroblasts derived from human CD34+ cells transduced using mock conditions or with lentivirus particles encoding for Saf. PMID:27141526

  4. Data in support of transcriptional regulation and function of Fas-antisense long noncoding RNA during human erythropoiesis.

    PubMed

    Villamizar, Olga; Chambers, Christopher B; Mo, Yin-Yuan; Torry, Donald S; Hofstrand, Reese; Riberdy, Janice M; Persons, Derek A; Wilber, Andrew

    2016-06-01

    This paper describes data related to a research article titled, "Fas-antisense long noncoding RNA is differentially expressed during maturation of human erythrocytes and confers resistance to Fas-mediated cell death" [1]. Long noncoding RNAs (lncRNAs) are increasingly appreciated for their capacity to regulate many steps of gene expression. While recent studies suggest that many lncRNAs are functional, the scope of their actions throughout human biology is largely undefined including human red blood cell development (erythropoiesis). Here we include expression data for 82 lncRNAs during early, intermediate and late stages of human erythropoiesis using a commercial qPCR Array. From these data, we identified lncRNA Fas-antisense 1 (Fas-AS1 or Saf) described in the research article. Also included are 5' untranslated sequences (UTR) for lncRNA Saf with transcription factor target sequences identified. Quantitative RT-PCR data demonstrate relative levels of critical erythroid transcription factors, GATA-1 and KLF1, in K562 human erythroleukemia cells and maturing erythroblasts derived from human CD34(+) cells. End point and quantitative RT-PCR data for cDNA prepared using random hexamers versus oligo(dT)18 revealed that lncRNA Saf is not effectively polyadenylated. Finally, we include flow cytometry histograms demonstrating Fas levels on maturing erythroblasts derived from human CD34(+) cells transduced using mock conditions or with lentivirus particles encoding for Saf. PMID:27141526

  5. RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

    PubMed Central

    Goulidaki, Nektaria; Alarifi, Saud; Alkahtani, Saad H; Al-Qahtani, Ahmed; Spandidos, Demetrios A; Stournaras, Christos; Sourvinos, George

    2015-01-01

    Human Cytomegalovirus (HCMV), an ubiquitous β-herpesvirus, is a significant pathogen that causes medically severe diseases in immunocompromised individuals and in congenitally infected neonates. RhoB belongs to the family of Rho GTPases, which regulates diverse cellular processes. Rho proteins are implicated in the entry and egress from the host cell of mainly α- and γ-herpesviruses, whereas β-herpesviruses are the least studied in this regard. Here, we studied the role of RhoB GTPase during HCMV lytic infection. Microscopy analysis, both in fixed and live infected cells showed that RhoB was translocated to the assembly complex/compartment (AC) of HCMV, a cytoplasmic zone in infected cells where many viral structural proteins are known to accumulate and assembly of new virions takes place. Furthermore, RhoB was localized at the AC even when the expression of the late HCMV AC proteins was inhibited. At the very late stages of infection, cellular projections were formed containing RhoB and HCMV virions, potentially contributing to the successful viral spread. Interestingly, the knockdown of RhoB in HCMV-infected cells resulted in a significant reduction of the virus titer and could also affect the accumulation of AC viral proteins at this subcellular compartment. RhoB knockdown also affected actin fibers' structure. Actin reorganization was observed at late stages of infection originating from the viral AC and surrounding the cellular projections, implying a potential interplay between RhoB and actin during HCMV assembly and egress. In conclusion, our results demonstrate for the first time that RhoB is a constituent of the viral AC and is required for HCMV productive infection. PMID:26114383

  6. High-performance beating pattern function of human induced pluripotent stem cell-derived cardiomyocyte-based biosensors for hERG inhibition recognition.

    PubMed

    Hu, Ning; Wang, Tianxing; Wang, Qin; Zhou, Jie; Zou, Ling; Su, Kaiqi; Wu, Jieying; Wang, Ping

    2015-05-15

    High-throughput and high clinical relevance methods are demanded to predict the drug-induced cardiotoxicity in pharmaceutical and biotechnology industries to effectively decrease late-stage drug attrition. In this study, human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were integrated into an interdigital impedance sensor array to fabricate a high performance iPSC-CM-based biosensor array with high-throughput and high-consistency beating pattern. Typical withdrawal approved drugs (astemizole, sertindole, cisapride, and droperidol) with hERG inhibition and positive control E-4031 were employed to determine the beating pattern function. From the results, it can be concluded that this iPSC-CM-based biosensor array can specifically differentiate the hERG inhibitors from the non-hERG inhibition compounds through beating pattern function. PMID:25153933

  7. Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection

    PubMed Central

    Cuypers, Bart; Lecordier, Laurence; Meehan, Conor J.; Van den Broeck, Frederik; Imamura, Hideo; Büscher, Philippe; Dujardin, Jean-Claude; Laukens, Kris; Schnaufer, Achim; Dewar, Caroline; Lewis, Michael; Balmer, Oliver; Azurago, Thomas; Kyei-Faried, Sardick; Ohene, Sally-Ann; Duah, Boateng; Homiah, Prince; Mensah, Ebenezer Kofi; Anleah, Francis; Franco, Jose Ramon; Pays, Etienne

    2016-01-01

    ABSTRACT African trypanosomes, except Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which cause human African trypanosomiasis, are lysed by the human serum protein apolipoprotein L1 (ApoL1). These two subspecies can resist human ApoL1 because they express the serum resistance proteins T. b. gambiense glycoprotein (TgsGP) and serum resistance-associated protein (SRA), respectively. Whereas in T. b. rhodesiense, SRA is necessary and sufficient to inhibit ApoL1, in T. b. gambiense, TgsGP cannot protect against high ApoL1 uptake, so different additional mechanisms contribute to limit this uptake. Here we report a complex interplay between trypanosomes and an ApoL1 variant, revealing important insights into innate human immunity against these parasites. Using whole-genome sequencing, we characterized an atypical T. b. gambiense infection in a patient in Ghana. We show that the infecting trypanosome has diverged from the classical T. b. gambiense strains and lacks the TgsGP defense mechanism against human serum. By sequencing the ApoL1 gene of the patient and subsequent in vitro mutagenesis experiments, we demonstrate that a homozygous missense substitution (N264K) in the membrane-addressing domain of this ApoL1 variant knocks down the trypanolytic activity, allowing the trypanosome to avoid ApoL1-mediated immunity. PMID:27073096

  8. MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple negative MDA-MB-231 human breast cancer cells

    PubMed Central

    Browne, Gillian; Dragon, Julie A.; Hong, Deli; Messier, Terri L.; Gordon, Jonathan A. R.; Farina, Nicholas H.; Boyd, Joseph R.; VanOudenhove, Jennifer J.; Perez, Andrew W.; Zaidi, Sayyed K.; Stein, Janet L.; Stein, Gary S.; Lian, Jane B.

    2016-01-01

    The Runx1 transcription factor, known for its essential role normal hematopoiesis, was reported in limited studies to be mutated or associated with human breast tumor tissues. Runx 1 increases concomitant with disease progression in the MMTV-PyMT transgenic mouse model of breast cancer. Compelling questions relate to mechanisms that regulate Runx1 expression in breast cancer. Here, we tested the hypothesis that dysregulation of Runx1-targeting microRNAs (miRNAs) allows for pathologic increase of Runx1 during breast cancer progression. Microarray profiling of the MMTV-PyMT model revealed significant down-regulation of numerous miRNAs predicted to target Runx1. One of these, miR-378, was inversely correlated with Runx1 expression during breast cancer progression in mouse, and in human breast cancer cell lines MCF7 and triple negative MDA-MB-231 that represent early and late stage disease, respectively. MiR-378 is nearly absent in MDA-MB-231 cells. Luciferase reporter assays revealed that miR-378 binds the Runx1 3′UTR and inhibits Runx1 expression. Functionally, we demonstrated that ectopic expression of miR-378 in MDA-MB-231 cells inhibited Runx1 and suppressed migration and invasion; while inhibition of miR-378 in MCF7 cells increased Runx1 levels and cell migration. Depletion of Runx1 in late stage breast cancer cells resulted in increased expression of both the miR-378 host gene PPARGC1B and pre-miR-378, suggesting a feedback loop. Taken together, our study identifies a novel and clinically relevant mechanism for regulation of Runx1 in breast cancer that is mediated by a PPARGC1B-miR-378-Runx1 regulatory pathway. Our results highlight the translational potential of miRNA replacement therapy for inhibiting Runx1 in breast cancer. PMID:26749280

  9. Renal denervation for human hypertension: is there a future?

    PubMed

    Izzo, Joseph L; Tobe, Sheldon W

    2016-05-01

    The sympathetic nervous system plays a permissive, if not primary causal role in the genesis and maintenance of human essential hypertension. Excessive sympathetic nervous system activity in man is most apparent in early forms of hypertension (prehypertension and white-coat type). Renal nerves are of particular interest because of their roles in modulating the activity of the renin-angiotensin system and renal sodium excretion. Renal denervation substantially ameliorates the development of hypertension in animal models such as renovascular, spontaneously hypertensive, and steroid-induced hypertension in rats and aortic coarctation in dogs. In man, catheter ablation of renal nerves has been undertaken in the late phases of hypertension; in a rigorously controlled trial in resistant hypertension (SYMPLICITY HTN-3), renal denervation did not reduce blood pressure over the long term. Is this because renal denervation is more appropriate to prevent than treat late-stage hypertension? Are there anatomical or technical barriers yet to be overcome in the procedure? These and other issues are addressed by two experts in this issue of the controversies series: Deepak L. Bhatt and Murray Epstein. PMID:27049792

  10. Punicalagin promotes autophagy to protect primary human syncytiotrophoblasts from apoptosis.

    PubMed

    Wang, Ying; Chen, Baosheng; Longtine, Mark S; Nelson, D Michael

    2016-02-01

    Punicalagin is a prominent polyphenol in pomegranate juice that protects cultured syncytiotrophoblasts from stress-induced apoptosis. Here, we test the hypothesis that punicalagin has this effect by inhibiting the mTOR kinase pathway to enhance autophagic turnover and limit apoptosis in cultured primary human syncytiotrophoblasts. In syncytiotrophoblasts, starvation, rapamycin, or punicalagin all decreased the expression of phosphorylated ribosomal protein S6, a downstream target of the mTOR kinase, and of the autophagy markers, LC3-II and p62. In contrast, in the presence of bafilomycin, an inhibitor of late stages of autophagy and degradation in the autophagolysosome, syncytiotrophoblasts exposed to starvation, rapamycin, or punicalagin all showed increased levels of LC3-II and p62. The number of LC3-II punctae also increased in punicalagin-treated syncytiotrophoblasts exposed to chloroquine, another inhibitor of autophagic degradation, and punicalagin increased the number of lysosomes. The apoptosis-reducing effect of punicalagin was attenuated by inhibition of autophagy using bafilomycin or knockdown of the autophagy related gene, ATG16L1. Collectively, these data support the hypothesis that punicalagin modulates the crosstalk between autophagy and apoptosis to promote survival in cultured syncytiotrophoblasts. PMID:26659860

  11. Distribution of distal femoral osteophytes in a human skeletal population

    PubMed Central

    Shepstone, L.; Rogers, J.; Kirwan, J.; Silverman, B.

    2000-01-01

    OBJECTIVES—To examine objectively spatial patterns of osteophytes around the distal end of the femur and to identify distinct subgroups.
METHODS—A sample of 107 human femora from a large skeletal population were selected for study. These femora included subjects with evidence of late stage osteoarthritis (that is, with eburnation present) and those with no such evidence. The location of osteophytes was recorded using a video camera and digitised computer images were extracted. Multidimensional scaling was used to identify clusters of femora based upon osteophyte location.
RESULTS—A distinct subgroup of femora was identified with osteophytes present only within the intercondylar notch region. None of these subjects had any evidence of eburnation.
CONCLUSIONS—This finding adds to an earlier study based on radiographs. Osteophytes located within the intercondylar notch of the femur appear to be a distinct subset, which may occur either as an early stage of knee osteoarthritis or for some independent reason.

 PMID:10873960

  12. Relaxin affects cell organization and early and late stages of spermatogenesis in a coculture of rat testicular cells.

    PubMed

    Pimenta, M T; Francisco, R A R; Silva, R P; Porto, C S; Lazari, M F M

    2015-07-01

    Relaxin and its receptor RXFP1 are co-expressed in Sertoli cells, and relaxin can stimulate proliferation of Sertoli cells. In this study, we investigated a role of relaxin in spermatogenesis, using a short-term culture of testicular cells of the rat that allowed differentiation of spermatogonia to spermatids. Sertoli, germ, and peritubular myoid cells were the predominant cell types in the culture. Sertoli and germ cells expressed RXFP1. Cultures were incubated without (control) or with 0.5% fetal bovine serum (FBS) or 100 ng/mL H2 relaxin (RLN) for 2 days. Cell organization, number, and differentiation were analyzed after 2 (D2), 5 (D5) or 8 (D8) days of culturing. Although the proportion of germ cells decayed from D2 to D5, the relative contribution of HC, 1C, 2C, and 4C germ cell populations remained constant in the control group during the whole culture. RLN did not affect the proportion of germ cell populations compared with control, but increased gene and/or protein expression of the undifferentiated and differentiated spermatogonia markers PLZF and c-KIT, and of the post-meiotic marker Odf2 in D5. RLN favored organization of cells in tubule-like structures, the arrangement of myoid cells around the tubules, arrangement of c-KIT-positive spermatogonia at the basal region of the tubules, and expression of the cell junction protein β-catenin close to the plasma membrane region. Knockdown of relaxin with small interfering RNA (siRNA) reduced expression of β-catenin at the cell junctions, and shifted its expression to the nucleus. We propose that relaxin may affect spermatogenesis by modulating spermatogonial self renewal and favoring cell contact. PMID:26041439

  13. Manipulation of Developing Juvenile Structures in Purple Sea Urchins (Strongylocentrotus purpuratus) by Morpholino Injection into Late Stage Larvae

    PubMed Central

    2014-01-01

    Sea urchins have been used as experimental organisms for developmental biology for over a century. Yet, as is the case for many other marine invertebrates, understanding the development of the juveniles and adults has lagged far behind that of their embryos and larvae. The reasons for this are, in large part, due to the difficulty of experimentally manipulating juvenile development. Here we develop and validate a technique for injecting compounds into juvenile rudiments of the purple sea urchin, Strongylocentrotus purpuratus. We first document the distribution of rhodaminated dextran injected into different compartments of the juvenile rudiment of sea urchin larvae. Then, to test the potential of this technique to manipulate development, we injected Vivo-Morpholinos (vMOs) designed to knock down p58b and p16, two proteins involved in the elongation of S. purpuratus larval skeleton. Rudiments injected with these vMOs showed a delay in the growth of some juvenile skeletal elements relative to controls. These data provide the first evidence that vMOs, which are designed to cross cell membranes, can be used to transiently manipulate gene function in later developmental stages in sea urchins. We therefore propose that injection of vMOs into juvenile rudiments, as shown here, is a viable approach to testing hypotheses about gene function during development, including metamorphosis. PMID:25436992

  14. Ultrasonic force microscopy for nanomechanical characterization of early and late-stage amyloid-β peptide aggregation

    PubMed Central

    Tinker-Mill, Claire; Mayes, Jennifer; Allsop, David; Kolosov, Oleg V.

    2014-01-01

    The aggregation of amyloid-β peptides into protein fibres is one of the main neuropathological features of Alzheimer's disease (AD). While imaging of amyloid-β aggregate morphology in vitro is extremely important for understanding AD pathology and in the development of aggregation inhibitors, unfortunately, potentially highly toxic, early aggregates are difficult to observe by current electron microscopy and atomic force microscopy (AFM) methods, due to low contrast and variability of peptide attachment to the substrate. Here, we use a poly-L-Lysine (PLL) surface that captures all protein components from monomers to fully formed fibres, followed by nanomechanical mapping via ultrasonic force microscopy (UFM), which marries high spatial resolution and nanomechanical contrast with the non-destructive nature of tapping mode AFM. For the main putative AD pathogenic component, Aβ1-42, the PLL-UFM approach reveals the morphology of oligomers, protofibrils and mature fibres, and finds that a fraction of small oligomers is still present at later stages of fibril assembly. PMID:24500006

  15. Developmental genes significantly afflicted by aberrant promoter methylation and somatic mutation predict overall survival of late-stage colorectal cancer

    PubMed Central

    An, Ning; Yang, Xue; Cheng, Shujun; Wang, Guiqi; Zhang, Kaitai

    2015-01-01

    Carcinogenesis is an exceedingly complicated process, which involves multi-level dysregulations, including genomics (majorly caused by somatic mutation and copy number variation), DNA methylomics, and transcriptomics. Therefore, only looking into one molecular level of cancer is not sufficient to uncover the intricate underlying mechanisms. With the abundant resources of public available data in the Cancer Genome Atlas (TCGA) database, an integrative strategy was conducted to systematically analyze the aberrant patterns of colorectal cancer on the basis of DNA copy number, promoter methylation, somatic mutation and gene expression. In this study, paired samples in each genomic level were retrieved to identify differentially expressed genes with corresponding genetic or epigenetic dysregulations. Notably, the result of gene ontology enrichment analysis indicated that the differentially expressed genes with corresponding aberrant promoter methylation or somatic mutation were both functionally concentrated upon developmental process, suggesting the intimate association between development and carcinogenesis. Thus, by means of random walk with restart, 37 significant development-related genes were retrieved from a priori-knowledge based biological network. In five independent microarray datasets, Kaplan–Meier survival and Cox regression analyses both confirmed that the expression of these genes was significantly associated with overall survival of Stage III/IV colorectal cancer patients. PMID:26691761

  16. Late-Stage Refocusing of Irish-Language Programme Evaluation: Maximizing the Potential for Productive Debate and Remediation

    ERIC Educational Resources Information Center

    Harris, John

    2009-01-01

    The teaching and learning of Irish in primary school is both an important educational issue and central to the national language revitalization effort. The findings of Irish-language programme evaluations, therefore, are invariably scrutinized very closely by different sectors. This paper examines how the later stages of a major evaluation took…

  17. Late-stage optimization of a tercyclic class of S1P3-sparing, S1P1 receptor agonists.

    PubMed

    Horan, Joshua C; Kuzmich, Daniel; Liu, Pingrong; DiSalvo, Darren; Lord, John; Mao, Can; Hopkins, Tamara D; Yu, Hui; Harcken, Christian; Betageri, Raj; Hill-Drzewi, Melissa; Patenaude, Lori; Patel, Monica; Fletcher, Kimberly; Terenzzio, Donna; Linehan, Brian; Xia, Heather; Patel, Mita; Studwell, Debbie; Miller, Craig; Hickey, Eugene; Levin, Jeremy I; Smith, Dustin; Kemper, Raymond A; Modis, Louise K; Bannen, Lynne C; Chan, Diva S; Mac, Morrison B; Ng, Stephanie; Wang, Yong; Xu, Wei; Lemieux, René M

    2016-01-15

    Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders. PMID:26687487

  18. Ultrasonic force microscopy for nanomechanical characterization of early and late-stage amyloid-β peptide aggregation

    NASA Astrophysics Data System (ADS)

    Tinker-Mill, Claire; Mayes, Jennifer; Allsop, David; Kolosov, Oleg V.

    2014-02-01

    The aggregation of amyloid-β peptides into protein fibres is one of the main neuropathological features of Alzheimer's disease (AD). While imaging of amyloid-β aggregate morphology in vitro is extremely important for understanding AD pathology and in the development of aggregation inhibitors, unfortunately, potentially highly toxic, early aggregates are difficult to observe by current electron microscopy and atomic force microscopy (AFM) methods, due to low contrast and variability of peptide attachment to the substrate. Here, we use a poly-L-Lysine (PLL) surface that captures all protein components from monomers to fully formed fibres, followed by nanomechanical mapping via ultrasonic force microscopy (UFM), which marries high spatial resolution and nanomechanical contrast with the non-destructive nature of tapping mode AFM. For the main putative AD pathogenic component, Aβ1-42, the PLL-UFM approach reveals the morphology of oligomers, protofibrils and mature fibres, and finds that a fraction of small oligomers is still present at later stages of fibril assembly.

  19. Localization of estrogen receptor in the central lymphoid organs of chickens during the late stage of embryogenesis.

    PubMed

    Katayama, Masafumi; Fukuda, Tomokazu; Narabara, Kiyoaki; Abe, Asaki; Kondo, Yasuhiro

    2012-01-01

    Immunological function in chicks is greatly affected by estrogen treatment during embryogenesis, but the mechanism of the estrogen effect is not fully understood. To elucidate the effect of estrogen on immune function, we observed estrogen receptor expression in the thymus and bursa of chick embryos by immunohistochemistry. We compared the distribution of estrogen receptor-positive cells with that of keratin-positive epithelial cells. Intense expression of estrogen receptors was detected in thymic and bursal lymphocytes. In peripheral lymphocytes, ER mRNA was detected by RT-PCR analysis. The results of fluorescence-activated cell sorting analysis indicated that the estrogen receptor was expressed in the cytoplasm of the lymphocytes. Furthermore, intense expression of the estrogen receptor was also confirmed in thymic Hassall's corpuscles, bursal follicle-associated epithelial cells, and the bursal interfollicular epithelium. Our results indicate that estrogen affects the differentiation of thymic and bursal lymphocytes, suggesting that the underlying role for estrogen in immune function. PMID:23132558

  20. A Circulating MicroRNA Profile Is Associated with Late-Stage Neovascular Age-Related Macular Degeneration

    PubMed Central

    Grassmann, Felix; Schoenberger, Peter G. A.; Brandl, Caroline; Schick, Tina; Hasler, Daniele; Meister, Gunter; Fleckenstein, Monika; Lindner, Moritz; Helbig, Horst; Fauser, Sascha; Weber, Bernhard H. F.

    2014-01-01

    Age-related macular degeneration (AMD) is the leading cause of severe vision impairment in Western populations over 55 years. A growing number of gene variants have been identified which are strongly associated with an altered risk to develop AMD. Nevertheless, gene-based biomarkers which could be dysregulated at defined stages of AMD may point toward key processes in disease mechanism and thus may support efforts to design novel treatment regimens for this blinding disorder. Circulating microRNAs (cmiRNAs) which are carried by nanosized exosomes or microvesicles in blood plasma or serum, have been recognized as valuable indicators for various age-related diseases. We therefore aimed to elucidate the role of cmiRNAs in AMD by genome-wide miRNA expression profiling and replication analyses in 147 controls and 129 neovascular AMD patients. We identified three microRNAs differentially secreted in neovascular (NV) AMD (hsa-mir-301-3p, pcorrected = 5.6*10−5, hsa-mir-361-5p, pcorrected = 8.0*10−4 and hsa-mir-424-5p, pcorrected = 9.6*10−3). A combined profile of the three miRNAs revealed an area under the curve (AUC) value of 0.727 and was highly associated with NV AMD (p = 1.2*10−8). To evaluate subtype-specificity, an additional 59 AMD cases with pure unilateral or bilateral geographic atrophy (GA) were analyzed for microRNAs hsa-mir-301-3p, hsa-mir-361-5p, and hsa-mir-424-5p. While we found no significant differences between GA AMD and controls neither individually nor for a combined microRNAs profile, hsa-mir-424-5p levels remained significantly higher in GA AMD when compared to NV (pcorrected<0.005). Pathway enrichment analysis on genes predicted to be regulated by microRNAs hsa-mir-301-3p, hsa-mir-361-5p, and hsa-mir-424-5p, suggests canonical TGFβ, mTOR and related pathways to be involved in NV AMD. In addition, knockdown of hsa-mir-361-5p resulted in increased neovascularization in an in vitro angiogenesis assay. PMID:25203061

  1. The Interaction Between Late-Stage Stellar Mass Loss and the Hot Interstellar Medium in Elliptical Galaxies

    NASA Astrophysics Data System (ADS)

    Parriott, Joel Richard

    Stellar mass loss is thought to be the dominant source of hot gas in elliptical galaxies, but calculations have yet to accurately treat the processes by which this mass loss enters the interstellar medium. The details of this interaction have direct implications for resolving several important disagreements between X-ray observations and the standard cooling flow model, and we suggest a mechanism for the interaction which could help to mitigate these disagreements. We test this new picture by conducting a series of highly accurate two dimensional numerical hydrodynamic simulations of the complex interaction between the stellar ejecta and the surrounding hot medium. We develop a distributed memory parallel processing version of the original Piecewise Parabolic Method (PPM) serial code using a portable message passing standard (MPI). Performance tests of this code on a Cray T3E and IBM SP2 show it to have a parallel efficiency of 80%-90% at N=32 processors despite its heavy data communication load. The results of our simulations, which sample a representative phase-space of the ambient gas density (n~10-3 cm-3) and the stellar velocity through this ambient medium (σ1D~200 km/s), show a reduction in the heating efficiency compared to the standard model. In this model, there is a 100% efficient and instantaneous thermalization of the stellar mass loss, to the local velocity dispersion temperature, by the contact discontinuity and bow shock established as the hot gas flows past the stellar outflow. We find that these shocks are not the primary heating mechanism; rather, the ambient flow imparts momentum to the stellar ejecta to push it into a wake behind the star, which is where the bulk of the heating is done by large amplitude Kelvin-Helmholtz instabilities in the flow that mix the cold (T<105 K) stellar material with the hotter (T=3×106 K) ambient gas. Although this mixing is sufficient to eventually heat and merge all of the ejecta in the adiabatic case, the addition of radiative cooling losses help to keep 10%-20% of stellar ejecta below 105 K until it exits the grid 25 parsecs downstream from the star. All of the heating that takes place in the cooling case does so within the first 5-10 parsecs of the wake, and so we expect this ~10% cold fraction to continue beyond the extent of our simulation grid. Our results suggest that the detailed study of this interaction could lead to a significant revision of the standard model, if future three-dimensional magnetic-field simulations sampling a more complete parameter space show that even more than 10%-20% of the stellar ejecta remains cold.

  2. Glial alterations from early to late stages in a model of Alzheimer's disease: Evidence of autophagy involvement in Aβ internalization.

    PubMed

    Pomilio, Carlos; Pavia, Patricio; Gorojod, Roxana Mayra; Vinuesa, Angeles; Alaimo, Agustina; Galvan, Veronica; Kotler, Monica Lidia; Beauquis, Juan; Saravia, Flavia

    2016-02-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease without effective therapy. Brain amyloid deposits are classical histopathological hallmarks that generate an inflammatory reaction affecting neuronal and glial function. The identification of early cell responses and of brain areas involved could help to design new successful treatments. Hence, we studied early alterations of hippocampal glia and their progression during the neuropathology in PDAPP-J20 transgenic mice, AD model, at 3, 9, and 15 months (m) of age. At 3 m, before deposits formation, microglial Iba1+ cells from transgenic mice already exhibited signs of activation and larger soma size in the hilus, alterations appearing later on stratum radiatum. Iba1 immunohistochemistry revealed increased cell density and immunoreactive area in PDAPP mice from 9 m onward selectively in the hilus, in coincidence with prominent amyloid Congo red + deposition. At pre-plaque stages, GFAP+ astroglia showed density alterations while, at an advanced age, the presence of deposits was associated with important glial volume changes and apparently being intimately involved in amyloid degradation. Astrocytes around plaques were strongly labeled for LC3 until 15 m in Tg mice, suggestive of increased autophagic flux. Moreover, β-Amyloid fibrils internalization by astrocytes in in vitro conditions was dependent on autophagy. Co-localization of Iba1 with ubiquitin or p62 was exclusively found in microglia contacting deposits from 9 m onward, suggesting torpid autophagy. Our work characterizes glial changes at early stages of the disease in PDAPP-J20 mice, focusing on the hilus as an especially susceptible hippocampal subfield, and provides evidence that glial autophagy could play a role in amyloid processing at advanced stages. PMID:26235241

  3. The role of the amygdala during emotional processing in Huntington's disease: From pre-manifest to late stage disease

    PubMed Central

    Mason, Sarah L.; Zhang, Jiaxiang; Begeti, Faye; Guzman, Natalie Valle; Lazar, Alpar S.; Rowe, James B.; Barker, Roger A.; Hampshire, Adam

    2015-01-01

    Background Deficits in emotional processing can be detected in the pre-manifest stage of Huntington's disease and negative emotion recognition has been identified as a predictor of clinical diagnosis. The underlying neuropathological correlates of such deficits are typically established using correlative structural MRI studies. This approach does not take into consideration the impact of disruption to the complex interactions between multiple brain circuits on emotional processing. Therefore, exploration of the neural substrates of emotional processing in pre-manifest HD using fMRI connectivity analysis may be a useful way of evaluating the way brain regions interrelate in the period prior to diagnosis. Methods We investigated the impact of predicted time to disease onset on brain activation when participants were exposed to pictures of faces with angry and neutral expressions, in 20 pre-manifest HD gene carriers and 23 healthy controls. On the basis of the results of this initial study went on to look at amygdala dependent cognitive performance in 79 Huntington's disease patients from a cross-section of disease stages (pre-manifest to late disease) and 26 healthy controls, using a validated theory of mind task: “the Reading the Mind in the Eyes Test” which has been previously been shown to be amygdala dependent. Results Psychophysiological interaction analysis identified reduced connectivity between the left amygdala and right fusiform facial area in pre-manifest HD gene carriers compared to controls when viewing angry compared to neutral faces. Change in PPI connectivity scores correlated with predicted time to disease onset (r=0.45, p<0.05). Furthermore, performance on the “Reading the Mind in the Eyes Test” correlated negatively with proximity to disease onset and became progressively worse with each stage of disease. Conclusion Abnormalities in the neural networks underlying social cognition and emotional processing can be detected prior to clinical diagnosis in Huntington's disease. Connectivity between the amygdala and other brain regions is impacted by the disease process in pre-manifest HD and may therefore be a useful way of identifying participants who are approaching a clinical diagnosis. Furthermore, the “Reading the Mind in the Eyes Test” is a surrogate measure of amygdala function that is clinically useful across the entire cross-section of disease stages in HD. PMID:25700742

  4. ERCC1 protein as a guide for individualized therapy of late-stage advanced non-small cell lung cancer

    PubMed Central

    GAO, ZHIQIANG; HAN, BAOHUI; SHEN, JIE; GU, AIQIN; QI, DAJIANG; HUANG, JINSU; SHI, CHUNLEI; XIONG, LIWEN; ZHAO, YIZHUO; JIANG, LIYAN; WANG, HUIMIN; CHEN, YURONG

    2011-01-01

    Excision repair cross-complementation group 1 (ERCC1) protein has been associated with cisplatin resistance. The objective of this study was to investigate the correlation between ERCC1 protein levels and the therapeutic effect of individualized therapy in advanced non-small cell lung cancer (NSCLC). A total of 190 advanced NSCLC patients were included in this study. Patients were randomized into either the individualized therapy group or the standard therapy group at a ratio of 2:1. Patients in the standard therapy group were treated with either gemcitabine plus cisplatin or vinorelbine plus cisplatin. The expression of ERCC1 protein in lung cancer tissues of patients from the individualized therapy group was detected with immunohistochemistry. Patients with low ERCC1 levels received either gemcitabine plus cisplatin or vinorelbine plus cisplatin, and patients with high levels received gemcitabine plus vinorelbine. The main outcome assessments were response rate (RR), overall survival (OS) and time to progression (TTP). Follow-up data were recorded until September 30, 2010. RR, 1-year survival rate and TTP were not statistically significant. The median survival time was 10.10 months in the standard therapy group (95% CI 8.48–11.92) and 13.59 months in the individualized therapy group (95% CI 11.86–14.74). The difference in median survival time was significantly different between these groups (P=0.036). The median survival time was longer in the individualized group compared to the standard therapy group. ERCC1 protein expression in advanced NSCLC patients, however, was not significantly correlated with RR, OS and TTP in the individualized therapy group. Therefore, this study suggests that ERCC1 protein levels should be assessed in combination with additional biomarkers to determine an optimal index for individualized therapy in advanced NSCLC patients. PMID:22977580

  5. Targeting activated integrin αvβ3 with patient-derived antibodies impacts late-stage multiorgan metastasis

    PubMed Central

    Staflin, Karin; Krueger, Joseph S; Hachmann, Janna; Forsyth, Jane S; Lorger, Mihaela; Steiniger, Sebastian CJ; Mee, Jenny; Pop, Cristina; Salvesen, Guy S; Janda, Kim D; Felding-Habermann, Brunhilde

    2016-01-01

    Advanced metastatic disease is difficult to manage and specific therapeutic targets are rare. We showed earlier that metastatic breast cancer cells use the activated conformer of adhesion receptor integrin αvβ3 for dissemination. We now investigated if targeting this form of the receptor can impact advanced metastatic disease, and we analyzed the mechanisms involved. Treatment of advanced multi-organ metastasis in SCID mice with patient-derived scFv antibodies specific for activated integrin αvβ3 caused stagnation and regression of metastatic growth. The antibodies specifically localized to tumor lesions in vivo and inhibited αvβ3 ligand binding at nanomolar levels in vitro. At the cellular level, the scFs associated rapidly with high affinity αvβ3 and dissociated extremely slowly. Thus, the scFvs occupy the receptor on metastatic tumor cells for prolonged periods of time, allowing for inhibition of established cell interaction with natural αvβ3 ligands. Potential apoptosis inducing effects of the antibodies through interaction with caspase-3 were studied as potential additional mechanism of treatment response. However, in contrast to a previous concept, neither the RGD-containing ligand mimetic scFvs nor RGD peptides bound or activated caspase-3 at the cellular or molecular level. This indicates that the treatment effects seen in the animal model are primarily due to antibody interference with αvβ3 ligation. Inhibition of advanced metastatic disease by treatment with cancer patient derived single chain antibodies against the activated conformer of integrin αvβ3 identifies this form of the receptor as a suitable target for therapy. PMID:20225083

  6. Targeted disruption of the LAMA3 gene in mice reveals abnormalities in survival and late stage differentiation of epithelial cells.

    PubMed

    Ryan, M C; Lee, K; Miyashita, Y; Carter, W G

    1999-06-14

    Laminin 5 regulates anchorage and motility of epithelial cells through integrins alpha6beta4 and alpha3beta1, respectively. We used targeted disruption of the LAMA3 gene, which encodes the alpha3 subunit of laminin 5 and other isoforms, to examine developmental functions that are regulated by adhesion to the basement membrane (BM). In homozygous null animals, profound epithelial abnormalities were detected that resulted in neonatal lethality, consistent with removal of all alpha3-laminin isoforms from epithelial BMs. Alterations in three different cellular functions were identified. First, using a novel tissue adhesion assay, we found that the mutant BM could not induce stable adhesion by integrin alpha6beta4, consistent with the presence of junctional blisters and abnormal hemidesmosomes. In the absence of laminin 5 function, we were able to detect a new ligand for integrin alpha3beta1 in the epidermal BM, suggesting that basal keratinocytes can utilize integrin alpha3beta1 to interact with an alternative ligand. Second, we identified a survival defect in mutant epithelial cells that could be rescued by exogenous laminin 5, collagen, or an antibody against integrin alpha6beta4, suggesting that signaling through beta1 or beta4 integrins is sufficient for survival. Third, we detected abnormalities in ameloblast differentiation in developing mutant incisors indicating that events downstream of adhesion are affected in mutant animals. These results indicate that laminin 5 has an important role in regulating tissue organization, gene expression, and survival of epithelium. PMID:10366601

  7. Improving Psychological Adjustment among Late-Stage Ovarian Cancer Patients: Examining the Role of Avoidance in Treatment

    ERIC Educational Resources Information Center

    Rost, Ann D.; Wilson, Kelly; Buchanan, Erin; Hildebrandt, Mikaela J.; Mutch, David

    2012-01-01

    Data suggest that individuals dealing with a cancer diagnosis are less likely to suffer from depression, anxiety, and psychological distress when they cope with their condition from a stance of emotional and cognitive acceptance (e.g. Dunkel, et al., 1992; Stanton, et al., 2000). Although traditional CBT often includes some acceptance-oriented…

  8. Deficit in late-stage contingent negative variation provides evidence for disrupted movement preparation in patients with conversion paresis.

    PubMed

    Blakemore, Rebekah L; Hyland, Brian I; Hammond-Tooke, Graeme D; Anson, J Greg

    2015-07-01

    Conversion paresis is the presence of unexplained weakness without detectable neuropathology that is not feigned. To examine the 'abnormal preparation' and 'disrupted execution' hypotheses proposed to explain the movement deficits in conversion paresis, electroencephalographic, electromyographic and kinematic measures were recorded during motor preparation and execution. Six patients with unilateral upper limb conversion weakness, 24 participants feigning weakness and 12 control participants performed a 2-choice precued reaction time task. Precues provided advance information about the responding hand or finger. Patients and feigners demonstrated similar diminished force, longer movement time and extended duration of muscle activity in their symptomatic limb. Patients showed significantly suppressed contingent negative variation (CNV) amplitudes, but only when the symptomatic limb was precued. Despite the similarity in performance measures, this CNV suppression was not seen in feigners. Diminished CNV for symptomatic hand precues may reflect engagement of an inhibitory mechanism suppressing cortical activity related to preparatory processes. PMID:25951783

  9. Ethics of palliative care in late-stage cancer management and end-of-life issues in a depressed economy.

    PubMed

    Chukwuneke, F N

    2015-12-01

    The Hippocratic Oath has often been referred to as the ethical foundation of medical practice with the key restriction "cause no harm" which is also the principle of benevolence in bioethics. In medical profession, the Oath still exemplifies the key virtues of a doctor in its emphasis on the obligations toward the well-being of the individual patient. In management of end-stage cancer in a depressed economy such as Nigeria, we frequently encounter a wide range of ethical issues that arise in the provision of palliative care mostly due to the prevailing economic situation and cultural setting. Since most of these patients came from a lower economic class of the society, with little or no formal education and lived at a subsistence level, they often find it difficult to provide the medications needed. In a poor setting where health inequity is rife, and ignorance and poverty are commonplace, a good understanding of medical ethics with a good model of health care system will contribute to the health professional's decision-making that will be in the best interest of the patients. Physicians must protect the lives of their patients and should never hasten their death. In end-stage cancer management, we have to relieve suffering and pains, promote palliative care, and give psychological support but never abandoning the patient or initiate terminating their life. This presentation is a clinical analysis of the ethical issues regarding the management of end-stage cancer patients in a poor economy with a critical overview of end-of-life issues in African perspective. PMID:26620617

  10. Scoping assessments of ATF impact on late-stage accident progression including molten core-concrete interaction

    NASA Astrophysics Data System (ADS)

    Farmer, M. T.; Leibowitz, L.; Terrani, K. A.; Robb, K. R.

    2014-05-01

    Simple scoping models that can be used to evaluate ATF performance under severe accident conditions have been developed. The methodology provides a fundamental technical basis (a.k.a. metric) based on the thermodynamic boundary for evaluating performance relative to that of traditional Zr-based claddings. The initial focus in this study was on UO2 fuel with the advanced claddings 310 SS, D9, FeCrAl, and SiC. The evaluation considered only energy release with concurrent combustible gas production from fuel-cladding-coolant interactions and, separately, molten core-concrete interactions at high temperatures. Other important phenomenological effects that can influence the rate and extent of cladding decomposition (e.g., eutectic interactions, degradation of other core constituents) were not addressed. For the cladding types addressed, potential combustible gas production under both in-vessel and ex-vessel conditions was similar to that for Zr. However, exothermic energy release from cladding oxidation was substantially less for iron-based alloys (by at least a factor of 4), and modestly less (by ∼20%) for SiC. Data on SiC-clad UO2 fuel performance under severe accident conditions are sparse in the literature; thus, assumptions on the nature of the cladding decomposition process were made in order to perform this initial screening evaluation. Experimental data for this system under severe accident conditions is needed for a proper evaluation and comparison to iron-based claddings.

  11. Biphasic Alteration of the Inhibitory Synapse Scaffold Protein Gephyrin in Early and Late Stages of an Alzheimer Disease Model.

    PubMed

    Kiss, Eva; Gorgas, Karin; Schlicksupp, Andrea; Groß, Dagmar; Kins, Stefan; Kirsch, Joachim; Kuhse, Jochen

    2016-09-01

    The pathogenesis of Alzheimer disease (AD) is thought to begin many years before the diagnosis of dementia. Accumulating evidence indicates the involvement of GABAergic neurotransmission in the physiopathology of AD. However, in comparison to excitatory synapses, the structural and functional alterations of inhibitory synapses in AD are less well characterized. We studied the expression and distribution of proteins specific for inhibitory synapses in hippocampal areas of APPPS1 mice at different ages. Interestingly, by immunoblotting and confocal fluorescence microscopy, we disclosed a robust increase in the expression of gephyrin, an organizer of ligand-gated ion channels at inhibitory synapses in hippocampus CA1 and dentate gyrus of young presymptomatic APPPS1 mice (1 to 3 months) as compared to controls. The postsynaptic γ2-GABA(A)-receptor subunit and the presynaptic vesicular inhibitory amino acid transporter protein showed similar expression patterns. In contrast, adult transgenic animals (12 months) displayed decreased levels of these proteins in comparison to wild type in hippocampus areas devoid of amyloid plaques. Within most plaques, strong gephyrin immunoreactivity was detected, partially colocalizing with vesicular amino acid transporter and GABA(A)-receptor γ2 subunit immunoreactivities. Our results indicate a biphasic alteration in expression of hippocampal inhibitory synapse components in AD. Altered inhibition of neurotransmission might be an early prognostic marker and might even be involved in the pathogenesis of AD. PMID:27423698

  12. The BH3-only protein BIM contributes to late-stage involution in the mouse mammary gland.

    PubMed

    Schuler, F; Baumgartner, F; Klepsch, V; Chamson, M; Müller-Holzner, E; Watson, C J; Oh, S; Hennighausen, L; Tymoszuk, P; Doppler, W; Villunger, A

    2016-01-01

    After cessation of lactation, involution of the mouse mammary gland proceeds in two distinct phases, a reversible and an irreversible one, which leads to the death and removal of alveolar cells. Cell death is preceded by the loss of STAT5 activity, which abrogates cell differentiation and gain of STAT3 activity. Despite early observations implicating BCL2 (B cell lymphoma 2) family proteins in this process, recent evidence suggests that STAT3-controlled cathepsin activity is most critical for cell death at the early stage of involution. Somewhat surprisingly, this cell death associates with but does not depend on the activation of pro-apoptotic effector caspases. However, transgenic overexpression of BCL2, that blocks caspase activation, delays involution while conditional deletion of BclX accelerates this process, suggesting that BCL2 family proteins are needed for the effective execution of involution. Here, we report on the transcriptional induction of multiple pro-apoptotic BCL2 family proteins of the 'BH3-only' subgroup during involution and the rate-limiting role of BIM in this process. Loss of Bim delayed epithelial cell clearance during involution after forced weaning in mice, whereas the absence of related Bmf had minor and loss of Bad or Noxa no impact on this process. Consistent with a contribution of BCL2 family proteins to the second wave of cell death during involution, loss of Bim reduced the number of apoptotic cells in this irreversible phase. Notably, the expression changes observed within the BCL2 family did not depend on STAT3 signalling, in line with its initiating role early in the process, but rather appear to result from relief of repression by STAT5. Our findings support the existence of a signalling circuitry regulating the irreversible phase of involution in mice by engaging BH3-only protein-driven mitochondrial apoptosis. PMID:26045049

  13. microRNA Alterations Driving Acute and Late Stages of Radiation-Induced Fibrosis in a Murine Skin Model

    SciTech Connect

    Simone, Brittany A.; Ly, David; Savage, Jason E.; Hewitt, Stephen M.; Dan, Tu D.; Ylaya, Kris; Shankavaram, Uma; Lim, Meng; Jin, Lianjin; Camphausen, Kevin; Mitchell, James B.; Simone, Nicole L.

    2014-09-01

    Purpose: Although ionizing radiation is critical in treating cancer, radiation-induced fibrosis (RIF) can have a devastating impact on patients' quality of life. The molecular changes leading to radiation-induced fibrosis must be elucidated so that novel treatments can be designed. Methods and Materials: To determine whether microRNAs (miRs) could be responsible for RIF, the fibrotic process was induced in the right hind legs of 9-week old CH3 mice by a single-fraction dose of irradiation to 35 Gy, and the left leg served as an unirradiated control. Fibrosis was quantified by measurements of leg length compared with control leg length. By 120 days after irradiation, the irradiated legs were 20% (P=.013) shorter on average than were the control legs. Results: Tissue analysis was done on muscle, skin, and subcutaneous tissue from irradiated and control legs. Fibrosis was noted on both gross and histologic examination by use of a pentachrome stain. Microarrays were performed at various times after irradiation, including 7 days, 14 days, 50 days, 90 days, and 120 days after irradiation. miR-15a, miR-21, miR-30a, and miR-34a were the miRs with the most significant alteration by array with miR-34a, proving most significant on confirmation by reverse transcriptase polymerase chain reaction, c-Met, a known effector of fibrosis and downstream molecule of miR-34a, was evaluated by use of 2 cell lines: HCT116 and 1522. The cell lines were exposed to various stressors to induce miR changes, specifically ionizing radiation. Additionally, in vitro transfections with pre-miRs and anti-miRs confirmed the relationship of miR-34a and c-Met. Conclusions: Our data demonstrate an inverse relationship with miR-34a and c-Met; the upregulation of miR-34a in RIF causes inhibition of c-Met production. miRs may play a role in RIF; in particular, miR-34a should be investigated as a potential target to prevent or treat this devastating side effect of irradiation.

  14. Late-stage stretching and subsidence rates in the Danakil Depression, evidenced from borehole records and seismic reflection data

    NASA Astrophysics Data System (ADS)

    Booth, Adam; Bastow, Ian; Magee, Craig; Keir, Derek; Corti, Giacomo; Jackson, Chris; Wilkinson, Jason

    2016-04-01

    The Ethiopian and Afar Rift systems provide a globally unique opportunity to study the incipient transition from continental rifting to sea-floor spreading. A consensus has emerged that a considerable proportion of plate extension in Ethiopia is accommodated by dyke intrusion, with smaller contributions from crustal thinning. However, observations of thinned crust and a pulse in Quaternary-Recent basaltic volcanism within Ethiopia's Danakil Depression have been cited (Bastow and Keir, 2011) as evidence that localised plate stretching may mark the final stages of continent-ocean transition. We explore this hypothesis using an archive of five 2-D seismic reflection profiles, each between 7-10 km in length, and ˜120 borehole records distributed over an area of 225 km2. From depth and age relationships of key marker horizons, we also suggest local subsidence and extension rates. The borehole archive reveals extensive evaporite sequences deposited in and around an asymmetric basin, bounded to the west by a network of east-dipping normal faults. West of the basin, the maximum observed thickness of evaporites is 150 m, beneath which are deposits of clastic sediment, but a sequence of evaporites at least 900 m thick is observed at the basin centre. The sedimentary architecture of these sequences suggests deposition in a shallow salt-pan environment, with seasonal - potentially diurnal - freshening of the brine supply (Warren, 2012). Isotopic analysis of reef carbonates in the basin flank dates the last marine incursion into the Danakil Depression at 24-230ka (Lalou et al., 1970; Bonatti et al., 1971; Bannert et al., 1971), therefore the evaporite sequence must be younger than this. A key marker horizon within the evaporites is the potash-bearing Houston Formation, also distinct in borehole records given its high porosity (25-40%) and radioactivity (50-250 API units). The elevation of the Houston Formation is ˜500 m deeper in the centre of the basin than on the flank. This depth change corresponds to a plausible vertical subsidence rate of between 2-20 mma‑1 and, assuming a 60° fault dip, a horizontal extension rate of 1-12 mma‑1 during the deposition of the Houston Formation, consistent with recent geodetic constraints offered by Ar Rajehi et al. (2010). The borehole archive shows no evidence of significant magmatism anywhere in the survey area, and the characteristic reflectivity of igneous bodies is absent in the seismic data. Extension of this basin is, therefore, not obviously explained by dyke intrusion. We consider that the ˜500 m change in elevation of the Houston Formation is instead diagnostic of rapid stretching, possibly indicating a late period of non-magmatic extension in the transition to sea-floor spreading in the Danakil Depression.

  15. Late-stage exhumation of metamorphic core complexes and landscape development during orogenic collapse of the North American Cordillera

    NASA Astrophysics Data System (ADS)

    Tokombayev, Askhat

    Renewable portfolio standards prescribe for penetration of high amounts of renewable energy sources (RES) that may change the structure of existing power systems. The load growth and changes in power flow caused by RES integration may result in requirements of new available transmission capabilities and upgrades of existing transmission paths. Construction difficulties of new transmission lines can become a problem in certain locations. The increase of transmission line thermal ratings by reconductoring using High Temperature Low Sag (HTLS) conductors is a comparatively new technology introduced to transmission expansion. A special design permits HTLS conductors to operate at high temperatures (e.g., 200°C), thereby allowing passage of higher current. The higher temperature capability increases the steady state and emergency thermal ratings of the transmission line. The main disadvantage of HTLS technology is high cost. The high cost may place special emphasis on a thorough analysis of cost to benefit of HTLS technology implementation. Increased transmission losses in HTLS conductors due to higher current may be a disadvantage that can reduce the attractiveness of this method. Studies described in this thesis evaluate the expenditures for transmission line reconductoring using HTLS and the consequent benefits obtained from the potential decrease in operating cost for thermally limited transmission systems. Studies performed consider the load growth and penetration of distributed renewable energy sources according to the renewable portfolio standards for power systems. An evaluation of payback period is suggested to assess the cost to benefit ratio of HTLS upgrades. The thesis also considers the probabilistic nature of transmission upgrades. The well-known Chebyshev inequality is discussed with an application to transmission upgrades. The Chebyshev inequality is proposed to calculate minimum payback period obtained from the upgrades of certain transmission lines. The cost to benefit evaluation of HTLS upgrades is performed using a 225 bus equivalent of the 2012 summer peak Arizona portion of the Western Electricity Coordinating Council (WECC).

  16. The early- and late stages in phenotypic modulation of vascular smooth muscle cells: differential roles for lysophosphatidic acid.

    PubMed

    Guo, Huazhang; Makarova, Natalia; Cheng, Yunhui; E, Shuyu; Ji, Rui-Rui; Zhang, Chunxiang; Farrar, Patricia; Tigyi, Gabor

    2008-09-01

    Lysophosphatidic acid (LPA) has been implicated as causative in phenotypic modulation (PM) of cultured vascular smooth muscle cells (VSMC) in their transition to the dedifferentiated phenotype. We evaluated the contribution of the three major LPA receptors, LPA1 and LPA2 GPCR and PPARgamma, on PM of VSMC. Expression of differentiated VSMC-specific marker genes, including smooth muscle alpha-actin, smooth muscle myosin heavy chain, calponin, SM-22alpha, and h-caldesmon, was measured by quantitative real-time PCR in VSMC cultures and aortic rings kept in serum-free chemically defined medium or serum- or LPA-containing medium using wild-type C57BL/6, LPA1, LPA2, and LPA1&2 receptor knockout mice. Within hours after cells were deprived of physiological cues, the expression of VSMC marker genes, regardless of genotype, rapidly decreased. This early PM was neither prevented by IGF-I, inhibitors of p38, ERK1/2, or PPARgamma nor significantly accelerated by LPA or serum. To elucidate the mechanism of PM in vivo, carotid artery ligation with/without replacement of blood with Krebs solution was used to evaluate contributions of blood flow and pressure. Early PM in the common carotid was induced by depressurization regardless of the presence/absence of blood, but eliminating blood flow while maintaining blood pressure or after sham surgery elicited no early PM. The present results indicate that LPA, serum, dissociation of VSMC, IGF-I, p38, ERK1/2, LPA1, and LPA2 are not causative factors of early PM of VSMC. Tensile stress generated by blood pressure may be the fundamental signal maintaining the fully differentiated phenotype of VSMC. PMID:18602022

  17. Initial receptor-ligand interactions modulate gene expression and phagosomal properties during both early and late stages of phagocytosis.

    PubMed

    Hoffmann, Eik; Marion, Sabrina; Mishra, Bibhuti Bhusan; John, Mathias; Kratzke, Ramona; Ahmad, Syed Furquan; Holzer, Daniela; Anand, Paras Kumar; Weiss, Dieter G; Griffiths, Gareth; Kuznetsov, Sergei A

    2010-09-01

    The receptors engaged during recognition and phagocytic uptake of microorganisms and particles influence signaling events and diverse subcellular responses that occur during phagosome formation and maturation. However, pathogens generally have multiple ligands on their surface, making it difficult to dissect the roles of individual receptors during phagocytosis. Moreover, it remains elusive to which extent receptor-ligand interactions and early binding events define the subsequent intracellular fate of phagosomes. Here, we used latex beads coupled to single ligands, focusing on immunoglobulin G, mannan, bacterial lipopolysaccharides and avidin, and monitored: (1) phagocytic uptake rates, (2) fusion of phagosomes with lysosomal compartments, (3) the gene expression profile during phagocytosis, (4) the protein composition of mature phagosomes and (5) time-dependent dynamics of protein association with phagosomes in J774.A1 mouse macrophages. The differently coated latex beads were internalized at different rates and exhibited different kinetics of phagolysosomal fusion events dependent on their specific ligand. Furthermore, less than 60% of identified phagosomal proteins and only 10-15% of changes in gene expression were common to all investigated ligands. These findings demonstrate that each single ligand induced a distinct pattern of genes and a different protein composition of phagosomes. Taken together, our data argue that phagocytic receptor-specific programs of signaling events direct phagosomes to different physiological states and support the existence of a specific receptor-ligand 'signature' during the whole process of phagocytosis. PMID:20579766

  18. Paragenetic link between organic matter and late-stage ore deposition in the Sweetwater mine, Viburnum Trend, southeast Missouri

    SciTech Connect

    Niewendorp, C.A. ); Clendenin, C.W.

    1993-03-01

    At the Sweetwater mine bitumen exudes from mine walls as a tacky liquid and is present as spherical blebs in vugs throughout the Bonneterre Formation. Bitumen blebs occur as overgrowths on older mineral phases and are frequently over-grown by late vug-filling sulfides. Slickensided bitumen interlayered with deformed galena occurs in Middle Bonneterre Formation collapse breccias. Anthraxolite, a coal-like bitumen, has also been identified in these collapse breccias and is commonly overgrown by cubic-form galena in vugs. Petrographic examination, verified by SEM analysis, reveals inclusions of dendritic-form galena intimately intergrown in such anthraxolite samples; pyrite and chalcopyrite also occur as inclusions. The presence of sulfide inclusions in anthraxolite establishes a direct paragenetic link between organic matter and ore deposition. Generation of bituminous material appears to correspond to a major period of solution-induced brecciation during main-stage mineralization. Observations indicate that precipitation of dendritic-form galena in anthraxolite coincides with subsequent deposition of cubic-form galena. Such a paragenetic link supports the proposal that nonbiologic sulfate reduction by organic matter has occurred and is a precipitation mechanism for sulfide ores in the Viburnum Trend.

  19. Foscarnet, zidovudine and dolutegravir combination efficacy and tolerability for late stage HIV salvage therapy: A case-series experience.

    PubMed

    Delory, Tristan; Papot, Emmanuelle; Rioux, Christophe; Charpentier, Charlotte; Auge-Courtoi, Claire; Michard, Florence; Peytavin, Gilles; Descamps, Diane; Matheron, Sophie; Yazdanpanah, Yazdan

    2016-07-01

    Salvage therapy including foscarnet (PFA), zidovudine (ZDV) and an optimized background ART (OBT) has been shown to be effective in patients with advanced HIV infection, and no therapeutic options. Dolutegravir (DTG) may offer a more active combination. Objective was to describe efficacy and tolerability of PFA-ZDV-DTG containing regimen. In our cohort, we identified patients who: (i) had plasma HIV-1 RNA load (pVL) >50 c/ml (>100 for HIV-2) on combination ART (cART); (ii) had at least 1 PI/r, 1 NRTI, 1 NNRTI (for HIV-1), and at least 1 raltegravir resistance mutations; (iii) were naive to DTG; and (iv) initiated on a PFA-ZDV-DTG containing-regimen with 48 weeks (W48) of follow-up. Out of 5 patients, 2 were infected with HIV-2. At PFA-ZDV-DTG initiation, CD4 cell count was (/mm(3) ) of 64, 40, 10, in HIV-1, and 37, 199, in HIV-2 infected patients; and pVL (log10 c/ml) of 4.8, 5.1, 4.4, in HIV-1, and 3.6, 4.2, in HIV-2 infected patients, respectively. Median OBT genotypic sensitivity score was 1.5 [1-2]. PFA was discontinued in one patient, due to an acute renal failure. At W48, one HIV-1 infected patient had a pVL <50 c/ml and two <200 c/ml; the two HIV-2 infected patients had pVL >100 c/ml. No lack of treatment adherence was observed. In treatment experienced HIV-infected patients, failing cART and without other therapeutic options, a PFA-ZDV-DTG combination therapy could be effective. Renal adverse events should be monitored. J. Med. Virol. 88:1204-1210, 2016. © 2015 Wiley Periodicals, Inc. PMID:26636432

  20. The BH3-only protein BIM contributes to late-stage involution in the mouse mammary gland

    PubMed Central

    Schuler, F; Baumgartner, F; Klepsch, V; Chamson, M; Müller-Holzner, E; Watson, C J; Oh, S; Hennighausen, L; Tymoszuk, P; Doppler, W; Villunger, A

    2016-01-01

    After cessation of lactation, involution of the mouse mammary gland proceeds in two distinct phases, a reversible and an irreversible one, which leads to the death and removal of alveolar cells. Cell death is preceded by the loss of STAT5 activity, which abrogates cell differentiation and gain of STAT3 activity. Despite early observations implicating BCL2 (B cell lymphoma 2) family proteins in this process, recent evidence suggests that STAT3-controlled cathepsin activity is most critical for cell death at the early stage of involution. Somewhat surprisingly, this cell death associates with but does not depend on the activation of pro-apoptotic effector caspases. However, transgenic overexpression of BCL2, that blocks caspase activation, delays involution while conditional deletion of BclX accelerates this process, suggesting that BCL2 family proteins are needed for the effective execution of involution. Here, we report on the transcriptional induction of multiple pro-apoptotic BCL2 family proteins of the ‘BH3-only' subgroup during involution and the rate-limiting role of BIM in this process. Loss of Bim delayed epithelial cell clearance during involution after forced weaning in mice, whereas the absence of related Bmf had minor and loss of Bad or Noxa no impact on this process. Consistent with a contribution of BCL2 family proteins to the second wave of cell death during involution, loss of Bim reduced the number of apoptotic cells in this irreversible phase. Notably, the expression changes observed within the BCL2 family did not depend on STAT3 signalling, in line with its initiating role early in the process, but rather appear to result from relief of repression by STAT5. Our findings support the existence of a signalling circuitry regulating the irreversible phase of involution in mice by engaging BH3-only protein-driven mitochondrial apoptosis. PMID:26045049

  1. A Novel Sperm-Delivered Toxin Causes Late-Stage Embryo Lethality and Transmission Ratio Distortion in C. elegans

    PubMed Central

    Seidel, Hannah S.; Ailion, Michael; Li, Jialing; van Oudenaarden, Alexander; Rockman, Matthew V.; Kruglyak, Leonid

    2011-01-01

    The evolutionary fate of an allele ordinarily depends on its contribution to host fitness. Occasionally, however, genetic elements arise that are able to gain a transmission advantage while simultaneously imposing a fitness cost on their hosts. We previously discovered one such element in C. elegans that gains a transmission advantage through a combination of paternal-effect killing and zygotic self-rescue. Here we demonstrate that this element is composed of a sperm-delivered toxin, peel-1, and an embryo-expressed antidote, zeel-1. peel-1 and zeel-1 are located adjacent to one another in the genome and co-occur in an insertion/deletion polymorphism. peel-1 encodes a novel four-pass transmembrane protein that is expressed in sperm and delivered to the embryo via specialized, sperm-specific vesicles. In the absence of zeel-1, sperm-delivered PEEL-1 causes lethal defects in muscle and epidermal tissue at the 2-fold stage of embryogenesis. zeel-1 is expressed transiently in the embryo and encodes a novel six-pass transmembrane domain fused to a domain with sequence similarity to zyg-11, a substrate-recognition subunit of an E3 ubiquitin ligase. zeel-1 appears to have arisen recently, during an expansion of the zyg-11 family, and the transmembrane domain of zeel-1 is required and partially sufficient for antidote activity. Although PEEL-1 and ZEEL-1 normally function in embryos, these proteins can act at other stages as well. When expressed ectopically in adults, PEEL-1 kills a variety of cell types, and ectopic expression of ZEEL-1 rescues these effects. Our results demonstrate that the tight physical linkage between two novel transmembrane proteins has facilitated their co-evolution into an element capable of promoting its own transmission to the detriment of organisms carrying it. PMID:21814493

  2. Adaptation of Trypanosoma rhodesiense to hypohaptoglobinaemic serum requires transcription of the APOL1 resistance gene in a RNA polymerase I locus.

    PubMed

    Lecordier, Laurence; Uzureau, Pierrick; Tebabi, Patricia; Brauner, Jonathan; Benghiat, Fleur Samantha; Vanhollebeke, Benoit; Pays, Etienne

    2015-08-01

    Human apolipoprotein L1 (APOL1) kills African trypanosomes except Trypanosoma rhodesiense and Trypanosoma gambiense, the parasites causing sleeping sickness. APOL1 uptake into trypanosomes is favoured by its association with the haptoglobin-related protein-haemoglobin complex, which binds to the parasite surface receptor for haptoglobin-haemoglobin. As haptoglobin-haemoglobin can saturate the receptor, APOL1 uptake is increased in haptoglobin-poor (hypohaptoglobinaemic) serum (HyHS). While T. rhodesiense resists APOL1 by RNA polymerase I (pol-I)-mediated expression of the serum resistance-associated (SRA) protein, T. gambiense resists by pol-II-mediated expression of the T. gambiense-specific glycoprotein (TgsGP). Moreover, in T. gambiense resistance to HyHS is linked to haptoglobin-haemoglobin receptor inactivation by mutation. We report that unlike T. gambiense, T. rhodesiense possesses a functional haptoglobin-haemoglobin receptor, and that like T. gambiense experimentally provided with active receptor, this parasite is killed in HyHS because of receptor-mediated APOL1 uptake. However, T. rhodesiense could adapt to low haptoglobin by increasing transcription of SRA. When assayed in Trypanosoma brucei, resistance to HyHS occurred with pol-I-, but not with pol-II-mediated SRA expression. Similarly, T. gambiense provided with active receptor acquired resistance to HyHS only when TgsGP was moved to a pol-I locus. Thus, transcription by pol-I favours adaptive gene regulation, explaining the presence of SRA in a pol-I locus. PMID:25899052

  3. Matriptase regulates proliferation and early, but not terminal, differentiation of human keratinocytes

    PubMed Central

    Chen, Ya-Wen; Wang, Jehng-Kang; Chou, Fen-Pai; Wu, Bai-Yao; Hsiao, Hui-Chung; Chiu, Han; Xu, Zhonghong; Baksh, Adrienne NH; Shi, Galen; Kaul, Malvika; Barndt, Robert; Shanmugam, Victoria K.; Johnson, Michael D.; Lin, Chen-Yong

    2013-01-01

    Genetic defects in matriptase are linked to two congenital ichthyosis, autosomal recessive ichthyosis with hypotrichosis (ARIH, OMIM 610765) and, ichthyosis, follicular atrophoderma, hypotrichosis, and hypohidrosis (IFAH, OMIM602400). Mouse models with matriptase deficiency indicate an involvement of matriptase in suprabasal keratinocytes in the maintenance of the epidermal barrier. In contrast to what has been reported for mouse skin, we show that in human skin, matriptase is primarily expressed in the basal and spinous keratinocytes, but not in the more differentiated keratinocytes of the granular layer. In addition, matriptase zymogen activation was predominantly detected in the basal cells. Furthermore, using skin organotypic cultures as a model system to monitor the course of human epidermal differentiation, we found elevated matriptase zymogen activation during early stages of epidermal differentiation, coupled with a loss of matriptase expression in the late stages of this process. We also show here that matriptase deficiency in HaCaT cells modestly reduces cell proliferation and temporally affects calcium-induced expression of differentiation markers. These collective data suggests that, unlike mouse matriptase, human matriptase may be involved in regulation of keratinocyte growth and early differentiation, rather than terminal differentiation, providing mechanistic insights for the pathology of the two congenital ichthyoses, ARIH and IFAH. PMID:23900022

  4. Th1/Th17 Plasticity Is a Marker of Advanced β Cell Autoimmunity and Impaired Glucose Tolerance in Humans

    PubMed Central

    Reinert-Hartwall, Linnea; Honkanen, Jarno; Salo, Harri M.; Nieminen, Janne K.; Luopajärvi, Kristiina; Härkönen, Taina; Veijola, Riitta; Simell, Olli; Ilonen, Jorma; Peet, Aleksandr; Tillmann, Vallo; Knip, Mikael; Knip, Mikael; Koski, Katriina; Koski, Matti; Härkönen, Taina; Ryhänen, Samppa; Hämäläinen, Anu-Maaria; Ormisson, Anne; Peet, Aleksandr; Tillmann, Vallo; Ulich, Valentina; Kuzmicheva, Elena; Mokurov, Sergei; Markova, Svetlana; Pylova, Svetlana; Isakova, Marina; Shakurova, Elena; Petrov, Vladimir; Dorshakova, Natalya V.; Karapetyan, Tatyana; Varlamova, Tatyana; Ilonen, Jorma; Kiviniemi, Minna; Alnek, Kristi; Janson, Helis; Uibo, Raivo; Salum, Tiit; von Mutius, Erika; Weber, Juliane; Ahlfors, Helena; Kallionpää, Henna; Laajala, Essi; Lahesmaa, Riitta; Lähdesmäki, Harri; Moulder, Robert; Nieminen, Janne; Ruohtula, Terhi; Vaarala, Outi; Honkanen, Hanna; Hyöty, Heikki; Kondrashova, Anita; Oikarinen, Sami; Harmsen, Hermie J. M.; De Goffau, Marcus C.; Welling, Gjalt; Alahuhta, Kirsi; Virtanen, Suvi M.

    2015-01-01

    Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late stage of preclinical diabetes in children with β cell autoimmunity and impaired glucose tolerance, but not in children with early β cell autoimmunity. We found an increased ratio of IFN-γ/IL-17 expression in Th17 cells in children with advanced β cell autoimmunity, which correlated with HbA1c and plasma glucose concentrations in an oral glucose tolerance test, and thus impaired β cell function. Low expression of Helios was seen in Th17 cells, suggesting that Th1/Th17 cells are not converted thymus-derived regulatory T cells. Our results suggest that the development of Th1/Th17 plasticity may serve as a biomarker of disease progression from β cell autoantibody positivity to type 1 diabetes. These data in human type 1 diabetes emphasize the role of Th1/Th17 plasticity as a potential contributor to tissue destruction in autoimmune conditions. PMID:25480564

  5. Neurogranin binds α-synuclein in the human superior temporal cortex and interaction is decreased in Parkinson’s disease

    PubMed Central

    Koob, Andrew O.; Shaked, Gideon M.; Bender, Andreas; Bisquertt, Alejandro; Rockenstein, Edward; Masliah, Eliezer

    2016-01-01

    Neurogranin is a calmodulin binding protein that has been implicated in learning and memory, long-term potentiation and synaptic plasticity. Neurons expressing neurogranin in the cortex degenerate in late stages of Parkinson’s disease with widespread α-synuclein pathology. While analyzing neurogranin gene expression levels through rtPCR in brains of mouse models overexpressing human α-synuclein, we found levels were elevated 2.5 times when compared to nontransgenic animals. Immunohistochemistry in the cortex revealed colocalization between α-synuclein and neurogranin in mouse transgenics when compared to control mice. Coimmunoprecipitation studies in the superior temporal cortex in humans confirmed interaction between α-synuclein and neurogranin, and decreased interaction between α-synuclein and neurogranin was noticed in patients diagnosed with Parkinson’s disease when compared to normal control brains. Additionally, phosphorylated neurogranin levels were also decreased in the human superior temporal cortex in patients diagnosed with Parkinson’s disease and patients diagnosed with dementia with Lewy bodies. Here, we show for the first time that neurogranin binds to α-synuclein in the human cortex, and this interaction decreases in Parkinson’s disease along with the phosphorylation of neurogranin, a molecular process thought to be involved in learning and memory. PMID:25446004

  6. Predictivity of dog co-culture model, primary human hepatocytes and HepG2 cells for the detection of hepatotoxic drugs in humans

    SciTech Connect

    Atienzar, Franck A.; Novik, Eric I.; Gerets, Helga H.; Parekh, Amit; Delatour, Claude; Cardenas, Alvaro; MacDonald, James; Yarmush, Martin L.; Dhalluin, Stéphane

    2014-02-15

    Drug Induced Liver Injury (DILI) is a major cause of attrition during early and late stage drug development. Consequently, there is a need to develop better in vitro primary hepatocyte models from different species for predicting hepatotoxicity in both animals and humans early in drug development. Dog is often chosen as the non-rodent species for toxicology studies. Unfortunately, dog in vitro models allowing long term cultures are not available. The objective of the present manuscript is to describe the development of a co-culture dog model for predicting hepatotoxic drugs in humans and to compare the predictivity of the canine model along with primary human hepatocytes and HepG2 cells. After rigorous optimization, the dog co-culture model displayed metabolic capacities that were maintained up to 2 weeks which indicates that such model could be also used for long term metabolism studies. Most of the human hepatotoxic drugs were detected with a sensitivity of approximately 80% (n = 40) for the three cellular models. Nevertheless, the specificity was low approximately 40% for the HepG2 cells and hepatocytes compared to 72.7% for the canine model (n = 11). Furthermore, the dog co-culture model showed a higher superiority for the classification of 5 pairs of close structural analogs with different DILI concerns in comparison to both human cellular models. Finally, the reproducibility of the canine system was also satisfactory with a coefficient of correlation of 75.2% (n = 14). Overall, the present manuscript indicates that the dog co-culture model may represent a relevant tool to perform chronic hepatotoxicity and metabolism studies. - Highlights: • Importance of species differences in drug development. • Relevance of dog co-culture model for metabolism and toxicology studies. • Hepatotoxicity: higher predictivity of dog co-culture vs HepG2 and human hepatocytes.

  7. Reduced graphene oxide-coated hydroxyapatite composites stimulate spontaneous osteogenic differentiation of human mesenchymal stem cells

    NASA Astrophysics Data System (ADS)

    Lee, Jong Ho; Shin, Yong Cheol; Jin, Oh Seong; Kang, Seok Hee; Hwang, Yu-Shik; Park, Jong-Chul; Hong, Suck Won; Han, Dong-Wook

    2015-07-01

    Human mesenchymal stem cells (hMSCs) have great potential as cell sources for bone tissue engineering and regeneration, but the control and induction of their specific differentiation into bone cells remain challenging. Graphene-based nanomaterials are considered attractive candidates for biomedical applications such as scaffolds in tissue engineering, substrates for SC differentiation and components of implantable devices, due to their biocompatible and bioactive properties. Despite the potential biomedical applications of graphene and its derivatives, only limited information is available regarding their osteogenic activity. This study concentrates upon the effects of reduced graphene oxide (rGO)-coated hydroxyapatite (HAp) composites on osteogenic differentiation of hMSCs. The average particle sizes of HAp and rGO were 1270 +/- 476 nm and 438 +/- 180 nm, respectively. When coated on HAp particulates, rGO synergistically enhanced spontaneous osteogenic differentiation of hMSCs, without hampering their proliferation. This result was confirmed by determining alkaline phosphatase activity and mineralization of calcium and phosphate as early and late stage markers of osteogenic differentiation. It is suggested that rGO-coated HAp composites can be effectively utilized as dental and orthopedic bone fillers since these graphene-based particulate materials have potent effects on stimulating the spontaneous differentiation of MSCs and show superior bioactivity and osteoinductive potential.Human mesenchymal stem cells (hMSCs) have great potential as cell sources for bone tissue engineering and regeneration, but the control and induction of their specific differentiation into bone cells remain challenging. Graphene-based nanomaterials are considered attractive candidates for biomedical applications such as scaffolds in tissue engineering, substrates for SC differentiation and components of implantable devices, due to their biocompatible and bioactive properties. Despite

  8. Adenosine Triphosphate stimulates differentiation and mineralization in human osteoblast-like Saos-2 cells.

    PubMed

    Cutarelli, Alessandro; Marini, Mario; Tancredi, Virginia; D'Arcangelo, Giovanna; Murdocca, Michela; Frank, Claudio; Tarantino, Umberto

    2016-05-01

    In the last years adenosine triphosphate (ATP) and subsequent purinergic system activation through P2 receptors were investigated highlighting their pivotal role in bone tissue biology. In osteoblasts ATP can regulate several activities like cell proliferation, cell death, cell differentiation and matrix mineralization. Since controversial results exist, in this study we analyzed the ATP effects on differentiation and mineralization in human osteoblast-like Saos-2 cells. We showed for the first time the altered functional activity of ATP receptors. Despite that, we found that ATP can reduce cell proliferation and stimulate osteogenic differentiation mainly in the early stages of in vitro maturation as evidenced by the enhanced expression of alkaline phosphatase (ALP), Runt-related transcription factor 2 (Runx2) and Osteocalcin (OC) genes and by the increased ALP activity. Moreover, we found that ATP can affect mineralization in a biphasic manner, at low concentrations ATP always increases mineral deposition while at high concentrations it always reduces mineral deposition. In conclusion, we show the osteogenic effect of ATP on both early and late stage activities like differentiation and mineralization, for the first time in human osteoblastic cells. PMID:27189526

  9. Opportunistic pathogen Candida albicans elicits a temporal response in primary human mast cells

    PubMed Central

    Lopes, José Pedro; Stylianou, Marios; Nilsson, Gunnar; Urban, Constantin F.

    2015-01-01

    Immunosuppressed patients are frequently afflicted with severe mycoses caused by opportunistic fungal pathogens. Besides being a commensal, colonizing predominantly skin and mucosal surfaces, Candida albicans is the most common human fungal pathogen. Mast cells are present in tissues prone to fungal colonization being expectedly among the first immune cells to get into contact with C. albicans. However, mast cell-fungus interaction remains a neglected area of study. Here we show that human mast cells mounted specific responses towards C. albicans. Collectively, mast cell responses included the launch of initial, intermediate and late phase components determined by the secretion of granular proteins and cytokines. Initially mast cells reduced fungal viability and occasionally internalized yeasts. C. albicans could evade ingestion by intracellular growth leading to cellular death. Furthermore, secreted factors in the supernatants of infected cells recruited neutrophils, but not monocytes. Late stages were marked by the release of cytokines that are known to be anti-inflammatory suggesting a modulation of initial responses. C. albicans-infected mast cells formed extracellular DNA traps, which ensnared but did not kill the fungus. Our results suggest that mast cells serve as tissue sentinels modulating antifungal immune responses during C. albicans infection. Consequently, these findings open new doors for understanding fungal pathogenicity. PMID:26192381

  10. p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans

    PubMed Central

    Wild, Peter J; Ikenberg, Kristian; Fuchs, Thomas J; Rechsteiner, Markus; Georgiev, Strahil; Fankhauser, Niklaus; Noske, Aurelia; Roessle, Matthias; Caduff, Rosmarie; Dellas, Athanassios; Fink, Daniel; Moch, Holger; Krek, Wilhelm; Frew, Ian J

    2012-01-01

    Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours. PMID:22678923

  11. Retinoic Acid Mediates Visceral-Specific Adipogenic Defects of Human Adipose-Derived Stem Cells.

    PubMed

    Takeda, Kosuke; Sriram, Sandhya; Chan, Xin Hui Derryn; Ong, Wee Kiat; Yeo, Chia Rou; Tan, Betty; Lee, Seung-Ah; Kong, Kien Voon; Hoon, Shawn; Jiang, Hongfeng; Yuen, Jason J; Perumal, Jayakumar; Agrawal, Madhur; Vaz, Candida; So, Jimmy; Shabbir, Asim; Blaner, William S; Olivo, Malini; Han, Weiping; Tanavde, Vivek; Toh, Sue-Anne; Sugii, Shigeki

    2016-05-01

    Increased visceral fat, rather than subcutaneous fat, during the onset of obesity is associated with a higher risk of developing metabolic diseases. The inherent adipogenic properties of human adipose-derived stem cells (ASCs) from visceral depots are compromised compared with those of ASCs from subcutaneous depots, but little is known about the underlying mechanisms. Using ontological analysis of global gene expression studies, we demonstrate that many genes involved in retinoic acid (RA) synthesis or regulated by RA are differentially expressed in human tissues and ASCs from subcutaneous and visceral fat. The endogenous level of RA is higher in visceral ASCs; this is associated with upregulation of the RA synthesis gene through the visceral-specific developmental factor WT1. Excessive RA-mediated activity impedes the adipogenic capability of ASCs at early but not late stages of adipogenesis, which can be reversed by antagonism of RA receptors or knockdown of WT1. Our results reveal the developmental origin of adipocytic properties and the pathophysiological contributions of visceral fat depots. PMID:26936961

  12. Bridging in vitro and in vivo metabolism and transport of faldaprevir in human using a novel cocultured human hepatocyte system, HepatoPac.

    PubMed

    Ramsden, Diane; Tweedie, Donald J; Chan, Tom S; Taub, Mitchell E; Li, Yongmei

    2014-03-01

    An increased appreciation of the importance of transporter and enzyme interplay in drug clearance and a desire to delineate these mechanisms necessitates the utilization of models that contain a full complement of enzymes and transporters at physiologically relevant activities. Additionally, the development of drugs with longer half-lives requires in vitro systems with extended incubation times that allow characterization of metabolic pathways for low-clearance drugs. A recently developed coculture hepatocyte model, HepatoPac, has been applied to meet these challenges. Faldaprevir is a drug in late-stage development for the treatment of hepatitis C. Faldaprevir is a low-clearance drug with the somewhat unique characteristic of being slowly metabolized, producing two abundant hydroxylated metabolites (M2a and M2b) in feces (∼40% of the dose) without exhibiting significant levels of circulating metabolites in humans. The human HepatoPac model was investigated to characterize the metabolism and transport of faldaprevir. In human HepatoPac cultures, M2a and M2b were the predominant metabolites formed, with extents of formation comparable to in vivo. Direct glucuronidation of faldaprevir was shown to be a minor metabolic pathway. HepatoPac studies also demonstrated that faldaprevir is concentrated in liver with active uptake by multiple transporters (including OATP1B1 and Na(+)-dependent transporters). Overall, human HepatoPac cultures provided valuable insights into the metabolism and disposition of faldaprevir in humans and demonstrated the importance of enzyme and transporter interplay in the clearance of the drug. PMID:24366904

  13. Human disease and drug pharmacology, complex as real life.

    PubMed

    Viayna, E; Sola, I; Di Pietro, O; Muñoz-Torrero, D

    2013-01-01

    In the past decades drug discovery practice has escaped from the complexity of the formerly used phenotypic screening in animals to focus on assessing drug effects on isolated protein targets in the search for drugs that exclusively and potently hit one selected target, thought to be critical for a given disease, while not affecting at all any other target to avoid the occurrence of side-effects. However, reality does not conform to these expectations, and, conversely, this approach has been concurrent with increased attrition figures in late-stage clinical trials, precisely due to lack of efficacy and safety. In this context, a network biology perspective of human disease and treatment has burst into the drug discovery scenario to bring it back to the consideration of the complexity of living organisms and particularly of the (patho)physiological environment where protein targets are (mal)functioning and where drugs have to exert their restoring action. Under this perspective, it has been found that usually there is not one but several disease-causing genes and, therefore, not one but several relevant protein targets to be hit, which do not work on isolation but in a highly interconnected manner, and that most known drugs are inherently promiscuous. In this light, the rationale behind the currently prevailing single-target-based drug discovery approach might even seem a Utopia, while, conversely, the notion that the complexity of human disease must be tackled with complex polypharmacological therapeutic interventions constitutes a difficult-to-refuse argument that is spurring the development of multitarget therapies. PMID:23410162

  14. Oncogenic roles of carbonic anhydrase 8 in human osteosarcoma cells.

    PubMed

    Wang, Tze-Kai; Lin, Yu-Ming; Lo, Che-Min; Tang, Chih-Hsin; Teng, Chieh-Lin Jerry; Chao, Wei-Ting; Wu, Min Huan; Liu, Chin-San; Hsieh, Mingli

    2016-06-01

    Carbonic anhydrase 8 (CA8), a member of the carbonic anhydrase family, is one of the three isozymes that do not catalyze the reversible hydration of carbon dioxide due to the lack of one important histidine. In the present study, we observed increased expression of CA8 in more aggressive types of human osteosarcoma (OS) cells and found that CA8 expression is correlated with disease stages, such that more intense expression occurs in the disease late stage. We also demonstrated that overexpression of CA8 in human OS (HOS) cells significantly increased cell proliferation both in vitro and in vivo. Downregulated CA8 sensitized cells to apoptotic stress induced by staurosporine and cisplatin, suggesting a specific role of CA8 to protect cells from stresses. In addition, downregulation of CA8 in HOS cells reduced cell invasion and colony formation ability in soft agar and further decreased matrix metalloproteinase 9 and focal adhesion kinase expression, indicating that CA8 might facilitate cancer cell invasion via the activation of FAK-MMP9 signaling. Interestingly, HOS cells with CA8 knockdown showed a significant decrease in glycolytic activity and cell death under glucose withdrawal, further indicating that CA8 may be involved in regulating aerobic glycolysis and enhancing cell viability. Knockdown of CA8 significantly decreased phosphorylated Akt expression suggesting that the oncogenic role of CA8 may be mediated by the regulation of Akt activation through p-Akt induction. Importantly, the inhibition of glycolysis by 2-deoxyglucose sensitized CA8 HOS-CA8-myc cells to cisplatin treatment under low glucose condition, highlighting a new therapeutic option for OS cancer. PMID:26711783

  15. Reprogramming of human cancer cells to pluripotency for models of cancer progression

    PubMed Central

    Kim, Jungsun; Zaret, Kenneth S

    2015-01-01

    The ability to study live cells as they progress through the stages of cancer provides the opportunity to discover dynamic networks underlying pathology, markers of early stages, and ways to assess therapeutics. Genetically engineered animal models of cancer, where it is possible to study the consequences of temporal-specific induction of oncogenes or deletion of tumor suppressors, have yielded major insights into cancer progression. Yet differences exist between animal and human cancers, such as in markers of progression and response to therapeutics. Thus, there is a need for human cell models of cancer progression. Most human cell models of cancer are based on tumor cell lines and xenografts of primary tumor cells that resemble the advanced tumor state, from which the cells were derived, and thus do not recapitulate disease progression. Yet a subset of cancer types have been reprogrammed to pluripotency or near-pluripotency by blastocyst injection, by somatic cell nuclear transfer and by induced pluripotent stem cell (iPS) technology. The reprogrammed cancer cells show that pluripotency can transiently dominate over the cancer phenotype. Diverse studies show that reprogrammed cancer cells can, in some cases, exhibit early-stage phenotypes reflective of only partial expression of the cancer genome. In one case, reprogrammed human pancreatic cancer cells have been shown to recapitulate stages of cancer progression, from early to late stages, thus providing a model for studying pancreatic cancer development in human cells where previously such could only be discerned from mouse models. We discuss these findings, the challenges in developing such models and their current limitations, and ways that iPS reprogramming may be enhanced to develop human cell models of cancer progression. PMID:25712212

  16. Human See, Human Do.

    ERIC Educational Resources Information Center

    Tomasello, Michael

    1997-01-01

    A human demonstrator showed human children and captive chimpanzees how to drag food or toys closer using a rakelike tool. One side of the rake was less efficient than the other for dragging. Chimps tried to reproduce results rather than methods while children imitated and used the more efficient rake side. Concludes that imitation leads to…

  17. Gene expression in human fungal pathogen Coccidioides immitis changes as arthroconidia differentiate into spherules and mature

    PubMed Central

    2013-01-01

    Background Coccidioides immitis is a dimorphic fungus that causes disease in mammals, including human beings. It grows as a mycelium containing arthroconidia in the soil and in the host arthroconidia differentiates into a unique structure called a spherule. We used a custom open reading frame oligonucleotide microarray to compare the transcriptome of C. immitis mycelia with early (day 2) and late stage (day 8) spherules grown in vitro. All hybridizations were done in quadruplicate and stringent criteria were used to identify significantly differentially expressed genes. Results 22% of C. immitis genes were differentially expressed in either day 2 or day 8 spherules compared to mycelia, and about 12% of genes were differentially expressed comparing the two spherule time points. Oxireductases, including an extracellular superoxide dismutase, were upregulated in spherules and they may be important for defense against oxidative stress. Many signal transduction molecules, including pleckstrin domain proteins, protein kinases and transcription factors were downregulated in day 2 spherules. Several genes involved in sulfur metabolism were downregulated in day 8 spherules compared to day 2 spherules. Transcription of amylase and α (1,3) glucan synthase was upregulated in spherules; these genes have been found to be important for differentiation to yeast in Histoplasma. There were two homologs of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD); transcription of one was up- and the other downregulated. We tested the effect of a 4-HPPD inhibitor, nitisinone, on mycelial and spherule growth and found that it inhibited mycelial but not spherule growth. Conclusions Transcription of many genes was differentially expressed in the process of arthroconidia to spherule conversion and spherule maturation, as would be expected given the magnitude of the morphologic change. The transcription profile of early stage (day 2) spherules was different than late stage (day 8) endosporulating

  18. Expression of HGF and c-Met Proteins in Human Keratoconus Corneas

    PubMed Central

    You, Jingjing; Wen, Li; Roufas, Athena; Hodge, Chris; Sutton, Gerard; Madigan, Michele C.

    2015-01-01

    Keratoconus (KC) is a progressive degenerative inflammatory-related disease of the human cornea leading to decreased visual function. The pathogenesis of KC remains to be understood. Recent genetic studies indicate that gene variants of an inflammation-related molecule, hepatocyte growth factor (HGF), are associated with an increased susceptibility for developing KC. However HGF protein expression in KC has not been explored. In this initial study, we investigated late-stage KC and control corneas for the expression of HGF and its receptor mesenchymal-epithelial transition factor (c-Met/Met). KC buttons (~8 mm diameter) (n = 10) and whole control corneas (n = 6) were fixed in 10% formalin or 2% paraformaldehyde, paraffin embedded and sectioned. Sections were immunolabelled with HGF and c-Met antibodies, visualised using immunofluorescence, and examined with scanning laser confocal microscopy. Semiquantitative grading was used to compare HGF and c-Met immunostaining in KC and control corneas. Overall, KC corneas showed increased HGF and c-Met immunostaining compared to controls. KC corneal epithelium displayed heterogeneous moderate-to-strong immunoreactivity for HGF and c-Met, particularly in the basal epithelium adjacent to the cone area. Taken together with the recent genetic studies, our results further support a possible role for HGF/c-Met in the pathogenesis of KC. PMID:26697215

  19. Structure-function studies of the human immunodeficiency virus type 1 matrix protein, p17.

    PubMed

    Cannon, P M; Matthews, S; Clark, N; Byles, E D; Iourin, O; Hockley, D J; Kingsman, S M; Kingsman, A J

    1997-05-01

    The human immunodeficiency virus type 1 (HIV-1) matrix protein, p17, plays important roles in both the early and late stages of the viral life cycle. Using our previously determined solution structure of p17, we have undertaken a rational mutagenesis program aimed at mapping structure-function relationships within the molecule. Amino acids hypothesized to be important for p17 function were mutated and examined for effect in an infectious proviral clone of HIV-1. In parallel, we analyzed by nuclear magnetic resonance spectroscopy the structure of recombinant p17 protein containing such substitutions. These analyses identified three classes of mutants that were defective in viral replication: (i) proteins containing substitutions at internal residues that grossly distorted the structure of recombinant p17 and prevented viral particle formation, (ii) mutations at putative p17 trimer interfaces that allowed correct folding of recombinant protein but produced virus that was defective in particle assembly, and (iii) substitution of basic residues in helix A that caused some relocation of virus assembly to intracellular locations and produced normally budded virions that were completely noninfectious. PMID:9094619

  20. Synthesis of Eupalinilide E, a Promoter of Human Hematopoietic Stem and Progenitor Cell Expansion.

    PubMed

    Johnson, Trevor C; Chin, Matthew R; Han, Tianxu; Shen, John Paul; Rana, Tariq; Siegel, Dionicio

    2016-05-11

    Improving the ex vivo and in vivo production of hematopoietic stem and progenitor cells (HSPCs) has the potential to address the short supply of these cells that are used in the treatment of various blood diseases and disorders. Eupalinilide E promotes the expansion of human HSPCs and inhibits subsequent differentiation, leading to increased numbers of clinically useful cells. This natural product represents an important tool to uncover new methods to drive expansion while inhibiting differentiation. However, in the process of examining these effects, which occur through a novel mechanism, the natural product was consumed, which limited additional investigation. To provide renewed and improved access to eupalinilide E, a laboratory synthesis has been developed and is reported herein. The synthetic route can access >400 mg in a single batch, employing reactions conducted on useful scales in a single vessel. Key transformations enabling the approach include a diastereoselective borylative enyne cyclization and a late-stage double allylic C-H oxidation as well as adapted Luche reduction and aluminum-mediated epoxidation reactions to maximize the synthetic efficiency. Retesting of the synthetic eupalinilide E confirmed the compound's ability to expand HSPCs and inhibit differentiation. PMID:27096704

  1. Pathway-Specific Engineered Mouse Allograft Models Functionally Recapitulate Human Serous Epithelial Ovarian Cancer

    PubMed Central

    Szabova, Ludmila; Bupp, Sujata; Kamal, Muhaymin; Householder, Deborah B.; Hernandez, Lidia; Schlomer, Jerome J.; Baran, Maureen L.; Yi, Ming; Stephens, Robert M.; Annunziata, Christina M.; Martin, Philip L.; Van Dyke, Terry A.

    2014-01-01

    The high mortality rate from ovarian cancers can be attributed to late-stage diagnosis and lack of effective treatment. Despite enormous effort to develop better targeted therapies, platinum-based chemotherapy still remains the standard of care for ovarian cancer patients, and resistance occurs at a high rate. One of the rate limiting factors for translation of new drug discoveries into clinical treatments has been the lack of suitable preclinical cancer models with high predictive value. We previously generated genetically engineered mouse (GEM) models based on perturbation of Tp53 and Rb with or without Brca1 or Brca2 that develop serous epithelial ovarian cancer (SEOC) closely resembling the human disease on histologic and molecular levels. Here, we describe an adaptation of these GEM models to orthotopic allografts that uniformly develop tumors with short latency and are ideally suited for routine preclinical studies. Ovarian tumors deficient in Brca1 respond to treatment with cisplatin and olaparib, a PARP inhibitor, whereas Brca1-wild type tumors are non-responsive to treatment, recapitulating the relative sensitivities observed in patients. These mouse models provide the opportunity for evaluation of effective therapeutics, including prediction of differential responses in Brca1-wild type and Brca1–deficient tumors and development of relevant biomarkers. PMID:24748377

  2. The Effects of Naproxen on Chondrogenesis of Human Mesenchymal Stem Cells.

    PubMed

    Antoniou, John; Wang, Hong Tian; Hadjab, Insaf; Aldebeyan, Sultan; Alaqeel, Motaz A; Meij, Björn P; Tryfonidou, Marianna A; Mwale, Fackson

    2015-07-01

    Currently, there are no established treatments to prevent, stop, or even retard the degeneration of articular cartilage in osteoarthritis (OA). Biological repair of the degenerating articular cartilage would be preferable to surgery. There is no benign site where autologous chondrocytes can be harvested and used as a cell source for cartilage repair, leaving mesenchymal stem cells (MSCs) as an attractive option. However, MSCs from OA patients have been shown to constitutively express collagen type X (COL-X), a marker of late-stage chondrocyte hypertrophy. We recently found that naproxen (Npx), but not other nonsteroidal anti-inflammatory drugs, can induce collagen type X alpha 1 (COL10A1) gene expression in bone marrow-derived MSCs from healthy and OA donors. In this study, we determined the effect of Npx on COL10A1 expression and investigated the intracellular signaling pathways that mediate such effect in normal human MSCs during chondrogenesis. MSCs were cultured in standard chondrogenic differentiation media supplemented with or without Npx. Our results show that Npx can regulate chondrogenic differentiation by affecting the gene expression of both Indian hedgehog and parathyroid hormone/parathyroid hormone-related protein signaling pathways in a time-dependent manner, suggesting a complex interaction of different signaling pathways during the process. PMID:25873236

  3. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer.

    PubMed

    Bindea, Gabriela; Mlecnik, Bernhard; Tosolini, Marie; Kirilovsky, Amos; Waldner, Maximilian; Obenauf, Anna C; Angell, Helen; Fredriksen, Tessa; Lafontaine, Lucie; Berger, Anne; Bruneval, Patrick; Fridman, Wolf Herman; Becker, Christoph; Pagès, Franck; Speicher, Michael R; Trajanoski, Zlatko; Galon, Jérôme

    2013-10-17

    The complex interactions between tumors and their microenvironment remain to be elucidated. Combining large-scale approaches, we examined the spatio-temporal dynamics of 28 different immune cell types (immunome) infiltrating tumors. We found that the immune infiltrate composition changed at each tumor stage and that particular cells had a major impact on survival. Densities of T follicular helper (Tfh) cells and innate cells increased, whereas most T cell densities decreased along with tumor progression. The number of B cells, which are key players in the core immune network and are associated with prolonged survival, increased at a late stage and showed a dual effect on recurrence and tumor progression. The immune control relevance was demonstrated in three endoscopic orthotopic colon-cancer mouse models. Genomic instability of the chemokine CXCL13 was a mechanism associated with Tfh and B cell infiltration. CXCL13 and IL21 were pivotal factors for the Tfh/B cell axis correlating with survival. This integrative study reveals the immune landscape in human colorectal cancer and the major hallmarks of the microenvironment associated with tumor progression and recurrence. PMID:24138885

  4. Laser immunotherapy: initial results from a human breast cancer pilot trial

    NASA Astrophysics Data System (ADS)

    Hode, Tomas; Guerra, Maria C.; Ferrel, Gabriela L.; Lunn, John A.; Adelsteinsson, Orn; Nordquist, Robert E.; Chen, Wei R.

    2010-02-01

    Laser Immunotherapy is an experimental treatment modality for late-stage, metastatic tumors, which targets solid primary and/or secondary tumors and utilizes an autologous vaccine-like approach to stimulate immune responses. Specifically, laser immunotherapy combines laser-induced in situ tumor devitalization with an immunoadjuvant for local immunostimulation. Here we report the initial results from a human breast cancer pilot trial with laser immunotherapy. Six stage III and IV cancer patients were treated, all of which were considered to be out of all other options, and preliminary data at the three-month examination are presented. The immediate goal of the trial was to determine the patient tolerance and the toxicity of the therapy, the optimal dose for the alteration of the course of the disease, and the reduction of the tumor burden. Each patient was individually evaluated for toxicity tolerance through physical exams and by appropriate supplemental and routine laboratory tests. Observable tumors in patients were followed with physical examination and radiological evaluations. Treatment efficacy was judged by the size and number of local and distant metastases before and after treatment.

  5. Global gene expression profiles induced by phytoestrogens in human breast cancer cells.

    PubMed

    Dip, Ramiro; Lenz, Sarah; Antignac, Jean-Philippe; Le Bizec, Bruno; Gmuender, Hans; Naegeli, Hanspeter

    2008-03-01

    The nutritional intake of phytoestrogens seems to reduce the risk of breast cancer or other neoplastic diseases. However, these epidemiological findings remain controversial because low doses of phytoestrogens, achievable through soy-rich diets, stimulate the proliferation of estrogen-sensitive tumor cells. The question of whether such phytochemicals prevent cancer or rather pose additional health hazards prompted us to examine global gene expression programs induced by a typical soy product. After extraction from soymilk, phytoestrogens were deconjugated and processed through reverse- and normal-phase cartridges. The resulting mixture was used to treat human target cells that represent a common model system for mammary tumorigenesis. Analysis of mRNA on high-density microarrays revealed that soy phytoestrogens induce a genomic fingerprint that is indistinguishable from the transcriptional effects of the endogenous hormone 17beta-estradiol. Highly congruent responses were also observed by comparing the physiologic estradiol with daidzein, coumestrol, enterolactone, or resveratrol, each representing distinct phytoestrogen structures. More diverging transcriptional profiles were generated when an inducible promoter was used to reconstitute the expression of estrogen receptor beta (ERbeta). Therefore, phytoestrogens appear to mitigate estrogenic signaling in the presence of both ER subtypes but, in late-stage cancer cells lacking ERbeta, these phytochemicals contribute to a tumor-promoting transcriptional signature. PMID:18310284

  6. Antiviral properties of palinavir, a potent inhibitor of the human immunodeficiency virus type 1 protease.

    PubMed Central

    Lamarre, D; Croteau, G; Wardrop, E; Bourgon, L; Thibeault, D; Clouette, C; Vaillancourt, M; Cohen, E; Pargellis, C; Yoakim, C; Anderson, P C

    1997-01-01

    Palinavir is a potent inhibitor of the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) proteases. Replication of laboratory strains (HIV-1, HIV-2, and simian immunodeficiency virus) and HIV-1 clinical isolates is inhibited by palinavir with 50% effective concentrations ranging from 0.5 to 30 nM. The average cytotoxic concentration of palinavir (35 microM) in the various target cells indicates a favorable therapeutic index. Potent antiviral activity is retained with increased doses of virus and with clinical isolates resistant to zidovudine (AZT), didanosine (ddI), or nevirapine. Combinations of palinavir with either AZT, ddI, or nevirapine demonstrate synergy or additivity in the inhibition of HIV-1 replication. Palinavir retains anti-HIV-1 activity when administered postinfection until times subsequent to the reverse transcription step. In chronically infected CR-10 cells, palinavir blocks Gag precursor polyprotein processing completely, reducing greater than 99% of infectious particle production. The results indicate that the antiviral activity of palinavir is specific to inhibition of the viral protease and occurs at a late stage in the replicative cycle of HIV-1. On the basis of the potent in vitro activity, low-level cytotoxicity, and other data, palinavir was selected for in-depth preclinical evaluation. PMID:9145853

  7. Erythropoietin critically regulates the terminal maturation of murine and human primitive erythroblasts.

    PubMed

    Malik, Jeffrey; Kim, Ah Ram; Tyre, Kaitlin A; Cherukuri, Anjuli R; Palis, James

    2013-11-01

    Primitive erythroid cells, the first red blood cells produced in the mammalian embryo, are necessary for embryonic survival. Erythropoietin and its receptor EpoR, are absolutely required for survival of late-stage definitive erythroid progenitors in the fetal liver and adult bone marrow. Epo- and Epor-null mice die at E13.5 with a lack of definitive erythrocytes. However, the persistence of circulating primitive erythroblasts raises questions about the role of erythropoietin/EpoR in primitive erythropoiesis. Using Epor-null mice and a novel primitive erythroid 2-step culture we found that erythropoietin is not necessary for specification of primitive erythroid progenitors. However, Epor-null embryos develop a progressive, profound anemia by E12.5 as primitive erythroblasts mature as a synchronous cohort. This anemia results from reduced primitive erythroblast proliferation associated with increased p27 expression, from advanced cellular maturation, and from markedly elevated rates of apoptosis associated with an imbalance in pro- and anti-apoptotic gene expression. Both mouse and human primitive erythroblasts cultured without erythropoietin also undergo accelerated maturation and apoptosis at later stages of maturation. We conclude that erythropoietin plays an evolutionarily conserved role in promoting the proliferation, survival, and appropriate timing of terminal maturation of primitive erythroid precursors. PMID:23894012

  8. The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma.

    PubMed

    Ma, Kai; Cao, Baoping; Guo, Mingzhou

    2016-01-01

    Esophageal cancer is one of the most common malignancies in the world. Squamous cell carcinoma accounts for approximately 90 % of esophageal cancer cases. Genetic and epigenetic changes have been found to accumulate during the development of various cancers, including esophageal squamous carcinoma (ESCC). Tobacco smoking and alcohol consumption are two major risk factors for ESCC, and both tobacco and alcohol were found to induce methylation changes in ESCC. Growing evidence demonstrates that aberrant epigenetic changes play important roles in the multiple-step processes of carcinogenesis and tumor progression. DNA methylation may occur in the key components of cancer-related signaling pathways. Aberrant DNA methylation affects genes involved in cell cycle, DNA damage repair, Wnt, TGF-β, and NF-κB signaling pathways, including P16, MGMT, SFRP2, DACH1, and ZNF382. Certain genes methylated in precursor lesions of the esophagus demonstrate that DNA methylation may serve as esophageal cancer early detection marker, such as methylation of HIN1, TFPI-2, DACH1, and SOX17. CHFR methylation is a late stage event in ESCC and is a sensitive marker for taxanes in human ESCC. FHIT methylation is associated with poor prognosis in ESCC. Aberrant DNA methylation changes may serve as diagnostic, prognostic, and chemo-sensitive markers. Characterization of the DNA methylome in ESCC will help to better understand its mechanisms and develop improved therapies. PMID:27110300

  9. Specialized proresolving mediators enhance human B cell differentiation to antibody secreting cells1

    PubMed Central

    Ramon, Sesquile; Gao, Fei; Serhan, Charles N.; Phipps, Richard P.

    2012-01-01

    The resolution of inflammation is an active and dynamic process critical in maintaining homeostasis. Newly identified lipid mediators have been recognized as key players during the resolution phase. These specialized proresolving mediators (SPM) constitute separate families that include lipoxins, resolvins, protectins and maresins each derived from essential polyunsaturated fatty acids. New results demonstrate that SPM regulate aspects of the immune response, including reduction of neutrophil infiltration, decreased T cell cytokine production and stimulation of macrophage phagocytic activity. The actions of SPM on B lymphocytes remain unknown. Our study shows for the first time that the novel SPM 17-hydroxydosahexaenoic acid (17-HDHA), resolvin D1 (RvD1) and protectin D1 (PD1) are present in the spleen. Interestingly, 17-HDHA, RvD1 but not PD1, strongly increase activated human B cell IgM and IgG production. Furthermore, increased antibody production by 17-HDHA is due to augmented B cell differentiation towards a CD27+CD38+ antibody-secreting cell phenotype. 17-HDHA did not affect proliferation and was non-toxic to cells. Increase of plasma cell differentiation and antibody production supports the involvement of SPM during the late stages of inflammation and pathogen clearance. The present study provides new evidence for SPM activity in the humoral response. These new findings highlight the potential applications of SPM as endogenous and non-toxic adjuvants, and as anti-inflammatory therapeutic molecules. PMID:22711890

  10. Slower evolution of human immunodeficiency virus type 1 quasispecies during progression to AIDS.

    PubMed Central

    Delwart, E L; Pan, H; Sheppard, H W; Wolpert, D; Neumann, A U; Korber, B; Mullins, J I

    1997-01-01

    The evolution of human immunodeficiency virus type 1 (HIV-1) quasispecies at the envelope gene was studied from the time of infection in 11 men who experienced different rates of CD4+ cell count decline and 6 men with unknown dates of infection by using DNA heteroduplex mobility assays. Quasispecies were genetically homogeneous near the time of seroconversion. Subsequently, slower proviral genetic diversification and higher plasma viremia correlated with rapid CD4+ cell count decline. Except for the fastest progressors to AIDS, highly diverse quasispecies developed in all subjects within 3 to 4 years. High quasispecies diversity was then maintained for years until again becoming more homogeneous in a subset of late-stage AIDS patients. Individuals who maintained high CD4+ cell counts showed continuous genetic turnover of their complex proviral quasispecies, while more closely related sets of variants were found in longitudinal samples of severely immunocompromised patients. The limited number of variants that grew out in short-term PBMC cocultures were rare in the uncultured proviral quasispecies of healthy, long-term infected individuals but more common in vivo in patients with low CD4+ cell counts. The slower evolution of HIV-1 observed during rapid progression to AIDS and in advanced patients may reflect ineffective host-mediated selection pressures on replicating quasispecies. PMID:9311829

  11. Knowledge Gaps in Rodent Pancreas Biology: Taking Human Pluripotent Stem Cell-Derived Pancreatic Beta Cells into Our Own Hands

    PubMed Central

    Santosa, Munirah Mohamad; Low, Blaise Su Jun; Pek, Nicole Min Qian; Teo, Adrian Kee Keong

    2016-01-01

    In the field of stem cell biology and diabetes, we and others seek to derive mature and functional human pancreatic β cells for disease modeling and cell replacement therapy. Traditionally, knowledge gathered from rodents is extended to human pancreas developmental biology research involving human pluripotent stem cells (hPSCs). While much has been learnt from rodent pancreas biology in the early steps toward Pdx1+ pancreatic progenitors, much less is known about the transition toward Ngn3+ pancreatic endocrine progenitors. Essentially, the later steps of pancreatic β cell development and maturation remain elusive to date. As a result, the most recent advances in the stem cell and diabetes field have relied upon combinatorial testing of numerous growth factors and chemical compounds in an arbitrary trial-and-error fashion to derive mature and functional human pancreatic β cells from hPSCs. Although this hit-or-miss approach appears to have made some headway in maturing human pancreatic β cells in vitro, its underlying biology is vaguely understood. Therefore, in this mini-review, we discuss some of these late-stage signaling pathways that are involved in human pancreatic β cell differentiation and highlight our current understanding of their relevance in rodent pancreas biology. Our efforts here unravel several novel signaling pathways that can be further studied to shed light on unexplored aspects of rodent pancreas biology. New investigations into these signaling pathways are expected to advance our knowledge in human pancreas developmental biology and to aid in the translation of stem cell biology in the context of diabetes treatments. PMID:26834702

  12. Histopathological Study of the Lungs of Mice Receiving Human Secretory IgA and Challenged with Mycobacterium tuberculosis

    PubMed Central

    ALVAREZ, Nadine; INFANTE, Juan Francisco; BORRERO, Reinier; MATA, Dulce; PAYAN, JORGE BARRIOS-; HOSSAIN, Md. Murad; MOHD NOR, Norazmi; SARMIENTO, María Elena; HERNANDEZ-PANDO, Rogelio; ACOSTA, Armando

    2014-01-01

    Background: Humoral and cellular immune responses are associated with protection against extracellular and intracellular pathogens, respectively. In the present study, we evaluated the effect of receiving human secretory immunoglobulin A (hsIgA) on the histopathology of the lungs of mice challenged with virulent Mycobacterium tuberculosis. Methods: The hsIgA was purified from human colostrum and administered to Balb/c mice by the intranasal route prior to infection with M. tuberculosis or in a pre-incubated formulation with mycobacteria, with the principal aim to study its effect on qualitative pulmonary histopathology. Results: The intranasal administration of hsIgA and the pre-incubation of mycobacteria with this preparation was associated with the presence of organised granulomas with signs of immune activation and histological features related to efficient disease control. This effect was highly evident during the late stage of infection (60 days), as demonstrated by numerous organised granulomas with numerous activated macrophages in the lungs of treated mice. Conclusion: The administration of hsIgA to mice before intratracheal infection with M. tuberculosis or the pre-incubation of the bacteria with the antibody formulation induced the formation of well-organised granulomas and inflammatory lesions in lungs compared with non-treated animals which correlates with the protective effect already demonstrated by these antibody formulations. PMID:25246833

  13. Breath isoprene: Muscle dystrophy patients support the concept of a pool of isoprene in the periphery of the human body

    PubMed Central

    King, J.; Mochalski, P.; Unterkofler, K.; Teschl, G.; Klieber, M.; Stein, M.; Amann, A.; Baumann, M.

    2016-01-01

    Breath isoprene accounts for most of the hydrocarbon removal via exhalation and is thought to serve as a non-invasive indicator for assaying several metabolic effects in the human body. The primary objective of this paper is to introduce a novel working hypothesis with respect to the endogenous source of this compound in humans: the idea that muscle tissue acts as an extrahepatic production site of substantial amounts of isoprene. This new perspective has its roots in quantitative modeling studies of breath isoprene dynamics under exercise conditions and is further investigated here by presenting pilot data from a small cohort of late stage Duchenne muscle dystrophy patients (median age 21, 4 male, 1 female). For these prototypic test subjects isoprene concentrations in end-tidal breath and peripheral venous blood range between 0.09–0.47 and 0.11–0.72 nmol/l, respectively, amounting to a reduction by a factor of 8 and more as compared to established nominal levels in normal healthy adults. While it remains unclear whether isoprene can be ascribed a direct physiological mechanism of action, some indications are given as to why isoprene production might have evolved in muscle. PMID:22683640

  14. Escherichia coli uropathogenesis in vitro: invasion, cellular escape, and secondary infection analyzed in a human bladder cell infection model.

    PubMed

    Andersen, Thomas E; Khandige, Surabhi; Madelung, Michelle; Brewer, Jonathan; Kolmos, Hans J; Møller-Jensen, Jakob

    2012-05-01

    Uropathogenic Escherichia coli (UPEC) strains are capable of invading bladder epithelial cells (BECs) on the bladder luminal surface. Based primarily on studies in mouse models, invasion is proposed to trigger an intracellular uropathogenic cascade involving intracellular bacterial proliferation followed by escape of elongated, filamentous bacteria from colonized BECs. UPEC filaments on the mouse bladder epithelium are able to revert to rod-shaped bacteria, which are believed to invade neighboring cells to initiate new rounds of intracellular colonization. So far, however, these late-stage infection events have not been replicated in vitro. We have established an in vitro model of human bladder cell infection by the use of a flow chamber (FC)-based culture system, which allows investigation of steps subsequent to initial invasion. Short-term bacterial colonization on the FC-BEC layer led to intracellular colonization. Exposing invaded BECs to a flow of urine, i.e., establishing conditions similar to those faced by UPEC reemerging on the bladder luminal surface, led to outgrowth of filamentous bacteria similar to what has been reported to occur in mice. These filaments were capable of reverting to rods that could invade other BECs. Hence, under growth conditions established to resemble those present in vivo, the elements of the proposed uropathogenic cascade were inducible in a human BEC model system. Here, we describe the model and show how these characteristics are reproduced in vitro. PMID:22354025

  15. Indian Hedgehog in Synovial Fluid Is a Novel Marker for Early Cartilage Lesions in Human Knee Joint

    PubMed Central

    Zhang, Congming; Wei, Xiaochun; Chen, Chongwei; Cao, Kun; Li, Yongping; Jiao, Qiang; Ding, Juan; Zhou, Jingming; Fleming, Braden C.; Chen, Qian; Shang, Xianwen; Wei, Lei

    2014-01-01

    To determine whether there is a correlation between the concentration of Indian hedgehog (Ihh) in synovial fluid (SF) and the severity of cartilage damage in the human knee joints, the knee cartilages from patients were classified using the Outer-bridge scoring system and graded using the Modified Mankin score. Expression of Ihh in cartilage and SF samples were analyzed with immunohistochemistry (IHC), western blot, and enzyme-linked immunosorbent assay (ELISA). Furthermore, we detected and compared Ihh protein levels in rat and mice cartilages between normal control and surgery-induced osteoarthritis (OA) group by IHC and fluorescence molecular tomography in vivo respectively. Ihh expression was increased 5.2-fold in OA cartilage, 3.1-fold in relative normal OA cartilage, and 1.71-fold in OA SF compared to normal control samples. The concentrations of Ihh in cartilage and SF samples was significantly increased in early-stage OA samples when compared to normal samples (r = 0.556; p < 0.001); however, there were no significant differences between normal samples and late-stage OA samples. Up-regulation of Ihh protein was also an early event in the surgery-induced OA models. Increased Ihh is associated with the severity of OA cartilage damage. Elevated Ihh content in human knee joint synovial fluid correlates with early cartilage lesions. PMID:24786088

  16. Retinal Remodeling and Metabolic Alterations in Human AMD

    PubMed Central

    Jones, Bryan W.; Pfeiffer, Rebecca L.; Ferrell, William D.; Watt, Carl B.; Tucker, James; Marc, Robert E.

