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Sample records for late-stage gambiense human

  1. Treatment of human late stage gambiense trypanosomiasis with alpha-difluoromethylornithine (eflornithine): efficacy and tolerance in 14 cases in Côte d'Ivoire.

    PubMed

    Doua, F; Boa, F Y; Schechter, P J; Miézan, T W; Diai, D; Sanon, S R; De Raadt, P; Haegele, K D; Sjoerdsma, A; Konian, K

    1987-11-01

    alpha-Difluoromethylornithine (DFMO; eflornithine), an inhibitor of polyamine biosynthesis, was used to treat 14 patients with late stage gambiense sleeping sickness, 12 cases having been previously treated with and considered refractory to melarsoprol. alpha-Difluoromethylornithine was administered intravenously at a dose of 400 mg/kg/day for 14 days followed by oral treatment, 300 mg/kg/day, for 21-28 days. In all patients treatment was associated with rapid disappearance of trypanosomes from body fluids (in several cases within 24 hr) and decreased cerebrospinal fluid white blood cell counts. In all but one patient, who died of a pulmonary infection during treatment, alpha-difluoromethylornithine produced a dramatic reversal of clinical signs and symptoms of the disease. Determination of drug concentrations in serum and cerebrospinal fluid of 5 patients demonstrated that alpha-difluoromethylornithine diffuses into the central nervous system with cerebrospinal fluid levels representing up to 51% of corresponding serum concentrations. Diarrhea, abdominal pain, and anemia were the most frequent side effects associated with therapy, but were reversible and did not necessitate discontinuation of treatment. Four patients have been followed for more than 2 years post-treatment without evidence of relapse.

  2. Estimates of the duration of the early and late stage of gambiense sleeping sickness

    PubMed Central

    Checchi, Francesco; Filipe, João AN; Haydon, Daniel T; Chandramohan, Daniel; Chappuis, François

    2008-01-01

    Background The durations of untreated stage 1 (early stage, haemo-lymphatic) and stage 2 (late stage, meningo-encephalitic) human African trypanosomiasis (sleeping sickness) due to Trypanosoma brucei gambiense are poorly quantified, but key to predicting the impact of screening on transmission. Here, we outline a method to estimate these parameters. Methods We first model the duration of stage 1 through survival analysis of untreated serological suspects detected during Médecins Sans Frontières interventions in Uganda and Sudan. We then deduce the duration of stage 2 based on the stage 1 to stage 2 ratio observed during active case detection in villages within the same sites. Results Survival in stage 1 appears to decay exponentially (daily rate = 0.0019; mean stage 1 duration = 526 days [95%CI 357 to 833]), possibly explaining past reports of abnormally long duration. Assuming epidemiological equilibrium, we estimate a similar duration of stage 2 (500 days [95%CI 345 to 769]), for a total of nearly three years in the absence of treatment. Conclusion Robust estimates of these basic epidemiological parameters are essential to formulating a quantitative understanding of sleeping sickness dynamics, and will facilitate the evaluation of different possible control strategies. PMID:18261232

  3. 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

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

    PubMed

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

    2014-11-01

    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.

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

    PubMed

    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

  6. 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

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

    PubMed

    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.

  8. 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

  9. The journey towards elimination of gambiense human African trypanosomiasis: not far, nor easy.

    PubMed

    Franco, J R; Simarro, P P; Diarra, A; Ruiz-Postigo, J A; Jannin, J G

    2014-05-01

    Considering the epidemic situation of gambiense human African trypanosomiasis (HAT) at the end of the twentieth century, the World Health Organization (WHO) and partners strengthened disease control and surveillance. Over the last 15 years, the activities implemented through the National Control Programmes have brought gambiense HAT under control and now its elimination is deemed as an achievable goal. In 2012, WHO targeted gambiense HAT for elimination as a public health problem by 2020. The final goal will be the sustainable disease elimination by 2030, defined as the interruption of the transmission of gambiense HAT. The elimination is considered feasible, because of the epidemiological vulnerability of the disease, the current state of control, the availability of strategies and tools and international commitment and political will. Integration of activities in the health system is needed to ensure the sustainability of the elimination. The development of user-friendly diagnostic and treatment tools will facilitate the integration process. Adequate funding is needed to implement activities, but also to support research that will make the elimination sustainable. A long-term commitment by donors is needed and ownership of the process by endemic countries is critical.

  10. Gambiense Human African Trypanosomiasis and Immunological Memory: Effect on Phenotypic Lymphocyte Profiles and Humoral Immunity

    PubMed Central

    Lejon, Veerle; Mumba Ngoyi, Dieudonné; Kestens, Luc; Boel, Luc; Barbé, Barbara; Kande Betu, Victor; van Griensven, Johan; Bottieau, Emmanuel; Muyembe Tamfum, Jean-Jacques; Jacobs, Jan; Büscher, Philippe

    2014-01-01

    In mice, experimental infection with Trypanosoma brucei causes decreased bone marrow B-cell development, abolished splenic B-cell maturation and loss of antibody mediated protection including vaccine induced memory responses. Nothing is known about this phenomenon in human African trypanosomiasis (HAT), but if occurring, it would imply the need of revaccination of HAT patients after therapy and abolish hope for a HAT vaccine. The effect of gambiense HAT on peripheral blood memory T- and B-cells and on innate and vaccine induced antibody levels was examined. The percentage of memory B- and T-cells was quantified in peripheral blood, prospectively collected in DR Congo from 117 Trypanosoma brucei gambiense infected HAT patients before and six months after treatment and 117 controls at the same time points. Antibodies against carbohydrate antigens on red blood cells and against measles were quantified. Before treatment, significantly higher percentages of memory B-cells, mainly T-independent memory B-cells, were observed in HAT patients compared to controls (CD20+CD27+IgM+, 13.0% versus 2.0%, p<0.001). The percentage of memory T-cells, mainly early effector/memory T-cells, was higher in HAT (CD3+CD45RO+CD27+, 19.4% versus 16.7%, p = 0.003). After treatment, the percentage of memory T-cells normalized, the percentage of memory B-cells did not. The median anti-red blood cell carbohydrate IgM level was one titer lower in HAT patients than in controls (p<0.004), and partially normalized after treatment. Anti-measles antibody concentrations were lower in HAT patients than in controls (medians of 1500 versus 2250 mIU/ml, p = 0.02), and remained so after treatment, but were above the cut-off level assumed to provide protection in 94.8% of HAT patients, before and after treatment (versus 98.3% of controls, p = 0.3). Although functionality of the B-cells was not verified, the results suggest that immunity was conserved in T.b. gambiense infected HAT patients and

  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. Distribution of elastic fibers in the head and neck: a histological study using late-stage human fetuses.

    PubMed

    Kinoshita, Hideaki; Umezawa, Takashi; Omine, Yuya; Kasahara, Masaaki; Rodríguez-Vázquez, José Francisco; Murakami, Gen; Abe, Shinichi

    2013-03-01

    There is little or no information about the distribution of elastic fibers in the human fetal head. We examined this issue in 15 late-stage fetuses (crown-rump length, 220-320 mm) using aldehyde-fuchsin and elastica-Masson staining, and we used the arterial wall elastic laminae and external ear cartilages as positive staining controls. The posterior pharyngeal wall, as well as the ligaments connecting the laryngeal cartilages, contained abundant elastic fibers. In contrast with the sphenomandibular ligament and the temporomandibular joint disk, in which elastic fibers were partly present, the discomalleolar ligament and the fascial structures around the pterygoid muscles did not have any elastic fibers. In addition, the posterior marginal fascia of the prestyloid space did contain such fibers. Notably, in the middle ear, elastic fibers accumulated along the tendons of the tensor tympani and stapedius muscles and in the joint capsules of the ear ossicle articulations. Elastic fibers were not seen in any other muscle tendons or vertebral facet capsules in the head and neck. Despite being composed of smooth muscle, the orbitalis muscle did not contain any elastic fibers. The elastic fibers in the sphenomandibular ligament seemed to correspond to an intermediate step of development between Meckel's cartilage and the final ligament. Overall, there seemed to be a mini-version of elastic fiber distribution compared to that in adults and a different specific developmental pattern of connective tissues. The latter morphology might be a result of an adaptation to hypoxic conditions during development.

  13. Syndromic Algorithms for Detection of Gambiense Human African Trypanosomiasis in South Sudan

    PubMed Central

    Palmer, Jennifer J.; Surur, Elizeous I.; Goch, Garang W.; Mayen, Mangar A.; Lindner, Andreas K.; Pittet, Anne; Kasparian, Serena; Checchi, Francesco; Whitty, Christopher J. M.

    2013-01-01

    Background Active screening by mobile teams is considered the best method for detecting human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense but the current funding context in many post-conflict countries limits this approach. As an alternative, non-specialist health care workers (HCWs) in peripheral health facilities could be trained to identify potential cases who need testing based on their symptoms. We explored the predictive value of syndromic referral algorithms to identify symptomatic cases of HAT among a treatment-seeking population in Nimule, South Sudan. Methodology/Principal Findings Symptom data from 462 patients (27 cases) presenting for a HAT test via passive screening over a 7 month period were collected to construct and evaluate over 14,000 four item syndromic algorithms considered simple enough to be used by peripheral HCWs. For comparison, algorithms developed in other settings were also tested on our data, and a panel of expert HAT clinicians were asked to make referral decisions based on the symptom dataset. The best performing algorithms consisted of three core symptoms (sleep problems, neurological problems and weight loss), with or without a history of oedema, cervical adenopathy or proximity to livestock. They had a sensitivity of 88.9–92.6%, a negative predictive value of up to 98.8% and a positive predictive value in this context of 8.4–8.7%. In terms of sensitivity, these out-performed more complex algorithms identified in other studies, as well as the expert panel. The best-performing algorithm is predicted to identify about 9/10 treatment-seeking HAT cases, though only 1/10 patients referred would test positive. Conclusions/Significance In the absence of regular active screening, improving referrals of HAT patients through other means is essential. Systematic use of syndromic algorithms by peripheral HCWs has the potential to increase case detection and would increase their participation in HAT programmes. The

  14. 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

  15. Trypanosoma brucei gambiense Spliced Leader RNA Is a More Specific Marker for Cure of Human African Trypanosomiasis Than T. b. gambiense DNA.

    PubMed

    Ilboudo, Hamidou; Camara, Oumou; Ravel, Sophie; Bucheton, Bruno; Lejon, Veerle; Camara, Mamadou; Kaboré, Jacques; Jamonneau, Vincent; Deborggraeve, Stijn

    2015-12-15

    To assess the efficacy of treatment for human African trypanosomiasis, accurate tests that can discriminate relapse from cure are needed. We report the first data that the spliced leader (SL) RNA is a more specific marker for cure of human African trypanosomiasis than parasite DNA. In blood samples obtained from 61 patients in whom human African trypanosomiasis was cured, SL RNA detection had specificities of 98.4%-100%, while DNA detection had a specificity of only 77%. Data from our proof-of-concept study show that SL RNA detection has high potential as a test of cure.

  16. 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

  17. 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

  18. Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness).

    PubMed

    Kennedy, Peter Ge

    2013-02-01

    Human African trypanosomiasis, or sleeping sickness, is caused by infection with parasites of the genus Trypanosoma, transmitted by the tsetse fly. The disease has two forms, Trypanosoma brucei (T b) rhodesiense and T b gambiense; and is almost always fatal if untreated. Despite a recent reduction in the number of reported cases, patients with African trypanosomiasis continue to present major challenges to clinicians. Because treatment for CNS-stage disease can be very toxic, diagnostic staging to distinguish early-stage from late-stage disease when the CNS in invaded is crucial but remains problematic. Melarsoprol is the only available treatment for late-stage T b rhodesiense infection, but can be lethal to 5% of patients owing to post-treatment reactive encephalopathy. Eflornithine combined with nifurtimox is the first-line treatment for late-stage T b gambiense. New drugs are in the pipeline for treatment of CNS human African trypanosomiasis, giving rise to cautious optimism.

  19. Human African trypanosomiasis (T.b. gambiense): a study of 16 fatal cases of sleeping sickness with some observations on acute reactive arsenical encephalopathy.

    PubMed

    Adams, J H; Haller, L; Boa, F Y; Doua, F; Dago, A; Konian, K

    1986-01-01

    The principal clinical and pathological findings in 16 fatal cases of human African trypanosomiasis caused by T.b. Gambiense are described. The changes in the brain took the form of a non-specific lymphoplasmacytic meningo-encephalitis of varying intensity. Other features included morular cells, diffuse microglial hyperplasia, and large reactive astrocytes in the white matter. Carditis was identified in 10 cases. Acute reactive arsenical encephalopathy appeared to be the principal cause of death in 10 patients. Convulsions figured prominently in this type of encephalopathy in seven patients and were sufficiently severe to produce hypoxic brain damage. In three cases of acute reactive arsenical encephalopathy the structural changes in the brain were those of acute haemorrhagic leucoencephalopathy.

  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. 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

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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

  7. Nutraceutical use in late-stage cancer

    PubMed Central

    Morris, Jay; Brown, Vondina; Ellis, Jane; Logothetis, Britt; Weber, Rebecca

    2012-01-01

    Access to a wealth of information on the internet has led many cancer patients to use complementary methods as an adjunct to traditional therapy for cancer, with, and more often, without informing their primary caregiver. Of the common complementary modalities, the use of dietary supplements appears to be highly prevalent in patients in active treatment for cancer, and later in cancer survivors. Emerging research suggests that some plant-based agents may, indeed, impact late-stage cancer, influencing molecular processes corrupted by tumor cells to evade detection, expand clonally, and invade surrounding tissues. The intent of this article is to review some of the current science underpinning the use of nutraceuticals in the latter stages of cancer. PMID:20714787

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. Late-Stage Deoxyfluorination of Alcohols with PhenoFluor™

    PubMed Central

    Sladojevich, Filippo; Arlow, Sophie I.; Tang, Pingping; Ritter, Tobias

    2013-01-01

    An operationally simple protocol for the selective deoxyfluorination of structurally complex alcohols is presented. Several fluorinated derivatives of natural products and pharmaceuticals have been prepared to showcase the potential of the method for late-stage diversification and its functional group compatibility. A series of simple guidelines for predicting selectivity in substrates with multiple alcohols is given. PMID:23397884

  14. Late-Stage Fluorination: From Fundamentals to Application

    PubMed Central

    2015-01-01

    In this brief account, we review work from our lab with a focus on late-stage introduction of fluorine and fluorinated functional groups into small molecules. We attempt to highlight practical developments, which we believe may have potential for industrial applications, and critically reflect on developments that may not yet meet the bar for practical use. PMID:25838756

  15. Late-stage deoxyfluorination of alcohols with PhenoFluor.

    PubMed

    Sladojevich, Filippo; Arlow, Sophie I; Tang, Pingping; Ritter, Tobias

    2013-02-20

    An operationally simple protocol for the selective deoxyfluorination of structurally complex alcohols is presented. Several fluorinated derivatives of natural products and pharmaceuticals have been prepared to showcase the potential of the method for late-stage diversification and its functional group compatibility. A series of simple guidelines for predicting the selectivity in substrates with multiple alcohols is given.

  16. Late-stage formation of carbon-fluorine bonds.

    PubMed

    Campbell, Michael G; Ritter, Tobias

    2014-06-01

    In this account, we review work from our lab on the development of methods for carbon-fluorine bond formation, with an emphasis on late-stage fluorination of functionalized small molecules and synthesis of (18) F-labeled molecules for potential use as tracers in positron emission tomography (PET). We attempt to highlight reactions that we feel are of particular practical relevance, as well as areas of research where there is still significant room for advancement.

  17. Late-stage fluorination: fancy novelty or useful tool?

    PubMed

    Neumann, Constanze N; Ritter, Tobias

    2015-03-01

    Charming fluorine: This Essay examines the recent surge in late-stage fluorination reactions and outlines challenges that need to be overcome to increase the impact of modern fluorination methods on the synthesis of complex organofluorine compounds. It is outlined how an improved understanding of the bonding interactions of fluoride could lead to a new class of mild fluorinating reagents and a range of functional-group-tolerant reactions.

  18. 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

  19. 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

  20. Trypanosoma brucei gambiense adaptation to different mammalian sera is associated with VSG expression site plasticity.

    PubMed

    Cordon-Obras, Carlos; Cano, Jorge; González-Pacanowska, Dolores; Benito, Agustin; Navarro, Miguel; Bart, Jean-Mathieu

    2013-01-01

    Trypanosoma brucei gambiense infection is widely considered an anthroponosis, although it has also been found in wild and domestic animals. Thus, fauna could act as reservoir, constraining the elimination of the parasite in hypo-endemic foci. To better understand the possible maintenance of T. b. gambiense in local fauna and investigate the molecular mechanisms underlying adaptation, we generated adapted cells lines (ACLs) by in vitro culture of the parasites in different mammalian sera. Using specific antibodies against the Variant Surface Glycoproteins (VSGs) we found that serum ACLs exhibited different VSG variants when maintained in pig, goat or human sera. Although newly detected VSGs were independent of the sera used, the consistent appearance of different VSGs suggested remodelling of the co-transcribed genes at the telomeric Expression Site (VSG-ES). Thus, Expression Site Associated Genes (ESAGs) sequences were analysed to investigate possible polymorphism selection. ESAGs 6 and 7 genotypes, encoding the transferrin receptor (TfR), expressed in different ACLs were characterised. In addition, we quantified the ESAG6/7 mRNA levels and analysed transferrin (Tf) uptake. Interestingly, the best growth occurred in pig and human serum ACLs, which consistently exhibited a predominant ESAG7 genotype and higher Tf uptake than those obtained in calf and goat sera. We also detected an apparent selection of specific ESAG3 genotypes in the pig and human serum ACLs, suggesting that other ESAGs could be involved in the host adaptation processes. Altogether, these results suggest a model whereby VSG-ES remodelling allows the parasite to express a specific set of ESAGs to provide selective advantages in different hosts. Finally, pig serum ACLs display phenotypic adaptation parameters closely related to human serum ACLs but distinct to parasites grown in calf and goat sera. These results suggest a better suitability of swine to maintain T. b. gambiense infection supporting

  1. Trypanosoma brucei gambiense adaptation to different mammalian sera is associated with VSG expression site plasticity.

    PubMed

    Cordon-Obras, Carlos; Cano, Jorge; González-Pacanowska, Dolores; Benito, Agustin; Navarro, Miguel; Bart, Jean-Mathieu

    2013-01-01

    Trypanosoma brucei gambiense infection is widely considered an anthroponosis, although it has also been found in wild and domestic animals. Thus, fauna could act as reservoir, constraining the elimination of the parasite in hypo-endemic foci. To better understand the possible maintenance of T. b. gambiense in local fauna and investigate the molecular mechanisms underlying adaptation, we generated adapted cells lines (ACLs) by in vitro culture of the parasites in different mammalian sera. Using specific antibodies against the Variant Surface Glycoproteins (VSGs) we found that serum ACLs exhibited different VSG variants when maintained in pig, goat or human sera. Although newly detected VSGs were independent of the sera used, the consistent appearance of different VSGs suggested remodelling of the co-transcribed genes at the telomeric Expression Site (VSG-ES). Thus, Expression Site Associated Genes (ESAGs) sequences were analysed to investigate possible polymorphism selection. ESAGs 6 and 7 genotypes, encoding the transferrin receptor (TfR), expressed in different ACLs were characterised. In addition, we quantified the ESAG6/7 mRNA levels and analysed transferrin (Tf) uptake. Interestingly, the best growth occurred in pig and human serum ACLs, which consistently exhibited a predominant ESAG7 genotype and higher Tf uptake than those obtained in calf and goat sera. We also detected an apparent selection of specific ESAG3 genotypes in the pig and human serum ACLs, suggesting that other ESAGs could be involved in the host adaptation processes. Altogether, these results suggest a model whereby VSG-ES remodelling allows the parasite to express a specific set of ESAGs to provide selective advantages in different hosts. Finally, pig serum ACLs display phenotypic adaptation parameters closely related to human serum ACLs but distinct to parasites grown in calf and goat sera. These results suggest a better suitability of swine to maintain T. b. gambiense infection supporting

  2. Trypanosoma brucei gambiense Adaptation to Different Mammalian Sera Is Associated with VSG Expression Site Plasticity

    PubMed Central

    Cordon-Obras, Carlos; Cano, Jorge; González-Pacanowska, Dolores; Benito, Agustin; Navarro, Miguel; Bart, Jean-Mathieu

    2013-01-01

    Trypanosoma brucei gambiense infection is widely considered an anthroponosis, although it has also been found in wild and domestic animals. Thus, fauna could act as reservoir, constraining the elimination of the parasite in hypo-endemic foci. To better understand the possible maintenance of T. b. gambiense in local fauna and investigate the molecular mechanisms underlying adaptation, we generated adapted cells lines (ACLs) by in vitro culture of the parasites in different mammalian sera. Using specific antibodies against the Variant Surface Glycoproteins (VSGs) we found that serum ACLs exhibited different VSG variants when maintained in pig, goat or human sera. Although newly detected VSGs were independent of the sera used, the consistent appearance of different VSGs suggested remodelling of the co-transcribed genes at the telomeric Expression Site (VSG-ES). Thus, Expression Site Associated Genes (ESAGs) sequences were analysed to investigate possible polymorphism selection. ESAGs 6 and 7 genotypes, encoding the transferrin receptor (TfR), expressed in different ACLs were characterised. In addition, we quantified the ESAG6/7 mRNA levels and analysed transferrin (Tf) uptake. Interestingly, the best growth occurred in pig and human serum ACLs, which consistently exhibited a predominant ESAG7 genotype and higher Tf uptake than those obtained in calf and goat sera. We also detected an apparent selection of specific ESAG3 genotypes in the pig and human serum ACLs, suggesting that other ESAGs could be involved in the host adaptation processes. Altogether, these results suggest a model whereby VSG-ES remodelling allows the parasite to express a specific set of ESAGs to provide selective advantages in different hosts. Finally, pig serum ACLs display phenotypic adaptation parameters closely related to human serum ACLs but distinct to parasites grown in calf and goat sera. These results suggest a better suitability of swine to maintain T. b. gambiense infection supporting

  3. 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

  4. 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

  5. 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

  6. 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

  7. Late stages of the synchronized macrophage fusion in osteoclast formation depend on dynamin.

    PubMed

    Verma, Santosh K; Leikina, Evgenia; Melikov, Kamran; Chernomordik, Leonid V

    2014-12-15

    Macrophage fusion that leads to osteoclast formation is one of the most important examples of cell-cell fusion in development, tissue homoeostasis and immune response. Protein machinery that fuses macrophages remains to be identified. In the present study, we explored the fusion stage of osteoclast formation for RAW macrophage-like murine cells and for macrophages derived from human monocytes. To uncouple fusion from the preceding differentiation processes, we accumulated fusion-committed cells in the presence of LPC (lysophosphatidylcholine) that reversibly blocks membrane merger. After 16 h, we removed LPC and observed cell fusion events that would normally develop within 16 h develop instead within 30-90 min. Thus, whereas osteoclastogenesis, generally, takes several days, our approach allowed us to focus on an hour in which we observe robust fusion between the cells. Complementing syncytium formation assay with a novel membrane merger assay let us study the synchronized fusion events downstream of a local merger between two plasma membranes, but before expansion of nascent membrane connections and complete unification of the cells. We found that the expansion of membrane connections detected as a growth of multinucleated osteoclasts depends on dynamin activity. In contrast, a merger between the plasma membranes of the two cells was not affected by inhibitors of dynamin GTPase. Thus dynamin that was recently found to control late stages of myoblast fusion also controls late stages of macrophage fusion, revealing an intriguing conserved mechanistic motif shared by diverse cell-cell fusion processes. PMID:25336256

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

    PubMed

    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.

  9. 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

  10. 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

  11. Manometric investigation of anorectal function in early and late stage Parkinson's disease

    PubMed Central

    Bassotti, G.; Maggio, D.; Battaglia, E.; Giulietti, O.; Spinozzi, F.; Reboldi, G.; Serra, A. M.; Emanuelli, G.; Chiarioni, G.

    2000-01-01

    Abnormal gastrointestinal function is relatively frequent in Parkinson's disease, and constipation is a disturbing symptom in many patients. However, it remains to be established whether anorectal abnormalities are characteristic of the late stages of the disease. Clinical and anorectal manometric function were investigated in groups of early and late stage parkinsonian patients. Thirty one patients (19 men, 12 women, age range 22 to 89 years) entered the study. The disease severity was assessed by Hoehn and Yahr staging: there were four (12.9%) stage I, seven (22.6%) stage II, 10 (32.2%) stage III, and 10 (32.2%) stage IV patients. Anorectal variables were measured by standard manometric equipment and techniques. Values obtained in early stage patients (Hoehn and Yahr stage I and II) were compared with those obtained in late stage patients (Hoehn and Yahr stage III and IV). Overall, more than 70% of patients complained of chronic constipation, with chronic laxative use reported in more than 30%. Late stage patients were slightly older than their early stage counterparts. Pelvic floor dyssynergia was documented in more than 60% of patients. Manometric variables were not different in the two groups. In conclusion, defecatory dysfunction is frequent in Parkinson's disease, it is not confined to late stage patients, and it is found early in the course of the disease. This has potential implications for a targeted therapeutic approach.

 PMID:10811703

  12. 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

  13. 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

  14. 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.

  15. 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

  16. Late stage spinodal decomposition in binary fluids: comparison between computer simulation and experimental results

    NASA Astrophysics Data System (ADS)

    Koga, Tsuyoshi; Kawasaki, Kyozi; Takenaka, Mikihito; Hashimoto, Takeji

    1993-09-01

    We present detailed comparisons of results on the late stage dynamics of spinodal decomposition obtained by the computer simulation of the time-dependent Ginzburg-Landau equation with hydrodynamic interaction and experiments of a polymer mixture of polybutadiene and polyisoprene. We show that the temporally linear domain growth law, which is characteristic for viscous fluids, is observed in both simulation and experiment in the late stage. Some quantities obtained in such a hydrodynamic domain growth region, such as the interface area density and the scaling function, are compared in detail. Especially, we show that the scaling functions for the two systems are in quantitative agreement.

  17. Late-stage [(18)F]Fluorination: New Solutions to Old Problems.

    PubMed

    Brooks, Allen F; Topczewski, Joseph J; Ichiishi, Naoko; Sanford, Melanie S; Scott, Peter J H

    2014-12-01

    The last 2-3 years have seen numerous relationships develop between organometallic chemists, fluorine chemists and PET Centers around the world. These collaborations have led to the development of many new strategies for the late-stage introduction of fluorine-18 into complex bioactive molecules. In this perspective we highlight recent developments and key milestones since 2011. PMID:25379166

  18. Late-stage [18F]Fluorination: New Solutions to Old Problems

    PubMed Central

    Brooks, Allen F.; Topczewski, Joseph J.; Ichiishi, Naoko; Sanford, Melanie S.; Scott, Peter J. H.

    2014-01-01

    The last 2–3 years have seen numerous relationships develop between organometallic chemists, fluorine chemists and PET Centers around the world. These collaborations have led to the development of many new strategies for the late-stage introduction of fluorine-18 into complex bioactive molecules. In this perspective we highlight recent developments and key milestones since 2011. PMID:25379166

  19. 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

  20. Functional architecture of two exclusively late stage pollen-specific promoters in rice (Oryza sativa L.).

    PubMed

    Yan, Shuo; Wang, Zhongni; Liu, Yuan; Li, Wei; Wu, Feng; Lin, Xuelei; Meng, Zheng

    2015-07-01

    Late stage pollen-specific promoters are important tools in crop molecular breeding. Several such promoters, and their functional motifs, have been well characterized in dicotyledonous plants such as tomato and tobacco. However, knowledge about the functional architecture of such promoters is limited in the monocotyledonous plant rice. Here, pollen-late-stage-promoter 1 (PLP1) and pollen-late-stage-promoter 2 (PLP2) were characterized using a stable transformation system in rice. Histochemical staining showed that the two promoters exclusively drive GUS expression in late-stage pollen grains in rice. 5' deletion analysis revealed that four regions, including the -1159 to -720 and the -352 to -156 regions of PLP1 and the -740 to -557 and the -557 to -339 regions of PLP2, are important in maintaining the activity and specificity of these promoters. Motif mutation analysis indicated that 'AGAAA' and 'CAAT' motifs in the -740 to -557 region of PLP2 act as enhancers in the promoter. Gain of function experiments indicated that the novel TA-rich motif 'TACATAA' and 'TATTCAT' in the core region of the PLP1 and PLP2 promoters is necessary, but not sufficient, for pollen-specific expression in rice. Our results provide evidence that the enhancer motif 'AGAAA' is conserved in the pollen-specific promoters of both monocots and eudicots, but that some functional architecture characteristics are different.

  1. 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 ...

  2. Understanding quality-of-life while living with late-stage lung cancer: an exploratory study.

    PubMed

    Adorno, Gail; Brownell, Gracie

    2014-01-01

    U.S. Veterans have a higher prevalence of advanced lung cancer and poorer survival outcomes compared to the general population; yet, no studies exist which specifically explore the psychosocial and existential quality-of-life (QOL) of late-stage lung cancer among this population. This article presents the perspectives of older veterans (N = 12) living with late-stage lung cancer who were receiving chemotherapy, routine hospice care, or both concurrently. Based on individual interviews, themes associated with loss of functionality, close relationships, and communicative acts contributed to veterans' perceptions of diminished or enhanced QOL while living with advanced disease. An overarching theme, loss of the person I know myself to be, suggests that personhood is an important concept to consider in QOL assessment. While findings suggest that the experiences of older Veterans with late-stage lung cancer are similar to other populations of lung cancer patients, and persons with incurable cancer in general, further research regarding the influence of veteran identity at end-of-life is warranted. Further research is needed which explores the influence of a whole person approach to QOL during life-limiting illness and end-of-life decision-making, particularly while receiving late-stage cancer-directed therapy.

  3. 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…

  4. Late-stage diversification of biologically active pyridazinones via a direct C-H functionalization strategy.

    PubMed

    Li, Wei; Fan, Zhoulong; Geng, Kaijun; Xu, Youjun; Zhang, Ao

    2015-01-14

    Divergent C-H functionalization reactions (arylation, carboxylation, olefination, thiolation, acetoxylation, halogenation, naphthylation) using a pyridazinone moiety as an internal directing group were successfully established. This approach offers a late-stage, ortho-selective diversification of a biologically active pyridazinone scaffold. Seven series of novel pyridazinone analogues were synthesized conveniently as the synthetic precursors of potential sortase A (SrtA) inhibitors.

  5. Problem solving, impulse control and planning in patients with early- and late-stage Huntington's disease.

    PubMed

    Mörkl, Sabrina; Müller, Nicole J; Blesl, Claudia; Wilkinson, Leonora; Tmava, Adelina; Wurm, Walter; Holl, Anna K; Painold, Annamaria

    2016-10-01

    Sub-domains of executive functions, including problems with planning, accuracy, impulsivity, and inhibition, are core features of Huntington's disease. It is known that the decline of cognitive function in Huntington's disease is related to the anatomical progression of pathology in the basal ganglia. However, it remains to be determined whether the severity of executive dysfunction depends on the stage of the disease. To examine the severity of sub-domains of executive dysfunction in early- and late-stage Huntington's disease, we studied performance in the Tower of London task of two groups of Huntington's disease patients (Group 1: early, n = 23, and Group 2: late stage, n = 29), as well as a third group of age, education, and IQ matched healthy controls (n = 34). During the task, we measured the total number of problems solved, total planning time, and total number of breaks taken. One aspect of executive function indexed by the number of solved problems seems to progress in the course of the disease. Late-stage Huntington's disease patients scored significantly worse than early-stage patients and controls, and early-stage patients scored significantly worse than controls on this measure of accuracy. In contrast, late- and early-stage HD patients did not differ in terms of planning time and number of breaks. Early- and late-stage HD pathology has a different impact on executive sub-domains. While accuracy differs between early- and late-stage HD patients, other domains like planning time and number of breaks do not. Striatal degeneration, which is a characteristic feature of the disease, might not affect all aspects of executive function in HD.

  6. Problem solving, impulse control and planning in patients with early- and late-stage Huntington's disease.

    PubMed

    Mörkl, Sabrina; Müller, Nicole J; Blesl, Claudia; Wilkinson, Leonora; Tmava, Adelina; Wurm, Walter; Holl, Anna K; Painold, Annamaria

    2016-10-01

    Sub-domains of executive functions, including problems with planning, accuracy, impulsivity, and inhibition, are core features of Huntington's disease. It is known that the decline of cognitive function in Huntington's disease is related to the anatomical progression of pathology in the basal ganglia. However, it remains to be determined whether the severity of executive dysfunction depends on the stage of the disease. To examine the severity of sub-domains of executive dysfunction in early- and late-stage Huntington's disease, we studied performance in the Tower of London task of two groups of Huntington's disease patients (Group 1: early, n = 23, and Group 2: late stage, n = 29), as well as a third group of age, education, and IQ matched healthy controls (n = 34). During the task, we measured the total number of problems solved, total planning time, and total number of breaks taken. One aspect of executive function indexed by the number of solved problems seems to progress in the course of the disease. Late-stage Huntington's disease patients scored significantly worse than early-stage patients and controls, and early-stage patients scored significantly worse than controls on this measure of accuracy. In contrast, late- and early-stage HD patients did not differ in terms of planning time and number of breaks. Early- and late-stage HD pathology has a different impact on executive sub-domains. While accuracy differs between early- and late-stage HD patients, other domains like planning time and number of breaks do not. Striatal degeneration, which is a characteristic feature of the disease, might not affect all aspects of executive function in HD. PMID:27372072

  7. Effects of Elevated In Ovo Selenium Exposure on Late Stage Development of Xenopus laevis Tadpoles.

    PubMed

    Massé, Anita J; Muscatello, Jorgelina R; Janz, David M

    2016-10-01

    The effects of elevated in ovo selenium (Se) exposure on late stage larval Xenopus laevis development were investigated. Adult females were fed diets augmented with selenomethionine for 68 days and bred with untreated males to obtain embryos with measured concentrations of 1.6 (control), 10.8, 28.1 and 81.7 μg Se/g dry mass. Embryos were reared under uncontaminated conditions until 50 % of individuals within an aquarium had completed metamorphosis. The highest in ovo Se exposure group exhibited greater froglet body mass and snout to vent length while having a higher proportion of tadpoles at earlier stages of development. No differences were detected among treatment groups for mortality or metamorphic timing during the rearing period. This research suggests that in ovo Se exposure has minimal effect on the survival and development of late stage larval X. laevis in a controlled laboratory environment with adequate food availability. PMID:27412338

  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. Neighborhood changes in concentrated immigration and late stage breast cancer diagnosis.

    PubMed

    Cho, Young Ik; Johnson, Timothy P; Barrett, Richard E; Campbell, Richard T; Dolecek, Therese A; Warnecke, Richard B

    2011-02-01

    Immigrant women are at greater risk for late stage breast cancer diagnosis. The rapid increase in the US foreign-born population and new immigration patterns lead us to investigate the association between changes in immigrant population and the likelihood of distant metastasis stage at diagnosis of breast cancer among women in Cook County, Illinois. Analyses employed Illinois State Cancer Registry data for 42,714 breast cancer cases diagnosed between 1994 and 2003 in conjunction with 1990 and 2000 Census tract data. We find that concentration of and increases in immigrant populations within neighborhoods contributed to the risk of late stage breast cancer diagnosis. These findings suggest that, although some health indicators for immigrant populations have improved in recent years, important health disparities in breast cancer diagnosis still remain at the neighborhood level. They further suggest that cancer screening and follow-up resources should be directed to areas experiencing rapid increases in immigrant populations.

  10. Effects of Elevated In Ovo Selenium Exposure on Late Stage Development of Xenopus laevis Tadpoles.

    PubMed

    Massé, Anita J; Muscatello, Jorgelina R; Janz, David M

    2016-10-01

    The effects of elevated in ovo selenium (Se) exposure on late stage larval Xenopus laevis development were investigated. Adult females were fed diets augmented with selenomethionine for 68 days and bred with untreated males to obtain embryos with measured concentrations of 1.6 (control), 10.8, 28.1 and 81.7 μg Se/g dry mass. Embryos were reared under uncontaminated conditions until 50 % of individuals within an aquarium had completed metamorphosis. The highest in ovo Se exposure group exhibited greater froglet body mass and snout to vent length while having a higher proportion of tadpoles at earlier stages of development. No differences were detected among treatment groups for mortality or metamorphic timing during the rearing period. This research suggests that in ovo Se exposure has minimal effect on the survival and development of late stage larval X. laevis in a controlled laboratory environment with adequate food availability.

  11. 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

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

    PubMed Central

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

    2015-01-01

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

  13. Numerical simulation of two-dimensional late-stage coarsening for nucleation and growth

    SciTech Connect

    Akaiwa, N.; Meiron, D.I.

    1995-06-01

    Numerical simulations of two-dimensional late-stage coarsening for nucleation and growth or Ostwald ripening are performed at area fractions 0.05 to 0.4 using the monopole and dipole approximations of a boundary integral formulation for the steady state diffusion equation. The simulations are performed using two different initial spatial distributions. One is a random spatial distribution, and the other is a random spatial distribution with depletion zones around the particles. We characterize the spatial correlations of particles by the radial distribution function, the pair correlation functions, and the structure function. Although the initial spatial correlations are different, we find time-independent scaled correlation functions in the late stage of coarsening. An important feature of the late-stage spatial correlations is that depletion zones exist around particles. A log-log plot of the structure function shows that the slope at small wave numbers is close to 4 and is {minus}3 at very large wave numbers for all area fractions. At large wave numbers we observe oscillations in the structure function. We also confirm the cubic growth law of the average particle radius. The rate constant of the cubic growth law and the particle size distribution functions are also determined. We find qualitatively good agreement between experiments and the present simulations. In addition, the present results agree well with simulation results using the Cahn-Hilliard equation.

  14. Identification of transcriptome induced in roots of maize seedlings at the late stage of waterlogging

    PubMed Central

    2010-01-01

    Background Plants respond to low oxygen stress, particularly that caused by waterlogging, by altering transcription and translation. Previous studies have mostly focused on revealing the mechanism of the response at the early stage, and there is limited information about the transcriptional profile of genes in maize roots at the late stage of waterlogging. The genetic basis of waterlogging tolerance is largely unknown. In this study, the transcriptome at the late stage of waterlogging was assayed in root cells of the tolerant inbred line HZ32, using suppression subtractive hybridization (SSH). A forward SSH library using RNA populations from four time points (12 h, 16 h, 20 h and 24 h) after waterlogging treatment was constructed to reveal up-regulated genes, and transcriptional and linkage data was integrated to identify candidate genes for waterlogging tolerance. Results Reverse Northern analysis of a set of 768 cDNA clones from the SSH library revealed a large number of genes were up-regulated by waterlogging. A total of 465 ESTs were assembled into 296 unigenes. Bioinformatic analysis revealed that the genes were involved in complex pathways, such as signal transduction, protein degradation, ion transport, carbon and amino acid metabolism, and transcriptional and translational regulation, and might play important roles at the late stage of the response to waterlogging. A significant number of unigenes were of unknown function. Approximately 67% of the unigenes could be aligned on the maize genome and 63 of them were co-located within reported QTLs. Conclusion The late response to waterlogging in maize roots involves a broad spectrum of genes, which are mainly associated with two response processes: defense at the early stage and adaption at the late stage. Signal transduction plays a key role in activating genes related to the tolerance mechanism for survival during prolonged waterlogging. The crosstalk between carbon and amino acid metabolism reveals that

  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. Practical Electrochemical Anodic Oxidation of Polycyclic Lactams for Late Stage Functionalization**

    PubMed Central

    Frankowski, Kevin J.; Liu, Ruzhang; Milligan, Gregory L.; Moeller, Kevin D.

    2015-01-01

    Electrochemistry provides a powerful tool for the late-stage functionalization of complex lactams. A two-stage protocol for converting lactams, many of which are preparable through the intramolecular Schmidt reaction of keto azides, is presented. In the first step, anodic oxidation in MeOH using a repurposed power source provides a convenient route to lactams bearing a methoxy group adjacent to nitrogen. Treatment of these intermediates with a Lewis acid in DCM permits the regeneration of a reactive acyliminium ion that is then reacted with a range of nucleophilic species. PMID:26371961

  19. 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

  20. 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

  1. 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

  2. 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

  3. Thermal drawdown and late-stage seismic-slip fault reactivation in enhanced geothermal reservoirs

    NASA Astrophysics Data System (ADS)

    Gan, Quan; Elsworth, Derek

    2014-12-01

    Late-stage seismic slip in geothermal reservoirs has been shown as a potential mechanism for inducing seismic events of magnitudes to ~2.6 as late as two decades into production. We investigate the propagation of fluid pressures and thermal stresses in a prototypical geothermal reservoir containing a centrally located critically stressed fault from a doublet injector and withdrawal well to define the likelihood, timing, and magnitude of events triggered by both fluid pressures and thermal stresses. We define two bounding modes of fluid production from the reservoir. For injection at a given temperature, these bounding modes relate to either low- or high-relative flow rates. At low relative dimensionless flow rates the pressure pulse travels slowly, the pressure-driven changes in effective stress are muted, but thermal drawdown propagates through the reservoir as a distinct front. This results in the lowest likelihood of pressure-triggered events but the largest likelihood of late-stage thermally triggered events. Conversely, at high relative non-dimensional flow rates the propagating pressure pulse is larger and migrates more quickly through the reservoir but the thermal drawdown is uniform across the reservoir and without the presence of a distinct thermal front, and less capable of triggering late-stage seismicity. We evaluate the uniformity of thermal drawdown as a function of a dimensionless flow rate QD that scales with fracture spacing s (m), injection rate q (kg/s), and the distance between the injector and the target point L∗ (QD ∝ qs2/L∗). This parameter enables the reservoir characteristics to be connected with the thermal drawdown response around the fault and from that the corresponding magnitude and timing of seismicity to be determined. These results illustrate that the dimensionless temperature gradient adjacent to the fault dTD/dxD is exclusively controlled by the factor QD. More significantly, this temperature gradient correlates directly

  4. [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

  5. 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

  6. Between Two Worlds: Liminality and Late-Stage Cancer-Directed Therapy.

    PubMed

    Adorno, Gail

    2015-01-01

    Disease-directed therapy near death is a growing trend among persons living with late-stage cancer. As a sociocultural phenomenon, cancer-directed therapy (e.g., chemotherapy) when given for very advanced disease is a process that offers questionable benefits and portends further suffering, but also suggests potential for growth and transcendence. Theories and concepts drawn from cultural anthropology, sociology, and existentialism illustrate how contextual factors contribute to the creation of a "liminal space"; the latter part of the cancer trajectory where living and dying can overlap. When applied to clinical practice, this theoretical framework gives the patient, family, and health care provider a way of "unmasking" a period of transition during terminal illness when aggressive disease-directed care continues to be provided. The liminal space may function as an existential plane; a gateway or threshold with inherent potential for psychospiritual development during the final stage of life.

  7. General guidance on exploratory and confirmatory subgroup analysis in late-stage clinical trials.

    PubMed

    Dmitrienko, Alex; Muysers, Christoph; Fritsch, Arno; Lipkovich, Ilya

    2016-01-01

    This article focuses on a broad class of statistical and clinical considerations related to the assessment of treatment effects across patient subgroups in late-stage clinical trials. This article begins with a comprehensive review of clinical trial literature and regulatory guidelines to help define scientifically sound approaches to evaluating subgroup effects in clinical trials. All commonly used types of subgroup analysis are considered in the article, including different variations of prospectively defined and post-hoc subgroup investigations. In the context of confirmatory subgroup analysis, key design and analysis options are presented, which includes conventional and innovative trial designs that support multi-population tailoring approaches. A detailed summary of exploratory subgroup analysis (with the purpose of either consistency assessment or subgroup identification) is also provided. The article promotes a more disciplined approach to post-hoc subgroup identification and formulates key principles that support reliable evaluation of subgroup effects in this setting.

  8. Two-dimensional late-stage coarsening for nucleation and growth at high-area fractions

    SciTech Connect

    Akaiwa, N.; Meiron, D.I.

    1996-07-01

    Numerical simulations of two-dimensional late-stage coarsening for nucleation and growth (Ostwald ripening) are performed at large-area fractions without shape restrictions. We employ efficient computational methods that allow us to study large systems. The free energy of the system we consider is composed of two different curves. Thus, the system consists of a set of isolated particles even at high-area fractions. This is totally different from the interconnected spinodal structures generated by the Cahn-Hilliard model, where the free energy is composed of a single curve. Although the domain structures are quite different, we find that the qualitative features of the structure function for both models are the same. {copyright} {ital 1996 The American Physical Society.}

  9. Between Two Worlds: Liminality and Late-Stage Cancer-Directed Therapy.

    PubMed

    Adorno, Gail

    2015-01-01

    Disease-directed therapy near death is a growing trend among persons living with late-stage cancer. As a sociocultural phenomenon, cancer-directed therapy (e.g., chemotherapy) when given for very advanced disease is a process that offers questionable benefits and portends further suffering, but also suggests potential for growth and transcendence. Theories and concepts drawn from cultural anthropology, sociology, and existentialism illustrate how contextual factors contribute to the creation of a "liminal space"; the latter part of the cancer trajectory where living and dying can overlap. When applied to clinical practice, this theoretical framework gives the patient, family, and health care provider a way of "unmasking" a period of transition during terminal illness when aggressive disease-directed care continues to be provided. The liminal space may function as an existential plane; a gateway or threshold with inherent potential for psychospiritual development during the final stage of life. PMID:26625508

  10. 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.

  11. HCN1 channels in cerebellar Purkinje cells promote late stages of learning and constrain synaptic inhibition

    PubMed Central

    Rinaldi, Arianna; Defterali, Cagla; Mialot, Antoine; Garden, Derek L F; Beraneck, Mathieu; Nolan, Matthew F

    2013-01-01

    Neural computations rely on ion channels that modify neuronal responses to synaptic inputs. While single cell recordings suggest diverse and neurone type-specific computational functions for HCN1 channels, their behavioural roles in any single neurone type are not clear. Using a battery of behavioural assays, including analysis of motor learning in vestibulo-ocular reflex and rotarod tests, we find that deletion of HCN1 channels from cerebellar Purkinje cells selectively impairs late stages of motor learning. Because deletion of HCN1 modifies only a subset of behaviours involving Purkinje cells, we asked whether the channel also has functional specificity at a cellular level. We find that HCN1 channels in cerebellar Purkinje cells reduce the duration of inhibitory synaptic responses but, in the absence of membrane hyperpolarization, do not affect responses to excitatory inputs. Our results indicate that manipulation of subthreshold computation in a single neurone type causes specific modifications to behaviour. PMID:24000178

  12. Late stages in the development of folds as deduced from model experiments

    NASA Astrophysics Data System (ADS)

    Dubey, Ashok Kumar

    1980-06-01

    A vein pattern around Bude, England, provides evidence that there has been a change in the direction of bulk extension during progressive development of folds. In the early history of fold development the direction of maximum extension was parallel to the axial surfaces of the folds and normal to the fold hinge whilst during the later stages of fold development the direction of maximum extension was along the fold hinge lines. An attempt has been made to understand the geometric evolution of such folds by performing experiments with plasticine models in the laboratory. Multilayer models were subjected to large deformation and late stages in the folding process have been observed. The experiments also show the effect of surfaces of décollment on fold geometry and the development of second order folds.

  13. Aqueous alteration on the parent bodies of carbonaceous chondrites: Computer simulations of late-stage oxidation

    NASA Technical Reports Server (NTRS)

    Bourcier, W. L.; Zolensky, Michael E.

    1991-01-01

    CI carbonaceous chondrites may be products of hydrous alteration of CV- or anhydrous CM-type materials. The CIs typically contain veins filled with carbonates and sulfates, probably indicating a period of late stage aqueous alteration under oxidizing conditions. To test this idea, computer simulations of aqueous alteration of CV- and CM-type carbonaceous were performed. Simulations were restricted to the oxidation of hydrous mineral assemblages produced in previous simulations in order to determine whether further reaction and oxidation results in the phyllosilicate, carbonate, sulfate and oxide vein assemblages typical of CI carbonaceous chondrites. Our simulations were performed at 1, 25, 100, and 150 C (the appropriate temperature range) for the CV and CM mineral assemblages and using the computer code EQ3/6.

  14. 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.

  15. Late-stage phases of glacial Lake Ojibway in the central Abitibi region, eastern Canada

    NASA Astrophysics Data System (ADS)

    Roy, Martin; Veillette, Jean J.; Daubois, Virginie; Ménard, Maxime

    2015-11-01

    The decay of the Laurentide ice sheet southern margin during the last deglaciation led to the development of Lake Ojibway that covered large expanses of northeastern Ontario and northwestern Quebec. The history of Ojibway lake phases is poorly detailed mainly because of the physical configuration of the lake basin and the dominance of fine-grained glaciolacustrine sediments that prevent the formation of well-developed and extensive sandy strandlines. Here we use a complex sequence of relict terraces carved in glaciolacustrine rhythmites to document the evolution of Lake Ojibway in northwestern Quebec. Specifically, lake levels were constrained by measuring the elevation of 154 raised wave-cut scarps present in the eastern Lake Abitibi region. Results provide evidence for four distinct shorelines with elevations of 299, 289, 282, and 272 m (± 1 m) at the latitude of La Sarre. The highest lake level documented appears to be linked to one of the two known (Kinojévis) phases of Lake Ojibway, while the three other lake levels project well below the main outlet system that controlled the elevation of the lake during the deglaciation. The elevation, uplift gradients, and areal extent of these lower shorelines suggest that the two intermediate lake levels likely formed during late stages of the deglaciation, following abrupt drawdowns of the lake's surface. The fourth and lowest shoreline is associated with a postglacial lake that developed after the complete withdrawal of Ojibway water from the region. These low-elevation shorelines bring new evidence for significant changes in the areal extent and depth of Lake Ojibway near the end of the deglaciation. Although the origin of these late-stage phases remains unspecified, the associated drawdowns likely implied routing events into newly deglaciated regions and/or (subglacial) meltwater discharges into the North Atlantic.

  16. 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

  17. 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

  18. 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

  19. 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

  20. Increased prevalence of late stage T cell activation antigen (VLA-1) in active juvenile chronic arthritis.

    PubMed Central

    Odum, N; Morling, N; Platz, P; Hofmann, B; Ryder, L P; Heilmann, C; Pedersen, F K; Nielsen, L P; Friis, J; Svejgaard, A

    1987-01-01

    The presence of activated T cells as judged from the reaction with monoclonal antibodies (MoAb) against (a) a late stage T cell activation antigen (VLA-1), (b) the interleukin 2 (IL2) receptor (CD25), and (c) four different HLA class II molecules (HLA-DR, DRw52, DQ, and DP) was studied in 15 patients with active juvenile chronic arthritis (JCA), 10 patients with JCA in remission, and 11 age matched, healthy controls. In addition, the distribution of T 'helper/inducer' (CD4+), T 'suppressor/inducer' (CD4+, Leu8+), T 'suppressor/cytotoxic' (CD8+), and 'natural killer' (NK) cells (CD16+) was studied. Twenty patients and six controls were investigated for the capability to stimulate alloreactivated primed lymphocytes. The prevalence of VLA-1 positive, large cells was significantly increased to 5% (median value) in active JCA as compared with JCA in remission (2%, p less than 0.05) and controls (1%, p less than 0.05), whereas no significant difference between JCA in remission and controls was observed. Except for two patients with active JCA, less than 1% IL2 receptor bearing cells were found in patients with JCA and controls. No significant difference in the prevalence and expression of the various HLA class II antigens was observed between the groups. Similarly, no significant differences in stimulatory capability in secondary mixed lymphocyte culture (MLC) were seen. The distribution of T helper/inducer (CD4+), T suppressor/cytotoxic (CD8+), and NK cells was similar in active JCA, JCA in remission, and controls. The prevalence of T suppressor/inducer (CD4+,Leu8+) cells was higher in remission JCA (17%) than in active JCA (11%) and controls (10%). This increase, however, did not reach statistical significance. In conclusion, late stage but not early stage T cell activation antigens were increased in patients with active JCA as compared with patients with JCA in remission and control, whereas some patients in remission had an increased prevalence of T suppressor

  1. [Traditional and Western medical treatment of 211 cases of late stage lung cancer].

    PubMed

    Xin, Y L

    1993-03-01

    211 cases of middle and late stage of lung cancers were treated. They were failed to response to other treatments, or not indicated for surgical, radio- or chemotherapy. The diameter of tumors was 3 to 13 cm. Method of treatment: Electrochemical treatment (ECT group, 130 cases): needles was inserted into the cancer served as electrodes, the amount of electricity varied according to the size of tumors, usually 100 coulomb per 1 cm3 of cancer; TCM group (40 cases): Chinese medicine named AC7851 was given. One course of treatment lasted two months of continuous medication; ECT-TCM group (41 cases): ECT and AC7851 were given simultaneously. According to international grading, the short term effective rate of ECT group was 69.2%; that of TCM group was 52.5%, and ECT-TCM group 85.3%. The difference between the effective rate of latter group and former two groups was significant, P < 0.05. After 1-4 years of follow up, the 4 year survival rate of the 3 groups were 46.3%, 40.0% and 53.8% respectively. Above-mentioned results indicated that the combined ECT-TCM therapy is the most effective treatment. PMID:8339028

  2. 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.

  3. 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.

  4. Perceptions of Home Health Nurses Regarding Suffering, Artificial Nutrition, and Hydration in Late-Stage Dementia.

    PubMed

    Smith, Lenora; Amella, Elaine J; Nemeth, Lynne

    2016-10-01

    The purpose of this study was to explore perceptions of home healthcare nurses related to suffering, artificial nutrition and hydration in people with late-stage dementia, and if these perceptions influence care to people with dementia and their families. Part of a mixed-methods study, the qualitative portion examined perceptions of home healthcare nurses in a rural area in the southern United States. Seventeen home healthcare nurses participated in this study. Semistructured focus group interview questions were used. Constant comparative analysis was the method used for coding transcripts. Three themes emerged from the analysis: patient/family comfort, futility, and symbols of suffering. Although many of the nurses reported that artificial nutrition and hydration was of comfort to the patient and family because of the potential for "starving," they also felt it prolonged the patient's suffering due to the invasive procedure, need for restraints, and possibility of fluid overload. Several nurses felt that artificial nutrition and hydration gave a sense of false hope to the family that the patient would live longer. The perceptions of these home healthcare nurses influence their care to people with dementia and their families related to artificial nutrition and hydration, possibly based on experience. Their perceptions could influence family decisions regarding treatment options. Further research and education with home healthcare nurses is vital to ensure nurses are appropriately caring for patients with dementia and their families.

  5. 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.

  6. 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.

  7. 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

  8. 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

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

    USGS Publications Warehouse

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

    1996-01-01

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

  10. VMAT2 identified as a regulator of late-stage β-cell differentiation.

    PubMed

    Sakano, Daisuke; Shiraki, Nobuaki; Kikawa, Kazuhide; Yamazoe, Taiji; Kataoka, Masateru; Umeda, Kahoko; Araki, Kimi; Mao, Di; Matsumoto, Shirou; Nakagata, Naomi; Andersson, Olov; Stainier, Didier; Endo, Fumio; Kume, Kazuhiko; Uesugi, Motonari; Kume, Shoen

    2014-02-01

    Cell replacement therapy for diabetes mellitus requires cost-effective generation of high-quality, insulin-producing, pancreatic β cells from pluripotent stem cells. Development of this technique has been hampered by a lack of knowledge of the molecular mechanisms underlying β-cell differentiation. The present study identified reserpine and tetrabenazine (TBZ), both vesicular monoamine transporter 2 (VMAT2) inhibitors, as promoters of late-stage differentiation of Pdx1-positive pancreatic progenitor cells into Neurog3 (referred to henceforth as Ngn3)-positive endocrine precursors. VMAT2-controlled monoamines, such as dopamine, histamine and serotonin, negatively regulated β-cell differentiation. Reserpine or TBZ acted additively with dibutyryl adenosine 3',5'-cyclic AMP, a cell-permeable cAMP analog, to potentiate differentiation of embryonic stem (ES) cells into β cells that exhibited glucose-stimulated insulin secretion. When ES cell-derived β cells were transplanted into AKITA diabetic mice, the cells reversed hyperglycemia. Our protocol provides a basis for the understanding of β-cell differentiation and its application to a cost-effective production of functional β cells for cell therapy.

  11. 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

  12. 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.

  13. 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

  14. Perceptions of Home Health Nurses Regarding Suffering, Artificial Nutrition, and Hydration in Late-Stage Dementia.

    PubMed

    Smith, Lenora; Amella, Elaine J; Nemeth, Lynne

    2016-10-01

    The purpose of this study was to explore perceptions of home healthcare nurses related to suffering, artificial nutrition and hydration in people with late-stage dementia, and if these perceptions influence care to people with dementia and their families. Part of a mixed-methods study, the qualitative portion examined perceptions of home healthcare nurses in a rural area in the southern United States. Seventeen home healthcare nurses participated in this study. Semistructured focus group interview questions were used. Constant comparative analysis was the method used for coding transcripts. Three themes emerged from the analysis: patient/family comfort, futility, and symbols of suffering. Although many of the nurses reported that artificial nutrition and hydration was of comfort to the patient and family because of the potential for "starving," they also felt it prolonged the patient's suffering due to the invasive procedure, need for restraints, and possibility of fluid overload. Several nurses felt that artificial nutrition and hydration gave a sense of false hope to the family that the patient would live longer. The perceptions of these home healthcare nurses influence their care to people with dementia and their families related to artificial nutrition and hydration, possibly based on experience. Their perceptions could influence family decisions regarding treatment options. Further research and education with home healthcare nurses is vital to ensure nurses are appropriately caring for patients with dementia and their families. PMID:27677061

  15. 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

  16. Risk Factors for Late-Stage HIV Disease Presentation at Initial HIV Diagnosis in Durban, South Africa

    PubMed Central

    Drain, Paul K.; Losina, Elena; Parker, Gary; Giddy, Janet; Ross, Douglas; Katz, Jeffrey N.; Coleman, Sharon M.; Bogart, Laura M.; Freedberg, Kenneth A.; Walensky, Rochelle P.; Bassett, Ingrid V.

    2013-01-01

    Background After observing persistently low CD4 counts at initial HIV diagnosis in South Africa, we sought to determine risk factors for late-stage HIV disease presentation among adults. Methods We surveyed adults prior to HIV testing at four outpatient clinics in Durban from August 2010 to November 2011. All HIV-infected adults were offered CD4 testing, and late-stage HIV disease was defined as a CD4 count <100 cells/mm3. We used multivariate regression models to determine the effects of sex, emotional health, social support, distance from clinic, employment, perceived barriers to receiving healthcare, and foregoing healthcare to use money for food, clothing, or housing (“competing needs to healthcare”) on presentation with late-stage HIV disease. Results Among 3,669 adults screened, 830 were enrolled, newly-diagnosed with HIV and obtained a CD4 result. Among those, 279 (33.6%) presented with late-stage HIV disease. In multivariate analyses, participants who lived ≥5 kilometers from the test site [adjusted odds ratio (AOR) 2.8, 95% CI 1.7–4.7], reported competing needs to healthcare (AOR 1.7, 95% CI 1.2–2.4), were male (AOR 1.7, 95% CI 1.2–2.3), worked outside the home (AOR 1.5, 95% CI 1.1–2.1), perceived health service delivery barriers (AOR 1.5, 95% CI 1.1–2.1), and/or had poor emotional health (AOR 1.4, 95% CI 1.0–1.9) had higher odds of late-stage HIV disease presentation. Conclusions Independent risk factors for late-stage HIV disease presentation were from diverse domains, including geographic, economic, demographic, social, and psychosocial. These findings can inform various interventions, such as mobile testing or financial assistance, to reduce the risk of presentation with late-stage HIV disease. PMID:23383147

  17. Enigmatic Late-Stage Textures In Mafic Cumulates: Skaergaard Intrusion, East Greenland.

    NASA Astrophysics Data System (ADS)

    Stripp, G.; Holness, M.; Veksler, I.

    2006-12-01

    The complexities of slow solidification in deep-seated silicate liquid bodies are poorly understood. Late-stage melt migration, due to compaction of the crystal mush, drives re-crystallisation and metasomatism which can have significant effects on chamber-wide chemical evolution. In this contribution we present novel textural observations from mafic cumulates of the Skaergaard Layered Intrusion which may shed light on liquid movement during the last stages of solidification of the crystal mush. Previously undescribed mafic symplectites are widespread in the Skaergaard Layered Series, and comprise vermicular intergrowths of plagioclase and olivine, which may be replaced by clinopyroxene in the outer parts of the symplectite. The symplectites grow outwards from Fe-Ti oxide grains, consuming adjacent cumulus plagioclase. In the Middle Zone of the Layered Series (where symplectites are best developed) symplectite plagioclase adjacent to the Fe-Ti oxide grains contains 1.2 wt% FeOtot which decreases to 0.6 wt% FeOtot at the symplectite margin, compared to a ~ 0.35 wt% average for adjacent cumulus plagioclase. Symplectite plagioclase is up to 40 mol% more An-rich than the adjacent cumulus grains. Olivine compositions range from Fo45 to Fo32 along the growth direction of the symplectite, compared to ~ Fo44 for cumulus olivine at this level in the intrusion. Biotite commonly replaces olivine. Texturally- and compositionally-related patches of intergrown clinopyroxene and An-rich plagioclase occur locally on plagioclase triple junctions and plagioclase grain boundaries. Symplectites are present, but rare, in the lower parts of the Skaergaard Layered Series; increase significantly in volumetric importance in Lower Zone b; are very common in Middle Zone and disappear in UZ. The symplectites resemble those formed by hydrous partial melting of oceanic gabbros (Koepke et al., 2005) but important differences include the presence of clinopyroxene and Fe-rich plagioclase, and the

  18. 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

  19. Immunohistochemical analyses at the late stage of tumor promotion by oxfendazole in a rat hepatocarcinogenesis model.

    PubMed

    Dewa, Yasuaki; Nishimura, Jihei; Jin, Meilan; Kawai, Masaomi; Saegusa, Yukie; Kenmochi, Sayaka; Shimamoto, Keisuke; Harada, Tomoaki; Shibutani, Makoto; Mitsumori, Kunitoshi

    2011-02-01

    The present study was performed to characterize immunohistochemically the expression levels of molecules related to not only xenobiotic and antioxidant functions but also cell proliferation and apoptosis in neoplastic lesions induced by the benzimidazole anthelmintic, oxfendazole (OX), at the late stage of its tumor promotion in a rat hepatocarcinogenesis model. Male F344 rats were initiated with an intraperitoneal injection of 200 mg/kg N-diethylnitrosamine, and 2 weeks later they were fed a diet containing 0% (basal diet) or 0.05% OX for 26 weeks. All animals were subjected to a two-thirds partial hepatectomy at week 3 and killed at week 28. Histopathologically, OX increased the incidence and multiplicity of altered foci (4.0- and 3.6-fold, respectively) and hepatocellular adenomas (HCAs) (3.0- and 5.5-fold, respectively). OX treatment induced 5.2- and 5.6-fold increases in the number of proliferating cell nuclear antigen (PCNA)-positive cells and single-stranded DNA (ssDNA)-positive cells in HCAs compared with the surrounding tissue, respectively. Staining for the cell cycle regulators P21 and C/EBPα and the AhR-regulated CYP1A1 molecules decreased but increased reactivity of the Nrf2-regulated, detoxifing/antioxidant molecules aldo-keto reductase 7 (AKR7) and glutathione peroxidase 2 (GPX2) were also seen in HCAs compared with the surrounding hepatocytes. These results suggest that dysregulation of cell proliferation and apoptosis and escape from oxidative stress elicited by OX treatment play an important role in OX-induced hepatocarcinogenesis in rats.

  20. 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.

  1. 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.

  2. Late stage erythroid precursor production is impaired in mice with chronic inflammation

    PubMed Central

    Prince, Olivier D.; Langdon, Jacqueline M.; Layman, Andrew J.; Prince, Ian C.; Sabogal, Miguel; Mak, Howard H.; Berger, Alan E.; Cheadle, Chris; Chrest, Francis J.; Yu, Qilu; Andrews, Nancy C.; Xue, Qian-Li; Civin, Curt I.; Walston, Jeremy D.; Roy, Cindy N.

    2012-01-01

    Background We and others have shown previously that over-expression of hepcidin antimicrobial peptide, independently of inflammation, induces several features of anemia of inflammation and chronic disease, including hypoferremia, sequestration of iron stores and iron-restricted erythropoiesis. Because the iron-restricted erythropoiesis evident in hepcidin transgenic mice differs from the normocytic, normochromic anemia most often observed in anemia of inflammation, we tested the hypothesis that chronic inflammation may contribute additional features to anemia of inflammation which continue to impair erythropoiesis following the acute phase of inflammation in which hepcidin is active. Design and Methods We compared erythropoiesis and iron handling in mice with turpentine-induced sterile abscesses with erythropoiesis and iron handling in hepcidin transgenic mice. We compared erythrocyte indices, expression of genes in the hepcidin regulatory pathway, tissue iron distribution, expression of heme and iron transport genes in splenic macrophages, the phenotype of erythroid maturation and chloromethyl dichlorodihydrofluorescein diacetate, acetyl ester fluorescence. Results Mice with sterile abscesses exhibited an intense, acute inflammatory phase followed by a mild to moderate chronic inflammatory phase. We found that erythrocytes in mice with sterile abscesses were normocytic and normochromic in contrast to those in hepcidin transgenic mice. We also observed that although hypoferremia resolved in the late phases of inflammation, erythropoiesis remained suppressed, with evidence of inefficient maturation of erythroid precursors in the bone marrow of mice with sterile abscesses. Finally, we observed increased oxidative stress in erythroid progenitors and circulating erythrocytes of mice with sterile abscesses which was not evident in hepcidin transgenic mice. Conclusions Our results suggest that chronic inflammation inhibits late stages of erythroid production in the

  3. Late stages of high rate tension of aluminum melt: Molecular dynamic simulation

    NASA Astrophysics Data System (ADS)

    Mayer, Polina N.; Mayer, Alexander E.

    2016-08-01

    With the help of molecular dynamic simulation, we investigate late stages of aluminum melt tension up to the deformation degree of about 10, including a stage of bubble liquid, a foamed melt, and a fragmentation with formation of droplets. Complete fracture of melt is a complex process, which includes nucleation of pores, growth and coalescence of neighboring pores, thinning and breaking of walls between them with the formation of a system of jets, and, finally, breaking of jets into droplets. The transition from the foamed melt to the system of jets and the subsequent fragmentation into droplets occur at the volume fraction of condensed matter considerably smaller than 0.1. The number of pores at the volume fraction of condensed matter about 0.5 and the number of droplets at the final stage of fragmentation are not directly connected with each other. At the same time, both numbers are increased together with the increase in the strain rate and have the same order of magnitude. At the stage of melt with pores, the growth and coalescence of pores are controlled by surface tension, which allows us to construct an analytical estimation for time dependence of the pore average radius. Also, we propose analytical estimations for the mean pressure of melt with pores, which remain negative, and for the work of tension. A few times larger work is spent on the tension of melt with pores if compared with the initial stage of tension near the dynamic strength threshold. The last fact is favorable for the production of the foamed aluminum by means of the high-rate tension of its melt.

  4. Association of caveolin with Chlamydia trachomatis inclusions at early and late stages of infection.

    PubMed

    Norkin, L C; Wolfrom, S A; Stuart, E S

    2001-06-10

    The mechanism by which the intracellular bacterial pathogen Chlamydia trachomatis enters eukaryotic cells is poorly understood. There are conflicting reports of entry occurring by clathrin-dependent and clathrin-independent processes. We report here that C. trachomatis serovar K enters HEp-2 and HeLa 229 epithelial cells and J-774A.1 mouse macrophage/monocyte cells via caveolin-containing sphingolipid and cholesterol-enriched raft microdomains in the host cell plasma membranes. First, filipin and nystatin, drugs that specifically disrupt raft function by cholesterol chelation, each impaired entry of C. trachomatis serovar K. In control experiments, filipin did not impair entry of the same organism by an antibody-mediated opsonic process, nor did it impair entry of BSA-coated microspheres. Second, the chlamydia-containing endocytic vesicles specifically reacted with antisera against the caveolae marker protein caveolin. These vesicles are known to become the inclusions in which parasite replication occurs. They avoid fusion with lysosomes and instead traffic to the Golgi region, where they intercept Golgi-derived vesicles that recycle sphingolipids and cholesterol to the plasma membrane. We also report that late-stage C. trachomatis inclusions continue to display high levels of caveolin, which they likely acquire from the exocytic Golgi vesicles. We suggest that the atypical raft-mediated entry process may have important consequences for the host-pathogen interaction well after entry has occurred. These consequences include enabling the chlamydial vesicle to avoid acidification and fusion with lysosomes, to traffic to the Golgi region, and to intercept sphingolipid-containing vesicles from the Golgi.

  5. Direct estradiol and diethylstilbestrol actions on early- vs. late-stage prostate cancer cells

    PubMed Central

    Koong, Luke Y.; Watson, Cheryl S.

    2014-01-01

    BACKGROUND: Diethylstilbestrol (DES) and other pharmaceutical estrogens have been used at ≥μM concentrations to treat advanced prostate tumors, with successes primarily attributed to indirect hypothalamic-pituitary-testicular axis control mechanisms. However, estrogens also directly affect tumor cells, though the mechanisms involved are not well understood. METHODS: LAPC-4 (androgen-dependent) and PC-3 (androgen-independent) cell viability was measured after estradiol (E2) or DES treatment across wide concentration ranges. We then examined multiple rapid signaling mechanisms at 0.1 nM E2 and 1μM DES optima including levels of: activation (phosphorylation) for mitogen-activated protein kinases, cell-cycle proteins, and caspase 3, necroptosis, and reactive oxygen species (ROS). RESULTS: LAPC-4 cells were more responsive than PC-3 cells. Robust and sustained extracellular-regulated kinase activation with E2, but not DES, correlated with ROS generation and cell death. c-Jun N-terminal kinase was only activated in E2-treated PC-3 cells and was not correlated with caspase 3-mediated apoptosis; necroptosis was not involved. The cell-cycle inhibitor protein p16INK4A was phosphorylated in both cell lines by both E2 and DES, but to differing extents. In both cell types, both estrogens activated p38 kinase, which subsequently phosphorylated cyclin D1, tagging it for degradation, except in DES-treated PC-3 cells. CONCLUSIONS: Cyclin D1 status correlated most closely with disrupted cell cycling as a cause of reduced cell numbers, though other mechanisms also contributed. As low as 0.1 nM E2 effectively elicited these mechanisms, and its use could dramatically improve outcomes for both early- and late-stage prostate cancer patients, while avoiding the side effects of high-dose DES treatment. PMID:25213831

  6. Dendritic cell appearance and differentiation during early and late stages of rat stomach carcinogenesis.

    PubMed

    Takeuchi, Motoi; Yamamoto, Masami; Tatematsu, Masae; Miki, Kazumasa; Sakaki, Yoshiyuki; Furihata, Chie

    2002-08-01

    Dendritic cell appearance and differentiation during early and late stages of rat stomach carcinogenesis were studied in the pyloric mucosa. Young male rats were given drinking water with or without N-methyl-N'-nitro-N-nitrosoguanidine (MNNG; 100 mg/liter) for 14 days. Use of competitive RT-PCR and northern blotting showed that MNNG exposure induced 3- to 4-fold greater expression of the genes for integrin beta7 and integrin alphaE2 (identical with antigen OX-62, a dendritic cell marker), as well as three cytokines, IL-4, GM-CSF and TNFalpha, in the stomach pyloric mucosa of resistant Buffalo rats compared to sensitive ACI rats. These genes were minimally expressed in control animals. The results confirm the appearance of dendritic cells in the target pyloric mucosa and suggest the possibility that dendritic cell differentiation and maturation are induced by various cytokines, at least in Buffalo rats. Competitive RT-PCR showed expression of integrin alphaE2 and beta7, MHC class II-associated invariant chain (Ii), MHC class II, B7-1, CD28, GM-CSF and TNFalpha genes in all 12 examined stomach adenocarcinomas and adenomas induced in male Lewis and WKY rats with 30 weeks' MNNG exposure, suggesting the presence of dendritic cells in tumors. OX-62 staining and western blotting for OX-62 also confirmed the presence of dendritic cells in tumors. However, the population of dendritic cells in tumors was less than that in the pyloric mucosa after 14 days' MNNG exposure. The present results suggest that immune defense involving dendritic cells is marshaled from the very early initiation stage during rat stomach cancer development, but is downgraded in developed tumors.

  7. Separation of Plasmodium falciparum Late Stage-infected Erythrocytes by Magnetic Means

    PubMed Central

    Coronado, Lorena Michelle; Tayler, Nicole Michelle; Correa, Ricardo; Giovani, Rita Marissa; Spadafora, Carmenza

    2013-01-01

    Unlike other Plasmodium species, P. falciparum can be cultured in the lab, which facilitates its study 1. While the parasitemia achieved can reach the ≈40% limit, the investigator usually keeps the percentage at around 10%. In many cases it is necessary to isolate the parasite-containing red blood cells (RBCs) from the uninfected ones, to enrich the culture and proceed with a given experiment. When P. falciparum infects the erythrocyte, the parasite degrades and feeds from haemoglobin 2, 3. However, the parasite must deal with a very toxic iron-containing haem moiety 4, 5. The parasite eludes its toxicity by transforming the haem into an inert crystal polymer called haemozoin 6, 7. This iron-containing molecule is stored in its food vacuole and the metal in it has an oxidative state which differs from the one in haem 8. The ferric state of iron in the haemozoin confers on it a paramagnetic property absent in uninfected erythrocytes. As the invading parasite reaches maturity, the content of haemozoin also increases 9, which bestows even more paramagnetism on the latest stages of P. falciparum inside the erythrocyte. Based on this paramagnetic property, the latest stages of P. falciparum infected-red blood cells can be separated by passing the culture through a column containing magnetic beads. These beads become magnetic when the columns containing them are placed on a magnet holder. Infected RBCs, due to their paramagnetism, will then be trapped inside the column, while the flow-through will contain, for the most part, uninfected erythrocytes and those containing early stages of the parasite. Here, we describe the methodology to enrich the population of late stage parasites with magnetic columns, which maintains good parasite viability 10. After performing this procedure, the unattached culture can be returned to an incubator to allow the remaining parasites to continue growing. PMID:23486405

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

    PubMed Central

    Tiberti, Natalia; Sanchez, Jean-Charles

    2015-01-01

    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

  9. Discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late-stage central nervous system african trypanosomiasis.

    PubMed

    Nare, Bakela; Wring, Stephen; Bacchi, Cyrus; Beaudet, Beth; Bowling, Tana; Brun, Reto; Chen, Daitao; Ding, Charles; Freund, Yvonne; Gaukel, Eric; Hussain, Ali; Jarnagin, Kurt; Jenks, Matthew; Kaiser, Marcel; Mercer, Luke; Mejia, Elena; Noe, Andy; Orr, Matt; Parham, Robin; Plattner, Jacob; Randolph, Ryan; Rattendi, Donna; Rewerts, Cindy; Sligar, Jessica; Yarlett, Nigel; Don, Robert; Jacobs, Robert

    2010-10-01

    We report the discovery of novel boron-containing molecules, exemplified by N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (AN3520) and 4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (SCYX-6759), as potent compounds against Trypanosoma brucei in vitro, including the two subspecies responsible for human disease T. b. rhodesiense and T. b. gambiense. These oxaborole carboxamides cured stage 1 (hemolymphatic) trypanosomiasis infection in mice when administered orally at 2.5 to 10 mg/kg of body weight for 4 consecutive days. In stage 2 disease (central nervous system [CNS] involvement), mice infected with T. b. brucei were cured when AN3520 or SCYX-6759 were administered intraperitoneally or orally (50 mg/kg) twice daily for 7 days. Oxaborole-treated animals did not exhibit gross signs of compound-related acute or subchronic toxicity. Metabolism and pharmacokinetic studies in several species, including nonhuman primates, demonstrate that both SCYX-6759 and AN3520 are low-clearance compounds. Both compounds were well absorbed following oral dosing in multiple species and also demonstrated the ability to cross the blood-brain barrier with no evidence of interaction with the P-glycoprotein transporter. Overall, SCYX-6759 demonstrated superior pharmacokinetics, and this was reflected in better efficacy against stage 2 disease in the mouse model. On the whole, oxaboroles demonstrate potent activity against all T. brucei subspecies, excellent physicochemical profiles, in vitro metabolic stability, a low potential for CYP450 inhibition, a lack of active efflux by the P-glycoprotein transporter, and high permeability. These properties strongly suggest that these novel chemical entities are suitable leads for the development of new and effective orally administered treatments for human African trypanosomiasis.

  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.

    PubMed

    Sharma, Ankit; Hartwig, John F

    2015-01-29

    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. Genome expression and mRNA maturation at late stages of productive adenovirus type 2 infection.

    PubMed

    Wold, W S; Green, M; Brackmann, K H; Cartas, M A; Devine, C

    1976-11-01

    RNA from adenovirus 2-infected KB cells was annealed in liquid with RNA in vast excess to viral heavy (l) and light (r) 32P-labeled DNA strands. Hybridization kinetics were analyzed by computer to estimate the number of viral RNA abundance classes, their relative concentrations, and the fraction of each DNA strand from which they originated. Early whole cell RNA extracted 5 h postinfection annealed rapidly to 10 to 15% of l and r strands and then slowly to final values of 60 and 40% of l and r strands. By 9 h postinfection the expression of late genes was apparent and whole cell RNA annealed to 20 and 75% of l and r strands. Whole cell RNA extracted between 12 and 36 h postinfection annealed to 7 to 15% and 75 to 90% of l and r strands. Late nuclear RNA hybridized to 10 and 90% of l and r strands, and late polyribosomal RNA hybridized to 20 and 75% of l and r strands. Based upon kinetic analyses, we estimate that mRNA synthesized exclusively during late stages arises from about 6 to 8% and 45 to 49% of l and r strands. This assumes that the early class I mRNA (in low concentration late) originates from 8 to 10% and 6 to 10% of l and r strands and that early class II mRNA (in high concentration late) is derived from 2% and 8 to 13% of l and r strands. Mixing experiments indicated that early mRNA is a subset of RNA extracted from polyribosomes late after infection and that late nuclear RNA contains sequences complementary to early l strand class I nRNA. RNA-RNA hybrids were isolated from late mRNA containing sequences from 60% of l and r strands, but it is not known when these were synthesized, and therefore whether complementary RNA transcripts are synthesized late after infection, as they are known to be synthesized early. These results demonstrate that portions of the genome are transcribed into RNA sequences that remain confined to the nucleus and are not exported to polyribosomes as mRNA.

  13. 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

  14. A vesicle cell under collision with a Janus or homogeneous nanoparticle: translocation dynamics and late-stage morphology

    NASA Astrophysics Data System (ADS)

    Arai, Noriyoshi; Yasuoka, Kenji; Zeng, Xiao Cheng

    2013-09-01

    We investigate translocation dynamics of a vesicle cell under collision with a Janus or a homogeneous hydrophobic/hydrophilic nanoparticle. To this end, we perform dissipative particle dynamics simulation by setting the nanoparticle with different initial velocities, different chemical patterns of the surface for the nanoparticle, and different orientations (for the Janus nanoparticle). Particular attention is given to translocation dynamics, in-cell water discharge, and the late-stage morphologies of the vesicle/nanoparticle system after the collision. We observe three late-stage states for the Janus nanoparticle, and four late-stage states for the homogeneous nanoparticles. We find that the late-stage state and the associated dynamical pathway not only depend on the relative velocity but also on the chemical pattern of the nanoparticle surface, as well as on the orientation of the incident Janus nanoparticle. We have examined the time-dependent mean radius of the vesicle, the number of in-cell water beads lost from the vesicle, as well as the collision-induced pore size on the lipid membrane during the course of collision. Our simulation provides microscopic insights into the resilience of the vesicle-cell membrane and dynamical behavior of the vesicle under the attack of a foreign nanoparticle. Knowledge and insights gained through the simulation will have implication to the drug delivery with different chemical coatings.We investigate translocation dynamics of a vesicle cell under collision with a Janus or a homogeneous hydrophobic/hydrophilic nanoparticle. To this end, we perform dissipative particle dynamics simulation by setting the nanoparticle with different initial velocities, different chemical patterns of the surface for the nanoparticle, and different orientations (for the Janus nanoparticle). Particular attention is given to translocation dynamics, in-cell water discharge, and the late-stage morphologies of the vesicle/nanoparticle system after the

  15. 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.

  16. 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

  17. A divergent approach to the synthesis of simplexides and congeners via a late-stage olefin cross-metathesis reaction.

    PubMed

    Li, Jiakun; Li, Wei; Yu, Biao

    2013-08-14

    Simplexides constitute a unique group of immunosuppressive glycolipids that demonstrate antiproliferative activities against activated T-cell lymphocytes via a unique non-cytotoxic inhibition. To investigate the structure-activity relationship of the varied long-chain secondary alcohols on simplexides, we developed an efficient and divergent route to the synthesis of simplexides and congeners, taking advantage of a late-stage olefin cross-metathesis reaction.

  18. Pharmacophore mapping in the laulimalide series: total synthesis of a vinylogue for a late-stage metathesis diversification strategy.

    PubMed

    Wender, Paul A; Hilinski, Michael K; Skaanderup, Philip R; Soldermann, Nicolas G; Mooberry, Susan L

    2006-08-31

    An efficient synthesis of the macrocyclic core of laulimalide with a pendant vinyl group at C20 is described, allowing for late-stage introduction of various side chains through a selective and efficient cross metathesis diversification step. Representative analogues reported herein are the first to contain modifications to only the side chain dihydropyran of laulimalide and des-epoxy laulimalide. This step-economical strategy enables the rapid synthesis of new analogues using alkenes as an inexpensive, abundantly available diversification feedstock.

  19. 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

  20. 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

  1. 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

  2. The Fate of Sulfur in Late-Stage Magmatic Processes: Insights From Quadruple Sulfur Isotopes

    NASA Astrophysics Data System (ADS)

    Keller, N. S.; Ono, S.; Shaw, A. M.

    2009-05-01

    Multiple sulfur isotopes (32S, 33S, 34S and 36S) have recently been shown to be useful tracers of fluid-rock interaction in seafloor hydrothermal systems [1]. Here we present the application of multiple sulfur isotopes to subaerial volcanoes with the aim of unraveling the various processes fractionating sulfur in the upper volcanic system. We take advantage of the fact that the ascent of volcanic gases through a hydrothermal system causes complex isotopic fractionation between the quaduple sulfur isotopes. δ34S is thought to trace the source of sulfur as well as magma degassing; at equilibrium, δ33S follows a mass-dependent fractionation relationship such that two phases in equilibrium with each other have equal Δ33S values (Δ33S ≡ ln(δ33S+1) - 0.515×ln(δ34S+1)). Disequilibrium Δ33S values can indicate isotope mixing and other fluid-rock interactions. The ultimate aim of this study is to assess the use of quadruple sulfur isotopes to obtain quantitative information on the sulfur cycle at convergent plate margins. The sulfur mass balance at convergent margins is poorly constrained, partly because late-stage processes are challenging to quantify and lead to large uncertainties in the global output fluxes. Quadruple sulfur isotopes provide a powerful tool to untangle the convoluted history of volcanic systems. Here we report the first quadruple sulfur isotopic values for H2S, SO2 and native sulfur from arc volcanoes. Fumarolic gases (˜100°C) and sulfur sublimates were collected from Poas and Turrialba, two actively degassing volcanoes in Costa Rica. The gases were bubbled in situ through chemical traps to separate H2S from SO2: H2S was reacted to form ZnS, and SO2 to form BaSO4. Sulfur was chemically extracted from the solid phases and precipitated as Ag2S, which was fluorinated to SF6 and analysed by IRMS. Poas and Turrialba have H2S/SO2 ˜1 and 0.01, respectively. δ34SH2S and δ34SSO2 are similar to gases measured at other arcs [2], - 7.9‰ and 0.6

  3. 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

  4. 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.

  5. 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

  6. The temporal characteristics of the early and late stages of the L- and M-cone pathways that signal color

    PubMed Central

    Petrova, Daniela; Henning, G. Bruce; Stockman, Andrew

    2013-01-01

    Flickering long-wavelength light appears more yellow than steady light of the same average intensity. The hue change is consistent with distortion of the visual signal at some nonlinear site (or sites) that produces temporal components not present in the original stimulus (known as distortion products). We extracted the temporal attenuation characteristics of the early (prenonlinearity) and late (post-nonlinearity) filter stages in the L- and M-cone chromatic pathway by varying the input stimulus to manipulate the distortion products and the measuring of the observers' sensitivity to them. The early, linear, filter stage acts like a band-pass filter peaking at 10–15 Hz with substantial sensitivity losses at both lower and higher frequencies. Its characteristics are consistent with nonlinearity being early in the visual pathway but following surround inhibition. The late stage, in contrast, acts like a low-pass filter with a cutoff frequency around 3 Hz. The response of the early stage speeds up with radiance, but the late stage does not. A plausible site for the nonlinearity, which modelling suggests may be smoothly compressive but with a hard limit at high input levels, is after surround inhibition from the horizontal cells. PMID:23457358

  7. VISUALIZING AND TESTING THE IMPACT OF PLACE ON LATE-STAGE BREAST CANCER INCIDENCE: A NON-PARAMETRIC GEOSTATISTICAL APPROACH

    PubMed Central

    Goovaerts, Pierre

    2009-01-01

    This paper describes the combination of three-way contingency tables and geostatistics to visualize the non-linear impact of two putative covariates on individual-level health outcomes and test the significance of this impact, accounting for the pattern of spatial correlation and correcting for multiple testing. The methodology is used to explore the influence of distance to mammography clinics and census-tract poverty level on the rate of late-stage breast cancer diagnosis in three Michigan counties. Incidence rates are significantly lower than the area-wide mean (18.04%) mainly in affluent neighbourhoods [0-5% poverty], while higher incidences are mainly controlled by distance to clinics. The new simulation-based multiple testing correction is very flexible and less conservative than the traditional false discovery rate approach that results in a majority of tests becoming non-significant. Classes with significantly higher frequency of late-stage diagnosis often translate into geographic clusters that are not detected by the spatial scan statistic. PMID:19959392

  8. 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.

  9. Different collagen types show distinct rates of increase from early to late stages of hepatitis C-related liver fibrosis.

    PubMed

    Chen, Wei; Rock, Jonathan B; Yearsley, Martha M; Ferrell, Linda D; Frankel, Wendy L

    2014-01-01

    During progression from normal liver to cirrhosis, total collagen increases nearly 10-fold with an abnormal increase in fibril-forming collagen and other extracellular matrix molecules. However, little is known regarding the changes each collagen type undergoes during fibrogenesis. We assessed the different collagen types by immunohistochemistry at various stages of hepatitis C-related liver fibrosis in core biopsies and compared changes in each with trichrome stain to better understand fibrogenesis. The possible utility in staging fibrosis was investigated. We found collagens III, IV, V, VI, vitronectin, and trichrome all showed statistically significant increases from early to late stages of fibrosis, but with temporal and quantitative differences. During the transition from early to late fibrosis, trichrome (stains primarily collagen I) and collagen IV showed the steepest increase and appear to be the most useful discriminators between early and late stages of fibrosis. Collagens V and VI have strong reactivity even in stage 1, which may be helpful in identifying early fibrosis when trichrome is weak or negative. Collagen III and vitronectin showed the most gradual increase. Interestingly, collagen V also showed increased staining in areas around inflammation/edema, which may overestimate established fibrosis as compared with trichrome.

  10. Infusion of Bone Marrow Mononuclear Cells Reduces Lung Fibrosis but Not Inflammation in the Late Stages of Murine Silicosis

    PubMed Central

    Lopes-Pacheco, Miquéias; Ventura, Túlio G.; de Oliveira, Helena D'Anunciação; Monção-Ribeiro, Leonardo C.; Gutfilen, Bianca; de Souza, Sergio A. L.; Rocco, Patrícia R. M.; Borojevic, Radovan; Morales, Marcelo M.; Takiya, Christina M.

    2014-01-01

    We hypothesized that infusion of bone marrow mononuclear cells (BMMCs) in the late stages of silica-induced damage would reduce the remodelling process in a murine model of silicosis. C57BL/6 mice were assigned to 2 groups. In the SIL group, mice were instilled with a silica particle suspension intratracheally. Control (C) mice received saline under the same protocol. On the 40th day, some of the animals from both groups were killed. The others were treated with either saline or BMMCs (1×106cells) intravenously (C+BMMC and SIL+BMMC), and the mice were killed 70 days after the start of the protocol. In the mice in the SIL+BMMC group, collagen deposition, the presence of silica particles inside nodules, the presence of macrophages and cells reactive for inducible nitric oxide synthase were reduced. Lung parameters also improved. Beyond that, the total and differential cellularity of bronchoalveolar lavage fluid, immunoexpression of transforming growth factor-β, the number of T regulatory cells and apoptosis were increased. However, the presence of male donor cells in lung tissue was not observed using GFP+ cells (40d) or Y chromosome DNA (70d). Therefore, BMMC therapy in the late stages of experimental silicosis improved lung function by diminishing fibrosis but inflammatory cells persisted, which could be related to expansion of T regulatory cells, responsible for the beneficial effects of cell therapy. PMID:25299237

  11. 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.

  12. 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

  13. Comparative Cost-Effectiveness of Drugs in Early versus Late Stages of Cancer; Review of the Literature and a Case Study in Breast Cancer

    PubMed Central

    Dvortsin, Evgeni; Postma, Maarten J.

    2016-01-01

    Background Many oncological drugs that are being used in the adjuvant setting were first submitted for reimbursement in the metastatic stage, with differences in incremental cost-effectiveness ratios (ICERs) in both settings having potential implications for reimbursement and pricing. The aim of this study is to identify a possible trend in the cost-effectiveness for the early/adjuvant and late/metastatic stages of oncological drugs through review and case study. Methods We reviewed pairs of cost-effectiveness analyses of the same oncological drug in different stages for Scotland and the Netherlands. The case study in this report was directed at trastuzumab in the Dutch situation. Using a simplified Markov model, the cost-effectiveness in early and late stage of breast cancer was calculated and compared to the findings from the review. Results Comparable studies were found for cetuximab, bortezomib and bosutinib. Treatments in the late stage were found to be more expensive per QALY by a factor ranging from 1.5 to 12. The case study provided a similar result; late stage treatment was more expensive by a factor 10. Using, for example, a threshold of €80,000/QALY, the early stage of cetuximab, bosutinib and trastuzumab are deemed cost-effective, while their compared late stage is lifted over the threshold and potentially considered not cost-effective. Conclusion ICERs of oncological drugs used in different stages are more unfavourable in the late stage than in the early stage. Applying a reasonable threshold may result in early stage treatment being deemed cost-effective while late stage potentially not. Authorities should be aware of this when assessing oncological drugs and interpreting the corresponding ICERs, in the situation where oncological drugs are generally most submitted for reimbursement in the late stage initially. PMID:26800029

  14. 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.

  15. 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.

  16. 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

  17. 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

  18. 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

  19. Differences in early and late stages of information processing between slow versus fast participants.

    PubMed

    Portella, Claudio; Machado, Sergio; Paes, Flávia; Cagy, Mauricio; Sack, Alexander T; Sandoval-Carrillo, Ada; Salas-Pacheco, Jose; Silva, Adriana Cardoso; Piedade, Roberto; Ribeiro, Pedro; Nardi, Antonio Egídio; Arias-Carrión, Oscar

    2014-01-01

    The human brain is a system consisting of various interconnected neural networks, with functional specialization coexisting with functional integration occurring both; temporally and spatially at many levels. The current study ranked and compared fast and slow participants in processing information by assessing latency and amplitude of early and late Event-Related Potential (ERP) components, including P200, N200, Premotor Potential (PMP) and P300. In addition, the Reaction Time (RT) of participants was compared and related to the respective ERP components. For this purpose, twenty right-handed and healthy individuals were subjected to a classical ERP "Oddball" paradigm. Principal Component Analysis (PCA) and Discriminant Function analyses (DFA) used PRE components and the Reaction Time (RT) to classify individuals. Our results indicate that latencies of P200 (O2 electrode), N200 (O2), PMP (C3) and P300 (Pz) components are significantly reduced in the group of fast responding participants. In addition, the P200 amplitude is significantly increased in the group of fast responding participants. Based on these findings, we suggest that the ERP is able to detect even minimal impairments, in the processing of somatosensory information and cognitive and motor stages. Hence, the study of ERP might also be capable of assessing sensorimotor dysfunctions in healthy old-aged people and in neuropsychiatric patients (suffering from dementia, Parkinson's disease, and other neurological disorders). PMID:25838842

  20. 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

  1. Analytical tools for planning cost-effective surveillance in Gambiense sleeping sickness.

    PubMed

    Shaw, A P; Cattand, P

    2001-01-01

    The re-emergence of sleeping sickness as a major health problem in parts of Africa, combined with the new sources of financial support and provision of drugs means that an investigation of the cost-effectiveness of the different approaches is timely. There has been very little work done on the economics of controlling either form of sleeping sickness. This paper builds on work done for WHO by the authors on developing a framework for analysing the cost-effectiveness of different methods for surveillance in gambiense sleeping sickness. The framework has been used to build a spreadsheet which makes it possible to simulate the effects of controlling the disease at different prevalences, for example using mobile teams or various forms of fixed post surveillance and screening different proportions of the population in a year. Prices, control strategies, prevalence, sensitivity and specificity of tests are all variables which can be altered to suit different situations or investigate how different approaches perform. As new research is beginning to produce calculations of the burden of sleeping sickness, in terms of disability-adjusted life years (DALY) potentially averted by controlling the disease, it is possible to combine these DALY estimates with the analyses of cost-effectiveness undertaken in these exercises to look at the cost-utility of the work, both to compare different approaches and demonstrate that controlling sleeping sickness represents good value for money as an investment in health.

  2. Predictors of HIV-1 disease progression in early- and late-stage patients: the U.S. Army Natural History Cohort. Military Medical Consortium for Applied Retrovirology.

    PubMed

    Gardner, L I; Brundage, J F; McNeil, J G; Milazzo, M J; Redfield, R R; Aronson, N E; Craig, D B; Davis, C; Gates, R H; Levin, L I

    1992-01-01

    HIV-infected individuals in both early and late stages of HIV disease were evaluated over 2 years to assess temporal trends and determinants of disease progression. The Walter Reed (WR) staging system was used to categorize patients into an early-stage cohort (WR Stages 1 and 2, N = 1183) and a late-stage cohort (WR Stage 5, N = 260) based on the initial clinical evaluation. Progression was defined as the occurrence of Stage 5 disease or beyond for the early cohort and Stage 6 disease or beyond for the late cohort. The cumulative incidence of progression was 15.7% (137 events) for the early-stage cohort, and 53.7% (85 events) for the late-stage cohort. Baseline CD4+ T lymphocyte (T4) count was the most significant marker of progression: 26% of WR Stage 1 or 2 patients with T4 lymphocytes below 500/mm3 progressed, compared with 12% with T4 lymphocytes at or above 500/mm3. In late-stage individuals, 83% with T4 lymphocytes under 200/mm3 progressed, compared with 27% with T4 lymphocytes at or above 200/mm3. Older age was associated with progression in both early- and late-stage groups. Differences in the rates of disease progression were not significant between blacks and whites or between men and women. Two-year rates of progression among the late-stage patients dropped from 78 to 47% between 1986 and 1988. This contrasted with progression rates in the early-stage cohort, which remained stable: 18% for those entering follow-up in 1986 and 17% for those entering follow-up in 1988. These data indicate a significant slowing of HIV disease progression rates and mortality rates among individuals with late-stage disease that is temporally associated with the increased availability and use of therapies. With control of T4 lymphocyte count, age, and calendar time, neither gender nor race was significantly associated with progression in either early- or late-stage patients. PMID:1517964

  3. 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

  4. 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

  5. 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 ...

  6. CCR7 ligands, SLC/6Ckine/Exodus2/TCA4 and CKbeta-11/MIP-3beta/ELC, are chemoattractants for CD56(+)CD16(-) NK cells and late stage lymphoid progenitors.

    PubMed

    Kim, C H; Pelus, L M; Appelbaum, E; Johanson, K; Anzai, N; Broxmeyer, H E

    1999-05-01

    Two human CC chemokines, SLC/6Ckine/Exodus2/TCA4 and CKbeta-11/MIP-3beta/ELC, are previously reported as efficacious chemoattractants for T- and B-cells and dendritic cells. SLC and CKbeta-11 share only 32% amino acid identity, but are ligands for the same chemokine receptor, CCR7. In this study, we examined chemotactic activity of SLC and CKbeta-11 for NK cells and lymphoid progenitors in bone marrow and thymus. It was found that these two CCR7 ligands are chemoattractants for neonatal cord blood and adult peripheral blood NK cells and cell lines. SLC and CKbeta-11 preferentially attract the CD56(+)CD16(-) NK cell subset over CD56(+)CD16(+) NK cells. SLC and CKbeta-11 also demonstrate selective chemotactic activity on late stage CD34(-)CD19(+)IgM- B-cell progenitors and CD4(+) and CD8(+) single-positive thymocytes, but not early stage progenitors. It was noted that SLC is an efficient desensitizer of CKbeta-11-dependent NK cell chemotaxis, while CKbeta-11 is a weak desensitizer of SLC-dependent chemotaxis. Taken together, these results suggest that SLC and CKbeta-11 have the potential to control trafficking of NK cell subsets and late stage lymphoid progenitors in bone marrow and thymus.

  7. The temporal characteristics of the early and late stages of L- and M-cone pathways that signal brightness.

    PubMed

    Petrova, Daniela; Henning, G Bruce; Stockman, Andrew

    2013-01-01

    Flickering 560-nm light appears brighter and less saturated than steady light of the same average intensity. The changes in appearance are consistent with the visual signal's being distorted at some nonlinear site (or sites) within the visual pathway at which new temporal components, not part of the original waveform, are produced. By varying the input stimulus to manipulate these new temporal components--called distortion products--and measuring our observers' sensitivity in detecting them, we derived the temporal attenuation characteristics of the early (prenonlinearity) and late (post-nonlinearity) stages of the L- and M-cone pathway that signals brightness. We found that the early stage acts like a band-pass filter peaking at 10-15 Hz with sensitivity losses at both lower and higher frequencies, whereas the late stage acts like a two-stage low-pass filter with a corner frequency near 3 Hz. Although brightness is often associated with the fast achromatic or luminance pathway, these filter characteristics, and particularly those of the late filter, are consistent with comparable features of the L-M chromatic pathway that produce mainly chromatic distortion products (Petrova, Henning, & Stockman, 2013). A plausible site for the nonlinearity is after surround antagonism from horizontal cells. Modeling suggested the form of the nonlinearity to be initially expansive but possibly with a hard limit at the highest input levels. PMID:23798031

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. RsgA releases RbfA from 30S ribosome during a late stage of ribosome biosynthesis

    PubMed Central

    Goto, Simon; Kato, Shingo; Kimura, Takatsugu; Muto, Akira; Himeno, Hyouta

    2011-01-01

    RsgA is a 30S ribosomal subunit-binding GTPase with an unknown function, shortage of which impairs maturation of the 30S subunit. We identified multiple gain-of-function mutants of Escherichia coli rbfA, the gene for a ribosome-binding factor, that suppress defects in growth and maturation of the 30S subunit of an rsgA-null strain. These mutations promote spontaneous release of RbfA from the 30S subunit, indicating that cellular disorders upon depletion of RsgA are due to prolonged retention of RbfA on the 30S subunit. We also found that RsgA enhances release of RbfA from the mature 30S subunit in a GTP-dependent manner but not from a precursor form of the 30S subunit. These findings indicate that the function of RsgA is to release RbfA from the 30S subunit during a late stage of ribosome biosynthesis. This is the first example of the action of a GTPase on the bacterial ribosome assembly described at the molecular level. PMID:21102555

  14. 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.

  15. 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.

  16. Late-stage HIV/AIDS patients' and their familial caregivers' agreement on the palliative care outcome scale.

    PubMed

    Krug, Rachel; Karus, Daniel; Selwyn, Peter A; Raveis, Victoria H

    2010-01-01

    This study compares the self-assessments of 67 late-stage HIV/AIDS patients regarding their symptomatology, sense of self-worth, and several other aspects of their health-care situation, to assessments of that situation provided by their informal caregivers. As part of a dyadic study of care preferences, the patients and caregivers independently completed nearly identical versions of the Palliative Care Outcome Scale, a short 10-item measure of the patient's current health, social, and psychological status. The participants in the study were recruited from inpatient and outpatient services at an urban medical center. Substantial or moderate agreement, assessed by weighted kappa, was found between patient and caregiver assessments with regard to only four items assessing physical or emotional states of the patient (pain, other symptoms, anxiety, and life worthwhile). Fair or slight agreement was found for the six remaining items, including those assessing the patient's sense of self-worth, family/friends' anxiety, interactions with family/friends, and practical matters. Mean ratings of self-worth were significantly different for patients and caregivers. These findings underscore the clinical need to assess patient care outcomes directly, and they suggest the importance of facilitating more effective communication about relevant health issues among seriously ill patients, caregivers, and health-care providers.

  17. 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.

  18. 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…

  19. 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

  20. 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

  1. 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

  2. Fluid-rock interaction in the Kangankunde Carbonatite Complex, Malawi: SEM based evidence for late stage pervasive hydrothermal mineralisation

    NASA Astrophysics Data System (ADS)

    Duraiswami, Raymond A.; Shaikh, Tahira N.

    2014-12-01

    The Kangankunde Carbonatite Complex from the Cretaceous Chilwa Alkaline Province in southern Malawi contains ankeritic and siderite carbonatite that are affected by late stage remobilisation by a carbothermal or hydrothermal fluid. The coarse pegmatitic siderite carbonatite that hosts exotic minerals like monazite, synchysite, bastnasite, strontianite and apatite in vugs and cavities constitutes some of the richest rare earth deposits in the world. Besides these minerals, our studies reveal the presence of collinsite and aragonite from the siderite carbonatite. Fine drusy monazites are seen as overgrowths on thin veinlets of siderite within the rare earth mineralised zones. We present unambiguous SEM-based surface textural evidence such as presence of dissolution-corrosion features like etching along cleavage, solution channels, solution pits, sinstered scaly surface, etc. along with rare earth mineralisation that suggests the exotic minerals in the siderite carbonatite did not crystallise from carbonate magma and are a result of sub-solidus processes involving carbonatite-derived fluids. We believe that the monazite-synchysitebastnasite-strontianite-collinsite assemblages were formed by juvenile post magmatic hydrothermal alteration of pre-existing carbonatite by a complex CO2-rich and alkali chloride-carbonate-bearing fluid at ˜250 to 400°C in an open system. This late `magmatic' to `hydrothermal' activity was responsible for considerable changes in rock texture and mineralogy leading to mobility of rare earth elements during fluid-rock interaction. These aspects need to be properly understood and addressed before using trace and rare earth element (REE) geochemistry in interpreting carbonatite genesis.

  3. 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.

  4. Effects of mastoparan upon the late stages of the ACTH secretory pathway of AtT-20 cells.

    PubMed Central

    McFerran, B. W.; Guild, S. B.

    1995-01-01

    1. The mouse AtT-20/D16-16 anterior pituitary tumour cell line was used as a model system for the study of the effects of mastoparan upon the late stages of the adrenocorticotrophin (ACTH) secretory pathway. 2. Mastoparan (10(-8)-10(-5) M), an activator of heterotrimeric guanosine 5'-triphosphate binding proteins (G-proteins), stimulated ACTH secretion from electrically-permeabilized AtT-20 cells in a concentration-dependent manner in the effective absence of calcium ions with a threshold of 10(-6) M. Guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) (10(-8)-10(-4) M) also stimulated ACTH secretion from electrically-permeabilized AtT-20 cells in a concentration-dependent manner in the effective absence of calcium ions with a threshold of 10(-6) M. This GTP-gamma-S-evoked secretion is consistent with previous studies which demonstrated that a G-protein, termed GE, mediates calcium evoked ACTH secretion from AtT-20 cells. GTP-gamma-S-evoked secretion however was not as great as that obtained in response to mastoparan. 3. Both mastoparan (10(-5) M) and GTP-gamma-S (10(-4) M) stimulated ACTH secretion from electrically-permeabilized AtT20 cells in a time-dependent manner. A time of 30 min was adopted as the standard incubation period for the study of both mastoparan and GTP-gamma-S-stimulated ACTH secretion from permeabilized AtT-20 cells. 4. Mastoparan (10(-8)-10(-5) M) stimulated ACTH secretion from permeabilized AtT-20 cells to the same extent in the presence and absence of the protein kinase C (PKC) inhibitor, chelerythrine chloride (10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582493

  5. Spatial association of racial/ethnic disparities between late-stage diagnosis and mortality for female breast cancer: where to intervene?

    PubMed Central

    2011-01-01

    Background Over the past twenty years, racial/ethnic disparities between late-stage diagnoses and mortality outcomes have widened due to disproportionate medical benefits that different racial/ethnic groups have received. Few studies to date have examined the spatial relationships of racial/ethnic disparities between breast cancer late-stage diagnosis and mortality as well as the impact of socioeconomic status (SES) on these two disparities at finer geographic scales. Methods Three methods were implemented to assess the spatial relationship between racial/ethnic disparities of breast cancer late-stage diagnosis and morality. First, this study used rate difference measure to test for racial/ethnic disparities in both late-stage diagnosis and mortality of female breast cancer in Texas during 1995-2005. Second, we used linear and logistic regression models to determine if there was a correlation between these two racial/ethnic disparities at the census tract level. Third, a geographically-weighted regression analysis was performed to evaluate if this correlation occurred after weighting for local neighbors. Results The spatial association of racial disparities was found to be significant between late-stage diagnosis and breast cancer mortality with odds ratios of 33.76 (CI: 23.96-47.57) for African Americans and 30.39 (CI: 22.09-41.82) for Hispanics. After adjusting for a SES cofounder, logistic regression models revealed a reduced, although still highly significant, odds ratio of 18.39 (CI: 12.79-26.44) for African-American women and 11.64 (CI: 8.29-16.34) for Hispanic women. Results of the logistic regression analysis indicated that census tracts with low and middle SES were more likely to show significant racial disparities of breast cancer late-stage diagnosis and mortality rates. However, values of local correlation coefficients suggested that the association of these two types of racial/ethnic disparities varied across geographic regions. Conclusions This study

  6. [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

  7. 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

  8. Age-dependent role for Ras-GRF1 in the late stages of adult neurogenesis in the dentate gyrus.

    PubMed

    Darcy, Michael J; Trouche, Stéphanie; Jin, Shan-Xue; Feig, Larry A

    2014-03-01

    The dentate gyrus of the hippocampus plays a pivotal role in pattern separation, a process required for the behavioral task of contextual discrimination. One unique feature of the dentate gyrus that contributes to pattern separation is adult neurogenesis, where newly born neurons play a distinct role in neuronal circuitry. Moreover,the function of neurogenesis in this brain region differs in adolescent and adult mice. The signaling mechanisms that differentially regulate the distinct steps of adult neurogenesis in adolescence and adulthood remain poorly understood. We used mice lacking RASGRF1(GRF1), a calcium-dependent exchange factor that regulates synaptic plasticity and participates in contextual discrimination performed by mice, to test whether GRF1 plays a role in adult neurogenesis.We show Grf1 knockout mice begin to display a defect in neurogenesis at the onset of adulthood (~2 months of age), when wild-type mice first acquire the ability to distinguish between closely related contexts. At this age, young hippocampal neurons in Grf1 knockout mice display severely reduced dendritic arborization. By 3 months of age, new neuron survival is also impaired. BrdU labeling of new neurons in 2-month-old Grf1 knockout mice shows they begin to display reduced survival between 2 and 3 weeks after birth, just as new neurons begin to develop complex dendritic morphology and transition into using glutamatergic excitatory input. Interestingly, GRF1 expression appears in new neurons at the developmental stage when GRF1 loss begins to effect neuronal function. In addition, we induced a similar loss of new hippocampal neurons by knocking down expression of GRF1 solely in new neurons by injecting retrovirus that express shRNA against GRF1 into the dentate gyrus. Together, these findings show that GRF1 expressed in new neurons promotes late stages of adult neurogenesis. Overall our findings show GRF1 to be an age-dependent regulator of adult hippocampal neurogenesis, which

  9. Determination of temperature dependent structure evolution by fast-Fourier transform at late stage spinodal decomposition in bicontinuous biopolymer mixtures

    NASA Astrophysics Data System (ADS)

    Lorén, Niklas; Langton, Maud; Hermansson, Anne-Marie

    2002-06-01

    the intermediate or transitional stages of spinodal decomposition. Similarly, after the crossover, it was found that phase separation was in the late stages of spinodal decomposition. Furukawa master plots showed that the structure growth obeyed dynamical scaling and that the dimensionality of the growth was three, given off-critical conditions.

  10. 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

  11. Glycidol induces axonopathy and aberrations of hippocampal neurogenesis affecting late-stage differentiation by exposure to rats in a framework of 28-day toxicity study.

    PubMed

    Akane, Hirotoshi; Shiraki, Ayako; Imatanaka, Nobuya; Akahori, Yumi; Itahashi, Megu; Abe, Hajime; Shibutani, Makoto

    2014-01-30

    Developmental exposure to glycidol induces aberrations of late-stage neurogenesis in the hippocampal dentate gyrus of rat offspring, whereas maternal animals develop axonopathy. To investigate the possibility whether similar effects on adult neurogenesis could be induced by exposure in a framework of 28-day toxicity study, glycidol was orally administered to 5-week-old male Sprague-Dawley rats by gavage at 0, 30 or 200 mg/kg for 28 days. At 200 mg/kg, animals revealed progressively worsening gait abnormalities as well as histopathological and immunohistochemical changes suggestive of axonal injury as evidenced by generation of neurofilament-L(+) spheroids in the cerebellar granule layer and dorsal funiculus of the medulla oblongata, central chromatolysis in the trigeminal nerve ganglion cells and axonal degeneration in the sciatic nerves. At the same dose, animals revealed aberrations in neurogenesis at late-stage differentiation as evidenced by decreases of both doublecortin(+) and dihydropyrimidinase-like 3(+) cells in the subgranular zone (SGZ) and increased reelin(+) or calbindin-2(+) γ-aminobutyric acid-ergic interneurons and neuron-specific nuclear protein(+) mature neurons in the dentate hilus. These effects were essentially similar to that observed in offspring after maternal exposure to glycidol. These results suggest that glycidol causes aberrations in adult neurogenesis in the SGZ at the late stage involving the process of neurite extension similar to the developmental exposure study in a standard 28-day toxicity study.

  12. Correlation between ultrasound reflection intensity and tumor ablation ratio of late-stage pancreatic carcinoma in HIFU therapy: dynamic observation on ultrasound reflection intensity.

    PubMed

    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.

  13. 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

  14. Kenyan purple tea anthocyanins and coenzyme-Q10 ameliorate post treatment reactive encephalopathy associated with cerebral human African trypanosomiasis in murine model.

    PubMed

    Rashid, Khalid; Wachira, Francis N; Nyariki, James N; Isaac, Alfred O

    2014-04-01

    Human African trypanosomiasis (HAT) is a tropical disease caused by two subspecies of Trypanosoma brucei, the East African variant T. b. rhodesiense and the West African variant T. b. gambiense. Melarsoprol, an organic arsenical, is the only drug used to treat late stage T. b. rhodesiense infection. Unfortunately, this drug induces an extremely severe post treatment reactive encephalopathy (PTRE) in up to 10% of treated patients, half of whom die from this complication. A highly reproducible mouse model was adapted to assess the use of Kenyan purple tea anthocyanins and/or coenzyme-Q10 in blocking the occurrence of PTRE. Female Swiss white mice were inoculated intraperitoneally with approximately 10(4) trypanosome isolate T. b. rhodesiense KETRI 2537 and treated sub-curatively 21days post infection with 5mg/kg diminazene aceturate (DA) daily for 3days to induce severe late CNS infection that closely mirrors PTRE in human subjects. Thereafter mice were monitored for relapse of parasitemia after which they were treated with melarsoprol at a dosage of 3.6mg/kg body weight for 4days and sacrificed 24h post the last dosage to obtain brain samples. Brain sections from mice with PTRE that did not receive any antioxidant treatment showed a more marked presence of inflammatory cells, microglial activation and disruption of the brain parenchyma when compared to PTRE mice supplemented with either coenzyme-Q10, purple tea anthocyanins or a combination of the two. The mice group that was treated with coenzyme-Q10 or purple tea anthocyanins had higher levels of GSH and aconitase-1 in the brain compared to untreated groups, implying a boost in brain antioxidant capacity. Overall, coenzyme-Q10 treatment produced more beneficial effects compared to anthocyanin treatment. These findings demonstrate that therapeutic intervention with coenzyme-Q10 and/or purple tea anthocyanins can be used in an experimental mouse model to ameliorate PTRE associated with cerebral HAT.

  15. 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

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

    PubMed Central

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

    2015-01-01

    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

  17. 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

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. Effects of feeding dried distillers grains with solubles (DDGS) on meat quality at the late stage of the fattening period of Holstein steers.

    PubMed

    Nade, Toshihiro; Uchida, Kyouhei; Omori, Kouhei; Matsubayashi, Kenta; Kimura, Nobuhiro

    2012-04-01

    Feeding dried distillers grains with solubles (DDGS) during the late stage of the fattening period of Holstein steers was studied in regard to the influence on meat quality. Sixteen Holstein steers approximately 18 months old were used in this study. Eight animals were fed commercial concentrated feed for the entire fattening period. The other eight animals were fed 15% DDGS in the concentrated feed for 3 months before slaughtering. The moisture, ether extract and crude protein from both groups was approximately the same. The thiobarbituric acid reactive substance (TBA) value of storage for 7 days at 5°C from the animals fed DDGS showed a tendency to be lower (P = 0.059). The change in the TBA value during storage was also lower for the animals not fed DDGS (P < 0.05). There were no differences in the subcutaneous fat color between the two groups. The a*(measure of redness) and b*(measure of yellowness) of the M. longissimus from the animals fed DDGS showed a tendency to be lower (P = 0.051, 0.070). The fatty acid composition of the M. longissimus, subcutaneous and perirenal fat were not widely influenced by the feeding of DDGS. It is suggested that feeding 15% DDGS during the late stage of the fattening period for Holstein steers reduced the oxidation of the beef.

  3. Melarsoprol Sensitivity Profile of Trypanosoma brucei gambiense Isolates from Cured and Relapsed Sleeping Sickness Patients from the Democratic Republic of the Congo

    PubMed Central

    Pyana Pati, Patient; Van Reet, Nick; Mumba Ngoyi, Dieudonné; Ngay Lukusa, Ipos; Karhemere Bin Shamamba, Stomy; Büscher, Philippe

    2014-01-01

    Background Sleeping sickness caused by Trypanosoma brucei (T.b.) gambiense constitutes a serious health problem in sub-Sahara Africa. In some foci, alarmingly high relapse rates were observed in patients treated with melarsoprol, which used to be the first line treatment for patients in the neurological disease stage. Particularly problematic was the situation in Mbuji-Mayi, East Kasai Province in the Democratic Republic of the Congo with a 57% relapse rate compared to a 5% relapse rate in Masi-Manimba, Bandundu Province. The present study aimed at investigating the mechanisms underlying the high relapse rate in Mbuji-Mayi using an extended collection of recently isolated T.b. gambiense strains from Mbuji-Mayi and from Masi-Manimba. Methodology/Principal Findings Forty five T.b. gambiense strains were used. Forty one were isolated from patients that were cured or relapsed after melarsoprol treatment in Mbuji-Mayi. In vivo drug sensitivity tests provide evidence of reduced melarsoprol sensitivity in these strains. This reduced melarsoprol sensitivity was not attributable to mutations in TbAT1. However, in all these strains, irrespective of the patient treatment outcome, the two aquaglyceroporin (AQP) 2 and 3 genes are replaced by chimeric AQP2/3 genes that may be associated with resistance to pentamidine and melarsoprol. The 4 T.b. gambiense strains isolated in Masi-Manimba contain both wild-type AQP2 and a different chimeric AQP2/3. These findings suggest that the reduced in vivo melarsoprol sensitivity of the Mbuji-Mayi strains and the high relapse rates in that sleeping sickness focus are caused by mutations in the AQP2/AQP3 locus and not by mutations in TbAT1. Conclusions/Significance We conclude that mutations in the TbAQP2/3 locus of the local T.b. gambiense strains may explain the high melarsoprol relapse rates in the Mbuji-Mayi focus but other factors must also be involved in the treatment outcome of individual patients. PMID:25275572

  4. 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

  5. Profound anterograde amnesia following routine anesthetic and dental procedure: a new classification of amnesia characterized by intermediate-to-late-stage consolidation failure?

    PubMed

    Burgess, Gerald H; Chadalavada, Bhanu

    2016-01-01

    Anterograde amnesia caused by bilateral hippocampal or diencephalon damage manifests in characteristic symptoms of preserved intellect and implicit learning, and short span of awareness with complete and rapid forgetting of episodic material. A new case, WO, 38-year-old male with anterograde amnesia, in the absence of structural brain changes or psychological explanation is presented, along with four comparison cases from the extant literature that share commonalities between them including preserved intellect, span of awareness greater than working memory, and complete forgetting within hours or days following successful learning, including notably for both explicit and implicit material. WO's amnesia onset coincided with anesthetic injection and root canal procedure, with extended vasovagal-like incident. The commonalities between the five cases presented may suggest a shared biological mechanism involving the breakdown of intermediate-to-late-stage consolidation that does not depend on the structural integrity of the hippocampi. Speculation on the mechanism of consolidation breakdown and diagnostic implications are discussed. PMID:25978125

  6. Profound anterograde amnesia following routine anesthetic and dental procedure: a new classification of amnesia characterized by intermediate-to-late-stage consolidation failure?

    PubMed

    Burgess, Gerald H; Chadalavada, Bhanu

    2016-01-01

    Anterograde amnesia caused by bilateral hippocampal or diencephalon damage manifests in characteristic symptoms of preserved intellect and implicit learning, and short span of awareness with complete and rapid forgetting of episodic material. A new case, WO, 38-year-old male with anterograde amnesia, in the absence of structural brain changes or psychological explanation is presented, along with four comparison cases from the extant literature that share commonalities between them including preserved intellect, span of awareness greater than working memory, and complete forgetting within hours or days following successful learning, including notably for both explicit and implicit material. WO's amnesia onset coincided with anesthetic injection and root canal procedure, with extended vasovagal-like incident. The commonalities between the five cases presented may suggest a shared biological mechanism involving the breakdown of intermediate-to-late-stage consolidation that does not depend on the structural integrity of the hippocampi. Speculation on the mechanism of consolidation breakdown and diagnostic implications are discussed.

  7. 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

  8. Gaining power and precision by using model-based weights in the analysis of late stage cancer trials with substantial treatment switching.

    PubMed

    Bowden, Jack; Seaman, Shaun; Huang, Xin; White, Ian R

    2016-04-30

    In randomised controlled trials of treatments for late-stage cancer, it is common for control arm patients to receive the experimental treatment around the point of disease progression. This treatment switching can dilute the estimated treatment effect on overall survival and impact the assessment of a treatment's benefit on health economic evaluations. The rank-preserving structural failure time model of Robins and Tsiatis (Comm. Stat., 20:2609-2631) offers a potential solution to this problem and is typically implemented using the logrank test. However, in the presence of substantial switching, this test can have low power because the hazard ratio is not constant over time. Schoenfeld (Biometrika, 68:316-319) showed that when the hazard ratio is not constant, weighted versions of the logrank test become optimal. We present a weighted logrank test statistic for the late stage cancer trial context given the treatment switching pattern and working assumptions about the underlying hazard function in the population. Simulations suggest that the weighted approach can lead to large efficiency gains in either an intention-to-treat or a causal rank-preserving structural failure time model analysis compared with the unweighted approach. Furthermore, violation of the working assumptions used in the derivation of the weights only affects the efficiency of the estimates and does not induce bias or inflate the type I error rate. The weighted logrank test statistic should therefore be considered for use as part of a careful secondary, exploratory analysis of trial data affected by substantial treatment switching. PMID:26576494

  9. Anti-LRP/LR–Specific Antibody IgG1-iS18 Significantly Impedes Adhesion and Invasion in Early- and Late-Stage Colorectal Carcinoma Cells

    PubMed Central

    Vania, Leila; Chetty, Carryn J; Ferreira, Eloise; Weiss, Stefan FT

    2016-01-01

    Cancer is a highly complex disease that has become one of the leading causes of death globally. Metastasis, a major cause of cancer deaths, requires two crucial events, adhesion and invasion. The 37kDa/67kDa laminin receptor (laminin receptor precursor/high-affinity laminin receptor [LRP/LR]) enhances these two steps, consequently aiding in cancer progression. In this study, the role of LRP/LR in adhesion and invasion of early-stage (SW-480 and HT-29) and late-stage (DLD-1) colorectal cancer cells was investigated. Western blotting revealed that early- and late-stage colorectal cancer cells contained significantly higher total LRP/LR levels compared with poorly invasive MCF-7 breast cancer control cells. Flow cytometry revealed that both stages of colorectal cancer displayed significantly higher cell surface LRP/LR levels. Furthermore, upon treatment of colorectal cancer cells with the anti-LRP/LR–specific antibody IgG1-iS18, adhesion to laminin-1 was significantly reduced in both stages. Each stage’s invasive potential was determined using the Matrigel™ invasion assay, showing that invasion was significantly impeded in both colorectal cancer stages when the cells were incubated with IgG1-iS18. In addition, Pearson’s correlation coefficients propose that both total and cell surface LRP/LR levels are directly proportional to the adhesive and invasive potential of both stages of colorectal cancer. Hence, these findings indicate potential for use of the IgG1-iS18 antibody as a promising therapeutic tool for colorectal cancer patients at both stages. PMID:27611822

  10. Propofol exposure during late stages of pregnancy impairs learning and memory in rat offspring via the BDNF-TrkB signalling pathway.

    PubMed

    Zhong, Liang; Luo, Foquan; Zhao, Weilu; Feng, Yunlin; Wu, Liuqin; Lin, Jiamei; Liu, Tianyin; Wang, Shengqiang; You, Xuexue; Zhang, Wei

    2016-10-01

    The brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) (BDNF-TrkB) signalling pathway plays a crucial role in regulating learning and memory. Synaptophysin provides the structural basis for synaptic plasticity and depends on BDNF processing and subsequent TrkB signalling. Our previous studies demonstrated that maternal exposure to propofol during late stages of pregnancy impaired learning and memory in rat offspring. The purpose of this study is to investigate whether the BDNF-TrkB signalling pathway is involved in propofol-induced learning and memory impairments. Propofol was intravenously infused into pregnant rats for 4 hrs on gestational day 18 (E18). Thirty days after birth, learning and memory of offspring was assessed by the Morris water maze (MWM) test. After the MWM test, BDNF and TrkB transcript and protein levels were measured in rat offspring hippocampus tissues using real-time PCR (RT-PCR) and immunohistochemistry (IHC), respectively. The levels of phosphorylated-TrkB (phospho-TrkB) and synaptophysin were measured by western blot. It was discovered that maternal exposure to propofol on day E18 impaired spatial learning and memory of rat offspring, decreased mRNA and protein levels of BDNF and TrkB, and decreased the levels of both phospho-TrkB and synaptophysin in the hippocampus. Furthermore, the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) reversed all of the observed changes. Treatment with 7,8-DHF had no significant effects on the offspring that were not exposed to propofol. The results herein indicate that maternal exposure to propofol during the late stages of pregnancy impairs spatial learning and memory of offspring by disturbing the BDNF-TrkB signalling pathway. The TrkB agonist 7,8-DHF might be a potential therapy for learning and memory impairments induced by maternal propofol exposure.

  11. ERCC1 C118T polymorphism has predictive value for platinum-based chemotherapy in patients with late-stage bladder cancer.

    PubMed

    Xu, Z C; Cai, H Z; Li, X; Xu, W Z; Xu, T; Yu, B; Zou, Q; Xu, L

    2016-01-01

    This study aims to investigate the association between ERCC1 codon C118T polymorphism and the response rate of platinum-based chemotherapy in patients with late-stage bladder cancer. A total of 41 eligible patients histologically confirmed as having stage IV muscle-invasive transitional cell carcinoma of the bladder were treated with platinum-based chemotherapy for 2-6 cycles. The genotypes of patients were determined by PCR amplification of genomic DNA followed by restriction enzyme digestion. Positive responses were categorized as complete and partial responses. In addition, progression-free survival (PFS) and overall survival (OS) were also determined as indicators of long-term outcomes. The genotype frequencies of C/C, C/T and T/T genotypes were 56.1, 34.1, and 9.8%, respectively. Positive response was observed in 14 patients (34.1%), while 27 patients (65.9%) were negative responders. As compared with individuals carrying the C/T and T/T genotypes, those with the C/C genotype had significantly improved short-term treatment responses (P = 0.018). The median PFS of patients carrying the C/C genotype was 6.3 months, while that of patients with C/T and T/T genotypes was 4.2 months (P = 0.023). Moreover, the median OS for patients carrying the C/C genotype was also longer as compared with that of patients carrying C/T and T/T (11.7 months vs 8.5 months, P = 0.040). Our results indicated that the ERCC1 codon 118 polymorphism may have predictive potential for chemotherapy treatment responses in late-stage bladder cancer patients. PMID:27323074

  12. 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

  13. 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.

  14. 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

  15. 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

  16. 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

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

    NASA Astrophysics Data System (ADS)

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

    2012-02-01

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

  18. Late-Stage HIMU-Type Volcanism on the Walvis Ridge: Not just Part of an Age-Progressive Tristan-Gough Hotspot Track

    NASA Astrophysics Data System (ADS)

    Homrighausen, S.; Hoernle, K.; Hauff, F.; Portnyagin, M.; Werner, R.; Geldmacher, J.; Garbe-Schoenberg, C. D.

    2015-12-01

    The Walvis Ridge forms the NE portion of the Tristan-Gough hotspot track. It links the Etendeka large igneous province (LIP) in Africa, initially connected to the Parana LIP in South America, to the Guyot Province, that ends at the active volcanic islands of Tristan da Cunha and Gough. After the plume head stage, the hotspot changed from a ridge-centered plume tail, forming the Walvis Ridge and Rio Grande Rise (130-60 Ma), to an intraplate setting resulting in the geochemical distinct Tristan and Gough subtracks (Rohde et al. 2013; Geology 41). New major and trace element and radiogenic isotope data have been generated from 36 new dredge locations on the Walvis Ridge during R/V Sonne cruises SO233 and SO234. Based on the bathymetric data, we have identified tectonic structures and subsidence rates which indicate a complex geodynamic interplay of the Walvis Ridge formation and westward migration of the Mid Atlantic Ridge and the Rio Grande Rise. Our new results confirm that the age-progressive basement of the Walvis Ridge reflects only the enriched Gough component with no evidence of the Tristan component being present (Hoernle et al., 2015; Nat. Comm.). Superimposed large seamounts (including ridge- and guyot-like structures), especially in the SE portion of the Walvis Ridge, belong to a later-stage of alkalic volcanism with distinct HIMU incompatible element and Sr-Nd-Pb-Hf isotopic composition. The HIMU late-stage volcanism (206Pb/204Pb up to 20.8) is similar in composition to St. Helena and a late-stage (Eocene) sample from the Rio Grande Rise (Rohde et al., 2013; Tectonophysics 604). The new geochemical, bathymetric and existing age data indicate a magmatic reactivation c. 20-40 Ma after the formation of the Walvis Ridge basement, which may be related to passage of the Walvis Ridge over a batch of upwelling St. Helena type plume material. Our new results indicate a more complex formation of the Walvis Ridge than previously thought, which included two major

  19. 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

  20. 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

  1. 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

  2. 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.

  3. 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

  4. Tectonic control on the late stage exhumation of the Aar Massif (Switzerland): Constraints from apatite fission track and (U-Th)/He data

    NASA Astrophysics Data System (ADS)

    Reinecker, John; DanišíK, Martin; Schmid, Claudia; Glotzbach, Christoph; Rahn, Meinert; Frisch, Wolfgang; Spiegel, Cornelia

    2008-12-01

    We examine the hypothesis that Pliocene exhumation of the external massifs in the central Alps is controlled by climatic change. New thermochronological data from the western Gastern-Aar massif are used to investigate the timing, extent, and reasons for Neogene exhumation. Our data reveal that exhumation was constant with 0.5 km/Ma over the last 10 Ma in the north. In the southern part, exhumation was of the same order until ˜3.5 Ma but then increased gradually toward the south to values of up to 1.2 km/Ma, resulting in overall northward tilting of the western Aar massif. We explain this accelerated exhumation in the south after ˜3.5 Ma mainly by tectonic denudation in the footwall of the Rhône-Simplon fault and discuss changes in deep crustal configuration, which may have triggered south directed normal faulting. We propose that the Rhône river was structurally trapped by the Rhône-Simplon normal fault zone, which additionally enhanced erosion in the southern section of the Aar massif. Climatic forcing may have an impact in the very late stage of exhumation due to Alpine glaciation in the late Pliocene.

  5. Glycidol induces axonopathy by adult-stage exposure and aberration of hippocampal neurogenesis affecting late-stage differentiation by developmental exposure in rats.

    PubMed

    Akane, Hirotoshi; Shiraki, Ayako; Imatanaka, Nobuya; Akahori, Yumi; Itahashi, Megu; Ohishi, Takumi; Mitsumori, Kunitoshi; Shibutani, Makoto

    2013-07-01

    To investigate the neurotoxicity profile of glycidol and its effect on developmental hippocampal neurogenesis, pregnant Sprague Dawley rats were given drinking water containing 0, 100, 300, or 1000 ppm glycidol from gestational day 6 until weaning on day 21 after delivery. At 1000 ppm, dams showed progressively worsening gait abnormalities, and histopathological examination showed generation of neurofilament-L(+) spheroids in the cerebellar granule layer and dorsal funiculus of the medulla oblongata, central chromatolysis in the trigeminal nerve ganglion cells, and axonal degeneration in the sciatic nerves. Decreased dihydropyrimidinase-like 3(+) immature granule cells in the subgranular zone (SGZ) and increased immature reelin(+) or calbindin-2(+) γ-aminobutyric acid-ergic interneurons and neuron-specific nuclear protein (NeuN)(+) mature neurons were found in the dentate hilus of the offspring of the 1000 ppm group on weaning. Hilar changes remained until postnatal day 77, with the increases in reelin(+) and NeuN(+) cells being present at ≥ 300 ppm, although the SGZ change disappeared. Thus, glycidol caused axon injury in the central and peripheral nervous systems of adult rats, suggesting that glycidol targets the newly generating nerve terminals of immature granule cells, resulting in the suppression of late-stage hippocampal neurogenesis. The sustained hilar changes may be a sign of continued aberrations in neurogenesis and migration. The no-observed-adverse-effect level was determined to be 300 ppm (48.8mg/kg body weight/day) for dams and 100 ppm (18.5mg/kg body weight/day) for offspring. The sustained developmental exposure effect on offspring neurogenesis was more sensitive than the adult axonal injury.

  6. Transient suppression of late-stage neuronal progenitor cell differentiation in the hippocampal dentate gyrus of rat offspring after maternal exposure to nicotine.

    PubMed

    Ohishi, Takumi; Wang, Liyun; Akane, Hirotoshi; Shiraki, Ayako; Itahashi, Megu; Mitsumori, Kunitoshi; Shibutani, Makoto

    2014-02-01

    To examine the developmental exposure effect of nicotine (NIC) on hippocampal neurogenesis, pregnant Sprague-Dawley rats were treated with (-)-NIC hydrogen tartrate salt through drinking water at 2, 10 or 50 ppm from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, immunohistochemically doublecortin (Dcx)(+) cells increased at ≥10 ppm in the dentate subgranular zone (SGZ) as examined in male offspring; however, dihydropyrimidinase-like 3 (TUC4)(+) cells decreased at 2 ppm, and T box brain 2 (Tbr2)(+) cells were unchanged at any dose. Double immunohistochemistry revealed decreases in TUC4(+)/Dcx(+) and TUC4(+)/Dcx(-) cells, an increase in TUC4(-)/Dcx(+) cells at 2 and 10 ppm and an increase in Tbr2(-)/Dcx(+) cells at 50 ppm, suggesting an increase in type-3 progenitor cells at ≥2 ppm and decrease in immature granule cells at 2 and 10 ppm. The number of mature neuron-specific NeuN(-) progenitor cells expressing nicotinic acetylcholine receptor α7 in the SGZ and mRNA levels of Chrna7 and Chrnb2 in the dentate gyrus was unchanged at any dose, suggesting a lack of direct nicotinic stimulation on progenitor cells. In the dentate hilus, glutamic acid decarboxylase 67(+) interneurons increased at ≥10 ppm. All changes disappeared on PND 77. Therefore, maternal exposure to NIC reversibly affects hippocampal neurogenesis targeting late-stage differentiation in rat offspring. An increase in interneurons suggested that their activation affected granule cell differentiation. The lowest observed adverse effect level was at 2 ppm (0.091 mg/kg/day as a free base) by the affection of hippocampal neurogenesis at ≥2 ppm.

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

    NASA Astrophysics Data System (ADS)

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

    2014-04-01

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

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

    PubMed

    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 600mg/kg body weight/day for 28days. In the subgranular zone (SGZ), 600mg/kg CPZ increased the number of cleaved caspase-3(+) apoptotic cells. At ≥120mg/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 ≥120mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥120mg/kg decreased phosphorylated TRKB(+) interneurons, although the number of reelin(+) interneurons was unchanged. At 600mg/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.

  9. 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.

  10. Reversible aberration of neurogenesis affecting late-stage differentiation in the hippocampal dentate gyrus of rat offspring after maternal exposure to manganese chloride.

    PubMed

    Ohishi, Takumi; Wang, Liyun; Akane, Hirotoshi; Shiraki, Ayako; Goto, Ken; Ikarashi, Yoshiaki; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2012-11-01

    To examine the effects of developmental manganese (Mn)-exposure on hippocampal neurogenesis, pregnant rats were treated with MnCl(2)·4H(2)O in the diet at 32, 160 or 800 ppm from gestation day 10 to day 21 after delivery. Serum concentrations of thyroid-related hormones were examined in offspring exposed to MnCl(2)·4H(2)O at 800 or 1600 ppm. Immunohistochemical analysis revealed increased doublecortin-positive cells in the subgranular zone of the dentate gyrus on postnatal day (PND) 21 following exposure to MnCl(2)·4H(2)O at 800 ppm, indicating an increase of type-3 progenitor or immature granule cells. Reelin-positive cells, suggestive of γ-aminobutyric acid-ergic interneurons in the dentate hilus, also increased at 800 ppm on PND 21. Brain Mn concentrations increased in offspring on PND 21 at 160 and 800 ppm, whereas brain concentrations in the dams were unchanged. Serum concentrations of triiodothyronine and thyroxine decreased at 800 and 1600 ppm, whereas thyroid-stimulating hormone increased only after exposure at 800 ppm. All changes disappeared on PND 77. Thus, maternal exposure to MnCl(2)·4H(2)O at 800 ppm mildly and reversibly affects neurogenesis targeting late-stage differentiation in the hippocampal dentate gyrus of rat offspring. Direct effects of accumulated Mn in the developing brain might be implicated in the mechanism of the development of aberrations in neurogenesis; however, indirect effects through thyroid hormone fluctuations might be rather minor.

  11. 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.

  12. 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.

  13. Disparate effects of depletion of CD1d-reactive T cells during early versus late stages of disease in a genetically susceptible model of lupus.

    PubMed

    Jacinto, J; Kim, P J; Singh, R R

    2012-04-01

    Some T cells react with lipid antigens bound to antigen-presenting molecule CD1d. Numbers and functions of a subset of such lipid-reactive T cells are reduced in patients with systemic lupus erythematosus (SLE) and their relatives, as well as in genetically susceptible and chemically induced animal models of lupus-like disease. We have reported that the germline deletion of CD1d exacerbates lupus, suggesting a protective role of these cells in the development of lupus. The use of a knockout mouse model in this study, however, did not allow examination of the role of these cells at different stages of disease. Here, we describe an approach to deplete CD1d-dependent T cells, which allowed us to investigate the role of these cells at different stages of disease in genetically lupus-prone NZB/NZW F1 (BWF1) mice. Repeated intravenous injections of large numbers of CD1d-transfected cells resulted in ∼50-75% reduction in these cells, as defined by the expression of CD4, NK1.1 and CD122, and lack of expression of CD62 ligand. TCR γδ (+)NK1.1(+) cells were also reduced in the recipients of CD1d-transfected cells as compared with control recipients. Such depletion of CD1d-reactive T cells in preclinical BWF1 mice resulted in disease acceleration with a significant increase in proteinuria and mortality. In older BWF1 mice having advanced nephritis, however, such depletion of CD1d-reactive T cells resulted in some disease improvement. Taken together, these data as well as our published studies suggest that CD1d-reactive T cells protect against the development of lupus in animal models. However, these cells appear to be unable to suppress established lupus nephritis in these animals, and might even play a disease aggravating role in late stages of disease.

  14. 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

  15. 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.

  16. 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

  17. 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

  18. 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.

  19. PGE-enrichment with late-stage Fe-Ti oxide crystallisation observed in the Dufek-Forrestal layered mafic intrusion, Antarctica

    NASA Astrophysics Data System (ADS)

    Hanemann, R.; Melcher, F.; Mukasa, S. B.; Viereck-Goette, L.; Abratis, M.

    2009-12-01

    either Pt-rich or Pd-rich alloys with semimetals such as As, Sb, Bi, and Te and a few mixed Pt-Pd phases. PGE-rich sulphides are notably absent and there are no discrete phases of Rh, Ir, Os and Ru. Common base-metal sulphides do not incorporate PGE detectable by EMPA, except of cobalt-rich pentlandite that contains up to 1.44 wt% Rh and 0.75 wt% Pd. The PGE variations within the Dufek-Forrestal intrusion are ascribed to an extensive differentiation history under mainly S-undersaturated conditions resulting in PGE-enrichment until the onset of late-stage Fe-Ti oxide crystallisation. This was accompanied by a delayed saturation and exsolution of sulphide melt scavenging the PGE from the highly evolved tholeiitic magma. However, there is evidence that the PGE in most of the studied rocks are not solely controlled by base-metal sulphides but by a variety of PGM indicating that both high-temperature and subsolidus processes influenced the PGE fractionation behaviour and caused the highly variable PGE totals and ratios throughout the exposed profile as well as the formation of the PGM assemblage identified.

  20. 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

  1. Human African trypanosomiasis in endemic populations and travellers.

    PubMed

    Blum, J A; Neumayr, A L; Hatz, C F

    2012-06-01

    Human African trypanosomiasis (HAT) or sleeping sickness is caused by the protozoan parasites Trypanosoma brucei (T.b.) gambiense (West African form) and T.b. rhodesiense (East African form) that are transmitted by the bite of the tsetse fly, Glossina spp.. Whereas most patients in endemic populations are infected with T.b. gambiense, most tourists are infected with T.b. rhodesiense. In endemic populations, T.b. gambiense HAT is characterized by chronic and intermittent fever, headache, pruritus, and lymphadenopathy in the first stage and by sleep disturbances and neuro-psychiatric disorders in the second stage. Recent descriptions of the clinical presentation of T.b. rhodesiense in endemic populations show a high variability in different foci. The symptomatology of travellers is markedly different from the usual textbook descriptions of African HAT patients. The onset of both infections is almost invariably an acute and febrile disease. Diagnosis and treatment are difficult and rely mostly on old methods and drugs. However, new molecular diagnostic technologies are under development. A promising new drug combination is currently evaluated in a phase 3 b study and further new drugs are under evaluation.

  2. Human African trypanosomiasis in endemic populations and travellers.

    PubMed

    Blum, J A; Neumayr, A L; Hatz, C F

    2012-06-01

    Human African trypanosomiasis (HAT) or sleeping sickness is caused by the protozoan parasites Trypanosoma brucei (T.b.) gambiense (West African form) and T.b. rhodesiense (East African form) that are transmitted by the bite of the tsetse fly, Glossina spp.. Whereas most patients in endemic populations are infected with T.b. gambiense, most tourists are infected with T.b. rhodesiense. In endemic populations, T.b. gambiense HAT is characterized by chronic and intermittent fever, headache, pruritus, and lymphadenopathy in the first stage and by sleep disturbances and neuro-psychiatric disorders in the second stage. Recent descriptions of the clinical presentation of T.b. rhodesiense in endemic populations show a high variability in different foci. The symptomatology of travellers is markedly different from the usual textbook descriptions of African HAT patients. The onset of both infections is almost invariably an acute and febrile disease. Diagnosis and treatment are difficult and rely mostly on old methods and drugs. However, new molecular diagnostic technologies are under development. A promising new drug combination is currently evaluated in a phase 3 b study and further new drugs are under evaluation. PMID:21901632

  3. Identification and Characterization of FTY720 for the Treatment of Human African Trypanosomiasis

    PubMed Central

    Kaiser, Marcel; Avery, Vicky M.

    2015-01-01

    The screening of a focused library identified FTY720 (Fingolimod; Gilenya) as a potent selective antitrypanosomal compound active against Trypanosoma brucei gambiense and T. brucei rhodesiense, the causative agents of human African trypanosomiasis (HAT). This is the first report of trypanocidal activity for FTY720, an oral drug registered for the treatment of relapsing multiple sclerosis, and the characterization of sphingolipids as a potential new class of compounds for HAT. PMID:26666915

  4. 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

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

    2015-07-22

    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.

  5. 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

  6. 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

  7. The geology and geochemistry of Isla Floreana, Galápagos: A different type of late-stage ocean island volcanism: Chapter 6 in The Galápagos: A natural laboratory for the earth sciences

    USGS Publications Warehouse

    Harpp, Karen S.; Geist, Dennis J.; Koleszar, Alison M.; Christensen, Branden; Lyons, John; Sabga, Melissa; Rollins, Nathan; Harpp, Karen S.; Mittelstaedt, Eric; d'Ozouville, Noémi; Graham, David W

    2014-01-01

    Isla Floreana, the southernmost volcano in the Galápagos Archipelago, has erupted a diverse suite of alkaline basalts continually since 1.5 Ma. Because these basalts have different compositions than xenoliths and older lavas from the deep submarine sector of the volcano, Floreana is interpreted as being in a rejuvenescent or late-stage phase of volcanism. Most lavas contain xenoliths, or their disaggregated remains. The xenolithic debris and large ranges in composition, including during single eruptions, indicate that the magmas do not reside in crustal magma chambers, unlike magmas in the western Galápagos. Floreana lavas have distinctive trace element compositions that are rich in fluid-immobile elements (e.g., Ta, Nb, Th, Zr) and even richer in fluid-mobile elements (e.g., Ba, Sr, Pb). Rare earth element (REE) patterns are light REE-enriched and distinctively concave-up. Neodymium isotopic ratios are comparable to those from Fernandina, at the core of the Galápagos plume, but Floreana has the most radiogenic Sr and Pb isotopic ratios in the archipelago. These trace element patterns and isotopic ratios are attributed to a mixed source originating within the Galápagos plume, which includes depleted upper mantle, plume material rich in TITAN elements (Ti, Ta, Nb), and recycled oceanic crust that has undergone partial dehydration in an ancient subduction zone. Because Floreana lies at the periphery of the Galápagos plume, melting occurs mostly in the spinel zone, and enriched components dominate; the Floreana recycled mantle component influence is detectable in volcanoes along the entire southern periphery of the archipelago as well. Floreana is the only Galápagos volcano known to have undergone late-stage volcanism. Here, however, the secondary stage activity is more compositionally enriched than the shield-building phase, in contrast to what is observed in Hawai‘i, suggesting that the mechanism driving late-stage volcanism may vary among ocean island

  8. 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.

  9. Effect of Debagging Time on Pigment Patterns in the Peel and Sugar and Organic Acid Contents in the Pulp of ‘Golden Delicious’ and ‘Qinguan’ Apple Fruit at Mid and Late Stages of Development

    PubMed Central

    Jing, Chenjuan; Ma, Changqing; Zhang, Juan; Jing, Shujuan; Jiang, Xiaobing; Yang, Yazhou; Zhao, Zhengyang

    2016-01-01

    This study examined the effect of debagging time on color and flavor / taste compounds in the non-red apple cultivar ‘Golden Delicious’ and red cultivar ‘Qinguan’ at mid and late stages of fruit development. Debagging briefly improved the red color in both cultivars, the peel of ‘Golden Delicious’ presenting pale-pink hue. However, rapid anthocyanin accumulation occurred in apple peel at a specific time (after 179 days after flowering (DAF) in ‘Qinguan’) and was unaltered by debagging time in the red cultivar ‘Qinguan’. Furthermore, untimely debagging had a detrimental effect on the content of anthocyanin. All sugars increased and organic acids decreased in apple pulp at mid to late stages of development. Bagging treatment reduced the content of most sugars and organic acids, as well as, the overall total. However, glucose and citric acid contents were higher in bagged fruit than non-bagged fruit; the maximum occurred in T7 treatment that was no-debagging at DAF 159 / 196 (‘Golden delicious’ / ‘Qinguan’), i.e., 24.35 and 0.07 mg g-1 FW in ‘Golden delicious’, and 38.86 and 0.06 mg g-1 FW in ‘Qinguan’, respectively. In a word, bagging treatment can alter the pattern of peel color development in apple fruit; however, it remains difficult to alter the timing of rapid anthocyanin accumulation as it is regulated solely by development. Moreover, bagging treatment reduced the total accumulation of sugars and organic acids, and even the over total in pulp, but increased the glucose and citric acid contents in apple pulp. PMID:27788164

  10. 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

  11. 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

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

    NASA Astrophysics Data System (ADS)

    Belkin, H. E.; Luo, K.

    2008-03-01

    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.

  13. 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.

  14. An inhibitor of fibroblast growth factor receptor-1 (FGFR1) promotes late-stage terminal differentiation from NGN3+ pancreatic endocrine progenitors

    PubMed Central

    Yamashita-Sugahara, Yzumi; Matsumoto, Masahito; Ohtaka, Manami; Nishimura, Ken; Nakanishi, Mahito; Mitani, Kohnosuke; Okazaki, Yasushi

    2016-01-01

    Human induced pluripotent stem cells (hiPSCs) provide a potential resource for regenerative medicine. To identify the signalling pathway(s) contributing to the development of functional β cells, we established a tracing model consisting of dual knock-in hiPSCs (INS-Venus/NGN3-mCherry) (hIveNry) expressing the fluorescent proteins Venus and mCherry under the control of intrinsic insulin (INS) and neurogenin 3 (NGN3) promoters, respectively. hIveNry iPSCs differentiated into NGN3- and mCherry-positive endocrine progenitors and then into Venus-positive β cells expressing INS, PDX1, NKX6.1, and glucokinase (GCK). Using these cells, we conducted high-throughput screening of chemicals and identified a specific kinase inhibitor of fibroblast growth factor receptor 1 (FGFR1) that acted in a stage-dependent manner to promote the terminal differentiation of pancreatic endocrine cells, including β cells, from the intermediate stage of pancreatic endocrine progenitors while blocking the early development of pancreatic progenitors. This FGFR1 inhibitor augmented the expression of functional β cell markers (SLC30A8 and ABCC8) and improved glucose-stimulated INS secretion. Our findings indicate that the hIveNry model could provide further insights into the mechanisms of hiPS-derived β cell differentiation controlled by FGFR1-mediated regulatory pathways in a temporal-dependent fashion. PMID:27786288

  15. 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

  16. Diffusion in late stages of stellar evolution

    NASA Astrophysics Data System (ADS)

    Michaud, Georges

    The abundances of the chemical elements observed at the surface of white dwarfs are the result of diffussion in the external regions of these stars. It is described how diffusion determines the abundances of such elements as carbon, that are now being observed in the far UV Diffusion is shown to play a minor role in giants but its effects start to appear rapidly after the planetary nebula stage. While the basic physical process of gravitational settling is well understood, the quantitative values of the diffusion coefficients involved are uncertain in some cases. They pose interesting statistical physics problems specially for the thermal diffusion coefficients. Depending on the model used it can vary by orders of magnitude. A number of the possible sources of uncertainty of the diffusion coefficients are described as well as the astrophysical context where the coefficients are most uncertain. L'abondance des éléments chimiques à la surface des naines blanches est le fruit de la diffusion des particules dans les régions externes de ces étoiles. On décrit comment la diffusion détermine l'abondance du carbone que l'on observe dans l'UV. La diffusion joue une rôle mineur dans les géantes mais ses effets commencent à faire sentir peu après l'étape des nébuleuses planétaires. Le tri gravitationnel est un processus bien compris mais les coefficients de diffusion impliqués sont incertains dans plusieurs cas. Leur détermination, en particulier celle du coefhcient de diffusion thermique, pose des problèmes intéressants de physique statistique. Dépendant du modèle utilisé, la valeur du coefficient de diffusion thermique peut varier par plusieurs ordres de grandeur. Plusieurs des causes d'incertitude sont décrites de même que le contexte astrophysique où les coefficients sont le plus incertains.

  17. Late Stage Azidation of Complex Molecules

    PubMed Central

    2016-01-01

    Selective functionalization of complex scaffolds is a promising approach to alter the pharmacological profiles of natural products and their derivatives. We report the site-selective azidation of benzylic and aliphatic C–H bonds in complex molecules catalyzed by the combination of Fe(OAc)2 and a PyBox ligand. The same system also catalyzes the trifluoromethyl azidation of olefins to form derivatives of natural products containing both fluorine atoms and azides. In general, both reactions tolerate a wide range of functional groups and occur with predictable regioselectivity. Azides obtained by functionalization of C–H and C=C bonds were converted to the corresponding amines, amides, and triazoles, thus providing a wide variety of nitrogen-containing complex molecules. PMID:27800554

  18. 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.

  19. Human African trypanosomiasis in non-endemic countries.

    PubMed

    Sudarshi, Darshan; Brown, Mike

    2015-02-01

    Human African trypanosomiasis (HAT) or sleeping sickness is a parasitic disease, acquired by the bite of an infected tsetse fly. In non-endemic countries HAT is rare, and therefore the diagnosis may be delayed leading to potentially fatal consequences. In this article the clinical presentation, diagnosis and treatment of the two forms of HAT are outlined. Rhodesiense HAT is an acute illness that presents in tourists who have recently visited game parks in Eastern or Southern Africa, whereas Gambiense HAT has a more chronic clinical course, in individuals from West or Central Africa.

  20. Temperature and ration effects on components of the IGF system and growth performance of rainbow trout (Oncorhynchus mykiss) during the transition from late stage embryos to early stage juveniles.

    PubMed

    Li, Mao; Leatherland, John

    2008-02-01

    The study investigated the effects of incubation temperature, and the size of ration fed to the transitional embryo/juvenile stage of rainbow trout (Oncorhynchus mykiss) on growth, liver and gastrointestinal (GI) tract IGF-1 content, and the expression of insulin-like growth factor-related genes (IGF-1, IGF-2, IGF-RIa, and IGF-RIb) by the liver and GI tract. Embryos were reared from zygote to "swim-up" at either 8.5 degrees C (E(8.5)) or 6.0 degrees C (E(6.0)); at "swim-up" (51-days post-fertilization [dpf] and 72-dpf for the E(8.5) and E(6.0) groups, respectively), the embryos were transferred to grow-up tanks supplied with water at 8.5 degrees C. Late stage embryos (LSEs) at the same developmental stage from the two temperature treatment groups (64-dpf and 86-dpf for the E(8.5) and E(6.0) groups, respectively) were fed with salmonid starter diet at levels of 5.0%, 2.0%, and 0.5% of live body mass per day. Embryos were sampled just prior to first feeding (PFEs), and before complete absorption of the yolk [late stage embryos (LSEs)], and early stage juveniles (ESJs) were sampled after yolk sac absorption when they were fully reliant on exogenous sources of food. The early incubation temperature and ration levels had significant affects on mortality (with lower mortalities in the E(6.0) group) and growth performance of the fish; dry body mass values for fish fed the 5.0% ration were significantly lower in the E(6.0) group of LSEs and ESJs compared with the respective treatment in the E(8.5) group; a similar pattern was seen for total body length, although this was only significant for the LSEs. Whole embryo IGF-1 content was significantly lower in the E(6.0) group compared with the E(8.5) group of PFEs, and hepatic IGF-1 content was significantly lower in the E(6.0) group fed the maintenance ration (0.5%) compared with the E(8.5) fed a similar ration; restricted ration significantly elevated hepatic IGF-1 content in the LSE stage for both temperature treatment

  1. Fluid regimes during late stages of a continental collision: Physical, chemical, and stable isotope measurements of fluid inclusions in fissure quartz from a geotraverse through the Central Alps, Switzerland

    SciTech Connect

    Mullis, J. ); Dubessy, J.; Poty, B. ); O'Neil, J. )

    1994-05-01

    Fluid evolution during neo-alpine metamorphism during late stages of the continental collision between Europe and Africa was studied by analyzing fluid inclusions in alpine fissure quartz collected in forty-nine localities along a geotraverse through the Central Alps, Switzerland. The methods employed include microthermometry, micro-Raman spectroscopy, K/Na thermometry, and stable isotope analysis. Early fluid inclusions provide evidence of close to peak metamorphic temperatures of the late Tertiary or neo-alpine metamorphic event. Fluid composition evolved along the geotraverse from north to south as follows: higher hydrocarbons were dominant in the low- and medium-grade diagenetic zones, methane was the main volatile in the high-grade diagenetic and low-grade anchizone, water dominated in the high-grade anchizone and low-grade epizone, with CO[sub 2] > 10 mol% in the high-grade epizone and in the mesozone. Higher hydrocarbons and CH[sub 4] were the products of kerogen maturation and cracking of preexisting petroleum. Large water supplies originated from the dehydration of cooler metasedimentary rocks that were overthrust by crystalline basements of the Lepontines, Aar, and Gotthard massifs. Carbon isotope analyses suggest that the CO[sub 2] component was derived from oxidation of graphitic matter, especially in the vicinity of sulfate-bearing metasediments and from decarbonation reactions. In the Aar and Gotthard massifs as well as in the Helvetic Axen nappe and its underlying North Helvetic flysch, high fluid pressures prevailed and favored nappe transport. By contrast, in the southern Lepontine area, very low early fluid pressures were probably related to dry rocks and scarce metasediments, and to high geothermal gradients that resulted from intense uplift and erosion between 26 and 18 Ma.

  2. Determinants of Human African Trypanosomiasis Elimination via Paratransgenesis.

    PubMed

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

    2016-03-01

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

  3. Determinants of Human African Trypanosomiasis Elimination via Paratransgenesis.

    PubMed

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

    2016-03-01

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

  4. 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

  5. [The different present-day clinical picture of human African trypanosomiasis caused by T. b. gambiense. Analysis of 300 cases from a focus in Daloa, Ivory Coast].

    PubMed

    Boa, Y F; Traore, M A; Doua, F; Kouassi-Traore, M T; Kouassi, B E; Giordano, C

    1988-01-01

    300 patients with sleeping sickness have been admitted, at the AHT clinic of Daloa, over a time period of 22 months. The sex ratio of the patients is 1.5 males for 1 female; the mean age is 25.5 years. The most frequent signs and symptoms observed by clinical examination are: fever (30%), nodes (86.3%), prurigo (43.3%), splenomegaly (15.3%), hepatomegaly (1%), headache (72.6%), vigilance and sleeping disturbances (68.7%), perioral reflexes (67.6%), cheiro-oral reflexes (64.3%), movement disorders consisting of tremor, choreo-athetosis movements, buccal dyskinesia or seizures (35%), motor palsy and gait disorders (15%), tonus disturbances (12.3%), sensitivity abnormalities (17%), endocrine disorders (16.3%), psychiatric symptoms (6.3%). According to CSF status, 261 patients have been classified in second period (P2). This group, although biologically well defined, is in fact a miscellaneous group of clinical signs and symptoms ranging from apparently normal patients to sleeping comatose and cachectic patients. 93% of the patients in this group have peripheral signs associated with neurological symptoms. They are as frequent in the first period as in the second period, with a statistical significance. This is an argument to think that the CNS is early affected in the course of the disease. The classification of the patients in groups of increasing neurological impairments, is in accordance with this hypothesis. 89% of the patients in the second period have only slight neurological signs. This explain how difficult it is for a physician to use melarsoprol in the treatment of all patients classified in second period.

  6. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD.

    PubMed

    Tramutola, Antonella; Triplett, Judy C; Di Domenico, Fabio; Niedowicz, Dana M; Murphy, Michael P; Coccia, Raffaella; Perluigi, Marzia; Butterfield, D Allan

    2015-06-01

    ) and late stage of Alzheimer Disease. The progression of the disease is associated with a reduction in autophagy (Beclin-1 and LC-3) observed in Inferior parietal lobe of PCAD, MCI, and AD subjects (light red). Related to the autophagy impairment, the graph shows the impairment of PI3K/Akt/mTOR in MCI and AD subjects (dark red).

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

    PubMed Central

    Changasi, Robert Emojong

    2016-01-01

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

  8. Human African trypanosomiasis with 7-year incubation period: clinical, laboratory and neuroimaging findings.

    PubMed

    Wengert, Oliver; Kopp, Marcel; Siebert, Eberhard; Stenzel, Werner; Hegasy, Guido; Suttorp, Norbert; Stich, August; Zoller, Thomas

    2014-06-01

    Human African trypanosomiasis (HAT), also referred to as "sleeping sickness", is caused by the parasite Trypanosoma brucei. Diagnosing imported HAT outside endemic areas is difficult and diagnosis is often delayed. We report a case of imported human African trypanosomiasis caused by Trypanosoma brucei gambiense with an unusually long incubation period of at least 7 years. A 33 year old male African patient, a former resident of Cameroon, presented with a 4-month history of progressive personality changes. A few weeks before presentation the patient had first been admitted to a psychiatric ward and received antidepressant treatment, until a lumbar puncture showed pleocytosis and then antibiotic treatment for suspected neuroborreliosis was initiated. The patient continued to deteriorate during antibiotic treatment and became increasingly lethargic. Under antiparasitic and anti-inflammatory treatment, the condition of the patient gradually improved over the following months and he recovered completely after 24 months of follow-up. This well-documented case illustrates typical difficulties in establishing the correct diagnosis outside endemic areas and provides an overview of typical clinical, neuropathological and neuroimaging findings in T. b. gambiense trypanosomiasis, guiding the clinician in establishing the correct diagnosis in this rare disease.

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

    PubMed Central

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

    2016-01-01

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

  10. Differential Expression of Viral Bcl-2 Encoded by Kaposi's Sarcoma-Associated Herpesvirus and Human Bcl-2 in Primary Effusion Lymphoma Cells and Kaposi's Sarcoma Lesions

    PubMed Central

    Widmer, Isabelle; Wernli, Marion; Bachmann, Felix; Gudat, Fred; Cathomas, Gieri; Erb, Peter

    2002-01-01

    Expression of human herpesvirus 8 viral Bcl-2 protein was demonstrated in spindle cells of late-stage Kaposi's sarcoma lesions but not in primary effusion lymphoma cell lines. In contrast, strong expression of human Bcl-2 was found in stimulated primary effusion lymphoma cells, whereas in Kaposi's sarcoma lesions preferential mononuclear cells, and to a lesser extent spindle cells, stained positive. PMID:11836434

  11. Photomodification of human immunocompetent blood cells

    SciTech Connect

    Krylenkov, V.A.; Ogurtsov, R.P.; Osmanov, M.A.; Kholmogorov, V.E.

    1987-10-01

    In this paper, processes of photomodification of lymphoid cells in human blood, developing immediately after exposure to visible radiation and also in the late stages after irradiation, were investigated by methods of spontaneous and immune rosette formation and the blast transformation test, combined with treatment with the antioxidant alpha-tocopherol and the radioactive assessment of spontaneous and stimulated DNA synthesis by tritium-thymidine-labelled cells.

  12. Control and surveillance of human African trypanosomiasis.

    PubMed

    2013-01-01

    In the 1960s, it appeared that human African trypanosomiasis (HAT) could be effectively controlled, but by the beginning of the twenty-first century several decades of neglect had led to alarming numbers of reported new cases, with an estimated 300 000 people infected. The World Health Organization (WHO) responded with a series of initiatives aimed at bringing HAT under control again. Since 2001, the pharmaceutical companies that produce drugs for HAT have committed themselves to providing them free of charge to WHO for distribution for the treatment of patients. In addition, funds have been provided to WHO to support national sleeping sickness control programmes to boost control and surveillance of the disease. That, coupled with bilateral cooperation and the work of nongovernmental organizations, helped reverse the upward trend in HAT prevalence. By 2012, the number of reported cases was fewer than 8000. This success in bringing HAT under control led to its inclusion in the WHO Roadmap for eradication, elimination and control of neglected tropical diseases, with a target set to eliminate the disease as a public health problem by 2020. A further target has been set, by countries in which HAT is endemic, to eliminate gambiense HAT by reducing the incidence of infection to zero in a defined geographical area. This report provides information about new diagnostic approaches, new therapeutic regimens and better understanding of the distribution of the disease with high-quality mapping. The roles of human and animal reservoirs and the tsetse fly vectors that transmit the parasites are emphasized. The new information has formed the basis for an integrated strategy with which it is hoped that elimination of gambiense HAT will be achieved. The report also contains recommendations on the approaches that will lead to elimination of the disease.

  13. Human African trypanosomiasis.

    PubMed

    Lejon, Veerle; Bentivoglio, Marina; Franco, José Ramon

    2013-01-01

    Human African trypanosomiasis or sleeping sickness is a neglected tropical disease that affects populations in sub-Saharan Africa. The disease is caused by infection with the gambiense and rhodesiense subspecies of the extracellular parasite Trypanosoma brucei, and is transmitted to humans by bites of infected tsetse flies. The disease evolves in two stages, the hemolymphatic and meningoencephalitic stages, the latter being defined by central nervous system infection after trypanosomal traversal of the blood-brain barrier. African trypanosomiasis, which leads to severe neuroinflammation, is fatal without treatment, but the available drugs are toxic and complicated to administer. The choice of medication is determined by the infecting parasite subspecies and disease stage. Clinical features include a constellation of nonspecific symptoms and signs with evolving neurological and psychiatric alterations and characteristic sleep-wake disturbances. Because of the clinical profile variability and insidiously progressive central nervous system involvement, disease staging is currently based on cerebrospinal fluid examination, which is usually performed after the finding of trypanosomes in blood or other body fluids. No vaccine being available, control of human African trypanosomiasis relies on diagnosis and treatment of infected patients, assisted by vector control. Better diagnostic tools and safer, easy to use drugs are needed to facilitate elimination of the disease.

  14. A current analysis of chemotherapy strategies for the treatment of human African trypanosomiasis.

    PubMed

    Babokhov, Peter; Sanyaolu, Adekunle O; Oyibo, Wellington A; Fagbenro-Beyioku, Adetayo F; Iriemenam, Nnaemeka C

    2013-07-01

    Despite the recent advances in drug research, finding a safe, effective, and easy to use chemotherapy for human African trypanosomiasis (HAT) remains a challenging task. The four current anti-trypanosomiasis drugs have major disadvantages that limit more widespread use of these drugs in the endemic regions of sub-Saharan Africa. Pentamidine and suramin are limited by their effectiveness against the only first stage of Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, respectively. In addition, melarsoprol and eflornithine (two second stage drugs) each have disadvantages of their own. The former is toxic and has increasing treatment failures while the latter is expensive, laborious to administer, and lacks efficacy against T. b. rhodesiense. Furthermore, melarsoprol's toxicity and decreasing efficacy are glaring problems and phasing out the drug as a frontline treatment against T. b. gambiense is now possible with the emergence of competent, safe combination chemotherapies such as nifurtimox-eflornithine combination treatment (NECT). The future of eflornithine, on the other hand, is more promising. The drug is useful in the context of combination chemotherapy and potential orally administered analogues. Due to the limits of monotherapies, greater emphasis should be placed on the research and development of combination chemotherapies, based on the successful clinical tests with NECT and its current use as a frontline anti-trypanosomiasis treatment. This review discussed the current and future chemotherapy strategies for the treatment of HAT.

  15. Genetically distinct Glossina fuscipes fuscipes populations in the Lake Kyoga region of Uganda and its relevance for human African trypanosomiasis.

    PubMed

    Echodu, Richard; Sistrom, Mark; Hyseni, Chaz; Enyaru, John; Okedi, Loyce; Aksoy, Serap; Caccone, Adalgisa

    2013-01-01

    Tsetse flies (Glossina spp.) are the sole vectors of Trypanosoma brucei--the agent of human (HAT) and animal (AAT) trypanosomiasis. Glossina fuscipes fuscipes (Gff) is the main vector species in Uganda--the only country where the two forms of HAT disease (rhodesiense and gambiense) occur, with gambiense limited to the northwest. Gff populations cluster in three genetically distinct groups in northern, southern, and western Uganda, respectively, with a contact zone present in central Uganda. Understanding the dynamics of this contact zone is epidemiologically important as the merger of the two diseases is a major health concern. We used mitochondrial and microsatellite DNA data from Gff samples in the contact zone to understand its spatial extent and temporal stability. We show that this zone is relatively narrow, extending through central Uganda along major rivers with south to north introgression but displaying no sex-biased dispersal. Lack of obvious vicariant barriers suggests that either environmental conditions or reciprocal competitive exclusion could explain the patterns of genetic differentiation observed. Lack of admixture between northern and southern populations may prevent the sympatry of the two forms of HAT disease, although continued control efforts are needed to prevent the recolonization of tsetse-free regions by neighboring populations.

  16. Genetically Distinct Glossina fuscipes fuscipes Populations in the Lake Kyoga Region of Uganda and Its Relevance for Human African Trypanosomiasis

    PubMed Central

    Echodu, Richard; Sistrom, Mark; Hyseni, Chaz; Enyaru, John; Okedi, Loyce; Aksoy, Serap; Caccone, Adalgisa

    2013-01-01

    Tsetse flies (Glossina spp.) are the sole vectors of Trypanosoma brucei—the agent of human (HAT) and animal (AAT) trypanosomiasis. Glossina fuscipes fuscipes (Gff) is the main vector species in Uganda—the only country where the two forms of HAT disease (rhodesiense and gambiense) occur, with gambiense limited to the northwest. Gff populations cluster in three genetically distinct groups in northern, southern, and western Uganda, respectively, with a contact zone present in central Uganda. Understanding the dynamics of this contact zone is epidemiologically important as the merger of the two diseases is a major health concern. We used mitochondrial and microsatellite DNA data from Gff samples in the contact zone to understand its spatial extent and temporal stability. We show that this zone is relatively narrow, extending through central Uganda along major rivers with south to north introgression but displaying no sex-biased dispersal. Lack of obvious vicariant barriers suggests that either environmental conditions or reciprocal competitive exclusion could explain the patterns of genetic differentiation observed. Lack of admixture between northern and southern populations may prevent the sympatry of the two forms of HAT disease, although continued control efforts are needed to prevent the recolonization of tsetse-free regions by neighboring populations. PMID:24199195

  17. Identification of a Late Stage of Small Noncycling pTα−  Pre-T Cells as Immediate Precursors of T Cell Receptor α/β+  Thymocytes

    PubMed Central

    Trigueros, César; Ramiro, Almudena R.; Carrasco, Yolanda R.; de Yebenes, Virginia G.; Albar, Juan P.; Toribio, María L.

    1998-01-01

    During thymocyte development, progression from T cell receptor (TCR)β to TCRα rearrangement is mediated by a CD3-associated pre-TCR composed of the TCRβ chain paired with pre-TCRα (pTα). A major issue is how surface expression of the pre-TCR is regulated during normal thymocyte development to control transition through this checkpoint. Here, we show that developmental expression of pTα is time- and stage-specific, and is confined in vivo to a limited subset of large cycling human pre-T cells that coexpress low density CD3. This restricted expression pattern allowed the identification of a novel subset of small CD3− thymocytes lacking surface pTα, but expressing cytoplasmic TCRβ, that represent late noncycling pre-T cells in which recombination activating gene reexpression and downregulation of T early α transcription are coincident events associated with cell cycle arrest, and immediately preceding TCRα gene expression. Importantly, thymocytes at this late pre-T cell stage are shown to be functional intermediates between large pTα+ pre-T cells and TCRα/β+ thymocytes. The results support a developmental model in which pre-TCR–expressing pre-T cells are brought into cycle, rapidly downregulate surface pre-TCR, and finally become small resting pre-T cells, before the onset of TCRα gene expression. PMID:9782117

  18. Innervation and functional characteristics of connective tissues, especially elastic fibers, in human fetal thoracic intervertebral articular capsule and its surroundings.

    PubMed

    Shiraishi, Yosuke; Kobayashi, Miya; Yasui, Masaya; Ozaki, Noriyuki; Sugiura, Yasuo

    2003-05-01

    The articular capsules between the thoracic vertebrae, which have physiologically different functions from those of other levels of the vertebrae, have yet to be subjected to neuro-anatomical and fine structural analysis. In the present study, we analyzed serial frozen sections of decalcified thoracic vertebrae in human fetuses, and identified the articular capsule tissue with its unique distribution of elastic fibers. The fine structure of the elastic fibers was studied by transmission electron microscopy. In the early-stage fetus, the fibrous membrane forming the lateral intervertebral articular capsule contained abundant thin elastic fibers consisting of microfibrils. In the late-stage fetus, the lateral capsule of fibrous membrane was occupied by thick elastic fibers. A medial articular capsule, namely the ligamenta flava, contained numerous thick elastic fibers in both early and late-stage fetuses. The distributional differences in nerve fibers between early and late-stage fetuses were determined by immunostaining, using antibodies raised against protein gene product 9.5 (PGP 9.5; ubiquitin carboxyl-terminal hydrolase). Innervation by PGP 9.5 immunoreactive fibers was limited to the areas of the articular capsules near the blood vessels, which may indicate their functional relation with blood flow. No PGP 9.5 immunoreactive fibers were found in the ligamenta flava of the late-stage fetus. Innervation might be directly involved in the development of the intervertebral articular capsules in normal human fetuses.

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

    PubMed Central

    Kennedy, Peter G.E.

    2004-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-03-01

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

  2. Late stages of massive star evolution and nucleosynthesis

    SciTech Connect

    Nomoto, Ken'ichi; Hashimoto, Masa-aki

    1986-01-01

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

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

    USGS Publications Warehouse

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

    2011-01-01

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

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

    NASA Technical Reports Server (NTRS)

    Plescia, J. B.

    1987-01-01

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

  5. Late Stages of Accretion of Uranus and Neptune

    NASA Technical Reports Server (NTRS)

    Stewart, Glen R.

    2002-01-01

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

  6. Recent Simulations of the Late Stages Growth of Jupiter

    NASA Technical Reports Server (NTRS)

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

    2012-01-01

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

  7. Late-stage accretion and habitability of terrestrial planets

    NASA Astrophysics Data System (ADS)

    Raymond, Sean Neylon

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

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

    NASA Technical Reports Server (NTRS)

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

    1991-01-01

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

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

    PubMed

    Provenzano, Robert

    2016-07-01

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

  10. Vortex ring structure at late stages of formation

    SciTech Connect

    Fabris, D.; Liepmann, D.

    1997-09-01

    High resolution DPIV measurements are made of a vortex ring formed by a piston/cylinder mechanism (Reynolds number 3700 and 7500). A complex ring structure is identified. The stopping condition of the piston leads to vortical fluid collecting near the forward stagnation point of the ring. In addition, the roll-up of the core produces a vorticity distribution that departs from a simple Gaussian profile. {copyright} {ital 1997 American Institute of Physics.}

  11. Gonadotropic axis and Trypanosoma brucei gambiense infection.

    PubMed

    Boersma, A; Noireau, F; Hublart, M; Boutignon, F; Lemesre, J L; Racadot, A; Degand, P

    1989-06-01

    A gonad endocrine survey on 46 Congolese patients (15 women and 31 men) with parasitologically confirmed trypanosomiasis found amenorrhoea in 60% of the women and impotence in 70% of the men. The basic gonad endocrine examination showed a decrease in oestradiol levels in about 65% of the women. Both amenorrhoea and low oestrogen levels were observed in the second phase (P2) of the disease, but low oestrogen levels were sometimes noted in the first phase of the disease (P1). In the men, about 50% of the cases (P2) showed a decrease in testosterone. However, as in the women, the variation of testosterone was also observed in the first phase (P1). A static and dynamic examination of the hypothalamic-pituitary-gonadal axis was undertaken in order to investigate the origin of these hypogonadisms. A supra - or extra-hypophyseal origin is discussed.

  12. Glossina fuscipes populations provide insights for human African trypanosomiasis transmission in Uganda.

    PubMed

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

    2013-08-01

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

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

    PubMed Central

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

    2013-01-01

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

  14. Xylosyltransferase-I regulates glycosaminoglycan synthesis during the pathogenic process of human osteoarthritis.

    PubMed

    Venkatesan, Narayanan; Barré, Lydia; Bourhim, Mustapha; Magdalou, Jacques; Mainard, Didier; Netter, Patrick; Fournel-Gigleux, Sylvie; Ouzzine, Mohamed

    2012-01-01

    Loss of glycosaminoglycan (GAG) chains of proteoglycans (PGs) is an early event of osteoarthritis (OA) resulting in cartilage degradation that has been previously demonstrated in both huma and experimental OA models. However, the mechanism of GAG loss and the role of xylosyltransferase-I (XT-I) that initiates GAG biosynthesis onto PG molecules in the pathogenic process of human OA are unknown. In this study, we have characterized XT-I expression and activity together with GAG synthesis in human OA cartilage obtained from different regions of the same joint, defined as "normal", "late-stage" or adjacent to "late-stage". The results showed that GAG synthesis and content increased in cartilage from areas flanking OA lesions compared to cartilage from macroscopically "normal" unaffected regions, while decreased in "late-stage" OA cartilage lesions. This increase in anabolic state was associated with a marked upregulation of XT-I expression and activity in cartilage "next to lesion" while a decrease in the "late-stage" OA cartilage. Importantly, XT-I inhibition by shRNA or forced-expression with a pCMV-XT-I construct correlated with the modulation of GAG anabolism in human cartilage explants. The observation that XT-I gene expression was down-regulated by IL-1β and up-regulated by TGF-β1 indicates that these cytokines may play a role in regulating GAG content in human OA. Noteworthy, expression of IL-1β receptor (IL-1R1) was down-regulated whereas that of TGF-β1 was up-regulated in early OA cartilage. Theses observations may account for upregulation of XT-I and sustained GAG synthesis prior to the development of cartilage lesions during the pathogenic process of OA.

  15. Identification of sVSG117 as an Immunodiagnostic Antigen and Evaluation of a Dual-Antigen Lateral Flow Test for the Diagnosis of Human African Trypanosomiasis

    PubMed Central

    Sullivan, Lauren; Fleming, Jennifer; Sastry, Lalitha; Mehlert, Angela; Wall, Steven J.; Ferguson, Michael A. J.

    2014-01-01

    Background The diagnosis of human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense relies mainly on the Card Agglutination Test for Trypanosomiasis (CATT). There is no immunodiagnostic for HAT caused by T. b. rhodesiense. Our principle aim was to develop a prototype lateral flow test that might be an improvement on CATT. Methodology/Principle Findings Pools of infection and control sera were screened against four different soluble form variant surface glycoproteins (sVSGs) by ELISA and one, sVSG117, showed particularly strong immunoreactivity to pooled infection sera. Using individual sera, sVSG117 was shown to be able to discriminate between T. b. gambiense infection and control sera by both ELISA and lateral flow test. The sVSG117 antigen was subsequently used with a previously described recombinant diagnostic antigen, rISG65, to create a dual-antigen lateral flow test prototype. The latter was used blind in a virtual field trial of 431 randomized infection and control sera from the WHO HAT Specimen Biobank. Conclusion/Significance In the virtual field trial, using two positive antigen bands as the criterion for infection, the sVSG117 and rISG65 dual-antigen lateral flow test prototype showed a sensitivity of 97.3% (95% CI: 93.3 to 99.2) and a specificity of 83.3% (95% CI: 76.4 to 88.9) for the detection of T. b. gambiense infections. The device was not as good for detecting T. b. rhodesiense infections using two positive antigen bands as the criterion for infection, with a sensitivity of 58.9% (95% CI: 44.9 to 71.9) and specificity of 97.3% (95% CI: 90.7 to 99.7). However, using one or both positive antigen band(s) as the criterion for T. b. rhodesiense infection improved the sensitivity to 83.9% (95% CI: 71.7 to 92.4) with a specificity of 85.3% (95% CI: 75.3 to 92.4). These results encourage further development of the dual-antigen device for clinical use. PMID:25033401

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

    SciTech Connect

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

    2014-01-24

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

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

    PubMed Central

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

    2015-01-01

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

  18. Sclerostin: how human mutations have helped reveal a new target for the treatment of osteoporosis.

    PubMed

    Robinson, Martyn K; Caminis, John; Brunkow, Mary E

    2013-07-01

    In the 1990s there was a tremendous mood of optimism among pharmaceutical scientists that identification of disease-associated variations in the human genome would result in a surge of new drug targets (the 'gene-to-drug' mantra). To date the expected deluge of new drugs has not arrived. However, a small number of drugs arising directly from the study of rare human disorders showing Mendelian inheritance are now entering late stage clinical trials. Here we describe the advantages of this approach and discuss the background and early clinical trial findings with antibodies directed at a target identified in this way.

  19. Emerging trends in the diagnosis of human African Trypanosomiasis.

    PubMed

    Radwanska, Magdalena

    2010-12-01

    Human African trypanosomiasis (HAT) or sleeping sickness is caused by protozoan parasites Trypanosoma brucei gambiense and T. b. rhodesiense. Despite the enormous technological progress in molecular parasitology in recent years, the diagnosis of HAT is still problematic due to the lack of specific tools. To date, there are two realities when it comes to HAT; the first one being the world of modern experimental laboratories, equipped with the latest state-of-the-art technology, and the second being the world of HAT diagnosis, where the latest semi-commercial test was introduced 30 years ago (Magnus et al. 1978). Hence, it appears that the lack of progress in HAT diagnosis is not primarily due to a lack of scientific interest or a lack of research funds, but mainly results from the many obstacles encountered in the translation of basic research into field-applicable diagnostics. This review will provide an overview of current diagnostic methods and highlight specific difficulties in solving the shortcomings of these methods. Future perspectives for accurate, robust, affordable diagnostics will be discussed as well.

  20. The development of human genetics in Germany; a personal view.

    PubMed

    Vogel, F

    2005-07-01

    A personal account is given of the reconstruction and development of human genetics in Germany during the years following World War 2. An important stimulus was funding, as a result of the recognition of the genetic hazards of atomic radiation. Starting from 1960, human genetics institutes were progressively established throughout West Germany; comparable development was later in East Germany because of political factors. The first genetic counselling units were formed in 1972, but molecular biology only became an integral part of human genetics institutes at a relatively late stage. Close international links have characterised post-war human genetics in Germany from the outset and a tradition of close links with developing countries has also been established.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  4. Functional Characterization of Human Stem Cell-Derived Cardiomyocytes

    PubMed Central

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

    2014-01-01

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

  5. Forecasting Human African Trypanosomiasis Prevalences from Population Screening Data Using Continuous Time Models

    PubMed Central

    Hasker, Epco; Lumbala, Crispin; Lutumba, Pascal; de Vlas, Sake J.; van de Klundert, Joris

    2016-01-01

    To eliminate and eradicate gambiense human African trypanosomiasis (HAT), maximizing the effectiveness of active case finding is of key importance. The progression of the epidemic is largely influenced by the planning of these operations. This paper introduces and analyzes five models for predicting HAT prevalence in a given village based on past observed prevalence levels and past screening activities in that village. Based on the quality of prevalence level predictions in 143 villages in Kwamouth (DRC), and based on the theoretical foundation underlying the models, we consider variants of the Logistic Model—a model inspired by the SIS epidemic model—to be most suitable for predicting HAT prevalence levels. Furthermore, we demonstrate the applicability of this model to predict the effects of planning policies for screening operations. Our analysis yields an analytical expression for the screening frequency required to reach eradication (zero prevalence) and a simple approach for determining the frequency required to reach elimination within a given time frame (one case per 10000). Furthermore, the model predictions suggest that annual screening is only expected to lead to eradication if at least half of the cases are detected during the screening rounds. This paper extends knowledge on control strategies for HAT and serves as a basis for further modeling and optimization studies. PMID:27657937

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

    PubMed

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

    2009-03-01

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

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

    PubMed

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

    2009-03-01

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

  8. Glanzmann Thrombasthenia Associated with Human Immunodeficiency Virus-Positive Patient

    PubMed Central

    Manne, Rakesh Kumar; Natarajan, Kannan; Patil, Rajendra; Prathi, Venkata Sarath; Beeraka, Swapna Sridevi; Kolaparthi, Venkata Suneel Kumar

    2014-01-01

    Glanzmann's thrombasthenia (GT) is an autosomal recessive inherited platelet function defect characterized by normal platelet count, prolonged bleeding time and abnormal clot retraction. This disease typically presents in infancy or early childhood and has proven to have very good prognosis. In this case study, a 22-year-old GT patient who also developed human immunodeficiency virus (HIV) infection after sometime is reported. The patient showed oral manifestations of gingival hyperplasia and petechial lesions. Unfortunately the detection of both thrombasthenia and HIV were done at considerably late stages which contributed to a poor prognosis. The patient died of cardiopulmonary arrest secondary to HIV, thrombasthenia and thrombocytopenia. The importance of early detection, supportive care and communication between the general and oral physician in management of the GT is also discussed. PMID:24829739

  9. [Intracellular localization of transcription factor PROX1 in the human retina in ontogeny].

    PubMed

    Markitantova, Iu V; Zinov'eva, R D

    2014-01-01

    The spatiotemporal intracellular localization of the transcription factor PROX1 in the human retina during prenatal development (fetal weeks 9.5 to 31) and in the adult human retina was studied for the first time. The PROX1 protein was identified in the cell nuclei of the neuroblast retinal layers at the stage of active cell proliferation (fetal week 9.5) as well as in the nuclei of differentiating neurons of the inner nuclear retinal layer (horizontal, amacrine, and bipolar cells) from weeks 13 to 31 of prenatal development. The PROX1 protein localization in the adult retina was the same as at the late stage of prenatal development. Our results indicate the involvement of the transcription factor PROX1 in the regulation of proliferation of progenitor cells and differentiation of the inner nuclear layer cells of the human retina. These results confirm the conservative functions of Prox1/PROX1 in the vertebrate retina.

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

    SciTech Connect

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

    2010-06-05

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

  11. Autophagy Inhibition Delays Early but Not Late-Stage Metastatic Disease.

    PubMed

    Barnard, Rebecca A; Regan, Daniel P; Hansen, Ryan J; Maycotte, Paola; Thorburn, Andrew; Gustafson, Daniel L

    2016-08-01

    The autophagy pathway has been recognized as a mechanism of survival and therapy resistance in cancer, yet the extent of autophagy's function in metastatic progression is still unclear. Therefore, we used murine models of metastatic cancer to investigate the effect of autophagy modulation on metastasis development. Pharmacologic and genetic autophagy inhibition were able to impede cell proliferation in culture, but did not impact the development of experimentally induced 4T1 and B16-F10 metastases. Similarly, autophagy inhibition by adjuvant chloroquine (CQ) treatment did not delay metastasis in an orthotopic 4T1, tumor-resection model. However, neoadjuvant CQ treatment or genetic autophagy inhibition resulted in delayed metastasis development, whereas stimulation of autophagy by trehalose hastened development. Cisplatin was also administered either as a single agent or in combination with CQ. The combination of cisplatin and CQ was antagonistic. The effects of autophagy modulation on metastasis did not appear to be due to alterations in the intrinsic metastatic capability of the cells, as modulating autophagy had no impact on migration, invasion, or anchorage-independent growth in vitro. To explore the possibility of autophagy's influence on the metastatic microenvironment, bone marrow-derived cells (BMDCs), which mediate the establishment of the premetastatic niche, were measured in the lung and in circulation. Trehalose-treated mice had significantly more BMDCs than either vehicle- or CQ-treated mice. Autophagy inhibition may be most useful as a treatment to impede early metastatic development. However, modulating autophagy may also alter the efficacy of platinum-based therapies, requiring caution when considering combination therapies. PMID:27231155

  12. Neuroprotective effects of electroacupuncture on early- and late-stage spinal cord injury.

    PubMed

    Wu, Min-Fei; Zhang, Shu-Quan; Liu, Jia-Bei; Li, Ye; Zhu, Qing-San; Gu, Rui

    2015-10-01

    Previous studies have shown that the neurite growth inhibitor Nogo-A can cause secondary neural damage by activating RhoA. In the present study, we hypothesized that electroacupuncture promotes neurological functional recovery after spinal cord injury by inhibiting RhoA expression. We established a rat model of acute spinal cord injury using a modification of Allen's method. The rats were given electroacupuncture treatment at Dazhui (Du14), Mingmen (Du4), Sanyinjiao (SP6), Huantiao (GB30), Zusanli (ST36) and Kunlun (BL60) acupoints with a sparse-dense wave at a frequency of 4 Hz for 30 minutes, once a day, for a total of 7 days. Seven days after injury, the Basso, Beattie and Bresnahan (BBB) locomotor scale and inclined plane test scores were significantly increased, the number of apoptotic cells in the spinal cord tissue was significantly reduced, and RhoA and Nogo-A mRNA and protein expression levels were decreased in rats given electroacupuncture compared with rats not given electroacupuncture. Four weeks after injury, pathological tissue damage in the spinal cord at the site of injury was alleviated, the numbers of glial fibrillary acidic protein- and neurofilament 200-positive fibers were increased, the latencies of somatosensory-evoked and motor-evoked potentials were shortened, and their amplitudes were increased in rats given electroacupuncture. These findings suggest that electroacupuncture treatment reduces neuronal apoptosis and decreases RhoA and Nogo-A mRNA and protein expression at the site of spinal cord injury, thereby promoting tissue repair and neurological functional recovery. PMID:26692861

  13. Neuroprotective effects of electroacupuncture on early- and late-stage spinal cord injury

    PubMed Central

    Wu, Min-fei; Zhang, Shu-quan; Liu, Jia-bei; Li, Ye; Zhu, Qing-san; Gu, Rui

    2015-01-01

    Previous studies have shown that the neurite growth inhibitor Nogo-A can cause secondary neural damage by activating RhoA. In the present study, we hypothesized that electroacupuncture promotes neurological functional recovery after spinal cord injury by inhibiting RhoA expression. We established a rat model of acute spinal cord injury using a modification of Allen's method. The rats were given electroacupuncture treatment at Dazhui (Du14), Mingmen (Du4), Sanyinjiao (SP6), Huantiao (GB30), Zusanli (ST36) and Kunlun (BL60) acupoints with a sparse-dense wave at a frequency of 4 Hz for 30 minutes, once a day, for a total of 7 days. Seven days after injury, the Basso, Beattie and Bresnahan (BBB) locomotor scale and inclined plane test scores were significantly increased, the number of apoptotic cells in the spinal cord tissue was significantly reduced, and RhoA and Nogo-A mRNA and protein expression levels were decreased in rats given electroacupuncture compared with rats not given electroacupuncture. Four weeks after injury, pathological tissue damage in the spinal cord at the site of injury was alleviated, the numbers of glial fibrillary acidic protein- and neurofilament 200-positive fibers were increased, the latencies of somatosensory-evoked and motor-evoked potentials were shortened, and their amplitudes were increased in rats given electroacupuncture. These findings suggest that electroacupuncture treatment reduces neuronal apoptosis and decreases RhoA and Nogo-A mRNA and protein expression at the site of spinal cord injury, thereby promoting tissue repair and neurological functional recovery. PMID:26692861

  14. Experimentally determined growth exponents during the late stage of spinodal demixing in binary liquid mixtures

    NASA Astrophysics Data System (ADS)

    Hobley, Jonathan; Kajimoto, Shinji; Takamizawa, Atsushi; Fukumura, Hiroshi

    2006-01-01

    Spinodal demixing was initiated in two systems, with critical and off-critical compositions, using nanosecond pulsed laser-induced temperature jumps (T-jumps) of various magnitude. In this way, deep quenches could be imposed on the systems. One system was the simple triethylamine (TEA)/water mixture and the other was the ionic mixture of 2-butoxyethanol (2BE)/water/KCl. The demixing process was followed using the technique of nanosecond time-resolved microscopic shadowgraphy. The growth of the evolving phase-separated domains followed a simple power law with respect to time in every case. For a given composition, the magnitude of the T-jump had little effect on the growth exponent, however the composition was found to influence the rate of domain growth. At off-critical mole fractions of 0.2 with respect to TEA, the domains grew according to the following expression: L(t)=t0.70 (where L(t)=the domain size) whereas at the critical TEA mole fraction of 0.08 the domains grew as L(t)=t0.52 . 2BE/water/KCl mixtures quenched at the just off-critical composition of 0.05mole fraction with respect to 2BE evolved as L(t)=t0.63 . These results will be compared to theoretical models and simulations and discussed in terms of estimated Reynolds numbers as well as the consumption and conversion of the available surface energy that fuels the demixing process.

  15. Patterns of seeking medical care among Egyptian breast cancer patients: relationship to late-stage presentation.

    PubMed

    Mousa, Shimaa M; Seifeldin, Ibrahim A; Hablas, Ahmed; Elbana, Eman S; Soliman, Amr S

    2011-12-01

    Breast cancer is the most common cancer among Egyptian women, accounting for 37.6% of female tumors, and is often diagnosed at later stages. The objective of this study was to investigate breast cancer patient navigation through the health care system in the Nile Delta. Interviews were conducted with 163 newly diagnosed breast cancer patients at the Tanta Cancer Center (TCC), the major cancer center of the region. Patients described their medical care pathway from the initial symptom experienced until their arrival at TCC. Patients whose initial contact was with a general surgeon (OR: 7.6, 95% CI: 2.1, 27.6), primary care provider (OR: 12.2, 95% CI: 2.9, 51.0), or gynecologist (OR: 8.6, 95% CI: 1.4, 53.4) were significantly more likely to experience a delay in reaching the TCC as compared to those visiting a surgical oncologist. Overcoming health care system and patient navigation barriers in developing countries may reduce the time for breast cancer patients to reach a cancer center for early management. PMID:21807518

  16. [Differential diagnosis of late-stage neuroborreliosis with affection of the central nervous system].

    PubMed

    Spirin, N N; Baranova, N S; Fadeeva, O A; Pakhomova, Iu A; Stepanov, I O; Shipova, E G; Kasatkin, D S; Spirina, N N

    2012-01-01

    Chronic neuroborreliosis is an actual problem in neurology due to its under-investigation in Russia, variety of clinical forms, and the absence of well established diagnostic criteria. We present clinical and laboratory differential diagnostic criteria of chronic borrelial encephalomyelitis in comparison with multiple sclerosis. Distinguishing characteristics of Lyme encephalopathy versus vascular encephalopathy are considered. Problems and possibilities of immunological methods for identification of B. burgdorferi are discussed. The results of the antibiotic treatment of different clinical forms of neuroborreliosis with affection of the central nervous system are described.

  17. Muscle fiber conduction velocity in different gait phases of early and late-stage diabetic neuropathy.

    PubMed

    Suda, Eneida Yuri; Gomes, Aline A; Butugan, Marco Kenji; Sacco, Isabel C N

    2016-10-01

    We investigated the muscle fiber conduction velocity (MFCV) during gait phases of the lower limb muscles in individuals with various degrees of diabetic peripheral neuropathy (DPN). Forty-five patients were classified into severity degrees of DPN by a fuzzy model. The stages were absent (n=11), mild (n=14), moderate (n=11) and severe (n=9), with 10 matched healthy controls. While walking, all subjects had their sEMG (4 linear electrode arrays) recorded for tibialis anterior (TA), gastrocnemius medialis (GM), vastus lateralis (VL) and biceps femoris (BF). MFCV was calculated using a maximum likelihood algorithm with 30ms standard deviation Gaussian windows. In general, individuals in the earlier stages of DPN showed lower MFCV of TA, GM and BF, whilst individuals with severe DPN presented higher MFCV of the same muscles. We observed that mild patients already showed lower MFCV of TA at early stance and swing, and lower MFCV of BF at swing. All diabetic groups showed a markedly reduction in MFCV of VL, irrespective of DPN. Severe patients presented higher MFCV mainly in distal muscles, TA at early and swing phases and GM at propulsion and midstance. The absent group already showed MFCV of VL and GM reductions at the propulsion phase and of VL at early stance. Although MFCV changes were not as progressive as the DPN was, we clearly distinguished diabetic patients from controls, and severe patients from all others.

  18. [New approach to gait disorders therapy in late stages of Parkinson's disease].

    PubMed

    Litvinenko, I V; Khalimov, R R; Trufanov, A G; Krasakov, I V; Khaĭmov, D A

    2012-01-01

    We conducted an open noncontrolled study of efficacy of repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) combined with acetylcholinesterase inhibitor (galantamine) therapy in 30 Parkinson's disease patients with cognitive impairment and higher level of gait disorders. Galantamine dose gradually increase to maximum of 16 mg/day (8 weeks) before rTMSand after that we start rTMS for 10 consecutive days. Cognitive, neuropsychiatric and motor symptoms were assessed clinically at baseline and at end of 10 weeks combined therapy using the Mini Mental State Examination (MMSE), Freezing Of Gait (FOG), Clinical Gait And Balance Scale (GABS), Tinetti scale, the clock drawing test, the Frontal Assessment Battery (FAB), PDQ-39 and Beck Depression Inventory (BDI). The metabolism in the frontal lobes, caudate nucleus, thalamus were assessed in 9 patients at baseline and end of rTMS by [18F]FDG-PET. Changes in total point scores on the scales at the ends of 10 weeks were compared with the baseline. Results were significant in the FOG (p = 0.00002), GABS (p = 0.000006), MMSE (p = 0.0001), FAB (0 = 0.003), PDQ-39 (p = 0.00009), BDI (p = 0.00004). Improvements in gait and decreases in freezing and falls were seen in the end of study period. Our study demonstrated the beneficial effect of rTMS of the DLPFC combined with acetylcholinesterase inhibitor treatment on metabolism in the frontal lobes, caudate nucleus, thalamus ([18F]FDG-PET), improving of gait and cognitive functions in PD patients. PMID:23130517

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

    NASA Astrophysics Data System (ADS)

    Kwok, Sun

    2016-07-01

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

  20. Distinct Actions of Rab3 and Rab27 GTPases on Late Stages of Exocytosis of Insulin

    PubMed Central

    Cazares, Victor A.; Subramani, Arasakumar; Saldate, Johnny J.; Hoerauf, Widmann; Stuenkel, Edward L.

    2014-01-01

    Rab GTPases associated with insulin containing secretory granules are key in targeting, docking and assembly of molecular complexes governing pancreatic β-cell exocytosis. Four Rab3 isoforms along with Rab27A are associated with insulin granules, yet elucidation of the distinct roles of these Rab families on exocytosis remains unclear. To define specific actions of these Rab families we employ Rab3GAP and/or EPI64A GTPase activating protein overexpression in β-cells from wild-type or Ashen mice to selectively transit the entire Rab3 family or Rab27A to a GDP-bound state. Ashen mice carry a spontaneous mutation that eliminates Rab27A expression. Using membrane capacitance measurements we find that GTP/GDP nucleotide cycling of Rab27A is essential for generation of the functionally defined immediately releasable pool and central to regulating the size of the readily releasable pool. By comparison, nucleotide cycling of Rab3 GTPases, but not of Rab27A, is essential for a kinetically rapid filling of the readily releasable pool with secretory granules. Aside from these distinct functions, Rab3 and Rab27A GTPases demonstrate considerable functional overlap in building the readily releasable granule pool. Hence, while Rab3 and Rab27A cooperate to generate release-ready secretory granules in β-cells, they also direct unique kinetic and functional properties of the exocytotic pathway. PMID:24909540

  1. Incidence estimates of late stages of trachoma among women in a hyperendemic area of central Tanzania.

    PubMed

    Munoz, B; Aron, J; Turner, V; West, S

    1997-11-01

    The purpose of this study is to estimate 5-year incidences of conjunctival scarring and trichiasis, and 10-year incidence of corneal opacities due to trachoma, using prevalence data from a population sample of 6038 women living in a trachoma-hyperendemic area of central Tanzania. Previous surveys have documented the age-specific prevalence of scarring, trichiasis, and corneal opacities in women in hyperendemic areas. Using the age-stratified prevalences of these different clinical signs, corresponding incidence rates were estimated. Transition rates from one sign to the next were also obtained by restricting the risk group to only women with a specific trachoma sign. Thus, the 5-year incidence of trichiasis among women with conjunctival scarring, and the 10-year incidence of corneal opacities among women with trichiasis were estimated. Incidences of all the signs markedly increased with age. For scarring, 5-year incidence rates increased from 3.1% in the 15-19 age category to 14.3% for women between 55 and 59 years. The 5-year incidence of trichiasis ranged from 0.3% in the 15-19 age category to 7.5% in the age group 55-59. Corneal opacities due to trachoma were highest in the age group 45-54; the 10-year incidence increased to 2.8%. The 5-year incidence of trichiasis among only women with scars increased from 3.2% in the 15-19 age group to 15.1% in women in the 55-59 age group. Once trichiasis is present, almost one-third of the women below 35 and more than 40% of the women older than 45 will develop corneal opacities in a 10-year interval. These estimates are important in understanding the dynamics of progression of trachoma from conjunctival scarring to the potentially blinding signs of trichiasis and corneal opacities. They provide important information for planning adequate services in areas where trachoma is endemic and surgery for trichiasis is a key factor to avoid blindness from trachoma. They also provide clues to the pathogenesis that may be useful in the development of new methods of control.

  2. Evolution of late stage differentiates in the Palisades Sill, New York and New Jersey

    NASA Astrophysics Data System (ADS)

    Block, Karin A.; Steiner, Jeffrey C.; Puffer, John H.; Jones, Kevin M.; Goldstein, Steven L.

    2015-08-01

    The Palisades Sill at Upper Nyack, NY contains evolved rocks that crystallized as ferrodiabase and ferrogranophyre and occupy 50% to 60% of the local thickness. 143Nd/144Nd isotope values for rocks representing Palisades diversity range between 0.512320 and 0.512331, and indicate a homogeneous source for the Palisades and little or no contamination from shallow crustal sediments. Petrographic analysis of ferrodiabase suggests that strong iron enrichment was the result of prolonged quiescence in cycles of magmatic input. Ferrogranophyres in the updip northern Palisades at Upper Nyack are members of a suite of cogenetic rocks with similar composition to 'sandwich horizon' rocks of the southern Palisades at Fort Lee, NJ, but display distinct mineralogical and textural features. Differences in textural and mineralogical features are attributed to a) updip (lateral) migration of residual liquid as the sill propagated closer to the surface; b) deformation caused by tectonic shifts; and c) crystallization in the presence of deuteric hydrothermal fluids resulting in varying degrees of alteration. A model connecting multiple magmatic pulses, compaction and mobilization of residual liquid by compositional convection, closed-system differentiation, synchronous with tapping of the sill for extrusion of coeval basaltic subaerial flows is presented. The persistence of a low-temperature mushy layer, represented by ferrogranophyres, supports the possibility of a long-lived conduit subject to reopening after periods of quiescence in magmatic input, leading to the extrusion of the multiple flows of the Orange Mountain Basalt and perhaps even subsequent Preakness Basalt flows, depending on solidification conditions. A sub-Newark Basin network of sills subjected to similar protracted input of pulses as hypothesized for the Palisades was likely responsible for 600 ka of magmatic activity required to emplace a third set of Watchung flood basalts, the Hook Mountain Basalt.

  3. Crevasse-squeeze ridge corridors: Diagnostic features of late-stage palaeo-ice stream activity

    NASA Astrophysics Data System (ADS)

    Evans, David J. A.; Storrar, Robert D.; Rea, Brice R.

    2016-04-01

    A 200-km-long and 10-km-wide linear assemblage of till-filled geometrical ridges on the bed of the Maskwa palaeo-ice stream of the late Wisconsinan southwest Laurentide Ice Sheet are interpreted as crevasse-squeeze ridges (CSR) developed during internal flow unit reorganization, immediately prior to ice stream shutdown. Ridge orientations are predominantly orientated WNW-ESE, with a subordinate WSW-ENE alignment, both indicative of ice fracture development transverse to former ice stream flow, as indicated by NNE-SSW aligned MSGL. Subglacial till injection into basal and/or full depth, mode I and II crevasses occurred at the approximate centreline of the ice stream, in response to extension and fracturing. Landform preservation indicates that this took place during the final stages of ice streaming, immediately prior to ice stream shutdown. This linear zone of ice fracturing therefore likely represents the narrowing of the fast-flowing trunk, similar to the plug flow identified in some surging valley glaciers. Lateral drag between the final active flow unit and the slower moving ice on either side is likely recorded by the up-ice bending of the CSR limbs. The resulting CSR corridor, here related to an individual ice stream flow unit, constitutes a previously unreported style of crevasse infilling and contrasts with two existing CSR patterns: (1) wide arcuate zones of CSRs related to widespread fracturing within glacier surge lobes; and (2) narrow concentric arcs of CSRs and recessional push moraines related to submarginal till deformation at active temperate glacier lobes.

  4. ECO fill: automated fill modification to support late-stage design changes

    NASA Astrophysics Data System (ADS)

    Davis, Greg; Wilson, Jeff; Yu, J. J.; Chiu, Anderson; Chuang, Yao-Jen; Yang, Ricky

    2014-03-01

    One of the most critical factors in achieving a positive return for a design is ensuring the design not only meets performance specifications, but also produces sufficient yield to meet the market demand. The goal of design for manufacturability (DFM) technology is to enable designers to address manufacturing requirements during the design process. While new cell-based, DP-aware, and net-aware fill technologies have emerged to provide the designer with automated fill engines that support these new fill requirements, design changes that arrive late in the tapeout process (as engineering change orders, or ECOs) can have a disproportionate effect on tapeout schedules, due to the complexity of replacing fill. If not handled effectively, the impacts on file size, run time, and timing closure can significantly extend the tapeout process. In this paper, the authors examine changes to design flow methodology, supported by new fill technology, that enable efficient, fast, and accurate adjustments to metal fill late in the design process. We present an ECO fill methodology coupled with the support of advanced fill tools that can quickly locate the portion of the design affected by the change, remove and replace only the fill in that area, while maintaining the fill hierarchy. This new fill approach effectively reduces run time, contains fill file size, minimizes timing impact, and minimizes mask costs due to ECO-driven fill changes, all of which are critical factors to ensuring time-to-market schedules are maintained.

  5. Perceptions of Burden in Patients With Late-Stage Cancer and Their Caregivers

    ClinicalTrials.gov

    2015-05-27

    Brain and Central Nervous System Tumors; Chronic Myeloproliferative Disorders; Depression; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Psychosocial Effects of Cancer and Its Treatment; Unspecified Adult Solid Tumor, Protocol Specific

  6. Integrated community education model: breast health awareness to impact late-stage breast cancer.

    PubMed

    Northington, LaDonna; Martin, Tina; Walker, Jean T; Williams, P Renée; Lofton, Susan P; Cooper, Janet R; Luther, Cynthia H; Keller, Sheila D

    2011-08-01

    Race and ethnicity play roles in breast cancer mortality, particularly for African American women. As a result, a three-pronged integrated community education model (i.e., faith-based, community, and state agencies) was generated and tested in a medically underserved area with high mortality rates from breast cancer to increase participation in breast health education, provide early screening and detection practices, and provide access to annual mammograms and referral sources. The model provided three women with life-saving early diagnoses, in addition to providing potentially hundreds of women with a network of breast health, self-monitoring, and referral sources for future issues.

  7. Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

    PubMed Central

    Gordon, Emile B.; Hart, Geoffrey T.; Tran, Tuan M.; Waisberg, Michael; Akkaya, Munir; Kim, Ann S.; Hamilton, Sara E.; Pena, Mirna; Yazew, Takele; Qi, Chen-Feng; Lee, Chen-Fang; Lo, Ying-Chun; Miller, Louis H.; Powell, Jonathan D.; Pierce, Susan K.

    2015-01-01

    The most deadly complication of Plasmodium falciparum infection is cerebral malaria (CM) with a case fatality rate of 15–25% in African children despite effective antimalarial chemotherapy. There are no adjunctive treatments for CM, so there is an urgent need to identify new targets for therapy. Here we show that the glutamine analog 6-diazo-5-oxo-l-norleucine (DON) rescues mice from CM when administered late in the infection a time at which mice already are suffering blood–brain barrier dysfunction, brain swelling, and hemorrhaging accompanied by accumulation of parasite-specific CD8+ effector T cells and infected red blood cells in the brain. Remarkably, within hours of DON treatment mice showed blood–brain barrier integrity, reduced brain swelling, decreased function of activated effector CD8+ T cells in the brain, and levels of brain metabolites that resembled those in uninfected mice. These results suggest DON as a strong candidate for an effective adjunctive therapy for CM in African children. PMID:26438846

  8. Malignant pheochromocytoma lacking clinical features of catecholamine excess until the late stage.

    PubMed

    Honda, M; Uesugi, K; Yamazaki, H; Dezawa, A; Mizuguchi, K; Yamaji, T; Ishibashi, M

    2000-10-01

    A malignant pheochromocytoma is described in a 71-year-old man. Osseous metastases became manifest 12 years after successful removal of the primary tumor which originated in paraganglionic tissue near the right adrenal gland. Although the patient had no symptoms of catecholamine excess initially, hypertension, tachycardia and excessive sweating appeared several months before his death, concomitantly with a sharp increase in noradrenaline secretion due to an accelerated growth of metastatic tumors. Since there is no histologic criterion of malignancy in this neoplasm, it would be prudent to consider every case of pheochromocytoma as potentially malignant and to follow-up carefully for a long time after removal of the primary tumor. PMID:11030207

  9. Transformation of endometrium and fertility in late stages of pseudopregnancy in the rabbit.

    PubMed

    Fischer, B; Winterhager, E; Busch, L C

    1986-11-01

    Ovulation was induced in rabbits between Days 14 and 18 of pseudopregnancy by an intravenous injection of hCG. Induction of ovulation from Day 16 onwards led to normal progestational endometrial transformation. In rabbits injected on Day 14 or 15, a normal preimplantation endometrial morphology developed, but not earlier than 7 days after hCG (Day 14/15 + 7). Uteroglobin secretion was advanced during the second pseudopregnancy. After mating or artificial insemination, fertility was greatest on Day 18 of pseudopregnancy. Conception failed on Day 14 and embryo transfers were unsuccessful on Day 14 + 1. Transfers performed on Day 14 + 3, however, led to implantation and offspring, even though endometrial morphology did not correspond to the normal Day 3 preimplantational morphology at the time of transfer. We conclude that endometrial transformation typical of normal pseudopregnancy can be induced by ovulation during the regeneration phase of pseudopregnancy from Day 16 onwards; fertilization and implantation can be achieved as early as Day 15 of pseudopregnancy; an oestrous period with high mating activity and fertility occurs about 3 days later; and Day 14 after hCG represents a limited time of functional change from pseudopregnancy to a fertile uterine cycle in the rabbit.

  10. Art Therapy for an Individual with Late Stage Dementia: A Clinical Case Description

    ERIC Educational Resources Information Center

    Tucknott-Cohen, Tisah; Ehresman, Crystal

    2016-01-01

    This article describes the healing benefits of art therapy for an individual with dementia of the Alzheimer's type. In this clinical case description, a woman diagnosed with Alzheimer's disease received individual art therapy for 17 weeks. The treatment concerns that arose, altered view of reality, agitation, and retrogenesis provide insight on…

  11. The I/S-to-illite reaction in the late stage diagenesis

    USGS Publications Warehouse

    Lanson, B.; Champion, D.

    1991-01-01

    XRF analyses of individual grains show that the I/S minerals become more illitic (near mica composition) with depth, but they always contain a portion of a smectite component, that is, silica-rich, low layer charge component. Both lath I/S and hexagonal illite minerals appear to grow by adding illite layers of the same composition (0.9 potassium atoms and a slight celadonite, phengite component) onto original crystallites. -from Authors

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  13. Impact vaporization of planetesimal cores in the late stages of planet formation

    NASA Astrophysics Data System (ADS)

    Kraus, Richard G.; Root, Seth; Lemke, Raymond W.; Stewart, Sarah T.; Jacobsen, Stein B.; Mattsson, Thomas R.

    2015-04-01

    Differentiated planetesimals delivered iron-rich material to the Earth and Moon in high-velocity collisions at the end stages of accretion. The physical process of accreting this late material has implications for the geochemical evolution of the Earth-Moon system and the timing of Earth’s core formation. However, the fraction of a planetesimal’s iron core that is vaporized by an impact is not well constrained as a result of iron’s poorly understood equation of state. Here we determine the entropy in the shock state of iron using a recently developed shock-and-release experimental technique implemented at the Sandia National Laboratory Z-Machine. We find that the shock pressure required to vaporize iron is 507 (+65, -85) GPa, which is lower than the previous theoretical estimate (887 GPa) and readily achieved by the high velocity impacts at the end stages of accretion. We suggest that impact vaporization of planetesimal cores dispersed iron over the surface of the growing Earth and enhanced chemical equilibration with the mantle. In addition, the comparatively low abundance of highly siderophile elements in the lunar mantle and crust can be explained by the retention of a smaller fraction of vaporized planetesimal iron on the Moon, as compared with Earth, due to the Moon’s lower escape velocity.

  14. [Studies on the kinetics of methaqualone during the late stage of pregnancy (author's transl)].

    PubMed

    Peiker, G; Müller, B; Nöschel, H; Bonow, A

    1979-04-01

    After oral administration of 0.4 g of methaqualone to pregnant and non-pregnant women, the authors stated that the half-life of this drug was significantly reduced during the last trimester of pregnancy. The two experimental groups showed no significant differences in the volume of distribution and the fictitious initial concentration. The commonly used therapeutical dosages are not likely to produce increased blood levels during normal pregnancy.

  15. A matter of race: early-versus late-stage cancer diagnosis.

    PubMed

    Virnig, Beth A; Baxter, Nancy N; Habermann, Elizabeth B; Feldman, Roger D; Bradley, Cathy J

    2009-01-01

    We compared the stage at which cancer is diagnosed and survival rates between African Americans and whites, for thirty-four solid tumors, using the population-based Surveillance Epidemiology and End Results (SEER) database. Whites were diagnosed at earlier stages than African Americans for thirty-one of the thirty-four tumor sites. Whites were significantly more likely than blacks to survive five years for twenty-six tumor sites; no cancer site had significantly superior survival among African Americans. These differences cannot be explained by screening behavior or risk factors; they point instead to the need for broad-based strategies to remedy racial inequality in cancer survival.

  16. Successes and Failures for Drugs in Late-Stage Development for Alzheimer's Disease

    PubMed Central

    Berk, Camryn; Sabbagh, Marwan

    2014-01-01

    To date, symptomatic medications prevail as the mainstay of treatment options for Alzheimer's disease (AD). There have been tremendous investments made to increase the numbers of drugs approved and the targets engaged, in an effort to alter the disease course or pathophysiology of AD. Unfortunately, almost all studies have not met expectations and no new drug (beyond medical foods) has been approved for the treatment of AD in the last decade. This review is a comparison of novel AD therapies in the late phases of clinical testing with recent high-profile clinical failures and agents in development with relatively unexplored mechanisms of action, with a focus on their potential as therapeutic agents and their proposed advantages over the treatments currently in use. PMID:23943247

  17. Late-stage functionalization of biologically active heterocycles through photoredox catalysis.

    PubMed

    Dirocco, Daniel A; Dykstra, Kevin; Krska, Shane; Vachal, Petr; Conway, Donald V; Tudge, Matthew

    2014-05-01

    The direct CH functionalization of heterocycles has become an increasingly valuable tool in modern drug discovery. However, the introduction of small alkyl groups, such as methyl, by this method has not been realized in the context of complex molecule synthesis since existing methods rely on the use of strong oxidants and elevated temperatures to generate the requisite radical species. Herein, we report the use of stable organic peroxides activated by visible-light photoredox catalysis to achieve the direct methyl-, ethyl-, and cyclopropylation of a variety of biologically active heterocycles. The simple protocol, mild reaction conditions, and unique tolerability of this method make it an important tool for drug discovery.

  18. Complex care needs of patients with late-stage HIV disease: A retrospective study

    PubMed Central

    Halman, Mark; Carusone, Soo Chan; Stranks, Sarah; Schaefer-McDaniel, Nicole; Stewart, Ann

    2013-01-01

    This retrospective chart review provides a profile of an emerging population of vulnerable HIV patients with complex comorbidities. Data were abstracted from all 87 patients admitted in 2008 to Casey House, a community-based hospital dedicated to supportive and palliative care for persons with HIV in Toronto, Canada. We describe patient characteristics, including medical and psychiatric conditions, and use a Venn diagram and case study to illustrate the frequency and reality of co-occurring conditions that contribute to the complexity of patients’ health and health care needs. The mean age at admission was 48.9 years (SD = 10.5). Eighty percent were male. Patients experienced a mean of 5.8 medical comorbidities (SD = 2.3) and 1.9 psychiatric disorders (lifetime axis I diagnoses). Forty-one patients (47%) experienced cognitive impairment including HIV-associated dementia. Patients were on a mean of 11.8 (SD = 5.3) medications at admission; 74% were on antiretroviral medications with 55% reporting full adherence. Current alcohol and drug use was common with 54% reporting active use at admission. Our Venn diagram illustrates the breadth of complexity in the clients with 9% of clients living in unstable housing with three or more medical comorbidites and two or more psychiatric diagnoses. Comprehensive HIV program planning should include interventions that can flexibly adapt to meet the multidimensional and complex needs of this segment of patients. Researchers, policymakers and clinicians need to have greater awareness of overlapping medical, psychiatric and psychosocial comorbidities. Inclusion of the needs of these most vulnerable patients in the development of evidence based guidelines is an important step for effectively treating, preventing and planning for the future of HIV/AIDS care.

  19. Continuous intraperitoneal carboplatin delivery for the treatment of late-stage ovarian cancer.

    PubMed

    Zhidkov, Nickholas; De Souza, Raquel; Ghassemi, Amir H; Allen, Christine; Piquette-Miller, Micheline

    2013-09-01

    The rate of failure of chemotherapy treatment in ovarian cancer remains high, resulting in a low 5-year survival rate of 20-40% in patients that present with advanced-stage disease. Treatment-free periods between cycles of chemotherapy may contribute to accelerated tumor cell proliferation and decreased treatment response. The elimination of treatment-free breaks has been deemed beneficial in the context of cell-cycle-specific agents. The potential benefit of this approach for non-cell-cycle-specific agents has not yet been elucidated. The present study is the first to address this issue by investigating the impact of continuous versus intermittent intraperitoneal administration of carboplatin over a 14 day period to SCID mice bearing SKOV-3 ovarian cancer xenografts. Immunostaining of tumor sections was employed to quantify tumor proliferation, angiogenesis, and apoptosis using Ki-67, CD-31, caspase-3 (CASP3), and terminal deoxytransferase-mediated dUTP nick-end labeling (TUNEL). Continuous ip administration of carboplatin resulted in greater tumor growth inhibition than intermittent therapy (p < 0.05). Significantly greater tumor cell apoptosis and less cell proliferation and angiogenesis were measured in tumors of mice treated with continuous carboplatin as compared to both intermittent and control groups. These results indicate that continuous local administration may be a promising approach to improve the effectiveness of platinum-based chemotherapy regimens.

  20. Gold deposition caused by carbonation of biotite during late-stage fluid flow

    NASA Astrophysics Data System (ADS)

    Pearce, Mark A.; White, Alistair J. R.; Fisher, Louise A.; Hough, Robert M.; Cleverley, James S.

    2015-12-01

    Alteration reactions associated with gold mineralisation can be used to elucidate the nature of the fluid that transported gold into a deposit. At the Junction gold deposit, Kambalda, Western Australia, gold is hosted in a metamorphosed and hydrothermally altered dolerite. Mineralisation at the deposit scale is associated with zones of K, CO2 and S metasomatism, as is common in many greenstone hosted gold deposits. However, at the thin-section scale gold is not closely associated with sulphide minerals but within zones of carbonate metasomatism and K-loss where pre-existing biotite has reacted to produce chlorite, muscovite and Fe-Mg carbonates. Gold precipitation is intimately associated with biotite breakdown where calcite is locally absent. Quantified mineral modes from detailed microstructural mapping are used to balance reactions describing the breakdown of biotite in the presence and absence of calcite. Using the basic assumption that Al is immobile during metasomatism the reactions are successfully balanced, even in a manifestly open system. Modelling of fluid-rock reactions using HCh constrains the fluid composition (0.11 < X(CO2) < 0.13) and fluid-rock ratios (< 12:1) that can produce the observed mineral assemblage. Additional modelling of solid solution mineral phases using THERMOCALC estimates alteration conditions of 390 °C, 4 kbar and also suggests a fluid X(CO2) ~ 0.1. Both these models show that the observed muscovite and chlorite compositions can be produced primarily through the removal of K from the measured precursor biotite. We show that it is not possible to transport and deposit all the gold observed in the alteration zone with the low fluid-rock ratios obtained from modelling of silicate alteration and inferred gold concentrations in these fluids. We suggest that this is typical of greenstone hosted gold deposits and that mechanisms other than aqueous solution, which can transport higher gold concentrations, must be considered.

  1. Metal-Catalyzed Azidation of Tertiary C–H Bonds Suitable for Late-Stage Functionalization

    PubMed Central

    Sharma, Ankit

    2014-01-01

    Some enzymes are able to selectively oxidize unactivated aliphatic C-H bonds to form alcohols; however biological systems do not possess enzymes that are able to catalyze the analogous amination of a C-H bond.1,2 The absence of such chemistry is limiting because nitrogen-containing groups are found in therapeutic agents and clinically useful natural products. In one prominent example, the conversion of the ketone of erythromycin to the –N(Me)CH2– group in azithromycin leads to a compound that can be dosed once daily with a shorter length of treatment.3,4 For such reasons, synthetic chemists are very interested in identifying catalysts that can directly convert C-H bonds to C-N bonds. Most currently used catalysts for C-H bond amination are ill suited for the functionalization of complex molecules, because they require excess substrate or directing groups, harsh reaction conditions, weak or acidic C-H bonds, or reagents containing specialized groups on the nitrogen atom.5-14 Among C-H bond amination reactions, those forming a carbon-nitrogen bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to generate enzymatically from ketone or alcohol precursors.15 In this manuscript, we report a mild, selective, iron-catalyzed azidation of tertiary C-H bonds with substrate as limiting reagent. The reaction tolerates aqueous environments and is suitable for “late-stage” functionalization of complex structures. Moreover, this azidation creates the ability to install a range of nitrogen functional groups, including those from bio-orthogonal Huisgen “click” cycloadditions and the Staudinger ligation.16-19 For these reasons, we anticipate this methodology will create opportunities to easily modify natural products, their precursors, and their derivatives to analogs that contain distinct polarity and charge from nitrogen-containing groups. It could also be used to help identify targets of biologically active molecules by creating a point of attachment, for example to fluorescent tags or ‘handles’ for affinity chromatography, directly onto complex molecular structures. PMID:25631448

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

    NASA Technical Reports Server (NTRS)

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

    1990-01-01

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

  3. Muscle fiber conduction velocity in different gait phases of early and late-stage diabetic neuropathy.

    PubMed

    Suda, Eneida Yuri; Gomes, Aline A; Butugan, Marco Kenji; Sacco, Isabel C N

    2016-10-01

    We investigated the muscle fiber conduction velocity (MFCV) during gait phases of the lower limb muscles in individuals with various degrees of diabetic peripheral neuropathy (DPN). Forty-five patients were classified into severity degrees of DPN by a fuzzy model. The stages were absent (n=11), mild (n=14), moderate (n=11) and severe (n=9), with 10 matched healthy controls. While walking, all subjects had their sEMG (4 linear electrode arrays) recorded for tibialis anterior (TA), gastrocnemius medialis (GM), vastus lateralis (VL) and biceps femoris (BF). MFCV was calculated using a maximum likelihood algorithm with 30ms standard deviation Gaussian windows. In general, individuals in the earlier stages of DPN showed lower MFCV of TA, GM and BF, whilst individuals with severe DPN presented higher MFCV of the same muscles. We observed that mild patients already showed lower MFCV of TA at early stance and swing, and lower MFCV of BF at swing. All diabetic groups showed a markedly reduction in MFCV of VL, irrespective of DPN. Severe patients presented higher MFCV mainly in distal muscles, TA at early and swing phases and GM at propulsion and midstance. The absent group already showed MFCV of VL and GM reductions at the propulsion phase and of VL at early stance. Although MFCV changes were not as progressive as the DPN was, we clearly distinguished diabetic patients from controls, and severe patients from all others. PMID:27567140

  4. Diversity of Planets in the Aftermath of Late Stage Accretion (Invited)

    NASA Astrophysics Data System (ADS)

    Asphaug, E. I.; Reufer, A.

    2013-12-01

    It is a mistake to view giant impacts or similar sized collisions between planets or planetary embryos as large-scale versions of impact cratering. Although much of the physics is the same (material mechanics, and shocks in the case of hypervelocity events), fundamentally a similar sized collision is a gravity-regime phenomenon where too much angular momentum is trying to accrete into one place, as the video linked below illustrates. When we see material 'escaping' from a collision, in simulations, it is not so much that it was blasted from the target (this is rarely the case) than that it was not accreted by the target. When we see a disk forming around the proto-Earth, in Moon-forming simulations, it was not ejected from the Earth (in the standard model) but rather it forms from impactor material that was only partially accreted (c.f. Canup 2004). Hence the quandary of oxygen isotopes in Moon formation. With this perspective, a number of novel pathways for meteorite petrogenesis and planetary origins open up: hit and run collisions, which can leave behind iron-rich relics (or rock-rich relics in the case of KBO collisions); partial accretion, which is the standard model for the silicate-rich Moon; and the formation of families of bodies (self-gravitating clumps formed in escaping tidal arms) which offer a new way of forming isotopically closely related bodies from a common parent that may have dramatically different bulk compositions. The concept of imperfect accretion creates a coeval timescale for planetary disruption, one that occurs while the planets are coming together, rather than long afterwards as battered pieces of the Main Belt or the Kuiper Belt -- disruption by accretion, and in many cases, disruption without shock. As time permits we shall present hypotheses invoking imperfect pairwise accretion as an origin scenario for specific planetary bodies such as Mercury and the satellites of Saturn. The linked video is from an origins model by Asphaug and Reufer (Icarus 2013) where differentiated Galilean-sized icy satellites accrete, spawning middle-sized moons. Similar models are presented for differentiated silicate bodies. The longer term problem is to track the dynamical fate of the bodies that are formed in similar sized collisions, because ultimately their fate is to be accreted (remaining close to the target in dynamical space) unless they are scattered into protected locations, so the talk ends with some progress on that front.

  5. Use of ultrasonography to identify late-stage maturity in rainbow trout Oncorhynchus mykiss

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Morphometric measurements by ultrasonography has been used to determine gonad and follicle size in many species of fish for purposes of identifying sex and estimating stage of maturation. We have been using a portable ultrasound system (SonoSite MicroMaxx, L25e/13-6 MHz transducer) to identify fem...

  6. Retinal remodeling in human retinitis pigmentosa.

    PubMed

    Jones, B W; Pfeiffer, R L; Ferrell, W D; Watt, C B; Marmor, M; Marc, R E

    2016-09-01

    Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies. PMID:27020758

  7. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells.

    PubMed

    Lee, John K; Phillips, John W; Smith, Bryan A; Park, Jung Wook; Stoyanova, Tanya; McCaffrey, Erin F; Baertsch, Robert; Sokolov, Artem; Meyerowitz, Justin G; Mathis, Colleen; Cheng, Donghui; Stuart, Joshua M; Shokat, Kevan M; Gustafson, W Clay; Huang, Jiaoti; Witte, Owen N

    2016-04-11

    MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention. PMID:27050099

  8. Potential Use of Bacterial Community Succession in Decaying Human Bone for Estimating Postmortem Interval.

    PubMed

    Damann, Franklin E; Williams, Daniel E; Layton, Alice C

    2015-07-01

    Bacteria are taphonomic agents of human decomposition, potentially useful for estimating postmortem interval (PMI) in late-stage decomposition. Bone samples from 12 individuals and three soil samples were analyzed to assess the effects of decomposition and advancing time on bacterial communities. Results indicated that partially skeletonized remains maintained a presence of bacteria associated with the human gut, whereas bacterial composition of dry skeletal remains maintained a community profile similar to soil communities. Variation in the UniFrac distances was significantly greater between groups than within groups (p < 0.001) for the unweighted metric and not the weighted metric. The members of the bacterial communities were more similar within than between decomposition stages. The oligotrophic environment of bone relative to soft tissue and the physical protection of organic substrates may preclude bacterial blooms during the first years of skeletonization. Therefore, community membership (unweighted) may be better for estimating PMI from skeletonized remains than community structure (weighted).

  9. Dynamics of the Major Histocompatibility Complex Class I Processing and Presentation Pathway in the Course of Malaria Parasite Development in Human Hepatocytes: Implications for Vaccine Development

    PubMed Central

    Ma, Jinxia; Trop, Stefanie; Baer, Samantha; Rakhmanaliev, Elian; Arany, Zita; Dumoulin, Peter; Zhang, Hao; Romano, Julia; Coppens, Isabelle; Levitsky, Victor; Levitskaya, Jelena

    2013-01-01

    Control of parasite replication exerted by MHC class I restricted CD8+ T-cells in the liver is critical for vaccination-induced protection against malaria. While many intracellular pathogens subvert the MHC class I presentation machinery, its functionality in the course of malaria replication in hepatocytes has not been characterized. Using experimental systems based on specific identification, isolation and analysis of human hepatocytes infected with P. berghei ANKA GFP or P. falciparum 3D7 GFP sporozoites we demonstrated that molecular components of the MHC class I pathway exhibit largely unaltered expression in malaria-infected hepatocytes until very late stages of parasite development. Furthermore, infected cells showed no obvious defects in their capacity to upregulate expression of different molecular components of the MHC class I machinery in response to pro-inflammatory lymphokines or trigger direct activation of allo-specific or peptide-specific human CD8+ T-cells. We further demonstrate that ectopic expression of circumsporozoite protein does not alter expression of critical genes of the MHC class I pathway and its response to pro-inflammatory cytokines. In addition, we identified supra-cellular structures, which arose at late stages of parasite replication, possessed the characteristic morphology of merosomes and exhibited nearly complete loss of surface MHC class I expression. These data have multiple implications for our understanding of natural T-cell immunity against malaria and may promote development of novel, efficient anti-malaria vaccines overcoming immune escape of the parasite in the liver. PMID:24086507

  10. A literature review of economic evaluations for a neglected tropical disease: human African trypanosomiasis ("sleeping sickness").

    PubMed

    Sutherland, C Simone; Yukich, Joshua; Goeree, Ron; Tediosi, Fabrizio

    2015-02-01

    Human African trypanosomiasis (HAT) is a disease caused by infection with the parasite Trypanosoma brucei gambiense or T. b. rhodesiense. It is transmitted to humans via the tsetse fly. Approximately 70 million people worldwide were at risk of infection in 1995, and approximately 20,000 people across Africa are infected with HAT. The objective of this review was to identify existing economic evaluations in order to summarise cost-effective interventions to reduce, control, or eliminate the burden of HAT. The studies included in the review were compared and critically appraised in order to determine if there were existing standardised methods that could be used for economic evaluation of HAT interventions or if innovative methodological approaches are warranted. A search strategy was developed using keywords and was implemented in January 2014 in several databases. The search returned a total of 2,283 articles. After two levels of screening, a total of seven economic evaluations were included and underwent critical appraisal using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist 6: Economic Evaluations. Results from the existing studies focused on the cost-effectiveness of interventions for the control and reduction of disease transmission. Modelling was a common method to forecast long-term results, and publications focused on interventions by category, such as case detection, diagnostics, drug treatments, and vector control. Most interventions were considered cost-effective based on the thresholds described; however, the current treatment, nifurtomix-eflornithine combination therapy (NECT), has not been evaluated for cost-effectiveness, and considerations for cost-effective strategies for elimination have yet to be completed. Overall, the current evidence highlights the main components that play a role in control; however, economic evaluations of HAT elimination strategies are needed to assist national decision makers, stakeholders, and

  11. A literature review of economic evaluations for a neglected tropical disease: human African trypanosomiasis ("sleeping sickness").

    PubMed

    Sutherland, C Simone; Yukich, Joshua; Goeree, Ron; Tediosi, Fabrizio

    2015-02-01

    Human African trypanosomiasis (HAT) is a disease caused by infection with the parasite Trypanosoma brucei gambiense or T. b. rhodesiense. It is transmitted to humans via the tsetse fly. Approximately 70 million people worldwide were at risk of infection in 1995, and approximately 20,000 people across Africa are infected with HAT. The objective of this review was to identify existing economic evaluations in order to summarise cost-effective interventions to reduce, control, or eliminate the burden of HAT. The studies included in the review were compared and critically appraised in order to determine if there were existing standardised methods that could be used for economic evaluation of HAT interventions or if innovative methodological approaches are warranted. A search strategy was developed using keywords and was implemented in January 2014 in several databases. The search returned a total of 2,283 articles. After two levels of screening, a total of seven economic evaluations were included and underwent critical appraisal using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist 6: Economic Evaluations. Results from the existing studies focused on the cost-effectiveness of interventions for the control and reduction of disease transmission. Modelling was a common method to forecast long-term results, and publications focused on interventions by category, such as case detection, diagnostics, drug treatments, and vector control. Most interventions were considered cost-effective based on the thresholds described; however, the current treatment, nifurtomix-eflornithine combination therapy (NECT), has not been evaluated for cost-effectiveness, and considerations for cost-effective strategies for elimination have yet to be completed. Overall, the current evidence highlights the main components that play a role in control; however, economic evaluations of HAT elimination strategies are needed to assist national decision makers, stakeholders, and

  12. Human Migratory Meniscus Progenitor Cells Are Controlled via the TGF-β Pathway

    PubMed Central

    Muhammad, Hayat; Schminke, Boris; Bode, Christa; Roth, Moritz; Albert, Julius; von der Heyde, Silvia; Rosen, Vicki; Miosge, Nicolai

    2014-01-01

    Summary Degeneration of the knee joint during osteoarthritis often begins with meniscal lesions. Meniscectomy, previously performed extensively after meniscal injury, is now obsolete because of the inevitable osteoarthritis that occurs following this procedure. Clinically, meniscus self-renewal is well documented as long as the outer, vascularized meniscal ring remains intact. In contrast, regeneration of the inner, avascular meniscus does not occur. Here, we show that cartilage tissue harvested from the avascular inner human meniscus during the late stages of osteoarthritis harbors a unique progenitor cell population. These meniscus progenitor cells (MPCs) are clonogenic and multipotent and exhibit migratory activity. We also determined that MPCs are likely to be controlled by canonical transforming growth factor β (TGF-β) signaling that leads to an increase in SOX9 and a decrease in RUNX2, thereby enhancing the chondrogenic potential of MPC. Therefore, our work is relevant for the development of novel cell biological, regenerative therapies for meniscus repair. PMID:25418724

  13. Bacillus anthracis Lethal Toxin Reduces Human Alveolar Epithelial Barrier Function

    PubMed Central

    Langer, Marybeth; Duggan, Elizabeth Stewart; Booth, John Leland; Patel, Vineet Indrajit; Zander, Ryan A.; Silasi-Mansat, Robert; Ramani, Vijay; Veres, Tibor Zoltan; Prenzler, Frauke; Sewald, Katherina; Williams, Daniel M.; Coggeshall, Kenneth Mark; Awasthi, Shanjana; Lupu, Florea; Burian, Dennis; Ballard, Jimmy Dale; Braun, Armin

    2012-01-01

    The lung is the site of entry for Bacillus anthracis in inhalation anthrax, the deadliest form of the disease. Bacillus anthracis produces virulence toxins required for disease. Alveolar macrophages were considered the primary target of the Bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target of Bacillus anthracis lethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination of Bacillus anthracis from the lung in early disease and promoting edema in late stages of the illness. PMID:23027535

  14. Control of human African trypanosomiasis in the Quiçama focus, Angola.

    PubMed Central

    Ruiz, José Antonio; Simarro, Pere P.; Josenando, Teofilo

    2002-01-01

    OBJECTIVE: To update the epidemiological status of human African trypanosomiasis (HAT), also known as sleeping sickness, in the Quiçama focus, province of Bengo, Angola, and to establish a HAT control programme. METHODS: In 1997, 8796 people (the population of 31 villages) were serologically screened for Trypanosoma brucei gambiense, the causative agent of HAT. In 1998 and 1999, surveys were carried out in villages where HAT cases had been identified in 1997. Individuals were screened using the card agglutination trypanosomiasis test (CATT), and then examined for the presence of the parasite. CATT- positive individuals in whom the presence of the parasite could not be confirmed were further tested with the CATT using serum dilutions, and those with a positive antibody end titre of 1-in-4 or above were followed-up. Patients with < or =10 white cells/micro l and no trypanosomes in their cerebrospinal fluid (CSF) were classified as being in the first stage of the disease. Vector control was not considered necessary or feasible. FINDINGS: The main transmission areas were on the Kwanza riverbanks, where 5042 inhabitants live. In 1997, the HAT prevalence was 1.97%, but this decreased to 0.55% in 1998 and to 0.33% in 1999. The relapse rate was 3% in patients treated with pentamidine and 3.5% in patients treated with melarsoprol. In patients treated with pentamidine, there was no difference in the relapse rate for patients with initial CSF white cell counts of 0-5 cells/ micro l or 6-10 cells/micro l. The overall mortality rate was 0.6% and the rate of reactive arsenical encephalopathy among the melarsoprol-treated patients was 1.7%. CONCLUSION: The epidemiological status of the disease was updated and the transmission areas were defined. The control methods implemented allowed the disease prevalence to be reduced. PMID:12378293

  15. Changes in the ultrastructure of human cells related to certain biological responses under hyperthermic culture conditions.

    PubMed

    Iwagami, Y

    1996-12-01

    It has been reported that human cancer cells are more sensitive to high temperatures than normal human cells, and that cell proliferation and viability are affected by the temperature environment. In this study, we proceeded further, and turning our attention to the close relationship between cell morphology and temperature, used two human cancer cell lines and two normal cell strains to investigate how intracellular fine structure changes in a high temperature environment. The results showed that 1) both of the human cancer cell lines were more sensitive to high temperature than the normal human cell strains, and a difference between the temperature sensitivity of the human cancer cell lines was also confirmed. 2) There is no clear difference between the manner in which normal human cells and malignant human cells are affected by hyperthermia. 3) Among other cell structures, effects on the membrane system were observed as early changes in cell structure. The mitochondria were particularly affected, followed by the rER. 4) Changes in the nucleoplasm, as well as the nuclear membrane (inner membrane), and then the intranuclear chromatin, etc., were observed as late changes. 5) Changes in mitochondria were observed in the early stage, but temporarily tended to recover, and were then fatally affected again in the late stage. We discuss the relationship between cell proliferation, cell viability, and cell ultrastructure based on the above results. PMID:9183669

  16. A Literature Review of Economic Evaluations for a Neglected Tropical Disease: Human African Trypanosomiasis (“Sleeping Sickness”)

    PubMed Central

    Sutherland, C. Simone; Yukich, Joshua; Goeree, Ron; Tediosi, Fabrizio

    2015-01-01

    Human African trypanosomiasis (HAT) is a disease caused by infection with the parasite Trypanosoma brucei gambiense or T. b. rhodesiense. It is transmitted to humans via the tsetse fly. Approximately 70 million people worldwide were at risk of infection in 1995, and approximately 20,000 people across Africa are infected with HAT. The objective of this review was to identify existing economic evaluations in order to summarise cost-effective interventions to reduce, control, or eliminate the burden of HAT. The studies included in the review were compared and critically appraised in order to determine if there were existing standardised methods that could be used for economic evaluation of HAT interventions or if innovative methodological approaches are warranted. A search strategy was developed using keywords and was implemented in January 2014 in several databases. The search returned a total of 2,283 articles. After two levels of screening, a total of seven economic evaluations were included and underwent critical appraisal using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist 6: Economic Evaluations. Results from the existing studies focused on the cost-effectiveness of interventions for the control and reduction of disease transmission. Modelling was a common method to forecast long-term results, and publications focused on interventions by category, such as case detection, diagnostics, drug treatments, and vector control. Most interventions were considered cost-effective based on the thresholds described; however, the current treatment, nifurtomix-eflornithine combination therapy (NECT), has not been evaluated for cost-effectiveness, and considerations for cost-effective strategies for elimination have yet to be completed. Overall, the current evidence highlights the main components that play a role in control; however, economic evaluations of HAT elimination strategies are needed to assist national decision makers, stakeholders, and

  17. Domestic Animal Hosts Strongly Influence Human-Feeding Rates of the Chagas Disease Vector Triatoma infestans in Argentina

    PubMed Central

    Gürtler, Ricardo E.; Cecere, María C.; Vázquez-Prokopec, Gonzalo M.; Ceballos, Leonardo A.; Gurevitz, Juan M.; Fernández, María del Pilar; Kitron, Uriel; Cohen, Joel E.

    2014-01-01

    Background The host species composition in a household and their relative availability affect the host-feeding choices of blood-sucking insects and parasite transmission risks. We investigated four hypotheses regarding factors that affect blood-feeding rates, proportion of human-fed bugs (human blood index), and daily human-feeding rates of Triatoma infestans, the main vector of Chagas disease. Methods A cross-sectional survey collected triatomines in human sleeping quarters (domiciles) of 49 of 270 rural houses in northwestern Argentina. We developed an improved way of estimating the human-feeding rate of domestic T. infestans populations. We fitted generalized linear mixed-effects models to a global model with six explanatory variables (chicken blood index, dog blood index, bug stage, numbers of human residents, bug abundance, and maximum temperature during the night preceding bug catch) and three response variables (daily blood-feeding rate, human blood index, and daily human-feeding rate). Coefficients were estimated via multimodel inference with model averaging. Findings Median blood-feeding intervals per late-stage bug were 4.1 days, with large variations among households. The main bloodmeal sources were humans (68%), chickens (22%), and dogs (9%). Blood-feeding rates decreased with increases in the chicken blood index. Both the human blood index and daily human-feeding rate decreased substantially with increasing proportions of chicken- or dog-fed bugs, or the presence of chickens indoors. Improved calculations estimated the mean daily human-feeding rate per late-stage bug at 0.231 (95% confidence interval, 0.157–0.305). Conclusions and Significance Based on the changing availability of chickens in domiciles during spring-summer and the much larger infectivity of dogs compared with humans, we infer that the net effects of chickens in the presence of transmission-competent hosts may be more adequately described by zoopotentiation than by zooprophylaxis

  18. Intrinsic functional brain architecture derived from graph theoretical analysis in the human fetus.

    PubMed

    Thomason, Moriah E; Brown, Jesse A; Dassanayake, Maya T; Shastri, Rupal; Marusak, Hilary A; Hernandez-Andrade, Edgar; Yeo, Lami; Mody, Swati; Berman, Susan; Hassan, Sonia S; Romero, Roberto

    2014-01-01

    The human brain undergoes dramatic maturational changes during late stages of fetal and early postnatal life. The importance of this period to the establishment of healthy neural connectivity is apparent in the high incidence of neural injury in preterm infants, in whom untimely exposure to ex-uterine factors interrupts neural connectivity. Though the relevance of this period to human neuroscience is apparent, little is known about functional neural networks in human fetal life. Here, we apply graph theoretical analysis to examine human fetal brain connectivity. Utilizing resting state functional magnetic resonance imaging (fMRI) data from 33 healthy human fetuses, 19 to 39 weeks gestational age (GA), our analyses reveal that the human fetal brain has modular organization and modules overlap functional systems observed postnatally. Age-related differences between younger (GA <31 weeks) and older (GA≥31 weeks) fetuses demonstrate that brain modularity decreases, and connectivity of the posterior cingulate to other brain networks becomes more negative, with advancing GA. By mimicking functional principles observed postnatally, these results support early emerging capacity for information processing in the human fetal brain. Current technical limitations, as well as the potential for fetal fMRI to one day produce major discoveries about fetal origins or antecedents of neural injury or disease are discussed.

  19. Potential for Pancreatic Maturation of Differentiating Human Embryonic Stem Cells Is Sensitive to the Specific Pathway of Definitive Endoderm Commitment

    PubMed Central

    Jaramillo, Maria; Mathew, Shibin; Task, Keith; Barner, Sierra; Banerjee, Ipsita

    2014-01-01

    This study provides a detailed experimental and mathematical analysis of the impact of the initial pathway of definitive endoderm (DE) induction on later stages of pancreatic maturation. Human embryonic stem cells (hESCs) were induced to insulin-producing cells following a directed-differentiation approach. DE was induced following four alternative pathway modulations. DE derivatives obtained from these alternate pathways were subjected to pancreatic progenitor (PP) induction and maturation and analyzed at each stage. Results indicate that late stage maturation is influenced by the initial pathway of DE commitment. Detailed quantitative analysis revealed WNT3A and FGF2 induced DE cells showed highest expression of insulin, are closely aligned in gene expression patterning and have a closer resemblance to pancreatic organogenesis. Conversely, BMP4 at DE induction gave most divergent differentiation dynamics with lowest insulin upregulation, but highest glucagon upregulation. Additionally, we have concluded that early analysis of PP markers is indicative of its potential for pancreatic maturation. PMID:24743345

  20. False Positivity of Non-Targeted Infections in Malaria Rapid Diagnostic Tests: The Case of Human African Trypanosomiasis

    PubMed Central

    Gillet, Philippe; Mumba Ngoyi, Dieudonné; Lukuka, Albert; Kande, Viktor; Atua, Benjamin; van Griensven, Johan; Muyembe, Jean-Jacques; Jacobs, Jan; Lejon, Veerle

    2013-01-01

    Background In endemic settings, diagnosis of malaria increasingly relies on the use of rapid diagnostic tests (RDTs). False positivity of such RDTs is poorly documented, although it is especially relevant in those infections that resemble malaria, such as human African trypanosomiasis (HAT). We therefore examined specificity of malaria RDT products among patients infected with Trypanosoma brucei gambiense. Methodology/Principal Findings Blood samples of 117 HAT patients and 117 matched non-HAT controls were prospectively collected in the Democratic Republic of the Congo. Reference malaria diagnosis was based on real-time PCR. Ten commonly used malaria RDT products were assessed including three two-band and seven three-band products, targeting HRP-2, Pf-pLDH and/or pan-pLDH antigens. Rheumatoid factor was determined in PCR negative subjects. Specificity of the 10 malaria RDT products varied between 79.5 and 100% in HAT-negative controls and between 11.3 and 98.8% in HAT patients. For seven RDT products, specificity was significantly lower in HAT patients compared to controls. False positive reactions in HAT were mainly observed for pan-pLDH test lines (specificities between 13.8 and 97.5%), but also occurred frequently for the HRP-2 test line (specificities between 67.9 and 98.8%). The Pf-pLDH test line was not affected by false-positive lines in HAT patients (specificities between 97.5 and 100%). False positivity was not associated to rheumatoid factor, detected in 7.6% of controls and 1.2% of HAT patients. Conclusions/Significance Specificity of some malaria RDT products in HAT was surprisingly low, and constitutes a risk for misdiagnosis of a fatal but treatable infection. Our results show the importance to assess RDT specificity in non-targeted infections when evaluating diagnostic tests. PMID:23638201

  1. In Silico Identification of a Candidate Synthetic Peptide (Tsgf118–43) to Monitor Human Exposure to Tsetse Flies in West Africa

    PubMed Central

    Dama, Emilie; Cornelie, Sylvie; Camara, Mamadou; Somda, Martin Bienvenu; Poinsignon, Anne; Ilboudo, Hamidou; Elanga Ndille, Emmanuel; Jamonneau, Vincent; Solano, Philippe; Remoue, Franck; Bengaly, Zakaria; Belem, Adrien Marie Gaston; Bucheton, Bruno

    2013-01-01

    Background The analysis of humoral responses directed against the saliva of blood-sucking arthropods was shown to provide epidemiological biomarkers of human exposure to vector-borne diseases. However, the use of whole saliva as antigen presents several limitations such as problems of mass production, reproducibility and specificity. The aim of this study was to design a specific biomarker of exposure to tsetse flies based on the in silico analysis of three Glossina salivary proteins (Ada, Ag5 and Tsgf1) previously shown to be specifically recognized by plasma from exposed individuals. Methodology/Principal Findings Synthetic peptides were designed by combining several linear epitope prediction methods and Blast analysis. The most specific peptides were then tested by indirect ELISA on a bank of 160 plasma samples from tsetse infested areas and tsetse free areas. Anti-Tsgf118–43 specific IgG levels were low in all three control populations (from rural Africa, urban Africa and Europe) and were significantly higher (p<0.0001) in the two populations exposed to tsetse flies (Guinean HAT foci, and South West Burkina Faso). A positive correlation was also found between Anti-Tsgf118–43 IgG levels and the risk of being infected by Trypanosoma brucei gambiense in the sleeping sickness foci of Guinea. Conclusion/Significance The Tsgf118–43 peptide is a suitable and promising candidate to develop a standardize immunoassay allowing large scale monitoring of human exposure to tsetse flies in West Africa. This could provide a new surveillance indicator for tsetse control interventions by HAT control programs. PMID:24086785

  2. FGF21 and the late adaptive response to starvation in humans.

    PubMed

    Fazeli, Pouneh K; Lun, Mingyue; Kim, Soo M; Bredella, Miriam A; Wright, Spenser; Zhang, Yang; Lee, Hang; Catana, Ciprian; Klibanski, Anne; Patwari, Parth; Steinhauser, Matthew L

    2015-11-03

    In mice, FGF21 is rapidly induced by fasting, mediates critical aspects of the adaptive starvation response, and displays a number of positive metabolic properties when administered pharmacologically. In humans, however, fasting does not consistently increase FGF21, suggesting a possible evolutionary divergence in FGF21 function. Moreover, many key aspects of FGF21 function in mice have been identified in the context of transgenic overexpression or administration of supraphysiologic doses, rather than in a physiologic setting. Here, we explored the dynamics and function of FGF21 in human volunteers during a 10-day fast. Unlike mice, which show an increase in circulating FGF21 after only 6 hours, human subjects did not have a notable surge in FGF21 until 7 to 10 days of fasting. Moreover, we determined that FGF21 induction was associated with decreased thermogenesis and adiponectin, an observation that directly contrasts with previous reports based on supraphysiologic dosing. Additionally, FGF21 levels increased after ketone induction, demonstrating that endogenous FGF21 does not drive starvation-mediated ketogenesis in humans. Instead, a longitudinal analysis of biologically relevant variables identified serum transaminases--markers of tissue breakdown--as predictors of FGF21. These data establish FGF21 as a fasting-induced hormone in humans and indicate that FGF21 contributes to the late stages of adaptive starvation, when it may regulate the utilization of fuel derived from tissue breakdown.

  3. FGF21 and the late adaptive response to starvation in humans

    PubMed Central

    Fazeli, Pouneh K.; Lun, Mingyue; Kim, Soo M.; Bredella, Miriam A.; Wright, Spenser; Zhang, Yang; Lee, Hang; Catana, Ciprian; Klibanski, Anne; Patwari, Parth; Steinhauser, Matthew L.

    2015-01-01

    In mice, FGF21 is rapidly induced by fasting, mediates critical aspects of the adaptive starvation response, and displays a number of positive metabolic properties when administered pharmacologically. In humans, however, fasting does not consistently increase FGF21, suggesting a possible evolutionary divergence in FGF21 function. Moreover, many key aspects of FGF21 function in mice have been identified in the context of transgenic overexpression or administration of supraphysiologic doses, rather than in a physiologic setting. Here, we explored the dynamics and function of FGF21 in human volunteers during a 10-day fast. Unlike mice, which show an increase in circulating FGF21 after only 6 hours, human subjects did not have a notable surge in FGF21 until 7 to 10 days of fasting. Moreover, we determined that FGF21 induction was associated with decreased thermogenesis and adiponectin, an observation that directly contrasts with previous reports based on supraphysiologic dosing. Additionally, FGF21 levels increased after ketone induction, demonstrating that endogenous FGF21 does not drive starvation-mediated ketogenesis in humans. Instead, a longitudinal analysis of biologically relevant variables identified serum transaminases — markers of tissue breakdown — as predictors of FGF21. These data establish FGF21 as a fasting-induced hormone in humans and indicate that FGF21 contributes to the late stages of adaptive starvation, when it may regulate the utilization of fuel derived from tissue breakdown. PMID:26529252

  4. Data in support of transcriptional regulation and function of Fas-antisense long noncoding RNA during human erythropoiesis

    PubMed Central

    Villamizar, Olga; Chambers, Christopher B.; Mo, Yin-Yuan; Torry, Donald S.; Hofstrand, Reese; Riberdy, Janice M.; Persons, Derek A.; Wilber, Andrew

    2016-01-01

    This paper describes data related to a research article titled, “Fas-antisense long noncoding RNA is differentially expressed during maturation of human erythrocytes and confers resistance to Fas-mediated cell death” [1]. Long noncoding RNAs (lncRNAs) are increasingly appreciated for their capacity to regulate many steps of gene expression. While recent studies suggest that many lncRNAs are functional, the scope of their actions throughout human biology is largely undefined including human red blood cell development (erythropoiesis). Here we include expression data for 82 lncRNAs during early, intermediate and late stages of human erythropoiesis using a commercial qPCR Array. From these data, we identified lncRNA Fas-antisense 1 (Fas-AS1 or Saf) described in the research article. Also included are 5′ untranslated sequences (UTR) for lncRNA Saf with transcription factor target sequences identified. Quantitative RT-PCR data demonstrate relative levels of critical erythroid transcription factors, GATA-1 and KLF1, in K562 human erythroleukemia cells and maturing erythroblasts derived from human CD34+ cells. End point and quantitative RT-PCR data for cDNA prepared using random hexamers versus oligo(dT)18 revealed that lncRNA Saf is not effectively polyadenylated. Finally, we include flow cytometry histograms demonstrating Fas levels on maturing erythroblasts derived from human CD34+ cells transduced using mock conditions or with lentivirus particles encoding for Saf. PMID:27141526

  5. RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

    PubMed Central

    Goulidaki, Nektaria; Alarifi, Saud; Alkahtani, Saad H; Al-Qahtani, Ahmed; Spandidos, Demetrios A; Stournaras, Christos; Sourvinos, George

    2015-01-01

    Human Cytomegalovirus (HCMV), an ubiquitous β-herpesvirus, is a significant pathogen that causes medically severe diseases in immunocompromised individuals and in congenitally infected neonates. RhoB belongs to the family of Rho GTPases, which regulates diverse cellular processes. Rho proteins are implicated in the entry and egress from the host cell of mainly α- and γ-herpesviruses, whereas β-herpesviruses are the least studied in this regard. Here, we studied the role of RhoB GTPase during HCMV lytic infection. Microscopy analysis, both in fixed and live infected cells showed that RhoB was translocated to the assembly complex/compartment (AC) of HCMV, a cytoplasmic zone in infected cells where many viral structural proteins are known to accumulate and assembly of new virions takes place. Furthermore, RhoB was localized at the AC even when the expression of the late HCMV AC proteins was inhibited. At the very late stages of infection, cellular projections were formed containing RhoB and HCMV virions, potentially contributing to the successful viral spread. Interestingly, the knockdown of RhoB in HCMV-infected cells resulted in a significant reduction of the virus titer and could also affect the accumulation of AC viral proteins at this subcellular compartment. RhoB knockdown also affected actin fibers' structure. Actin reorganization was observed at late stages of infection originating from the viral AC and surrounding the cellular projections, implying a potential interplay between RhoB and actin during HCMV assembly and egress. In conclusion, our results demonstrate for the first time that RhoB is a constituent of the viral AC and is required for HCMV productive infection. PMID:26114383

  6. High-performance beating pattern function of human induced pluripotent stem cell-derived cardiomyocyte-based biosensors for hERG inhibition recognition.

    PubMed

    Hu, Ning; Wang, Tianxing; Wang, Qin; Zhou, Jie; Zou, Ling; Su, Kaiqi; Wu, Jieying; Wang, Ping

    2015-05-15

    High-throughput and high clinical relevance methods are demanded to predict the drug-induced cardiotoxicity in pharmaceutical and biotechnology industries to effectively decrease late-stage drug attrition. In this study, human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were integrated into an interdigital impedance sensor array to fabricate a high performance iPSC-CM-based biosensor array with high-throughput and high-consistency beating pattern. Typical withdrawal approved drugs (astemizole, sertindole, cisapride, and droperidol) with hERG inhibition and positive control E-4031 were employed to determine the beating pattern function. From the results, it can be concluded that this iPSC-CM-based biosensor array can specifically differentiate the hERG inhibitors from the non-hERG inhibition compounds through beating pattern function. PMID:25153933

  7. Different roles of GNAS and cAMP signaling during early and late stages of osteogenic differentiation.

    PubMed

    Zhang, S; Kaplan, F S; Shore, E M

    2012-09-01

    Progressive osseous heteroplasia (POH) and fibrous dysplasia (FD) are genetic diseases of bone formation at opposite ends of the osteogenic spectrum: imperfect osteogenesis of the skeleton occurs in FD, while heterotopic ossification in skin, subcutaneous fat, and skeletal muscle forms in POH. POH is caused by heterozygous inactivating germline mutations in GNAS, which encodes G-protein subunits regulating the cAMP pathway, while FD is caused by GNAS somatic activating mutations. We used pluripotent mouse ES cells to examine the effects of Gnas dysregulation on osteoblast differentiation. At the earliest stages of osteogenesis, Gnas transcripts Gsα, XLαs and 1A are expressed at low levels and cAMP levels are also low. Inhibition of cAMP signaling (as in POH) by 2',5'-dideoxyadenosine enhanced osteoblast differentiation while conversely, increased cAMP signaling (as in FD), induced by forskolin, inhibited osteoblast differentiation. Notably, increased cAMP was inhibitory for osteogenesis only at early stages after osteogenic induction. Expression of osteogenic and adipogenic markers showed that increased cAMP enhanced adipogenesis and impaired osteoblast differentiation even in the presence of osteogenic factors, supporting cAMP as a critical regulator of osteoblast and adipocyte lineage commitment. Furthermore, increased cAMP signaling decreased BMP pathway signaling, indicating that G protein-cAMP pathway activation (as in FD) inhibits osteoblast differentiation, at least in part by blocking the BMP-Smad pathway, and suggesting that GNAS inactivation as occurs in POH enhances osteoblast differentiation, at least in part by stimulating BMP signaling. These data support that differences in cAMP levels during early stages of cell differentiation regulate cell fate decisions. Supporting information available online at http:/www.thieme-connect.de/ejournals/toc/hmr. PMID:22903279

  8. Targeted disruption of the LAMA3 gene in mice reveals abnormalities in survival and late stage differentiation of epithelial cells.

    PubMed

    Ryan, M C; Lee, K; Miyashita, Y; Carter, W G

    1999-06-14

    Laminin 5 regulates anchorage and motility of epithelial cells through integrins alpha6beta4 and alpha3beta1, respectively. We used targeted disruption of the LAMA3 gene, which encodes the alpha3 subunit of laminin 5 and other isoforms, to examine developmental functions that are regulated by adhesion to the basement membrane (BM). In homozygous null animals, profound epithelial abnormalities were detected that resulted in neonatal lethality, consistent with removal of all alpha3-laminin isoforms from epithelial BMs. Alterations in three different cellular functions were identified. First, using a novel tissue adhesion assay, we found that the mutant BM could not induce stable adhesion by integrin alpha6beta4, consistent with the presence of junctional blisters and abnormal hemidesmosomes. In the absence of laminin 5 function, we were able to detect a new ligand for integrin alpha3beta1 in the epidermal BM, suggesting that basal keratinocytes can utilize integrin alpha3beta1 to interact with an alternative ligand. Second, we identified a survival defect in mutant epithelial cells that could be rescued by exogenous laminin 5, collagen, or an antibody against integrin alpha6beta4, suggesting that signaling through beta1 or beta4 integrins is sufficient for survival. Third, we detected abnormalities in ameloblast differentiation in developing mutant incisors indicating that events downstream of adhesion are affected in mutant animals. These results indicate that laminin 5 has an important role in regulating tissue organization, gene expression, and survival of epithelium. PMID:10366601

  9. A specific CBP/p300-dependent gene expression programme drives the metabolic remodelling in late stages of spermatogenesis.

    PubMed

    Boussouar, F; Goudarzi, A; Buchou, T; Shiota, H; Barral, S; Debernardi, A; Guardiola, P; Brindle, P; Martinez, G; Arnoult, C; Khochbin, S; Rousseaux, S

    2014-05-01

    Histone hyperacetylation is thought to drive the replacement of histones by transition proteins that occur in elongating spermatids (ElS) after a general shut down of transcription. The molecular machineries underlying this histone hyperacetylation remain still undefined. Here, we focused our attention on the role of Cbp and p300 in histone hyperacetylation and in the preceding late-gene transcriptional activity in ElS. A strategy was designed to partially deplete Cbp and p300 in ElS. These cells progressed normally through spermiogenesis and showed normal histone hyperacetylation and removal. However, a genome-wide transcriptomic analysis, performed in the round spermatids (RS) and ElS, revealed the existence of a gene regulatory circuit encompassing genes presenting high expression levels in pre-meiotic cells, undergoing a repressed state in spermatocytes and early post-meiotic cells, but becoming reactivated in ElS, just prior to the global shutdown of transcription. Interestingly, this group of genes was over-represented within the genes affected by Cbp/p300 knock down and were all involved in metabolic remodelling. This study revealed the occurrence of a tightly regulated Cbp/p300-dependent gene expression programme that drives a specific metabolic state both in progenitor spermatogenic cells and in late transcriptionally active spermatids and confirmed a special link between Cpb/p300 and cell metabolism programming previously shown in somatic cells.

  10. Minor non-carbonate authigenic components as indicators of late-stage diagenetic processes in the Smackover limestones

    SciTech Connect

    Denham, M.E. Jr.

    1992-01-01

    Variations in mineralogy and composition of late authigenic sulfur-bearing minerals in upper Smackover limestones recorded diagenetic events associated with hydrocarbon migration. This suite of minerals occurs in samples taken from 18 subsurface cores of the upper Smackover from northern Louisiana and southern Arkansas. Spatial variations in cadmium concentration of sphalerite, Ba concentration of celestite, and the [sigma][sup 34]S values of galena and sphalerite suggest that fluids associated with hydrocarbons in the lower Smackover migrated into the upper Smackover along faults at the Louisiana-Arkansas border. A second generation of sulfide mineralization and a [sigma][sup 34]S = +10.8[per thousand] CDT of a wurtzite-sphalerite mixture suggests that thermochemical sulfate reduction occurred after hydrocarbon migration resulting in the formation of the [open quotes]sour gas belt.[close quotes] Uranium concentration, as revealed by fission track imaging and instrumental neutron activation analyses, varies on a microscopic and regional scale in the upper Smackover limestones. Uranium is locally concentrated in stylolites and fine grained opaque material. Comparison of uranium and thorium concentrations in stylolites suggests these elements are insoluble residue of the pressure solution process. Regionally, uranium concentration varies with clay content of the host limestone indicating that sorption plays a major role in the geochemical behavior of uranium in the subsurface. Comparison of U/Th ratios of upper Smackover limestones to those of black shales from the Gray Sands tentatively suggests that uranium was redistributed from hydrocarbon source rocks to reservoir rocks. However, better understanding of the association of uranium with organic-rich rocks and the role of sorption are required before uranium can be used reliably as a pore fluid tracer.

  11. The role of the amygdala during emotional processing in Huntington's disease: From pre-manifest to late stage disease

    PubMed Central

    Mason, Sarah L.; Zhang, Jiaxiang; Begeti, Faye; Guzman, Natalie Valle; Lazar, Alpar S.; Rowe, James B.; Barker, Roger A.; Hampshire, Adam

    2015-01-01

    Background Deficits in emotional processing can be detected in the pre-manifest stage of Huntington's disease and negative emotion recognition has been identified as a predictor of clinical diagnosis. The underlying neuropathological correlates of such deficits are typically established using correlative structural MRI studies. This approach does not take into consideration the impact of disruption to the complex interactions between multiple brain circuits on emotional processing. Therefore, exploration of the neural substrates of emotional processing in pre-manifest HD using fMRI connectivity analysis may be a useful way of evaluating the way brain regions interrelate in the period prior to diagnosis. Methods We investigated the impact of predicted time to disease onset on brain activation when participants were exposed to pictures of faces with angry and neutral expressions, in 20 pre-manifest HD gene carriers and 23 healthy controls. On the basis of the results of this initial study went on to look at amygdala dependent cognitive performance in 79 Huntington's disease patients from a cross-section of disease stages (pre-manifest to late disease) and 26 healthy controls, using a validated theory of mind task: “the Reading the Mind in the Eyes Test” which has been previously been shown to be amygdala dependent. Results Psychophysiological interaction analysis identified reduced connectivity between the left amygdala and right fusiform facial area in pre-manifest HD gene carriers compared to controls when viewing angry compared to neutral faces. Change in PPI connectivity scores correlated with predicted time to disease onset (r=0.45, p<0.05). Furthermore, performance on the “Reading the Mind in the Eyes Test” correlated negatively with proximity to disease onset and became progressively worse with each stage of disease. Conclusion Abnormalities in the neural networks underlying social cognition and emotional processing can be detected prior to clinical diagnosis in Huntington's disease. Connectivity between the amygdala and other brain regions is impacted by the disease process in pre-manifest HD and may therefore be a useful way of identifying participants who are approaching a clinical diagnosis. Furthermore, the “Reading the Mind in the Eyes Test” is a surrogate measure of amygdala function that is clinically useful across the entire cross-section of disease stages in HD. PMID:25700742

  12. Developmental genes significantly afflicted by aberrant promoter methylation and somatic mutation predict overall survival of late-stage colorectal cancer

    PubMed Central

    An, Ning; Yang, Xue; Cheng, Shujun; Wang, Guiqi; Zhang, Kaitai

    2015-01-01

    Carcinogenesis is an exceedingly complicated process, which involves multi-level dysregulations, including genomics (majorly caused by somatic mutation and copy number variation), DNA methylomics, and transcriptomics. Therefore, only looking into one molecular level of cancer is not sufficient to uncover the intricate underlying mechanisms. With the abundant resources of public available data in the Cancer Genome Atlas (TCGA) database, an integrative strategy was conducted to systematically analyze the aberrant patterns of colorectal cancer on the basis of DNA copy number, promoter methylation, somatic mutation and gene expression. In this study, paired samples in each genomic level were retrieved to identify differentially expressed genes with corresponding genetic or epigenetic dysregulations. Notably, the result of gene ontology enrichment analysis indicated that the differentially expressed genes with corresponding aberrant promoter methylation or somatic mutation were both functionally concentrated upon developmental process, suggesting the intimate association between development and carcinogenesis. Thus, by means of random walk with restart, 37 significant development-related genes were retrieved from a priori-knowledge based biological network. In five independent microarray datasets, Kaplan–Meier survival and Cox regression analyses both confirmed that the expression of these genes was significantly associated with overall survival of Stage III/IV colorectal cancer patients. PMID:26691761

  13. Late stages of T cell maturation in the thymus involve NF-κB and tonic type I interferon signaling.

    PubMed

    Xing, Yan; Wang, Xiaodan; Jameson, Stephen C; Hogquist, Kristin A

    2016-05-01

    Positive selection occurs in the thymic cortex, but critical maturation events occur later in the medulla. Here we defined the precise stage at which T cells acquired competence to proliferate and emigrate. Transcriptome analysis of late gene changes suggested roles for the transcription factor NF-κB and interferon signaling. Mice lacking the inhibitor of NF-κB (IκB) kinase (IKK) kinase TAK1 underwent normal positive selection but exhibited a specific block in functional maturation. NF-κB signaling provided protection from death mediated by the cytokine TNF and was required for proliferation and emigration. The interferon signature was independent of NF-κB; however, thymocytes deficient in the interferon-α (IFN-α) receptor IFN-αR showed reduced expression of the transcription factor STAT1 and phenotypic abnormality but were able to proliferate. Thus, both NF-κB and tonic interferon signals are involved in the final maturation of thymocytes into naive T cells. PMID:27043411

  14. Late-Stage Refocusing of Irish-Language Programme Evaluation: Maximizing the Potential for Productive Debate and Remediation

    ERIC Educational Resources Information Center

    Harris, John

    2009-01-01

    The teaching and learning of Irish in primary school is both an important educational issue and central to the national language revitalization effort. The findings of Irish-language programme evaluations, therefore, are invariably scrutinized very closely by different sectors. This paper examines how the later stages of a major evaluation took…

  15. Late-stage stretching and subsidence rates in the Danakil Depression, evidenced from borehole records and seismic reflection data

    NASA Astrophysics Data System (ADS)

    Booth, Adam; Bastow, Ian; Magee, Craig; Keir, Derek; Corti, Giacomo; Jackson, Chris; Wilkinson, Jason

    2016-04-01

    The Ethiopian and Afar Rift systems provide a globally unique opportunity to study the incipient transition from continental rifting to sea-floor spreading. A consensus has emerged that a considerable proportion of plate extension in Ethiopia is accommodated by dyke intrusion, with smaller contributions from crustal thinning. However, observations of thinned crust and a pulse in Quaternary-Recent basaltic volcanism within Ethiopia's Danakil Depression have been cited (Bastow and Keir, 2011) as evidence that localised plate stretching may mark the final stages of continent-ocean transition. We explore this hypothesis using an archive of five 2-D seismic reflection profiles, each between 7-10 km in length, and ˜120 borehole records distributed over an area of 225 km2. From depth and age relationships of key marker horizons, we also suggest local subsidence and extension rates. The borehole archive reveals extensive evaporite sequences deposited in and around an asymmetric basin, bounded to the west by a network of east-dipping normal faults. West of the basin, the maximum observed thickness of evaporites is 150 m, beneath which are deposits of clastic sediment, but a sequence of evaporites at least 900 m thick is observed at the basin centre. The sedimentary architecture of these sequences suggests deposition in a shallow salt-pan environment, with seasonal - potentially diurnal - freshening of the brine supply (Warren, 2012). Isotopic analysis of reef carbonates in the basin flank dates the last marine incursion into the Danakil Depression at 24-230ka (Lalou et al., 1970; Bonatti et al., 1971; Bannert et al., 1971), therefore the evaporite sequence must be younger than this. A key marker horizon within the evaporites is the potash-bearing Houston Formation, also distinct in borehole records given its high porosity (25-40%) and radioactivity (50-250 API units). The elevation of the Houston Formation is ˜500 m deeper in the centre of the basin than on the flank. This depth change corresponds to a plausible vertical subsidence rate of between 2-20 mma-1 and, assuming a 60° fault dip, a horizontal extension rate of 1-12 mma-1 during the deposition of the Houston Formation, consistent with recent geodetic constraints offered by Ar Rajehi et al. (2010). The borehole archive shows no evidence of significant magmatism anywhere in the survey area, and the characteristic reflectivity of igneous bodies is absent in the seismic data. Extension of this basin is, therefore, not obviously explained by dyke intrusion. We consider that the ˜500 m change in elevation of the Houston Formation is instead diagnostic of rapid stretching, possibly indicating a late period of non-magmatic extension in the transition to sea-floor spreading in the Danakil Depression.

  16. Late Stage of Corneal Decompensation Caused by Progressive Keratoconus: Can We Treat It and Save the Cornea?

    PubMed

    Knezović, Igor; Belovari Višnjić, Mirna; Raguž, Hrvoje

    2015-01-01

    Aim. To report a case of 40-year-old male with progressive bilateral keratoconus who had undergone transepithelial phototherapeutic keratectomy (TE-PTK) and corneal collagen cross-linking (CXL) using hypoosmolar riboflavin solution in a same day procedure. Methods. Eye examination showed that UCDVA on both eyes was 0,01 according to Snellen charts, and slit lamp biomicroscopy showed paracentral diffuse intrastromal corneal haze. Anterior OCT marked stromal hyperreflective zones and localized paracentral thinning of the cornea. Scheimpflug tomography noted keratoconus stages III-IV on both eyes. After 40/35 microns TE-PTK, a CXL was performed for 30 minutes using hypoosmolar riboflavin solution. The left eye was treated first and the right eye 1 month after. Follow-up period was 10 months. Results. One month after the treatment both eyes showed improvement in corneal topography and the UCDVA was better. Eight months after the treatment BSCVA improved to 0,6 in both eyes using Rose K2 contact lenses and remained stable. Conclusion. TE-PTK and CXL using hypotonic riboflavin solution as a same day procedure have been shown to be a safe and promising method in this case of progressive keratoconus. It was necessary to consider certain parameters that could influence the safety and the final outcome of this combined protocol. PMID:26064737

  17. Scoping assessments of ATF impact on late-stage accident progression including molten core-concrete interaction

    NASA Astrophysics Data System (ADS)

    Farmer, M. T.; Leibowitz, L.; Terrani, K. A.; Robb, K. R.

    2014-05-01

    Simple scoping models that can be used to evaluate ATF performance under severe accident conditions have been developed. The methodology provides a fundamental technical basis (a.k.a. metric) based on the thermodynamic boundary for evaluating performance relative to that of traditional Zr-based claddings. The initial focus in this study was on UO2 fuel with the advanced claddings 310 SS, D9, FeCrAl, and SiC. The evaluation considered only energy release with concurrent combustible gas production from fuel-cladding-coolant interactions and, separately, molten core-concrete interactions at high temperatures. Other important phenomenological effects that can influence the rate and extent of cladding decomposition (e.g., eutectic interactions, degradation of other core constituents) were not addressed. For the cladding types addressed, potential combustible gas production under both in-vessel and ex-vessel conditions was similar to that for Zr. However, exothermic energy release from cladding oxidation was substantially less for iron-based alloys (by at least a factor of 4), and modestly less (by ∼20%) for SiC. Data on SiC-clad UO2 fuel performance under severe accident conditions are sparse in the literature; thus, assumptions on the nature of the cladding decomposition process were made in order to perform this initial screening evaluation. Experimental data for this system under severe accident conditions is needed for a proper evaluation and comparison to iron-based claddings.

  18. Late-stage exhumation of metamorphic core complexes and landscape development during orogenic collapse of the North American Cordillera

    NASA Astrophysics Data System (ADS)

    Tokombayev, Askhat

    Renewable portfolio standards prescribe for penetration of high amounts of renewable energy sources (RES) that may change the structure of existing power systems. The load growth and changes in power flow caused by RES integration may result in requirements of new available transmission capabilities and upgrades of existing transmission paths. Construction difficulties of new transmission lines can become a problem in certain locations. The increase of transmission line thermal ratings by reconductoring using High Temperature Low Sag (HTLS) conductors is a comparatively new technology introduced to transmission expansion. A special design permits HTLS conductors to operate at high temperatures (e.g., 200°C), thereby allowing passage of higher current. The higher temperature capability increases the steady state and emergency thermal ratings of the transmission line. The main disadvantage of HTLS technology is high cost. The high cost may place special emphasis on a thorough analysis of cost to benefit of HTLS technology implementation. Increased transmission losses in HTLS conductors due to higher current may be a disadvantage that can reduce the attractiveness of this method. Studies described in this thesis evaluate the expenditures for transmission line reconductoring using HTLS and the consequent benefits obtained from the potential decrease in operating cost for thermally limited transmission systems. Studies performed consider the load growth and penetration of distributed renewable energy sources according to the renewable portfolio standards for power systems. An evaluation of payback period is suggested to assess the cost to benefit ratio of HTLS upgrades. The thesis also considers the probabilistic nature of transmission upgrades. The well-known Chebyshev inequality is discussed with an application to transmission upgrades. The Chebyshev inequality is proposed to calculate minimum payback period obtained from the upgrades of certain transmission lines. The cost to benefit evaluation of HTLS upgrades is performed using a 225 bus equivalent of the 2012 summer peak Arizona portion of the Western Electricity Coordinating Council (WECC).

  19. Quantification of microvascular cerebral blood flux and late-stage tumor compartmentalization in 9L gliosarcoma using flow enhanced MRI.

    PubMed

    Reynaud, Olivier; Geffroy, Françoise; Ciobanu, Luisa

    2013-06-01

    Measurements of tumor microvasculature are important to obtain an understanding of tumor angiogenesis and for the evaluation of therapies. In this work, we characterize the evolution of the microvascular flux at different stages of tumor growth in the 9L rat brain tumor model. The absolute quantification of cerebral blood flux is achieved with MRI at 7 T using the flow enhanced signal intensity (FENSI) method. FENSI flux maps were obtained between 5 and 14 days after glioma cell inoculation. Based on cerebral blood flux maps, we highlighted two main stages of tumor growth, below and above 3 mm, presenting distinct flux patterns and vascular properties. No significant difference emerged from the group analysis performed on the data collected at an early developmental stage (tumor size < 3 mm) when compared with healthy tissue. At a late developmental stage (tumor size > 3 mm), we observed a significant decrease in the cerebral blood flux inside the gliosarcoma (-33%, p < 0.01) and compartmentalization of the tumor (p < 0.05). FENSI flux maps delineated a low-flux tumor core (58 ± 17 μL/min/cm(2) ) and higher vascularized regions around the tumor periphery (85 ± 21 μL/min/cm(2) ). Histology was performed on 11 animals to finely probe the intratumor heterogeneity and microvessel density, and the results were compared with the information derived from FENSI flux maps. The hyper- and hypoperfused tumor regions revealed with FENSI at the late tumor developmental stage correlated well with the ratios of high and low blood vessel density (R(2) = 0.41) and fractional vascular surface (R(2) = 0.67) observed with fluorescence microscopy [cluster of differentiation 31 (CD31) staining].

  20. Late stages of T cell maturation in the thymus involve NF-κB and tonic type I interferon signaling.

    PubMed

    Xing, Yan; Wang, Xiaodan; Jameson, Stephen C; Hogquist, Kristin A

    2016-05-01

    Positive selection occurs in the thymic cortex, but critical maturation events occur later in the medulla. Here we defined the precise stage at which T cells acquired competence to proliferate and emigrate. Transcriptome analysis of late gene changes suggested roles for the transcription factor NF-κB and interferon signaling. Mice lacking the inhibitor of NF-κB (IκB) kinase (IKK) kinase TAK1 underwent normal positive selection but exhibited a specific block in functional maturation. NF-κB signaling provided protection from death mediated by the cytokine TNF and was required for proliferation and emigration. The interferon signature was independent of NF-κB; however, thymocytes deficient in the interferon-α (IFN-α) receptor IFN-αR showed reduced expression of the transcription factor STAT1 and phenotypic abnormality but were able to proliferate. Thus, both NF-κB and tonic interferon signals are involved in the final maturation of thymocytes into naive T cells.

  1. RNA Oxidation Adducts 8-OHG and 8-OHA Change with Aβ42 Levels in Late-Stage Alzheimer's Disease

    PubMed Central

    Niedowicz, Dana M.; Dowling, Amy L. S.; Matveev, Sergey V.; LeVine, Harry; Lovell, Mark A.; Murphy, M. Paul

    2011-01-01

    While research supports amyloid-β (Aβ) as the etiologic agent of Alzheimer's disease (AD), the mechanism of action remains unclear. Evidence indicates that adducts of RNA caused by oxidation also represent an early phenomenon in AD. It is currently unknown what type of influence these two observations have on each other, if any. We quantified five RNA adducts by gas chromatography/mass spectroscopy across five brain regions from AD cases and age-matched controls. We then used a reductive directed analysis to compare the RNA adducts to common indices of AD neuropathology and various pools of Aβ. Using data from four disease-affected brain regions (Brodmann's Area 9, hippocampus, inferior parietal lobule, and the superior and middle temporal gyri), we found that the RNA adduct 8-hydroxyguanine (8-OHG) decreased, while 8-hydroxyadenine (8-OHA) increased in AD. The cerebellum, which is generally spared in AD, did not show disease related changes, and no RNA adducts correlated with the number of plaques or tangles. Multiple regression analysis revealed that SDS-soluble Aβ42 was the best predictor of changes in 8-OHG, while formic acid-soluble Aβ42 was the best predictor of changes in 8-OHA. This study indicates that although there is a connection between AD related neuropathology and RNA oxidation, this relationship is not straightforward. PMID:21949792

  2. Management of early- and late-stage rheumatoid arthritis: are physiotherapy students' intended behaviours consistent with canadian best practice guidelines?

    PubMed

    Macintyre, Norma J; Lineker, Sydney C; Hallett, Christina; Tumber, Jake; Fernando, Nalin; Hul, Magdalena

    2012-01-01

    Objectif : Avec cette étude, on souhaitait voir si les étudiants en physiothérapie, dans le cadre de cours qui font appel à une méthode d'apprentissage axée sur les problèmes, tentaient de mettre en pratique les pratiques exemplaires pour la gestion des clients aux prises avec la polyarthrite rhumatoïde. Méthode : Des étudiants en physiothérapie (n=49) ont rempli une sous-section du sondage de l'ACREU sur les soins de santé primaires en vue d'évaluer la concordance entre les comportements recherchés et les pratiques exemplaires canadiennes pour les patients en stade précoce et avancé de polyarthrite rhumatoïde avant et après avoir complété le contenu de la formation axée sur les problèmes. Les variations dans les pointages obtenus ont été évaluées à l'aide du test de McNemar sur les proportions dépendantes. Résultats : La plupart des étudiants ont indiqué qu'ils recommanderaient des traitements ou une consultation en physiothérapie pour des exercices, de l'éducation et de l'ergothérapie ou une protection des articulations, avant et après leur apprentissage axé sur les problèmes (>83 % et >95 %, respectivement). Pour la polyarthrite en stade précoce ou avancé, plus d'étudiants ont recommandé une consultation auprès d'un rhumatologue et de DMARD (disease-modifying anti-rheumatic drugs ; médicaments antirhumatismaux) à la suite de leur formation ; toutefois, l'augmentation était considérable uniquement pour les cas de polyarthrite précoce (p=0,013 et 0,031 pour les consultations chez un rhumatologue et les DMARD, respectivement). Après leur formation, plus d'étudiants ont recommandé un soutien psychosocial aux deux stades de la maladie (PA précoce : p<0,001 ; PA avancée : p=0,031). Même si plus d'étudiants ont recommandé le recours à des DMARD après leur apprentissage axé sur les problèmes, 8 étudiants seulement ont formulé cette recommandation (16 %) et encore moins d'étudiants ont envisagé le recours à des anti-inflammatoires non stéroïdiens. La plupart des étudiants (94 %) n'ont pas recommandé une consultation par un chirurgien pour la PA précoce ou avancée. Conclusion : Les comportements recherchés chez les étudiants en physiothérapie étaient plus fidèles aux lignes directrices canadiennes sur les pratiques exemplaires pour la gestion de clients avec PR en stade précoce ou avancé une fois qu'ils avaient reçu la formation axée sur les problèmes. Des études supplémentaires seront nécessaires pour déterminer si les étudiants étaient moins bien informés des pratiques exemplaires touchant les interventions pharmacologiques et le renvoi en consultation chez les spécialistes appropriés, ou s'ils considèrent ces tâches comme étant hors de la portée de leur pratique.

  3. Late-stage optimization of a tercyclic class of S1P3-sparing, S1P1 receptor agonists.

    PubMed

    Horan, Joshua C; Kuzmich, Daniel; Liu, Pingrong; DiSalvo, Darren; Lord, John; Mao, Can; Hopkins, Tamara D; Yu, Hui; Harcken, Christian; Betageri, Raj; Hill-Drzewi, Melissa; Patenaude, Lori; Patel, Monica; Fletcher, Kimberly; Terenzzio, Donna; Linehan, Brian; Xia, Heather; Patel, Mita; Studwell, Debbie; Miller, Craig; Hickey, Eugene; Levin, Jeremy I; Smith, Dustin; Kemper, Raymond A; Modis, Louise K; Bannen, Lynne C; Chan, Diva S; Mac, Morrison B; Ng, Stephanie; Wang, Yong; Xu, Wei; Lemieux, René M

    2016-01-15

    Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders. PMID:26687487

  4. Biphasic Alteration of the Inhibitory Synapse Scaffold Protein Gephyrin in Early and Late Stages of an Alzheimer Disease Model.

    PubMed

    Kiss, Eva; Gorgas, Karin; Schlicksupp, Andrea; Groß, Dagmar; Kins, Stefan; Kirsch, Joachim; Kuhse, Jochen

    2016-09-01

    The pathogenesis of Alzheimer disease (AD) is thought to begin many years before the diagnosis of dementia. Accumulating evidence indicates the involvement of GABAergic neurotransmission in the physiopathology of AD. However, in comparison to excitatory synapses, the structural and functional alterations of inhibitory synapses in AD are less well characterized. We studied the expression and distribution of proteins specific for inhibitory synapses in hippocampal areas of APPPS1 mice at different ages. Interestingly, by immunoblotting and confocal fluorescence microscopy, we disclosed a robust increase in the expression of gephyrin, an organizer of ligand-gated ion channels at inhibitory synapses in hippocampus CA1 and dentate gyrus of young presymptomatic APPPS1 mice (1 to 3 months) as compared to controls. The postsynaptic γ2-GABA(A)-receptor subunit and the presynaptic vesicular inhibitory amino acid transporter protein showed similar expression patterns. In contrast, adult transgenic animals (12 months) displayed decreased levels of these proteins in comparison to wild type in hippocampus areas devoid of amyloid plaques. Within most plaques, strong gephyrin immunoreactivity was detected, partially colocalizing with vesicular amino acid transporter and GABA(A)-receptor γ2 subunit immunoreactivities. Our results indicate a biphasic alteration in expression of hippocampal inhibitory synapse components in AD. Altered inhibition of neurotransmission might be an early prognostic marker and might even be involved in the pathogenesis of AD. PMID:27423698

  5. Improving Psychological Adjustment among Late-Stage Ovarian Cancer Patients: Examining the Role of Avoidance in Treatment

    ERIC Educational Resources Information Center

    Rost, Ann D.; Wilson, Kelly; Buchanan, Erin; Hildebrandt, Mikaela J.; Mutch, David

    2012-01-01

    Data suggest that individuals dealing with a cancer diagnosis are less likely to suffer from depression, anxiety, and psychological distress when they cope with their condition from a stance of emotional and cognitive acceptance (e.g. Dunkel, et al., 1992; Stanton, et al., 2000). Although traditional CBT often includes some acceptance-oriented…

  6. Effects of dietary lysine levels on plasma free amino acid profile in late-stage finishing pigs.

    PubMed

    Regmi, Naresh; Wang, Taiji; Crenshaw, Mark A; Rude, Brian J; Wu, Guoyao; Liao, Shengfa F

    2016-01-01

    Muscle growth requires a constant supply of amino acids (AAs) from the blood. Therefore, plasma AA profile is a critical factor for maximizing the growth performance of animals, including pigs. This research was conducted to study how dietary lysine intake affects plasma AA profile in pigs at the late production stage. Eighteen crossbred (Large White × Landrace) finishing pigs (nine barrows and nine gilts; initial BW 92.3 ± 6.9 kg) were individually penned in an environment controlled barn. Pigs were assigned randomly to one of the three dietary treatments according to a randomized complete block design with sex as block and pig as experiment unit (6 pigs/treatment). Three corn- and soybean meal-based diets contained 0.43 % (lysine-deficient, Diet I), 0.71 % (lysine-adequate, Diet II), and 0.98 % (lysine-excess, Diet III) l-lysine, respectively. After a 4-week period of feeding, jugular vein blood samples were collected from the pigs and plasma was obtained for AA analysis using established HPLC methods. The change of plasma lysine concentration followed the same pattern as that of dietary lysine supply. The plasma concentrations of threonine, histidine, phenylalanine, isoleucine, valine, arginine, and citrulline of pigs fed Diet II or III were lower (P < 0.05) than that of pigs fed Diet I. The plasma concentrations of alanine, glutamate, and glycine of pigs fed Diet II or III were higher (P < 0.05) than that of pigs fed Diet I. The change of plasma leucine and asparagine concentrations followed the patterns similar to that of plasma lysine. Among those affected AAs, arginine was decreased (P < 0.05) in the greatest proportion with the lysine-excess diet. We suggest that the skeletal muscle growth of finishing pigs may be further increased with a lysine-excess diet if the plasma concentration of arginine can be increased through dietary supplementation or other practical nutritional management strategies. PMID:27386336

  7. Pair Box 8 (PAX8) protein expression in high grade, late stage (stages III and IV) ovarian serous carcinoma

    PubMed Central

    Mhawech-Fauceglia, Paulette; Wang, Dan; Samrao, Damanzoopinder; Godoy, Heidi; Ough, Faith; Liu, Song; Pejovic, Tanja; Lele, Shashikant

    2016-01-01

    Objectives Pair-Box 8 (PAX8) is a transcription factor which has been found to be overexpressed in ovarian serous carcinoma (OSC). Silencing PAX8 by using shRNA led to a drop in cell viability in ovarian cancer cell lines, suggesting its use as a targeted therapeutic agent. The prognostic value of PAX8 in OSC is still widely unknown. The aim of this study was to evaluate PAX8 as a prognostic biomarker in patients with advanced stage OSC. Methods PAX8 was evaluated using immunohistochemistry on a tissue microarray of 148 OSC and the expression was correlated to the following clinico-pathologic variables; age of diagnosis, tumor stage, optimal debulking, recurrence free survival (RFS) and overall survival (OS). Results We found that PAX8 was expressed in 61% of cases. There was no association between PAX8 and tumor stage, optimal debulking and disease recurrence. In addition, PAX8 failed to have a predictive value in disease outcome. Conclusion Despite showing that PAX8 protein is not a useful predictive marker in patients with high grade, advanced stage OSC, its overexpression in a large number of these cases makes the inhibition of PAX8 a very attractive targeted therapy. PMID:22705448

  8. Late-stage stretching and subsidence rates in the Danakil Depression, evidenced from borehole records and seismic reflection data

    NASA Astrophysics Data System (ADS)

    Booth, Adam; Bastow, Ian; Magee, Craig; Keir, Derek; Corti, Giacomo; Jackson, Chris; Wilkinson, Jason

    2016-04-01

    The Ethiopian and Afar Rift systems provide a globally unique opportunity to study the incipient transition from continental rifting to sea-floor spreading. A consensus has emerged that a considerable proportion of plate extension in Ethiopia is accommodated by dyke intrusion, with smaller contributions from crustal thinning. However, observations of thinned crust and a pulse in Quaternary-Recent basaltic volcanism within Ethiopia's Danakil Depression have been cited (Bastow and Keir, 2011) as evidence that localised plate stretching may mark the final stages of continent-ocean transition. We explore this hypothesis using an archive of five 2-D seismic reflection profiles, each between 7-10 km in length, and ˜120 borehole records distributed over an area of 225 km2. From depth and age relationships of key marker horizons, we also suggest local subsidence and extension rates. The borehole archive reveals extensive evaporite sequences deposited in and around an asymmetric basin, bounded to the west by a network of east-dipping normal faults. West of the basin, the maximum observed thickness of evaporites is 150 m, beneath which are deposits of clastic sediment, but a sequence of evaporites at least 900 m thick is observed at the basin centre. The sedimentary architecture of these sequences suggests deposition in a shallow salt-pan environment, with seasonal - potentially diurnal - freshening of the brine supply (Warren, 2012). Isotopic analysis of reef carbonates in the basin flank dates the last marine incursion into the Danakil Depression at 24-230ka (Lalou et al., 1970; Bonatti et al., 1971; Bannert et al., 1971), therefore the evaporite sequence must be younger than this. A key marker horizon within the evaporites is the potash-bearing Houston Formation, also distinct in borehole records given its high porosity (25-40%) and radioactivity (50-250 API units). The elevation of the Houston Formation is ˜500 m deeper in the centre of the basin than on the flank. This depth change corresponds to a plausible vertical subsidence rate of between 2-20 mma‑1 and, assuming a 60° fault dip, a horizontal extension rate of 1-12 mma‑1 during the deposition of the Houston Formation, consistent with recent geodetic constraints offered by Ar Rajehi et al. (2010). The borehole archive shows no evidence of significant magmatism anywhere in the survey area, and the characteristic reflectivity of igneous bodies is absent in the seismic data. Extension of this basin is, therefore, not obviously explained by dyke intrusion. We consider that the ˜500 m change in elevation of the Houston Formation is instead diagnostic of rapid stretching, possibly indicating a late period of non-magmatic extension in the transition to sea-floor spreading in the Danakil Depression.

  9. microRNA Alterations Driving Acute and Late Stages of Radiation-Induced Fibrosis in a Murine Skin Model

    SciTech Connect

    Simone, Brittany A.; Ly, David; Savage, Jason E.; Hewitt, Stephen M.; Dan, Tu D.; Ylaya, Kris; Shankavaram, Uma; Lim, Meng; Jin, Lianjin; Camphausen, Kevin; Mitchell, James B.; Simone, Nicole L.

    2014-09-01

    Purpose: Although ionizing radiation is critical in treating cancer, radiation-induced fibrosis (RIF) can have a devastating impact on patients' quality of life. The molecular changes leading to radiation-induced fibrosis must be elucidated so that novel treatments can be designed. Methods and Materials: To determine whether microRNAs (miRs) could be responsible for RIF, the fibrotic process was induced in the right hind legs of 9-week old CH3 mice by a single-fraction dose of irradiation to 35 Gy, and the left leg served as an unirradiated control. Fibrosis was quantified by measurements of leg length compared with control leg length. By 120 days after irradiation, the irradiated legs were 20% (P=.013) shorter on average than were the control legs. Results: Tissue analysis was done on muscle, skin, and subcutaneous tissue from irradiated and control legs. Fibrosis was noted on both gross and histologic examination by use of a pentachrome stain. Microarrays were performed at various times after irradiation, including 7 days, 14 days, 50 days, 90 days, and 120 days after irradiation. miR-15a, miR-21, miR-30a, and miR-34a were the miRs with the most significant alteration by array with miR-34a, proving most significant on confirmation by reverse transcriptase polymerase chain reaction, c-Met, a known effector of fibrosis and downstream molecule of miR-34a, was evaluated by use of 2 cell lines: HCT116 and 1522. The cell lines were exposed to various stressors to induce miR changes, specifically ionizing radiation. Additionally, in vitro transfections with pre-miRs and anti-miRs confirmed the relationship of miR-34a and c-Met. Conclusions: Our data demonstrate an inverse relationship with miR-34a and c-Met; the upregulation of miR-34a in RIF causes inhibition of c-Met production. miRs may play a role in RIF; in particular, miR-34a should be investigated as a potential target to prevent or treat this devastating side effect of irradiation.

  10. Biphasic Alteration of the Inhibitory Synapse Scaffold Protein Gephyrin in Early and Late Stages of an Alzheimer Disease Model.

    PubMed

    Kiss, Eva; Gorgas, Karin; Schlicksupp, Andrea; Groß, Dagmar; Kins, Stefan; Kirsch, Joachim; Kuhse, Jochen

    2016-09-01

    The pathogenesis of Alzheimer disease (AD) is thought to begin many years before the diagnosis of dementia. Accumulating evidence indicates the involvement of GABAergic neurotransmission in the physiopathology of AD. However, in comparison to excitatory synapses, the structural and functional alterations of inhibitory synapses in AD are less well characterized. We studied the expression and distribution of proteins specific for inhibitory synapses in hippocampal areas of APPPS1 mice at different ages. Interestingly, by immunoblotting and confocal fluorescence microscopy, we disclosed a robust increase in the expression of gephyrin, an organizer of ligand-gated ion channels at inhibitory synapses in hippocampus CA1 and dentate gyrus of young presymptomatic APPPS1 mice (1 to 3 months) as compared to controls. The postsynaptic γ2-GABA(A)-receptor subunit and the presynaptic vesicular inhibitory amino acid transporter protein showed similar expression patterns. In contrast, adult transgenic animals (12 months) displayed decreased levels of these proteins in comparison to wild type in hippocampus areas devoid of amyloid plaques. Within most plaques, strong gephyrin immunoreactivity was detected, partially colocalizing with vesicular amino acid transporter and GABA(A)-receptor γ2 subunit immunoreactivities. Our results indicate a biphasic alteration in expression of hippocampal inhibitory synapse components in AD. Altered inhibition of neurotransmission might be an early prognostic marker and might even be involved in the pathogenesis of AD.

  11. Late stages of T cell maturation in the thymus involve NF-κB and tonic type I interferon signaling

    PubMed Central

    Xing, Yan; Wang, Xiaodan; Jameson, Stephen C.; Hogquist, Kristin A.

    2016-01-01

    Positive selection occurs in the thymic cortex, but critical maturation events occur later in the medulla. We defined the precise stage at which T cells acquire competence to proliferate and emigrate. Transcriptome analysis of late gene changes suggested roles for NF-κB and interferon (IFN) signaling. Mice lacking the IKK kinase TAK1 underwent normal positive selection, but exhibited a specific block in functional maturation. NF-κB signaling provided protection from tumor necrosis factor (TNF) mediated death, and was required for proliferation and emigration. The interferon signature was independent of NF-κB, however IFN-αR–deficient thymocytes showed reduced STAT1 expression and phenotypic abnormality, but were competent to proliferate. Thus, both NF-κB and tonic IFN signals are involved in the final maturation of thymocytes into naïve T cells. PMID:27043411

  12. MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple negative MDA-MB-231 human breast cancer cells

    PubMed Central

    Browne, Gillian; Dragon, Julie A.; Hong, Deli; Messier, Terri L.; Gordon, Jonathan A. R.; Farina, Nicholas H.; Boyd, Joseph R.; VanOudenhove, Jennifer J.; Perez, Andrew W.; Zaidi, Sayyed K.; Stein, Janet L.; Stein, Gary S.; Lian, Jane B.

    2016-01-01

    The Runx1 transcription factor, known for its essential role normal hematopoiesis, was reported in limited studies to be mutated or associated with human breast tumor tissues. Runx 1 increases concomitant with disease progression in the MMTV-PyMT transgenic mouse model of breast cancer. Compelling questions relate to mechanisms that regulate Runx1 expression in breast cancer. Here, we tested the hypothesis that dysregulation of Runx1-targeting microRNAs (miRNAs) allows for pathologic increase of Runx1 during breast cancer progression. Microarray profiling of the MMTV-PyMT model revealed significant down-regulation of numerous miRNAs predicted to target Runx1. One of these, miR-378, was inversely correlated with Runx1 expression during breast cancer progression in mouse, and in human breast cancer cell lines MCF7 and triple negative MDA-MB-231 that represent early and late stage disease, respectively. MiR-378 is nearly absent in MDA-MB-231 cells. Luciferase reporter assays revealed that miR-378 binds the Runx1 3′UTR and inhibits Runx1 expression. Functionally, we demonstrated that ectopic expression of miR-378 in MDA-MB-231 cells inhibited Runx1 and suppressed migration and invasion; while inhibition of miR-378 in MCF7 cells increased Runx1 levels and cell migration. Depletion of Runx1 in late stage breast cancer cells resulted in increased expression of both the miR-378 host gene PPARGC1B and pre-miR-378, suggesting a feedback loop. Taken together, our study identifies a novel and clinically relevant mechanism for regulation of Runx1 in breast cancer that is mediated by a PPARGC1B-miR-378-Runx1 regulatory pathway. Our results highlight the translational potential of miRNA replacement therapy for inhibiting Runx1 in breast cancer. PMID:26749280

  13. Treatment outcomes and risk factors for relapse in patients with early-stage human African trypanosomiasis (HAT) in the Republic of the Congo.

    PubMed Central

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

    2006-01-01

    OBJECTIVE: In 2002-03, the Republic of the Congo increased the threshold separating stage 1 and 2 cases of human African trypanosomiasis (HAT) from a cerebrospinal fluid (CSF) white cell count of 5 cells/mm(3) to 10 cells/mm(3). We aimed to assess whether the increased threshold of 10 cells/mm(3) is a safe indicator of stage 2 disease. METHODS: We assessed patients treated for stage 1 HAT caused by Trypanosoma brucei gambiense in the Republic of the Congo between April 2001 and April 2005. Patients with 0-10 cells/mm(3) in CSF were classed as stage 1 and treated with pentamidine. Patients with CSF of > 10 cells/mm(3) were classed as stage 2 and treated with either melarsoprol or eflornithine. We did a retrospective analysis of all patients treated after the September 2002 increase in threshold for classification of HAT disease stage 2, and who were eligible for at least 1 year of follow-up. Primary outcome was survival without death or relapse within 1 year of discharge. Risk factors for treatment failure, in particular CSF white cell count on diagnosis, were assessed. FINDINGS: Between September 2002 to April 2004, 692 patients eligible for our analysis were treated with pentamidine. All were discharged alive. Relapse rate was 5% (n = 33). The only identified risk factor for relapse was a CSF white cell count of 6-10 cells/mm(3) rather than 0-5 cells/mm(3) (adjusted hazard ratio 3.27 (95% confidence interval, 1.52-7.01); P = 0.002). CONCLUSION: A threshold of 5 white cells/mm(3) in CSF is safer than 10 cells/mm(3) to determine stage 2 HAT and reduce risk of relapse. PMID:17128357

  14. Polysomnography as a diagnosis and post-treatment follow-up tool in human African trypanosomiasis: a case study in an infant.

    PubMed

    Mpandzou, Ghislain; Cespuglio, Raymond; Ngampo, Stéphane; Bandzouzi, Bébène; Bouteille, Bernard; Vincendeau, Philippe; Buguet, Alain

    2011-06-15

    Gambian (Trypanosoma brucei gambiense) human African trypanosomiasis (HAT) evolves from the hemolymphatic stage 1, treated with pentamidine, to the meningoencephalitic stage 2, often treated with melarsoprol. This arseniate may provoke a deadly reactive encephalopathy. It is therefore crucial to diagnose precisely the stages of HAT, especially when clinical and biological examinations are doubtful. We present here the case of a 30-month old girl (E20 KOLNG) diagnosed with stage 1 HAT during a field survey in June 2007 in Congo. She was followed-up every six months for 18 months in a village dispensary facility at Mpouya. Her health status deteriorated in December 2008, although cerebrospinal fluid (CSF) white blood cell (WBC) count was normal. The child was hospitalized at Brazzaville and a daytime polysomnographic recording (electroencephalogram, electrooculogram, and electromyogram) was performed (Temec Vitaport 3® portable recorder) to avoid a new lumbar puncture. The child presented a complete polysomnographic syndrome of HAT with a major disturbance of the distribution of sleep and wake episodes and the occurrence of sleep onset REM periods (SOREMPs). The relapse at stage 2 was confirmed by a new CSF examination that showed an elevated WBC count (23cells·μL(-1)) with the presence of B lymphocytes. Melarsoprol treatment was undertaken. A post-treatment recording was immediately performed, showing the resolution of sleepwake pattern abnormalities. Another polysomnography, taken four months later, confirmed the normalization of sleep-wake patterns indicating healing. We therefore propose that polysomnography, being a non-invasive technique, should be used in children to alleviate burden caused by HAT staging procedures, especially regarding lumbar punctures in remote African villages.

  15. Polysomnography as a diagnosis and post-treatment follow-up tool in human African trypanosomiasis: a case study in an infant.

    PubMed

    Mpandzou, Ghislain; Cespuglio, Raymond; Ngampo, Stéphane; Bandzouzi, Bébène; Bouteille, Bernard; Vincendeau, Philippe; Buguet, Alain

    2011-06-15

    Gambian (Trypanosoma brucei gambiense) human African trypanosomiasis (HAT) evolves from the hemolymphatic stage 1, treated with pentamidine, to the meningoencephalitic stage 2, often treated with melarsoprol. This arseniate may provoke a deadly reactive encephalopathy. It is therefore crucial to diagnose precisely the stages of HAT, especially when clinical and biological examinations are doubtful. We present here the case of a 30-month old girl (E20 KOLNG) diagnosed with stage 1 HAT during a field survey in June 2007 in Congo. She was followed-up every six months for 18 months in a village dispensary facility at Mpouya. Her health status deteriorated in December 2008, although cerebrospinal fluid (CSF) white blood cell (WBC) count was normal. The child was hospitalized at Brazzaville and a daytime polysomnographic recording (electroencephalogram, electrooculogram, and electromyogram) was performed (Temec Vitaport 3® portable recorder) to avoid a new lumbar puncture. The child presented a complete polysomnographic syndrome of HAT with a major disturbance of the distribution of sleep and wake episodes and the occurrence of sleep onset REM periods (SOREMPs). The relapse at stage 2 was confirmed by a new CSF examination that showed an elevated WBC count (23cells·μL(-1)) with the presence of B lymphocytes. Melarsoprol treatment was undertaken. A post-treatment recording was immediately performed, showing the resolution of sleepwake pattern abnormalities. Another polysomnography, taken four months later, confirmed the normalization of sleep-wake patterns indicating healing. We therefore propose that polysomnography, being a non-invasive technique, should be used in children to alleviate burden caused by HAT staging procedures, especially regarding lumbar punctures in remote African villages. PMID:21470639

  16. Distribution of distal femoral osteophytes in a human skeletal population

    PubMed Central

    Shepstone, L.; Rogers, J.; Kirwan, J.; Silverman, B.

    2000-01-01

    OBJECTIVES—To examine objectively spatial patterns of osteophytes around the distal end of the femur and to identify distinct subgroups.
METHODS—A sample of 107 human femora from a large skeletal population were selected for study. These femora included subjects with evidence of late stage osteoarthritis (that is, with eburnation present) and those with no such evidence. The location of osteophytes was recorded using a video camera and digitised computer images were extracted. Multidimensional scaling was used to identify clusters of femora based upon osteophyte location.
RESULTS—A distinct subgroup of femora was identified with osteophytes present only within the intercondylar notch region. None of these subjects had any evidence of eburnation.
CONCLUSIONS—This finding adds to an earlier study based on radiographs. Osteophytes located within the intercondylar notch of the femur appear to be a distinct subset, which may occur either as an early stage of knee osteoarthritis or for some independent reason.

 PMID:10873960

  17. Punicalagin promotes autophagy to protect primary human syncytiotrophoblasts from apoptosis.

    PubMed

    Wang, Ying; Chen, Baosheng; Longtine, Mark S; Nelson, D Michael

    2016-02-01

    Punicalagin is a prominent polyphenol in pomegranate juice that protects cultured syncytiotrophoblasts from stress-induced apoptosis. Here, we test the hypothesis that punicalagin has this effect by inhibiting the mTOR kinase pathway to enhance autophagic turnover and limit apoptosis in cultured primary human syncytiotrophoblasts. In syncytiotrophoblasts, starvation, rapamycin, or punicalagin all decreased the expression of phosphorylated ribosomal protein S6, a downstream target of the mTOR kinase, and of the autophagy markers, LC3-II and p62. In contrast, in the presence of bafilomycin, an inhibitor of late stages of autophagy and degradation in the autophagolysosome, syncytiotrophoblasts exposed to starvation, rapamycin, or punicalagin all showed increased levels of LC3-II and p62. The number of LC3-II punctae also increased in punicalagin-treated syncytiotrophoblasts exposed to chloroquine, another inhibitor of autophagic degradation, and punicalagin increased the number of lysosomes. The apoptosis-reducing effect of punicalagin was attenuated by inhibition of autophagy using bafilomycin or knockdown of the autophagy related gene, ATG16L1. Collectively, these data support the hypothesis that punicalagin modulates the crosstalk between autophagy and apoptosis to promote survival in cultured syncytiotrophoblasts. PMID:26659860

  18. Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection

    PubMed Central

    Cuypers, Bart; Lecordier, Laurence; Meehan, Conor J.; Van den Broeck, Frederik; Imamura, Hideo; Büscher, Philippe; Dujardin, Jean-Claude; Laukens, Kris; Schnaufer, Achim; Dewar, Caroline; Lewis, Michael; Balmer, Oliver; Azurago, Thomas; Kyei-Faried, Sardick; Ohene, Sally-Ann; Duah, Boateng; Homiah, Prince; Mensah, Ebenezer Kofi; Anleah, Francis; Franco, Jose Ramon; Pays, Etienne

    2016-01-01

    ABSTRACT African trypanosomes, except Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which cause human African trypanosomiasis, are lysed by the human serum protein apolipoprotein L1 (ApoL1). These two subspecies can resist human ApoL1 because they express the serum resistance proteins T. b. gambiense glycoprotein (TgsGP) and serum resistance-associated protein (SRA), respectively. Whereas in T. b. rhodesiense, SRA is necessary and sufficient to inhibit ApoL1, in T. b. gambiense, TgsGP cannot protect against high ApoL1 uptake, so different additional mechanisms contribute to limit this uptake. Here we report a complex interplay between trypanosomes and an ApoL1 variant, revealing important insights into innate human immunity against these parasites. Using whole-genome sequencing, we characterized an atypical T. b. gambiense infection in a patient in Ghana. We show that the infecting trypanosome has diverged from the classical T. b. gambiense strains and lacks the TgsGP defense mechanism against human serum. By sequencing the ApoL1 gene of the patient and subsequent in vitro mutagenesis experiments, we demonstrate that a homozygous missense substitution (N264K) in the membrane-addressing domain of this ApoL1 variant knocks down the trypanolytic activity, allowing the trypanosome to avoid ApoL1-mediated immunity. PMID:27073096

  19. [The human genome project as a scientific background of preventive medicine].

    PubMed

    Baranov, V S

    2000-01-01

    Conspicuous achievements in the Human Genome Project have already found spectacular implementation in both basic research and practice. The Human Genome Diversity, Functional Genomics, and numerous Social Programmes are under way and they are rapidly expanding the scientific area induced by the Human Genome Project. Its practical implication is mainly confined to molecular medicine and to its quickly growing area Predictive (Preventive) Medicine. The paper briefly considers the existing concepts of molecular genetic tests of "predisposition" genes, including such groups as "environmental" genes and "trigger"-genes to detect subjects highly susceptible to different common multifactorial diseases and the expediency for testing the genes whose mutations cause diseases showing their manifestations at the late stage. Evidence is provided for that there is a progressive increase in population, family, and personal predisposition gene DNA databanks. There is need for close interaction between researchers and all strata of society, including the clergy, governments, political parties, etc. in order to optimize perception of scientific achievements of modern genetics and their effective used for the welfare of mankind. PMID:11247123

  20. Th1/Th17 Plasticity Is a Marker of Advanced β Cell Autoimmunity and Impaired Glucose Tolerance in Humans

    PubMed Central

    Reinert-Hartwall, Linnea; Honkanen, Jarno; Salo, Harri M.; Nieminen, Janne K.; Luopajärvi, Kristiina; Härkönen, Taina; Veijola, Riitta; Simell, Olli; Ilonen, Jorma; Peet, Aleksandr; Tillmann, Vallo; Knip, Mikael; Knip, Mikael; Koski, Katriina; Koski, Matti; Härkönen, Taina; Ryhänen, Samppa; Hämäläinen, Anu-Maaria; Ormisson, Anne; Peet, Aleksandr; Tillmann, Vallo; Ulich, Valentina; Kuzmicheva, Elena; Mokurov, Sergei; Markova, Svetlana; Pylova, Svetlana; Isakova, Marina; Shakurova, Elena; Petrov, Vladimir; Dorshakova, Natalya V.; Karapetyan, Tatyana; Varlamova, Tatyana; Ilonen, Jorma; Kiviniemi, Minna; Alnek, Kristi; Janson, Helis; Uibo, Raivo; Salum, Tiit; von Mutius, Erika; Weber, Juliane; Ahlfors, Helena; Kallionpää, Henna; Laajala, Essi; Lahesmaa, Riitta; Lähdesmäki, Harri; Moulder, Robert; Nieminen, Janne; Ruohtula, Terhi; Vaarala, Outi; Honkanen, Hanna; Hyöty, Heikki; Kondrashova, Anita; Oikarinen, Sami; Harmsen, Hermie J. M.; De Goffau, Marcus C.; Welling, Gjalt; Alahuhta, Kirsi; Virtanen, Suvi M.

    2015-01-01

    Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late stage of preclinical diabetes in children with β cell autoimmunity and impaired glucose tolerance, but not in children with early β cell autoimmunity. We found an increased ratio of IFN-γ/IL-17 expression in Th17 cells in children with advanced β cell autoimmunity, which correlated with HbA1c and plasma glucose concentrations in an oral glucose tolerance test, and thus impaired β cell function. Low expression of Helios was seen in Th17 cells, suggesting that Th1/Th17 cells are not converted thymus-derived regulatory T cells. Our results suggest that the development of Th1/Th17 plasticity may serve as a biomarker of disease progression from β cell autoantibody positivity to type 1 diabetes. These data in human type 1 diabetes emphasize the role of Th1/Th17 plasticity as a potential contributor to tissue destruction in autoimmune conditions. PMID:25480564

  1. Neurogranin binds α-synuclein in the human superior temporal cortex and interaction is decreased in Parkinson's disease.

    PubMed

    Koob, Andrew O; Shaked, Gideon M; Bender, Andreas; Bisquertt, Alejandro; Rockenstein, Edward; Masliah, Eliezer

    2014-12-01

    Neurogranin is a calmodulin binding protein that has been implicated in learning and memory, long-term potentiation and synaptic plasticity. Neurons expressing neurogranin in the cortex degenerate in late stages of Parkinson's disease with widespread α-synuclein pathology. While analyzing neurogranin gene expression levels through rtPCR in brains of mouse models overexpressing human α-synuclein, we found levels were elevated 2.5 times when compared to nontransgenic animals. Immunohistochemistry in the cortex revealed colocalization between α-synuclein and neurogranin in mouse transgenics when compared to control mice. Coimmunoprecipitation studies in the superior temporal cortex in humans confirmed interaction between α-synuclein and neurogranin, and decreased interaction between α-synuclein and neurogranin was noticed in patients diagnosed with Parkinson's disease when compared to normal control brains. Additionally, phosphorylated neurogranin levels were also decreased in the human superior temporal cortex in patients diagnosed with Parkinson's disease and patients diagnosed with dementia with Lewy bodies. Here, we show for the first time that neurogranin binds to α-synuclein in the human cortex, and this interaction decreases in Parkinson's disease along with the phosphorylation of neurogranin, a molecular process thought to be involved in learning and memory.

  2. Reduced graphene oxide-coated hydroxyapatite composites stimulate spontaneous osteogenic differentiation of human mesenchymal stem cells

    NASA Astrophysics Data System (ADS)

    Lee, Jong Ho; Shin, Yong Cheol; Jin, Oh Seong; Kang, Seok Hee; Hwang, Yu-Shik; Park, Jong-Chul; Hong, Suck Won; Han, Dong-Wook

    2015-07-01

    Human mesenchymal stem cells (hMSCs) have great potential as cell sources for bone tissue engineering and regeneration, but the control and induction of their specific differentiation into bone cells remain challenging. Graphene-based nanomaterials are considered attractive candidates for biomedical applications such as scaffolds in tissue engineering, substrates for SC differentiation and components of implantable devices, due to their biocompatible and bioactive properties. Despite the potential biomedical applications of graphene and its derivatives, only limited information is available regarding their osteogenic activity. This study concentrates upon the effects of reduced graphene oxide (rGO)-coated hydroxyapatite (HAp) composites on osteogenic differentiation of hMSCs. The average particle sizes of HAp and rGO were 1270 +/- 476 nm and 438 +/- 180 nm, respectively. When coated on HAp particulates, rGO synergistically enhanced spontaneous osteogenic differentiation of hMSCs, without hampering their proliferation. This result was confirmed by determining alkaline phosphatase activity and mineralization of calcium and phosphate as early and late stage markers of osteogenic differentiation. It is suggested that rGO-coated HAp composites can be effectively utilized as dental and orthopedic bone fillers since these graphene-based particulate materials have potent effects on stimulating the spontaneous differentiation of MSCs and show superior bioactivity and osteoinductive potential.Human mesenchymal stem cells (hMSCs) have great potential as cell sources for bone tissue engineering and regeneration, but the control and induction of their specific differentiation into bone cells remain challenging. Graphene-based nanomaterials are considered attractive candidates for biomedical applications such as scaffolds in tissue engineering, substrates for SC differentiation and components of implantable devices, due to their biocompatible and bioactive properties. Despite

  3. Predictivity of dog co-culture model, primary human hepatocytes and HepG2 cells for the detection of hepatotoxic drugs in humans

    SciTech Connect

    Atienzar, Franck A.; Novik, Eric I.; Gerets, Helga H.; Parekh, Amit; Delatour, Claude; Cardenas, Alvaro; MacDonald, James; Yarmush, Martin L.; Dhalluin, Stéphane

    2014-02-15

    Drug Induced Liver Injury (DILI) is a major cause of attrition during early and late stage drug development. Consequently, there is a need to develop better in vitro primary hepatocyte models from different species for predicting hepatotoxicity in both animals and humans early in drug development. Dog is often chosen as the non-rodent species for toxicology studies. Unfortunately, dog in vitro models allowing long term cultures are not available. The objective of the present manuscript is to describe the development of a co-culture dog model for predicting hepatotoxic drugs in humans and to compare the predictivity of the canine model along with primary human hepatocytes and HepG2 cells. After rigorous optimization, the dog co-culture model displayed metabolic capacities that were maintained up to 2 weeks which indicates that such model could be also used for long term metabolism studies. Most of the human hepatotoxic drugs were detected with a sensitivity of approximately 80% (n = 40) for the three cellular models. Nevertheless, the specificity was low approximately 40% for the HepG2 cells and hepatocytes compared to 72.7% for the canine model (n = 11). Furthermore, the dog co-culture model showed a higher superiority for the classification of 5 pairs of close structural analogs with different DILI concerns in comparison to both human cellular models. Finally, the reproducibility of the canine system was also satisfactory with a coefficient of correlation of 75.2% (n = 14). Overall, the present manuscript indicates that the dog co-culture model may represent a relevant tool to perform chronic hepatotoxicity and metabolism studies. - Highlights: • Importance of species differences in drug development. • Relevance of dog co-culture model for metabolism and toxicology studies. • Hepatotoxicity: higher predictivity of dog co-culture vs HepG2 and human hepatocytes.

  4. p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans

    PubMed Central

    Wild, Peter J; Ikenberg, Kristian; Fuchs, Thomas J; Rechsteiner, Markus; Georgiev, Strahil; Fankhauser, Niklaus; Noske, Aurelia; Roessle, Matthias; Caduff, Rosmarie; Dellas, Athanassios; Fink, Daniel; Moch, Holger; Krek, Wilhelm; Frew, Ian J

    2012-01-01

    Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours. PMID:22678923

  5. The interaction between human enteroviruses and type I IFN signaling pathway.

    PubMed

    Lu, Jing; Yi, Lina; Ke, Changwen; Zhang, Yonghui; Liu, Ren; Chen, Jinfei; Kung, Hsiang-Fu; He, Ming-Liang

    2015-06-01

    Human enteroviruses (HEV), very common and important human pathogens, cause infections in diverse ways. Recently, the large epidemic of HFMD caused by HEV infection became a growing threat to public health in China. As the first line of immune response, the type I interferon (IFN-α/β) pathway plays an essential role in antiviral infection, particularly in limiting both the early and late stages of infection. Because of co-evolution with the host, the viruses have evolved multiple strategies to evade or subvert the host immunity to ensure their survival. In this paper, we systematically reviewed and summarized the interaction between HEV infections and host type I IFN responses. We firstly described the recent findings of HEV recognition and IFN induction, specifically on host pattern-recognition receptors (PRRs) in HEV infection. Then we discussed the antiviral effect of IFN in HEV infection. Finally, we timely summarized the mechanisms of HEV to circumvent the IFN responses. Clarification of the complexity in this battle may provide us new strategies for prevention and antiviral treatment.

  6. High levels of SOX5 decrease proliferative capacity of human B cells, but permit plasmablast differentiation.

    PubMed

    Rakhmanov, Mirzokhid; Sic, Heiko; Kienzler, Anne-Kathrin; Fischer, Beate; Rizzi, Marta; Seidl, Maximilian; Melkaoui, Kerstina; Unger, Susanne; Moehle, Luisa; Schmit, Nadine E; Deshmukh, Sachin D; Ayata, Cemil Korcan; Schuh, Wolfgang; Zhang, Zhibing; Cosset, François-Loic; Verhoeyen, Els; Peter, Hans-Hartmut; Voll, Reinhard E; Salzer, Ulrich; Eibel, Hermann; Warnatz, Klaus

    2014-01-01

    Currently very little is known about the differential expression and function of the transcription factor SOX5 during B cell maturation. We identified two new splice variants of SOX5 in human B cells, encoding the known L-SOX5B isoform and a new shorter isoform L-SOX5F. The SOX5 transcripts are highly expressed during late stages of B-cell differentiation, including atypical memory B cells, activated CD21low B cells and germinal center B cells of tonsils. In tonsillar sections SOX5 expression was predominantly polarized to centrocytes within the light zone. After in vitro stimulation, SOX5 expression was down-regulated during proliferation while high expression levels were permissible for plasmablast differentiation. Overexpression of L-SOX5F in human primary B lymphocytes resulted in reduced proliferation, less survival of CD138neg B cells, but comparable numbers of CD138+CD38hi plasmablasts compared to control cells. Thus, our findings describe for the first time a functional role of SOX5 during late B cell development reducing the proliferative capacity and thus potentially affecting the differentiation of B cells during the germinal center response. PMID:24945754

  7. STUDIES ON THE TREATMENT OF HUMAN TRYPANOSOMIASIS WITH TRYPARSAMIDE (THE SODIUM SALT OF N-PHENYLGLYCINEAMIDE-p-ARSONIC ACID)

    PubMed Central

    Pearce, Louise

    1921-01-01

    The present study of the action of tryparsamide in human trypanosomiasis concludes a series of chemical and biological investigations in a particular problem of chemotherapy and thus represents the final step in a logical method of approach to such a problem. It has been shown that tryparsamide, the sodium salt of N-phenylglycineamide-p-arsonic acid, possesses a marked trypanocidal activity in human trypanosomiasis caused by Tr. gambiense. Single doses of from 0.5 to 5.0 gm. produced a peripheral sterilization of lymph glands and blood in an average of 6 to 12 hours. The duration of the peripheral sterilization following single doses of 17 to 83 mg. per kilo ranged from 17 to 58 days in patients who ultimately showed a return of trypanosomes to the peripheral blood. In a number of patients, however, treated with single doses of 9 to 68 mg. per kilo, no such relapse was detected during an observation period of from 40 to 111 days. The drug is extremely soluble in water and may be administered intramuscularly as well as intravenously. The immediate trypanocidal action after intramuscular administration was as rapid as that following the intravenous route while the duration of peripheral sterilization was appreciably longer. