Science.gov

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 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

  7. 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

  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 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

  13. 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

  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. 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

  17. [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

  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. 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

  17. 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

  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. 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 ...

  4. 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

  5. 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…

  6. 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

  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. 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.

  11. 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

  12. 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

  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. 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

  17. 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

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  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 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

  13. 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

  14. 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.

  15. 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

  16. 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

  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. 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

  2. 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

  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. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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

  18. 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.

  19. 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

  20. 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

  1. 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

  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. 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

  4. 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

  5. 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

  6. 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

  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

    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.

  9. 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.

  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. 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

  17. 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

  18. 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

  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. 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

  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. 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

  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. 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

  8. 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

  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. 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

  12. 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.

  13. 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

  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. 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 ...

  3. 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

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. 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.

  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. 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.

  17. 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

  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. 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

  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.

    2009-10-01

    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

  4. 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

  5. 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

  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

    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

  17. 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

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. 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

  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 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