    2016-01-01

    Age-related macular degeneration (AMD) is a progressive retinal degeneration resulting in central visual field loss, ultimately causing debilitating blindness. AMD affects 18% of Americans from 65 to 74, 30% older than 74 years of age and is the leading cause of severe vision loss and blindness in Western populations. While many genetic and environmental risk factors are known for AMD, we currently know less about the mechanisms mediating disease progression. The pathways and mechanisms through which genetic and non-genetic risk factors modulate development of AMD pathogenesis remain largely unexplored. Moreover, current treatment for AMD is palliative and limited to wet/exudative forms. Retina is a complex, heterocellular tissue and most retinal cell classes are impacted or altered in AMD. Defining disease and stage-specific cytoarchitectural and metabolic responses in AMD is critical for highlighting targets for intervention. The goal of this article is to illustrate cell types impacted in AMD and demonstrate the implications of those changes, likely beginning in the retinal pigment epithelium (RPE), for remodeling of the the neural retina. Tracking heterocellular responses in disease progression is best achieved with computational molecular phenotyping (CMP), a tool that enables acquisition of a small molecule fingerprint for every cell in the retina. CMP uncovered critical cellular and molecular pathologies (remodeling and reprogramming) in progressive retinal degenerations such as retinitis pigmentosa (RP). We now applied these approaches to normal human and AMD tissues mapping progression of cellular and molecular changes in AMD retinas, including late-stage forms of the disease. PMID:27199657

  17. A molecular switch underlies a human telomerase disease

    PubMed Central

    Comolli, Luis R.; Smirnov, Ivan; Xu, Lifeng; Blackburn, Elizabeth H.; James, Thomas L.

    2002-01-01

    Telomerase is a ribonucleoprotein (RNP) required for maintenance of telomeres. Although up-regulated telomerase activity is closely linked to the cellular immortality characteristic of late stage carcinogenesis, recently, mutations in the telomerase RNA gene in humans have been associated with dyskeratosis congenita and aplastic anemia, both typified by impaired haemopoietic function. These mutations include base changes in a highly conserved putative telomerase RNA pseudoknot. Here, by using in vitro telomerase assays, NMR, and UV absorbance melting analyses of model oligonucleotides designed to form a “trans-pseudoknot,” we describe functional, structural, and energetic properties of this structure. We demonstrate that the pseudoknot domain exists in two alternative states of nearly equal stability in solution: one is the previously proposed pseudoknot formed by pairing P3 with the loop domain of P2b, and the other is a structured P2b loop alone. We show that the two-base mutation (GC107/8 → AG) present in one gene copy in a family with dyskeratosis congenita abrogates telomerase activity. This mutation hyperstabilizes the P2b intraloop structure, blocking pseudoknot formation. Conversely, when the P3 pseudoknot pairing is hyperstabilized by deleting a conserved bulge in P3, telomerase activity also decreases. We propose that the P2b/P3 pseudoknot domain acts as a molecular switch, and interconversion between its two states is important for telomerase function. Phylogenetic covariation in the P2b and P3 sequences of 35 species provides a compelling set of “natural” compensatory base pairing changes supporting the existence of the crucial molecular switch. PMID:12482936

  18. Human Development, Human Evolution.

    ERIC Educational Resources Information Center

    Smillie, David

    One of the truly remarkable events in human evolution is the unprecedented increase in the size of the brain of "Homo" over a brief span of 2 million years. It would appear that some significant selective pressure or opportunity presented itself to this branch of the hominid line and caused a rapid increase in the brain, introducing a wholly new…

  19. Knockout of Epstein-Barr Virus BPLF1 Retards B-Cell Transformation and Lymphoma Formation in Humanized Mice

    PubMed Central

    Li, Guangming; Montgomery, Stephanie A.; Montgomery, Nathan D.; Su, Lishan; Pagano, Joseph S.

    2015-01-01

    ABSTRACT BPLF1 of Epstein-Barr virus (EBV) is classified as a late lytic cycle protein but is also found in the viral tegument, suggesting its potential involvement at both initial and late stages of viral infection. BPLF1 possesses both deubiquitinating and deneddylating activity located in its N-terminal domain and is involved in processes that affect viral infectivity, viral DNA replication, DNA repair, and immune evasion. A recently constructed EBV BPLF1-knockout (KO) virus was used in conjunction with a humanized mouse model that can be infected with EBV, enabling the first characterization of BPLF1 function in vivo. Results demonstrate that the BPLF1-knockout virus is approximately 90% less infectious than wild-type (WT) virus. Transformation of human B cells, a hallmark of EBV infection, was delayed and reduced with BPLF1-knockout virus. Humanized mice infected with EBV BPLF1-knockout virus showed less weight loss and survived longer than mice infected with equivalent infectious units of WT virus. Additionally, splenic tumors formed in 100% of mice infected with WT EBV but in only 25% of mice infected with BPLF1-KO virus. Morphological features of spleens containing tumors were similar to those in EBV-induced posttransplant lymphoproliferative disease (PTLD) and were almost identical to cases seen in human diffuse large B-cell lymphoma. The presence of EBV genomes was detected in all mice that developed tumors. The results implicate BPLF1 in human B-cell transformation and tumor formation in humanized mice. PMID:26489865

  20. Dysfunctional Patterns of Gamma-Band Activity in Response to Human Faces Compared to Non-Facial Stimuli in Patients with Schizophrenia

    PubMed Central

    Lee, Seung-Hwan; Kim, Sangrae; Shim, Mi-Seon; Kim, Do-Won

    2016-01-01

    Objective Healthy individuals show stronger gamma-band activities (GBAs) for socially relevant stimuli (human faces) than for non-relevant ones. This study aimed to examine whether this gamma-band preference occurs in patients with schizophrenia. Methods EEG was recorded for 24 patients with schizophrenia and 23 healthy controls while they viewed pictures of human faces, chairs, and nature scenes. The spectral powers of high-beta (20–30 Hz) and gamma (30–80 Hz) frequencies were analyzed along 3 midline cortical regions, and phase synchronization was calculated. Results Compared to the response to non-facial stimuli, higher event related deactivation to facial stimuli was observed for the high-beta frequency across groups. For the gamma frequency, early-stage GBA was increased and late-stage GBA was decreased for all 3 stimuli in patients with schizophrenia compared to healthy controls. Preferential GBA patterns (100–200 and 200–300 ms) were found in healthy controls, but not in patients with schizophrenia. Significant correlation existed between negative symptoms and GBA in the frontal region for chair and scene stimuli. There was no significant intergroup difference in phase synchronization pattern. Conclusion Our results suggest that patients with schizophrenia have deficits in the preferential pattern of GBA for human faces and the deficits in the preferential pattern were mainly influenced by over-response to socially non-relevant stimuli. PMID:27247603

  1. Human Health

    MedlinePlus

    ... effects of climate change Video not supported Human Health Climate change threatens human health and well-being ... Copy link to clipboard Key Message: Wide-ranging Health Impacts Climate change threatens human health and well- ...

  2. Mercury-induced externalization of phosphatidylserine and caspase 3 activation in human liver carcinoma (HepG2) cells.

    PubMed

    Sutton, Dwayne J; Tchounwou, Paul B

    2006-03-01

    Apoptosis arises from the active initiation and propagation of a series of highly orchestrated specific biochemical events leading to the demise of the cell. It is a normal physiological process, which occurs during embryonic development as well as in the maintenance of tissue homeostasis. Diverse groups of molecules are involved in the apoptosis pathway and it functions as a mechanism to eliminate unwanted or irreparably damaged cells. However, inappropriate induction of apoptosis by environmental agents has broad ranging pathologic implications and has been associated with several diseases including cancer. The toxicity of several heavy metals such as mercury has been attributed to their high affinity to sulfhydryl groups of proteins and enzymes, and their ability to disrupt cell cycle progression and/or apoptosis in various tissues. The aim of this study was to assess the potential for mercury to induce early and late-stage apoptosis in human liver carcinoma (HepG2) cells. The Annexin-V and Caspase 3 assays were performed by flow cytometric analysis to determine the extent of phosphatidylserine externalization and Caspase 3 activation in mercury-treated HepG2 cells. Cells were exposed to mercury for 10 and 48 hours respectively at doses of 0, 1, 2, and 3 microg/mL based on previous cytotoxicity results in our laboratory indicating an LD50 of 3.5 +/- 0.6 microg/mL for mercury in HepG2 cells. The study data indicated a dose response relationship between mercury exposure and the degree of early and late-stage apoptosis in HepG2 cells. The percentages of cells undergoing early apoptosis were 0.03 +/- 0.03%, 5.19 +/- 0.04%, 6.36 +/- 0.04%, and 8.84 +/- 0.02% for 0, 1, 2, and 3 microg/mL of mercury respectively, indicating a gradual increase in apoptotic cells with increasing doses of mercury. The percentages of Caspase 3 positive cells undergoing late apoptosis were 3.58 +/- 0.03%, 17.06 +/- 0.05%, 23.32 +/- 0.03%, and 34.51 +/- 0.01% for 0, 1, 2, and 3 microg/mL of

  3. RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development.

    PubMed

    Verma, Rakesh; Su, Su; McCrann, Donald J; Green, Jennifer M; Leu, Karen; Young, Peter R; Schatz, Peter J; Silva, Jeffrey C; Stokes, Matthew P; Wojchowski, Don M

    2014-08-25

    Ligation of erythropoietin (EPO) receptor (EPOR) JAK2 kinase complexes propagates signals within erythroid progenitor cells (EPCs) that are essential for red blood cell production. To reveal hypothesized novel EPOR/JAK2 targets, a phosphotyrosine (PY) phosphoproteomics approach was applied. Beyond known signal transduction factors, 32 new targets of EPO-modulated tyrosine phosphorylation were defined. Molecular adaptors comprised one major set including growth factor receptor-bound protein 2 (GRB2)-associated binding proteins 1-3 (GAB1-3), insulin receptor substrate 2 (IRS2), docking protein 1 (DOK1), Src homology 2 domain containing transforming protein 1 (SHC1), and sprouty homologue 1 (SPRY1) as validating targets, and SPRY2, SH2 domain containing 2A (SH2D2A), and signal transducing adaptor molecule 2 (STAM2) as novel candidate adaptors together with an ORF factor designated as regulator of human erythroid cell expansion (RHEX). RHEX is well conserved in Homo sapiens and primates but absent from mouse, rat, and lower vertebrate genomes. Among tissues and lineages, RHEX was elevated in EPCs, occurred as a plasma membrane protein, was rapidly PY-phosphorylated >20-fold upon EPO exposure, and coimmunoprecipitated with the EPOR. In UT7epo cells, knockdown of RHEX inhibited EPO-dependent growth. This was associated with extracellular signal-regulated kinase 1,2 (ERK1,2) modulation, and RHEX coupling to GRB2. In primary human EPCs, shRNA knockdown studies confirmed RHEX regulation of erythroid progenitor expansion and further revealed roles in promoting the formation of hemoglobinizing erythroblasts. RHEX therefore comprises a new EPO/EPOR target and regulator of human erythroid cell expansion that additionally acts to support late-stage erythroblast development. PMID:25092874

  4. K2P—A Novel Cross-Link from Human Lens Protein

    PubMed Central

    CHENG, RONGZHU; FENG, QI; ARGIROV, OGNYAN K.; ORTWERTH, BERYL J.

    2006-01-01

    We report here the isolation of a novel acid-labile yellow chromophore from the enzymatic digest of human lens proteins and the identification of its chemical structure by LC-MS and NMR. This new chromophore exhibited a UV absorbance maximum at 343 nm and a molecular mass of 370 Da. One- and two-dimensional NMR analyses elucidated the structure as being 1-(5-amino-5-carboxypentyl)-4-(5-amino-5-carboxypentyl-amino)-3-hydroxy-2, 3-dihydropyridinium, a cross-link between the _-amino groups of two lysine residues and a five-carbon atom ring. We assigned it the trivial name of K2P. Quantitative determinations of K2P in individual normal human lens or cataract lens water-soluble and water-insoluble protein digests revealed a significant enhancement of K2P in the early stage of brunescent cataract lens proteins (type I/II, 613 ± 362 pmol/mg of water-insoluble sonicate supernatant (WISS) protein or 85 ± 51 pmol/mg of water-soluble [WS] protein) when compared with aged normal human lens proteins (261 ± 93 pmol/mg of WISS protein or 23 ± 15 pmol/mg of WS protein). Furthermore, a gradual decrease of K2P in the late stages of brunescent cataract lenses with the development of the browning color in the lens argues different coloration mechanisms during the processes of normal aging and cataract development. This new cross-link may serve as a quantitatively significant biomarker for assessing the role of lens protein modifications during aging and in the pathogenesis of cataract. PMID:16037238

  5. Epidemiology of Sleeping Sickness in Boffa (Guinea): Where Are the Trypanosomes?

    PubMed Central

    Kagbadouno, Moise Saa; Camara, Mamadou; Rouamba, Jeremi; Rayaisse, Jean-Baptiste; Traoré, Ibrahima Sory; Camara, Oumou; Onikoyamou, Mory Fassou; Courtin, Fabrice; Ravel, Sophie; de Meeûs, Thierry; Bucheton, Bruno; Jamonneau, Vincent; Solano, Philippe

    2012-01-01

    Human African Trypanosomiasis (HAT) in West Africa is a lethal, neglected disease caused by Trypanosoma brucei gambiense transmitted by the tsetse Glossina palpalis gambiensis. Although the littoral part of Guinea with its typical mangrove habitat is the most prevalent area in West Africa, very few data are available on the epidemiology of the disease in such biotopes. As part of a HAT elimination project in Guinea, we carried a cross-sectional study of the distribution and abundance of people, livestock, tsetse and trypanosomes in the focus of Boffa. An exhaustive census of the human population was done, together with spatial mapping of the area. Entomological data were collected, a human medical survey was organized together with a survey in domestic animals. In total, 45 HAT cases were detected out of 14445 people who attended the survey, these latter representing 50.9% of the total population. Potential additional carriers of T. b. gambiense were also identified by the trypanolysis test (14 human subjects and two domestic animals). No trypanosome pathogenic to animals were found, neither in the 874 tsetse dissected nor in the 300 domestic animals sampled. High densities of tsetse were found in places frequented by humans, such as pirogue jetties, narrow mangrove channels and watering points. The prevalence of T. b. gambiense in humans, combined to low attendance of the population at risk to medical surveys, and to an additional proportion of human and animal carriers of T. b. gambiense who are not treated, highlights the limits of strategies targeting HAT patients only. In order to stop T. b. gambiense transmission, vector control should be added to the current strategy of case detection and treatment. Such an integrated strategy will combine medical surveillance to find and treat cases, and vector control activities to protect people from the infective bites of tsetse. PMID:23272259

  6. Annexin 2: a novel human immunodeficiency virus type 1 Gag binding protein involved in replication in monocyte-derived macrophages.

    PubMed

    Ryzhova, Elena V; Vos, Robin M; Albright, Andrew V; Harrist, Alexia V; Harvey, Thomas; González-Scarano, Francisco

    2006-03-01

    Human immunodeficiency virus (HIV) replication in the major natural target cells, CD4+ T lymphocytes and macrophages, is parallel in many aspects of the virus life cycle. However, it differs as to viral assembly and budding, which take place on plasma membranes in T cells and on endosomal membranes in macrophages. It has been postulated that cell type-specific host factors may aid in directing viral assembly to distinct destinations. In this study we defined annexin 2 (Anx2) as a novel HIV Gag binding partner in macrophages. Anx2-Gag binding was confined to productively infected macrophages and was not detected in quiescently infected monocyte-derived macrophages (MDM) in which an HIV replication block was mapped to the late stages of the viral life cycle (A. V. Albright, R. M. Vos, and F. Gonzalez-Scarano, Virology 325:328-339, 2004). We demonstrate that the Anx2-Gag interaction likely occurs at the limiting membranes of late endosomes/multivesicular bodies and that Anx2 depletion is associated with a significant decline in the infectivity of released virions; this coincided with incomplete Gag processing and inefficient incorporation of CD63. Cumulatively, our data suggest that Anx2 is essential for the proper assembly of HIV in MDM. PMID:16501079

  7. Andrographolide inhibits intracellular Chlamydia trachomatis multiplication and reduces secretion of proinflammatory mediators produced by human epithelial cells

    PubMed Central

    Hua, Ziyu; Frohlich, Kyla M.; Zhang, Yan; Feng, Xiaogeng; Zhang, Jiaxing; Shen, Li

    2014-01-01

    Chlamydia trachomatis is the most common sexually transmitted bacterial disease worldwide. Untreated C. trachomatis infections may cause inflammation and ultimately damage tissues. Here, we evaluated the ability of Andrographolide (Andro), a natural diterpenoid lactone component of Andrographis paniculata, to inhibit C. trachomatis infection in cultured human cervical epithelial cells. We found that Andro exposure inhibited C. trachomatis growth in a dose- and time-dependent manner. The greatest inhibitory effect was observed when exponentially growing C. trachomatis was exposed to Andro. Electron micrographs demonstrated the accumulation of unusual, structurally deficient chlamydial organisms, correlated with a decrease in levels of OmcB expressed at the late stage of infection. Additionally, Andro significantly reduced the secretion of interleukin6, CXCL8 and interferon-γ-induced protein10 produced by host cells infected with C. trachomatis. These results indicate the efficacy of Andro to perturb C. trachomatis transition from the metabolically active reticulate body to the infectious elementary body and concurrently reduce the production of a proinflammatory mediator by epithelial cells in vitro. Further dissection of Andro's anti-Chlamydia action may provide identification of novel therapeutic targets. PMID:25854005

  8. Formation of a Human Immunodeficiency Virus Type 1 Core of Optimal Stability Is Crucial for Viral Replication

    PubMed Central

    Forshey, Brett M.; von Schwedler, Uta; Sundquist, Wesley I.; Aiken, Christopher

    2002-01-01

    Virions of human immunodeficiency virus type 1 (HIV-1) and other lentiviruses contain conical cores consisting of a protein shell composed of the viral capsid protein (CA) surrounding an internal viral ribonucleoprotein complex. Although genetic studies have implicated CA in both early and late stages of the virus replication cycle, the mechanism of core disassembly following penetration of target cells remains undefined. Using quantitative assays for analyzing HIV-1 core stability in vitro, we identified point mutations in CA that either reduce or increase the stability of the HIV-1 core without impairing conical core formation in virions. Alterations in core stability resulted in severely attenuated HIV-1 replication and impaired reverse transcription in target cells with only minimal effects on viral DNA synthesis in permeabilized virions in vitro. We conclude that formation of a viral core of optimal stability is a prerequisite for efficient HIV-1 infection and suggest that disassembly of the HIV-1 core is a regulated step in infection that may be an attractive target for pharmacologic intervention. PMID:11991995

  9. Regulation of CCAAT/enhancer-binding protein (C/EBP) α in human-cytomegalovirus-infected fibroblasts.

    PubMed

    Lee, Junsub; Kim, Sunyoung

    2016-05-01

    CCAAT/enhancer-binding protein (C/EBP) α, a member of the C/EBP family of transcription factors, is known to be involved in gene expression and DNA replication of human cytomegalovirus (HCMV). This study aimed to understand the regulation of endogenous C/EBPα during HCMV infection using an in vitro infection model. The expression and localization of C/EBPα were investigated in fibroblasts infected with HCMV. The overexpression of C/EBP homologous protein (CHOP), the endogenous inhibitor of C/EBP, was also employed to test the involvement of C/EBPα during HCMV infection. Our data showed that HCMV infection increases the expression of the full-length C/EBPα isoform (p42) especially during the late stage of infection at the transcriptional and post-translational levels. The increased p42 accumulated in the viral DNA replication compartment. p42 expression was not induced in cells treated with UV-irradiated virus or in cells infected with normal virus in the presence of ganciclovir. CHOP-mediated inhibition of C/EBP activity suppressed viral gene expression and DNA replication, which lowered the level of viral production. Together, our data suggest that HCMV-mediated C/EBPα regulation might play a beneficial role in the lytic cycle of HCMV. PMID:26831934

  10. Andrographolide inhibits intracellular Chlamydia trachomatis multiplication and reduces secretion of proinflammatory mediators produced by human epithelial cells.

    PubMed

    Hua, Ziyu; Frohlich, Kyla M; Zhang, Yan; Feng, Xiaogeng; Zhang, Jiaxing; Shen, Li

    2015-02-01

    Chlamydia trachomatis is the most common sexually transmitted bacterial disease worldwide. Untreated C. trachomatis infections may cause inflammation and ultimately damage tissues. Here, we evaluated the ability of Andrographolide (Andro), a natural diterpenoid lactone component of Andrographis paniculata, to inhibit C. trachomatis infection in cultured human cervical epithelial cells. We found that Andro exposure inhibited C. trachomatis growth in a dose- and time-dependent manner. The greatest inhibitory effect was observed when exponentially growing C. trachomatis was exposed to Andro. Electron micrographs demonstrated the accumulation of unusual, structurally deficient chlamydial organisms, correlated with a decrease in levels of OmcB expressed at the late stage of infection. Additionally, Andro significantly reduced the secretion of interleukin6, CXCL8 and interferon-γ-induced protein10 produced by host cells infected with C. trachomatis. These results indicate the efficacy of Andro to perturb C. trachomatis transition from the metabolically active reticulate body to the infectious elementary body and concurrently reduce the production of a proinflammatory mediator by epithelial cells in vitro. Further dissection of Andro's anti-Chlamydia action may provide identification of novel therapeutic targets. PMID:25854005

  11. Filamin A Protein Interacts with Human Immunodeficiency Virus Type 1 Gag Protein and Contributes to Productive Particle Assembly*

    PubMed Central

    Cooper, JoAnn; Liu, Ling; Woodruff, Elvin A.; Taylor, Harry E.; Goodwin, J. Shawn; D'Aquila, Richard T.; Spearman, Paul; Hildreth, James E. K.; Dong, Xinhong

    2011-01-01

    HIV-1 Gag precursor directs virus particle assembly and release. In a search for Gag-interacting proteins that are involved in late stages of the HIV-1 replication cycle, we performed yeast two-hybrid screening against a human cDNA library and identified the non-muscle actin filament cross-linking protein filamin A as a novel Gag binding partner. The 280-kDa filamin A regulates cortical actin network dynamics and participates in the anchoring of membrane proteins to the actin cytoskeleton. Recent studies have shown that filamin A facilitates HIV-1 cell-to-cell transmission by binding to HIV receptors and coreceptors and regulating their clustering on the target cell surface. Here we report a novel role for filamin A in HIV-1 Gag intracellular trafficking. We demonstrate that filamin A interacts with the capsid domain of HIV-1 Gag and that this interaction is involved in particle release in a productive manner. Disruption of this interaction eliminated Gag localization at the plasma membrane and induced Gag accumulation within internal compartments. Moreover, blocking clathrin-dependent endocytic pathways did not relieve the restriction to particle release induced by filamin A depletion. These results suggest that filamin A is involved in the distinct step of the Gag trafficking pathway. The discovery of the Gag-filamin A interaction may provide a new therapeutic target for the treatment of HIV infection. PMID:21705339

  12. Shape of the intercondylar notch of the human femur: a comparison of osteoarthritic and non-osteoarthritic bones from a skeletal sample

    PubMed Central

    Shepstone, L; Rogers, J; Kirwan, J; Silverman, B

    2001-01-01

    OBJECTIVES—To compare objectively the shape of the intercondylar notch in human osteoarthritic and non-osteoarthritic femora.
METHODS—A sample of 96 human femora from a large skeletal population were selected for study. These femora included subjects with evidence of late stage osteoarthritis (that is, with eburnation present) and subjects with no such evidence. The distal end of the femur, viewed axially, was recorded with a video camera, and digitised computer images were produced. The outline of the intercondylar notch was extracted and represented mathematically as two functions. A functional principal components analysis was used to identify important modes of shape variation. These variations in shape were compared between eburnated and non-eburnated femora.
RESULTS—A statistically significant difference in the shape of the intercondylar notch was found between the two groups. The difference related mostly to the shape of the edge of the medial condyle: in the non-osteoarthritic group this tended to exhibit a concavity; in the osteoarthritic group it tended to be straight.
CONCLUSIONS—This observed difference may be a predisposing factor to the development of osteoarthritis. The morphology of the intercondylar notch is related to the functioning of and possible damage to the cruciate ligaments, and damage to the cruciate ligaments is a known risk factor for osteoarthritis. Alternatively, this difference may be due to bony remodelling secondary to the onset of osteoarthritis, perhaps in response to altered biomechanics.

 PMID:11557655

  13. Human Trafficking

    MedlinePlus

    ... to debt bondage or peonage in which traffickers demand labor as a means repayment for a real ... human smuggling are two separate crimes under federal law. There are several important differences between them. Human ...

  14. Human Trafficking

    MedlinePlus

    ... TRAFFICKING (English) Listen < Back to Search FACT SHEET: HUMAN TRAFFICKING (English) Published: August 2, 2012 Topics: Public Awareness , ... organizations that protect and serve trafficking victims. National Human Trafficking Resource Center at 1.888.373.7888 Last ...

  15. Human genome-wide expression analysis reorients the study of inflammatory mediators and biomechanics in osteoarthritis.

    PubMed

    Sandy, J D; Chan, D D; Trevino, R L; Wimmer, M A; Plaas, A

    2015-11-01

    A major objective of this article is to examine the research implications of recently available genome-wide expression profiles of cartilage from human osteoarthritis (OA) joints. We propose that, when viewed in the light of extensive earlier work, this novel data provides a unique opportunity to reorient the design of experimental systems toward clinical relevance. Specifically, in the area of cartilage explant biology, this will require a fresh evaluation of existing paradigms, so as to optimize the choices of tissue source, cytokine/growth factor/nutrient addition, and biomechanical environment for discovery. Within this context, we firstly discuss the literature on the nature and role of potential catabolic mediators in OA pathology, including data from human OA cartilage, animal models of OA, and ex vivo studies. Secondly, due to the number and breadth of studies on IL-1β in this area, a major focus of the article is a critical analysis of the design and interpretation of cartilage studies where IL-1β has been used as a model cytokine. Thirdly, the article provides a data-driven perspective (including genome-wide analysis of clinical samples, studies on mutant mice, and clinical trials), which concludes that IL-1β should be replaced by soluble mediators such as IL-17 or TGF-β1, which are much more likely to mimic the disease in OA model systems. We also discuss the evidence that changes in early OA can be attributed to the activity of such soluble mediators, whereas late-stage disease results more from a chronic biomechanical effect on the matrix and cells of the remaining cartilage and on other local mediator-secreting cells. Lastly, an updated protocol for in vitro studies with cartilage explants and chondrocytes (including the use of specific gene expression arrays) is provided to motivate more disease-relevant studies on the interplay of cytokines, growth factors, and biomechanics on cellular behavior. PMID:26521740

  16. High Resolution Methylome Analysis Reveals Widespread Functional Hypomethylation during Adult Human Erythropoiesis*

    PubMed Central

    Yu, Yiting; Mo, Yongkai; Ebenezer, David; Bhattacharyya, Sanchari; Liu, Hui; Sundaravel, Sriram; Giricz, Orsolya; Wontakal, Sandeep; Cartier, Jessy; Caces, Bennett; Artz, Andrew; Nischal, Sangeeta; Bhagat, Tushar; Bathon, Kathleen; Maqbool, Shahina; Gligich, Oleg; Suzuki, Masako; Steidl, Ulrich; Godley, Lucy; Skoultchi, Art; Greally, John; Wickrema, Amittha; Verma, Amit

    2013-01-01

    Differentiation of hematopoietic stem cells to red cells requires coordinated expression of numerous erythroid genes and is characterized by nuclear condensation and extrusion during terminal development. To understand the regulatory mechanisms governing these widespread phenotypic changes, we conducted a high resolution methylomic and transcriptomic analysis of six major stages of human erythroid differentiation. We observed widespread epigenetic differences between early and late stages of erythropoiesis with progressive loss of methylation being the dominant change during differentiation. Gene bodies, intergenic regions, and CpG shores were preferentially demethylated during erythropoiesis. Epigenetic changes at transcription factor binding sites correlated significantly with changes in gene expression and were enriched for binding motifs for SCL, MYB, GATA, and other factors not previously implicated in erythropoiesis. Demethylation at gene promoters was associated with increased expression of genes, whereas epigenetic changes at gene bodies correlated inversely with gene expression. Important gene networks encoding erythrocyte membrane proteins, surface receptors, and heme synthesis proteins were found to be regulated by DNA methylation. Furthermore, integrative analysis enabled us to identify novel, potential regulatory areas of the genome as evident by epigenetic changes in a predicted PU.1 binding site in intron 1 of the GATA1 gene. This intronic site was found to be conserved across species and was validated to be a novel PU.1 binding site by quantitative ChIP in erythroid cells. Altogether, our study provides a comprehensive analysis of methylomic and transcriptomic changes during erythroid differentiation and demonstrates that human terminal erythropoiesis is surprisingly associated with hypomethylation of the genome. PMID:23306203

  17. High resolution methylome analysis reveals widespread functional hypomethylation during adult human erythropoiesis.

    PubMed

    Yu, Yiting; Mo, Yongkai; Ebenezer, David; Bhattacharyya, Sanchari; Liu, Hui; Sundaravel, Sriram; Giricz, Orsolya; Wontakal, Sandeep; Cartier, Jessy; Caces, Bennett; Artz, Andrew; Nischal, Sangeeta; Bhagat, Tushar; Bathon, Kathleen; Maqbool, Shahina; Gligich, Oleg; Suzuki, Masako; Steidl, Ulrich; Godley, Lucy; Skoultchi, Art; Greally, John; Wickrema, Amittha; Verma, Amit

    2013-03-29

    Differentiation of hematopoietic stem cells to red cells requires coordinated expression of numerous erythroid genes and is characterized by nuclear condensation and extrusion during terminal development. To understand the regulatory mechanisms governing these widespread phenotypic changes, we conducted a high resolution methylomic and transcriptomic analysis of six major stages of human erythroid differentiation. We observed widespread epigenetic differences between early and late stages of erythropoiesis with progressive loss of methylation being the dominant change during differentiation. Gene bodies, intergenic regions, and CpG shores were preferentially demethylated during erythropoiesis. Epigenetic changes at transcription factor binding sites correlated significantly with changes in gene expression and were enriched for binding motifs for SCL, MYB, GATA, and other factors not previously implicated in erythropoiesis. Demethylation at gene promoters was associated with increased expression of genes, whereas epigenetic changes at gene bodies correlated inversely with gene expression. Important gene networks encoding erythrocyte membrane proteins, surface receptors, and heme synthesis proteins were found to be regulated by DNA methylation. Furthermore, integrative analysis enabled us to identify novel, potential regulatory areas of the genome as evident by epigenetic changes in a predicted PU.1 binding site in intron 1 of the GATA1 gene. This intronic site was found to be conserved across species and was validated to be a novel PU.1 binding site by quantitative ChIP in erythroid cells. Altogether, our study provides a comprehensive analysis of methylomic and transcriptomic changes during erythroid differentiation and demonstrates that human terminal erythropoiesis is surprisingly associated with hypomethylation of the genome. PMID:23306203

  18. DDX6 recruits translational silenced human reticulocyte 15-lipoxygenase mRNA to RNP granules

    PubMed Central

    Naarmann, Isabel S.; Harnisch, Christiane; Müller-Newen, Gerhard; Urlaub, Henning; Ostareck-Lederer, Antje; Ostareck, Dirk H.

    2010-01-01

    Erythroid precursor cells lose the capacity for mRNA synthesis due to exclusion of the nucleus during maturation. Therefore, the stability and translation of mRNAs that code for specific proteins, which function in late stages of maturation when reticulocytes become erythrocytes, are controlled tightly. Reticulocyte 15-lipoxygenase (r15-LOX) initiates the breakdown of mitochondria in mature reticulocytes. Through the temporal restriction of mRNA translation, the synthesis of r15-LOX is prevented in premature cells. The enzyme is synthesized only in mature reticulocytes, although r15-LOX mRNA is already present in erythroid precursor cells. Translation of r15-LOX mRNA is inhibited by hnRNP K and hnRNP E1, which bind to the differentiation control element (DICE) in its 3′ untranslated region (3′UTR). The hnRNP K/E1-DICE complex interferes with the joining of the 60S ribosomal subunit to the 40S subunit at the AUG. We took advantage of the inducible human erythroid K562 cell system that fully recapitulates this process to identify so far unknown factors, which are critical for DICE-dependent translational regulation. Applying RNA chromatography with the DICE as bait combined with hnRNP K immunoprecipitation, we specifically purified the DEAD-box RNA helicase 6 (DDX6) that interacts with hnRNP K and hnRNP E1 in a DICE-dependent manner. Employing RNA interference and fluorescence in situ hybridization, we show that DDX6 colocalizes with endogenous human (h)r15-LOX mRNA to P-body–like RNP granules, from which 60S ribosomal subunits are excluded. Our data suggest that in premature erythroid cells translational silencing of hr15-LOX mRNA is maintained by DDX6 mediated storage in these RNP granules. PMID:20884783

  19. Extracellular matrix receptors and the differentiation of human megakaryocytes in vitro.

    PubMed

    Molla, A; Mossuz, P; Berthier, R

    1999-03-01

    We investigated the expression and functions of extracellular matrix receptors (or integrins) in the course of the differentiation of human megakaryocytes (Mks) leading to the formation of platelets. Integrins beta1 or Very Late Antigens (VLA) are specialized transmembrane receptors allowing the attachment of the cells to collagen (VLA-2), fibronectin (VLA-4 and -5) and laminin (VLA-6). A proportion of committed megakaryocytic progenitor cells (CFU-MK) adhere to fibronectin but not to collagen or laminin. The early immature Mks are retained on fibronectin (30%) and laminin (12%) but not on collagen whereas large mature Mks are still adherent to fibronectin and laminin and also acquired the capacity to adhere to collagen. The expression of the different VLA in the maturation of Mks correlates well with their adhesive properties. Hence, VLA-2 is not expressed on immature Mks but is present on the mature polyploid cells. VLA-4 is detected only on immature Mks which do not seem to bear VLA-5, while this last integrin appears on late Mks. VLA-6 showed a broad distribution from the early to late stages of Mks differentiation. Integrins beta3 of the cytoadhesin family are represented by alphaIIb beta3 that is the receptor for fibrinogen and alphaV beta3 which mediates adhesion to vitronectin. AlphaIIb beta3 is present on the CFU-MK and highly expressed throughout the Mks maturation stages while alphaV beta3 expression is much lower and seems to be detected only on the late Mks. The regulation of the expression of these receptors by cytokines and their respective roles in the maturation of Mks and the final production of platelets, are discussed. The development of efficient culture systems of human Mks in the presence of the recently cloned thrombopoietin will undoubtedly help to shed more light on the molecular mechanisms of their interactions via integrins with the BM microenvironment. PMID:10194117

  20. Dopamine Receptors in Human Embryonic Stem Cell Neurodifferentiation

    PubMed Central

    Belinsky, Glenn S.; Sirois, Carissa L.; Rich, Matthew T.; Short, Shaina M.; Moore, Anna R.; Gilbert, Sarah E.

    2013-01-01

    We tested whether dopaminergic drugs can improve the protocol for in vitro differentiation of H9 human embryonic stem cells (hESCs) into dopaminergic neurons. The expression of 5 dopamine (DA) receptor subtypes (mRNA and protein) was analyzed at each protocol stage (1, undifferentiated hESCs; 2, embryoid bodies [EBs]; 3, neuroepithelial rosettes; 4, expanding neuroepithelium; and 5, differentiating neurons) and compared to human fetal brain (gestational week 17–19). D2-like DA receptors (D2, D3, and D4) predominate over the D1-like receptors (D1 and D5) during derivation of neurons from hESCs. D1 was the receptor subtype with the lowest representation in each protocol stage (Stages 1–5). D1/D5-agonist SKF38393 and D2/D3/D4-agonist quinpirole (either alone or combined) evoked Ca2+ responses, indicating functional receptors in hESCs. To identify when receptor activation causes a striking effect on hESC neurodifferentiation, and what ligands and endpoints are most interesting, we varied the timing, duration, and drug in the culture media. Dopaminergic agonists or antagonists were administered either early (Stages 1–3) or late (Stages 4–5). Early DA exposure resulted in more neuroepithelial colonies, more neuronal clusters, and more TH+ clusters. The D1/D5 antagonist SKF83566 had a strong effect on EB morphology and the expression of midbrain markers. Late exposure to DA resulted in a modest increase in TH+ neuron clusters (∼75%). The increase caused by DA did not occur in the presence of dibutyryl cAMP (dbcAMP), suggesting that DA acts through the cAMP pathway. However, a D2-antagonist (L741) decreased TH+ cluster counts. Electrophysiological parameters of the postmitotic neurons were not significantly affected by late DA treatment (Stages 4–5). The mRNA of mature neurons (VGLUT1 and GAD1) and the midbrain markers (GIRK2, LMX1A, and MSX1) were lower in hESCs treated by DA or a D2-antagonist. When hESCs were neurodifferentiated on PA6 stromal cells, DA also

  1. Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

    PubMed Central

    Pizzuto, Matteo S.; Silic-Benussi, Micol; Pavone, Silvia; Ciminale, Vincenzo; Capua, Ilaria

    2014-01-01

    ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of human cancer, with dismal survival rates due to late-stage diagnoses and a lack of efficacious therapies. Building on the observation that avian influenza A viruses (IAVs) have a tropism for the pancreas in vivo, the present study was aimed at testing the efficacy of IAVs as oncolytic agents for killing human PDA cell lines. Receptor characterization confirmed that human PDA cell lines express the alpha-2,3- and the alpha-2,6-linked glycan receptor for avian and human IAVs, respectively. PDA cell lines were sensitive to infection by human and avian IAV isolates, which is consistent with this finding. Growth kinetic experiments showed preferential virus replication in PDA cells over that in a nontransformed pancreatic ductal cell line. Finally, at early time points posttreatment, infection with IAVs caused higher levels of apoptosis in PDA cells than gemcitabine and cisplatin, which are the cornerstone of current therapies for PDA. In the BxPC-3 PDA cell line, apoptosis resulted from the engagement of the intrinsic mitochondrial pathway. Importantly, IAVs did not induce apoptosis in nontransformed pancreatic ductal HPDE6 cells. Using a model based on the growth of a PDA cell line as a xenograft in SCID mice, we also show that a slightly pathogenic avian IAV significantly inhibited tumor growth following intratumoral injection. Taken together, these results are the first to suggest that IAVs may hold promise as future agents of oncolytic virotherapy against pancreatic ductal adenocarcinomas. IMPORTANCE Despite intensive studies aimed at designing new therapeutic approaches, PDA still retains the most dismal prognosis among human cancers. In the present study, we provide the first evidence indicating that avian IAVs of low pathogenicity display a tropism for human PDA cells, resulting in viral RNA replication and a potent induction of apoptosis in vitro and antitumor effects in vivo. These

  2. Expression of mitogen-activated protein kinase phosphatase-1 in the early phases of human epithelial carcinogenesis.

    PubMed Central

    Loda, M.; Capodieci, P.; Mishra, R.; Yao, H.; Corless, C.; Grigioni, W.; Wang, Y.; Magi-Galluzzi, C.; Stork, P. J.

    1996-01-01

    Many mitogens and human oncogenes activate extracellular regulated kinases (ERKs), which in turn convey proliferation signals. ERKs or mitogen-activated protein (MAP) kinases are inactivated in vitro by MAP kinase phosphatases (MKPs). The gene encoding one of these MKPs, MKP-1, is a serum-inducible gene and is transcriptionally activated by mitogenic signals in cultured cells. As MKP-1 has been shown to block DNA synthesis by inhibiting ERKs when expressed at elevated levels in cultured cells, it has been suggested that it may act as a tumor suppressor. MKP-1 mRNA and MAP kinase (ERK-1 and -2) protein expression was assessed in 164 human epithelial tumors of diverse tissue origin by in situ hybridization and immunohistochemistry. MKP-1 was overexpressed in the early phases of prostate, colon, and bladder carcinogenesis, with progressive loss of expression with higher histological grade and in metastases. In contrast, breast carcinomas showed significant MKP-1 expression even when poorly differentiated or in late stages of the disease. MKP-1, ERK-1, and ERK-2 were co-expressed in most tumors examined. In a subset of 15 tumors, ERK-1 enzymatic activity as well as structural alterations that might be responsible for loss of function of MKP-1 during tumor progression, were examined. ERK-1 enzymatic activity was found to be elevated despite MKP-1 overexpression. No loss of 5q35-ter (containing the MKP-1 locus) was detected by polymerase chain reaction in metastases compared with primary tumors. Finally, no mutations were found in the catalytic domain of MKP-1. These data indicate that MKP-1 is an early marker for a wide range of human epithelial tumors and suggest that MKP-1 does not behave as a tumor suppressor in epithelial tumors. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8909245

  3. 76 FR 61713 - Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-05

    ... HUMAN SERVICES Food and Drug Administration Pediatric Oncology Subcommittee of the Oncologic Drugs... (FDA). The meeting will be open to the public. Name of Committee: Pediatric Oncology Subcommittee of..., are in late stage development for an adult oncology indication, or in late stage development...

  4. U-Pb geochronology and geochemistry of Bibi-Maryam pluton, eastern Iran: Implication for the late stage of the tectonic evolution of the Sistan Ocean

    NASA Astrophysics Data System (ADS)

    Delavari, Morteza; Amini, Sadraddin; Schmitt, Axel K.; McKeegan, Kevin D.; Mark Harrison, T.

    2014-07-01

    The Bibi-Maryam pluton crops out in the Sistan suture zone, eastern Iran. This pluton is a 1.5 × 2 km stock composed of leucocratic tonalite, granodiorite and granite. U-Pb zircon geochronology of a leucogranite indicates an emplacement age of 58.6 ± 2.1 Ma (95% confidence). The Bibi-Maryam rock suite is sodic with elevated Na2O/K2O (2.9 to 5.5), Sr/Y (15.6-62.2), La/Yb (13.3-22.2), and low MgO (0.86-1.81) abundances. It lacks significant Eu anomalies. Because of these geochemical characteristics, Bibi-Maryam rocks are similar to high-SiO2 adakites. Trace element modeling indicates that the Bibi-Maryam adakitic rocks could be produced by 5-8% non-modal batch partial melting from a source with composition of 95% N-MORB + 5% sediment in the presence of 35-40% amphibole + 5-10% garnet + 55-60% clinopyroxene + 1% apatite + 1% rutile. This source mineralogy is similar to hornblende eclogite or garnet amphibolites. Collectively, these data provide new constraints for the evolution of the Sistan suture zone and suggest that the Bibi-Maryam pluton formed via slab melting in an oceanic arc and pre-plate collision tectonic setting. This implies that the closure of the Sistan Ocean and Lut-Afghan continental blocks collision happened after the Bibi-Maryam emplacement at 58.6 ± 2.1 Ma.

  5. U-Pb geochronology and geochemistry of Zahedan and Shah kuh plutons, eastern Iran: Implication for the late stage of the tectonic evolution of the South Sistan Zone

    NASA Astrophysics Data System (ADS)

    Mohammadi, Ali; Burg, Jean-Pierre; Ruh, Jonas; Von Quadt, Albrecht; Peytcheva, Irena

    2015-04-01

    The N-S trending Sistan Suture Zone (SSZ) in eastern Iran is attributed to eastward subduction beneath the Afghan continental block of an inlet of the Mesozoic Tethys Ocean. We present U-Pb zircon crystallization ages combined with petrography, major and trace element analyses, Hf isotopes, Rb-Sr and Sm-Nd isotopes of intermediate to granitic intrusions stretched along the southern segment of the SSZ. We obtained two clearly separated clusters of concordant ages, which are taken as the crystallization age of the host plutonic rocks. The first cluster, between ca 42.5 and ca 44.5 Ma from euhedral zircons of the main granodiorite to diorite and related dykes. The second age cluster span from ca 28.3 to ca 31 Ma. These ages were obtained for granites and dykes, the latter being consistently slightly younger than the country rock. The high SiO2 content (62-75 wt %) of Eocene magmatic rocks points to melts with a high crustal contribution in consistency with their relatively high-K (3-4.4 wt %) calc-alkaline nature. The high SiO2 and K contents in the Oligocene calk-alkaline rocks series shows adakite-like fractionation. Oligocene adakite-like rocks have relatively low to medium 87Sr/86Sr and 143Nd/144Nd ratios, which are similar to typical lower thick crust-derived adakites. The mix positive and negative ɛHf(T) values of all zircons from the 42.5-44.5 Ma shows mix nature of magma (the contamination of subduction related magma with partial melting of crust). The positive ɛHf(T) values of all zircons from the 28-31 Ma adakite-like rocks indicate that the magma was not produced from pure depleted mantle. Instead, they are consistent with a host magma source within a largely juvenile and subduction-related mafic lower crust. Eocene granitoids represent anatectic melts emplaced at higher crustal levels; in addition slab melts modified the mantle wedge and subsequent, contaminated mantle magmas fed intrusions such as the Zahedan diorite.

  6. Glycation, glycoxidation, and cross-linking of collagen by glucose. Kinetics, mechanisms, and inhibition of late stages of the Maillard reaction.

    PubMed

    Fu, M X; Wells-Knecht, K J; Blackledge, J A; Lyons, T J; Thorpe, S R; Baynes, J W

    1994-05-01

    The Maillard or browning reaction between sugar and protein contributes to the increased chemical modification and cross-linking of long-lived tissue proteins in diabetes. To evaluate the role of glycation and oxidation in these reactions, we have studied the effects of oxidative and antioxidative conditions and various types of inhibitors on the reaction of glucose with rat tail tendon collagen in phosphate buffer at physiological pH and temperature. The chemical modifications of collagen that were measured included fructoselysine, the glycoxidation products N epsilon-(carboxymethyl)lysine and pentosidine and fluorescence. Collagen cross-linking was evaluated by analysis of cyanogen bromide peptides using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by changes in collagen solubilization on treatment with pepsin or sodium dodecylsulfate. Although glycation was unaffected, formation of glycoxidation products and cross-linking of collagen were inhibited by antioxidative conditions. The kinetics of formation of glycoxidation products proceeded with a short lag phase and were independent of the amount of Amadori adduct on the protein, suggesting that autoxidative degradation of glucose was a major contributor to glycoxidation and cross-linking reactions. Chelators, sulfhydryl compounds, antioxidants, and aminoguanidine also inhibited formation of glycoxidation products, generation of fluorescence, and cross-linking of collagen without significant effect on the extent of glycation of the protein. We conclude that autoxidation of glucose or Amadori compounds on protein plays a major role in the formation of glycoxidation products and cross-liking of collagen by glucose in vitro and that chelators, sulfhydryl compounds, antioxidants, and aminoguanidine act as uncouplers of glycation from subsequent glycoxidation and cross-linking reactions. PMID:8168645

  7. Use of the Novel Plk1 Inhibitor ZK-Thiazolidinone to Elucidate Functions of Plk1 in Early and Late Stages of Mitosis

    PubMed Central

    Santamaria, Anna; Neef, Rüdiger; Eberspächer, Uwe; Eis, Knut; Husemann, Manfred; Mumberg, Dominik; Prechtl, Stefan; Schulze, Volker; Siemeister, Gerhard; Wortmann, Lars; Barr, Francis A.

    2007-01-01

    Polo-like kinase 1 (Plk1) is a key regulator of mitotic progression and cell division in eukaryotes. It is highly expressed in tumor cells and considered a potential target for cancer therapy. Here, we report the discovery and application of a novel potent small-molecule inhibitor of mammalian Plk1, ZK-Thiazolidinone (TAL). We have extensively characterized TAL in vitro and addressed TAL specificity within cells by studying Plk1 functions in sister chromatid separation, centrosome maturation, and spindle assembly. Moreover, we have used TAL for a detailed analysis of Plk1 in relation to PICH and PRC1, two prominent interaction partners implicated in spindle assembly checkpoint function and cytokinesis, respectively. Specifically, we show that Plk1, when inactivated by TAL, spreads over the arms of chromosomes, resembling the localization of its binding partner PICH, and that both proteins are mutually dependent on each other for correct localization. Finally, we show that Plk1 activity is essential for cleavage furrow formation and ingression, leading to successful cytokinesis. PMID:17671160

  8. Melt solidification and late-stage evaporation in the evolution of a FUN inclusion from the Vigarano C3V chondrite

    NASA Astrophysics Data System (ADS)

    Davis, A. M.; MacPherson, G. J.; Clayton, R. N.; Mayeda, T. K.; Sylvester, P. J.; Grossman, L.; Hinton, R. W.; Laughlin, J. R.

    1991-02-01

    Results are presented on a detailed petrologic, chemical, and isotopic study of the so-called FUN inclusion (1623-5) from the Vigarano C3V chondrite. It is shown that the precursor material from which the Vigarano 1623-5 has formed contained some nuclear isotopic anomalies; this precursor was composed of melted and crystallized spinel, olivine, fassaite, and melilite. The results on the petrologic and isotopic properties of 1623-5 indicate unambiguously the action of volatilization in the evolution of this inclusion.

  9. Developmental exposure of aflatoxin B1 reversibly affects hippocampal neurogenesis targeting late-stage neural progenitor cells through suppression of cholinergic signaling in rats.

    PubMed

    Tanaka, Takeshi; Mizukami, Sayaka; Hasegawa-Baba, Yasuko; Onda, Nobuhiko; Sugita-Konishi, Yoshiko; Yoshida, Toshinori; Shibutani, Makoto

    2015-10-01

    To elucidate the maternal exposure effects of aflatoxin B1 (AFB1) and its metabolite aflatoxin M1, which is transferred into milk, on postnatal hippocampal neurogenesis, pregnant Sprague-Dawley rats were provided a diet containing AFB1 at 0, 0.1, 0.3, or 1.0 ppm from gestational day 6 to day 21 after delivery on weaning. Offspring were maintained through postnatal day (PND) 77 without AFB1 exposure. Following exposure to 1.0 ppm AFB1, offspring showed no apparent systemic toxicity at weaning, whereas dams showed increased liver weight and DNA repair gene upregulation in the liver. In the hippocampal dentate gyrus of male PND 21 offspring, the number of doublecortin(+) progenitor cells were decreased, which was associated with decreased proliferative cell population in the subgranular zone at ≥ 0.3 ppm, although T-box brain 2(+) cells, tubulin beta III(+) cells, gamma-H2A histone family, member X(+) cells, and cyclin-dependent kinase inhibitor 1A(+) cells did not fluctuate in number. AFB1 exposure examined at 1.0 ppm also resulted in transcript downregulation of the cholinergic receptor subunit Chrna7 and dopaminergic receptor Drd2 in the dentate gyrus, although there was no change in transcript levels of DNA repair genes. In the hippocampal dentate hilus, interneurons expressing CHRNA7 or phosphorylated tropomyosin receptor kinase B (TRKB) decreased at ≥ 0.3 ppm. On PND 77, there were no changes in neurogenesis-related parameters. These results suggested that maternal AFB1 exposure reversibly affects hippocampal neurogenesis targeting type-3 progenitor cells. This mechanism likely involves suppression of cholinergic signals on hilar GABAergic interneurons and brain-derived neurotrophic factor-TRKB signaling from granule cells. The no-observed-adverse-effect level for offspring neurogenesis was determined to be 0.1 ppm (7.1-13.6 mg/kg body weight/day). PMID:26260870

  10. InCVAX - A novel strategy for treatment of late-stage, metastatic cancers through photoimmunotherapy induced tumor-specific immunity

    PubMed Central

    Zhou, Feifan; Li, Xiaosong; Naylor, Mark F.; Hode, Tomas; Nordquist, Robert E.; Alleruzzo, Luciano; Raker, Joseph; Lam, Samuel S.K.; Du, Nan; Shi, Lei; Wang, Xiuli; Chen, Wei R.

    2015-01-01

    A novel, promising potential cancer vaccine strategy was proposed to use a two-injection procedure for solid tumors to prompt the immune system to identify and systemically eliminate the primary and metastatic cancers. The two-injection procedure consists of local photothermal application on a selected tumor intended to liberate whole cell tumor antigens, followed by a local injection of an immunoadjuvant that consists of a semi-synthetic functionalized glucosamine polymer, N-dihydro-galacto-chitosan (GC), which is intended to activate antigen presenting cells and facilitate an increased uptake of tumor antigens. This strategy is thus proposed as an in situ autologous cancer vaccine (inCVAX) that may activate antigen presenting cells and expose them to tumor antigens in situ, with the intention of inducing a systemic tumor specific T-cell response. Here, the development of inCVAX for the treatment of metastatic cancers in the past decades are systematically reviewed. The antitumor immune responses of local photothermal treatment and immunological stimulation with GC are also discussed. This treatment approach is also commonly referred to as laser immunotherapy (LIT). PMID:25633839

  11. Experimental oral transmission of chronic wasting disease to red deer (Cervus elaphus elaphus): Early detection and late stage distribution of protease-resistant prion protein

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic wasting disease CWD is the transmissible spongiform encephalopathy or prion disease of wild and farmed cervid ruminants, including Rocky Mountain elk (Cervus elaphus nelsoni), white tailed deer (Odocoileus virginianus), mule deer (Odocoileus hemionus), or moose (Alces alces). Reliable data ...

  12. Late stage Imbrium volcanism on the Moon: Evidence for two source regions and implications for the thermal history of Mare Imbrium

    NASA Astrophysics Data System (ADS)

    Zhang, F.; Zhu, M.-H.; Zou, Y. L.

    2016-07-01

    Large open fissures or volcanic rifts can form in volcanic terrain and they are also conduits for magma ascending through the lunar crust. On the Moon, we investigated two volcanic source regions within Mare Imbrium by tracking surface morphologic features and compositional information. The Euler source region is situated at the southwest edge of the basin, while the Lambert source region lies off the south margin of the Imbrium mascon. Survey of dike surface manifestations in Euler source site suggest that dikes are the possible source of the local upper basaltic flows and the last lava phases with well developed scarps near the Euler crater, which extend northeast to the basin center. The Euler dike swarm are radial to the basin and reveal possible dike-to-conduit transition mechanism. They reveal radial subsurface fractures which may be tensional cracks preceding to the emplacement of the last stage of the mare fill. Of these, the largest dike has a more than 100 km length. The spatial arrangement of tectonic and volcanic features in Lambert source site is directly or indirectly controlled by the regional compression and extension stresses associated with flexure in response to mascon and basalt loading. In addition, compositional variation trends show a general southwest-to-northeast flooding direction of the exposed high-Ti basalts. This will have important implications for both the Imbrium basin's mare volcanism and for the thermal evolution of Mare Imbrium and the Moon.

  13. Changes during late-stage embryonic development from egg-juvenile to free-living hatchling in Chinese freshwater crab Sinopotamon yangtsekiense (Decapoda, Brachyura, Potamidae)

    NASA Astrophysics Data System (ADS)

    Xue, Junzeng; Liu, Yan; Cumberlidge, Neil; Wu, Huixian

    2013-05-01

    This study expands on recent reports that direct development in the Chinese potamid freshwater crab Sinopotamon yangtsekiense involves the completion of all brachyuran larval stages (nauplius, zoea, and megalopa) inside the egg case during embryonic development. Detailed studies of embryonic development in this species revealed the presence of an additional larval stage (the egg-juvenile) between the megalopa and the free-living hatchling crab. We described and compared the appendages of the head, thorax, and abdomen of the egg-juvenile with those of the hatchling crab in S. yangtsekiense. Significant differences were found between most of the appendages of these two stages with a soft exoskeleton in the egg-juvenile, no joint articulation, a slimmer appearance, and a lack of setae when compared with the newly emerged free-living hatchling crab. These modifications of the appendages are related to the confinement within the egg case of the egg-megalopa and egg-juvenile during direct development, and the need for the free-living hatchling freshwater crab to move, feed, and respire. In marine crabs, the megalopa gives rise to the first crab stage whereas in freshwater crabs the egg-juvenile follows the megalopa and immediately precedes the free-living first crab stage.

  14. Late-stage volcano geomorphic evolution of the Pleistocene San Francisco Mountain, Arizona (USA), based on high-resolution DEM analysis and 40Ar/39Ar chronology

    NASA Astrophysics Data System (ADS)

    Karátson, Dávid; Telbisz, Tamás; Singer, Brad S.

    2010-09-01

    The cone-building volcanic activity and subsequent erosion of San Francisco Mountain, AZ, USA, were studied by using high-resolution digital elevation model (DEM) analysis and new 40Ar/39Ar dating. By defining remnants or planèzes of the volcano flanks in DEM-derived images, the original edifice can be reconstructed. We propose a two-cone model with adjacent summit vents which were active in different times. The reconstructed cones were 4,460 and 4,350 m high a.s.l., corresponding to ˜2,160 and 2,050 m relative height, respectively. New 40Ar/39Ar data allow us to decipher the chronological details of the cone-building activity. We dated the Older and Younger Andesites of the volcano that, according to previous mapping, built the stage 2 and stage 3 stratocones, respectively. The new 40Ar/39Ar plateau ages yielded 589-556 ka for the Older and 514-505 ka for the Younger Andesites, supporting their distinct nature with a possible dormant period between. The obtained ages imply an intense final (≤100 ka long) cone-building activity, terminating ˜100 ka earlier than indicated by previous K-Ar ages. Moreover, 40Ar/39Ar dating constrains the formation of the Inner Basin, an elliptical depression in the center of the volcano initially created by flank collapse. A 530 ka age (with a ±58.4 ka 2σ error) for a post-depression dacite suggests that the collapse event is geochronologically indistinguishable from the termination of the andesitic cone-building activity. According to our DEM analysis, the original cone of San Francisco Mountain had a volume of about 80 km3. Of this volume, ˜7.5 km3 was removed by the flank collapse and subsequent glacial erosion, creating the present-day enlarged Inner Basin, and ˜2 km3 was removed from the outer valleys by erosion. Based on volumetric analysis and previous and new radiometric ages, the average long-term eruption rate of San Francisco Mountain was ˜0.2 km3/ka, which is a medium rate for long-lived stratovolcanoes. However, according to the new 40Ar/39Ar dates for the last ≤100 ka period, the final stratovolcanic activity was characterized by a greater ˜0.3 km3/ka rate.

  15. Potent efficacy of metronomic topotecan and pazopanib combination therapy in preclinical models of primary or late stage metastatic triple-negative breast cancer

    PubMed Central

    Man, Shan; Bocci, Guido; Kerbel, Robert S.

    2015-01-01

    Metronomic chemotherapy has shown promising activity in numerous preclinical studies and also some phase II clinical studies involving various tumor types, and is currently undergoing phase III trial evaluation. Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Herein, we evaluated the potential therapeutic impact and molecular mechanisms of topotecan administered in a continuous low-dose metronomic (LDM) manner, alone or in concurrent combination with pazopanib, an antiangiogenic tyrosine kinase inhibitor (TKI), in a triple-negative, primary and metastatic breast cancer orthotopic model; potential molecular mechanisms of efficacy were also studied, especially the impact of hypoxic conditions. The combination of metronomic topotecan and pazopanib significantly enhanced antitumor activity compared to monotherapy with either drug and prolonged survival, even in the advanced metastatic survival setting, with a marked decrease in tumor vascularity, proliferative index, and the induction of apoptosis. Significant changes in tumor angiogenesis, cancer cell proliferation, apoptosis, HIF1α levels, HIF-1 target genes and ABCG2 were found both in vitro and in tumor tissue. Notably, the pazopanib and metronomic topotecan combination treatment inhibited expression of HIF1α and ABCG2 genes in cells grown under hypoxic conditions, and this was associated with an increased intracellular concentration of the active form of topotecan. Our results suggest a potential novel therapeutic option for the treatment of metastatic triple-negative breast cancer patients. PMID:26623560

  16. Experimental oral transmission of chronic wasting disease to red deer (Cervus elaphus elaphus): Early detection and late stage distribution of protease-resistant prion protein

    PubMed Central

    Balachandran, Aru; Harrington, Noel P.; Algire, James; Soutyrine, Andrei; Spraker, Terry R.; Jeffrey, Martin; González, Lorenzo; O’Rourke, Katherine I.

    2010-01-01

    Chronic wasting disease (CWD), an important emerging prion disease of cervids, is readily transmitted by intracerebral or oral inoculation from deer-to-deer and elk-to-elk, suggesting the latter is a natural route of exposure. Studies of host range susceptibility to oral infection, particularly of those species found in habitats where CWD currently exists are imperative. This report describes the experimental transmission of CWD to red deer following oral inoculation with infectious CWD material of elk origin. At 18 to 20 months post-inoculation, mild to moderate neurological signs and weight loss were observed and animals were euthanized and tested using 3 conventional immunological assays. The data indicate that red deer are susceptible to oral challenge and that tissues currently used for CWD diagnosis show strong abnormal prion (PrPCWD) accumulation. Widespread peripheral PrPCWD deposition involves lymphoreticular tissues, endocrine tissues, and cardiac muscle and suggests a potential source of prion infectivity, a means of horizontal transmission and carrier state. PMID:20436863

  17. The formation and evolution of youthful gullies on Mars: Gullies as the late-stage phase of Mars’ most recent ice age

    NASA Astrophysics Data System (ADS)

    Dickson, James L.; Head, James W.

    2009-11-01

    Gullies are extremely young erosional/depositional systems on Mars that have been carved by an agent that was likely to have been comprised in part by liquid water [Malin, M.C., Edgett, K.S., 2000. Evidence for recent groundwater seepage and surface runoff on Mars. Science 288, 2330-2335; McEwen, A.S. et al., 2007. A closer look at water-related geologic activity on Mars. Science 317, 1706-1709]. The strong latitude and orientation dependencies that have been documented for gullies require (1) a volatile near the surface, and (2) that insolation is an important factor for forming gullies. These constraints have led to two categories of interpretations for the source of the volatiles: (1) liquid water at depth beneath the melting isotherm that erupts suddenly ("groundwater"), and (2) ice at the surface or within the uppermost layer of soil that melts during optimal insolation conditions ("surface/near-surface melting"). In this contribution we synthesize global, hemispheric, regional and local studies of gullies across Mars and outline the criteria that must be met by any successful explanation for the formation of gullies. We further document trends in both hemispheres that emphasize the importance of top-down melting of recent ice-rich deposits and the cold-trapping of atmospherically-derived H 2O frost/snow as important components in the formation of gullies. This provides context for the incorporation of high-resolution multi-spectral and hyper-spectral data from the Mars Reconnaissance Orbiter that show that (1) cold-trapping of seasonal H 2O frost occurs at the alcove/channel-level on contemporary Mars; (2) gullies are episodically active systems; (3) gullies preferentially form in the presence of deposits plausibly interpreted as remnants of the Late Amazonian emplacement of ice-rich material; and (4) gully channels frequently emanate from the crest of alcoves instead of the base, showing that alcove generation is not necessarily a product of undermining and collapse at these locations, a prediction of the groundwater model. We interpret these various lines of evidence to mean that the majority of gullies on Mars are explained by the episodic melting of atmospherically emplaced snow/ice under spin-axis/orbital conditions characteristic of the last several Myr.

  18. Identification of genes expressed by Phakopsora pachyrhizi, the pathogen causing soybean rust, at a late stage of infection of susceptible soybean leaves

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soybean is one of the top five agricultural products in the United States and is highly susceptible to P. pachyrhizi, an exotic obligate biotrophic fungus. The amount of genomic information about P. pachyrhizi is small, which limits our understanding of the soybean-soybean rust pathogen interaction ...

  19. EXTENDED CYTOPROTECTIVE EFFECT OF AUTOPHAGY IN THE LATE STAGES OF SEPSIS AND FLUCTUATIONS IN SIGNAL TRANSDUCTION PATHWAYS IN A RAT EXPERIMENTAL MODEL OF KIDNEY INJURY

    PubMed Central

    Karagiannidis, Ioannis; Kataki, Agapi; Glustianou, Georgia; Memos, Nikolaos; Papalois, Apostolos; Alexakis, Nikolaos; Zografos, George C.; Konstadoulakis, Manoussos M.

    2016-01-01

    ABSTRACT The impact of a potential autophagy (LC3a/b) deregulation in hyper and in hypo stages during sepsis-induced kidney injury and the temporal profile of phosphorylated extracellular signal-related kinase, P38 (pP38), Akt (pAKT), and 13-3-3β protein were investigated in the current study, using a rat cecal ligation and puncture (CLP) model, by means of flow cytometry and immunohistochemistry. Cell viability was assessed by protein C zymogen concentrate (PC), 7-aminoactinomycin D (7-AAD) staining and inflammation by S100 protein immunostaining. The impact of reduced kidney inflammation in autophagy was assessed by PC administration, an anti-inflammatory and cytoprotective substance. Sepsis induction increased LC3a/b expression, which presented two peaks at 6 and 36 h after CLP, both in the percentage of positive cells (P = 0.024, P = 0.025, respectively) and in fluorescence intensity. At 6 h when inflammation was already apparent, LC3a/b increase was escorted by phosphorylated extracellular signal-related kinase stimulation and high cell viability (65%), designating autophagy as a cytoprotective mechanism against microbial infection. The phosphorylation of P38 was delayed to 12 h after CLP, when autophagy was reduced. pAkt and 14-3-3β expression was stimulated between 6 and 36 h after CLP, although a slight inhibition of pAkt within each cell was detected (lower MnIX value). During the second peak, inflammation was intensified, necrosis was significantly increased with LC3a/b+/7-AAD + cells to present a 1.5-fold increase. Protein C zymogen concentrate administration declined autophagy at 6 and 36 h after CLP and reduced necrosis, whereas double positive LC3a/b and 7-AAD cells were increased by 1.68 and 2.78-fold, respectively. These data open new prospectives in sepsis treatment, since they further support that autophagy represents a cytoprotective mechanism triggered by stress conditions, rather than an alternative cell death pathway. PMID:26513702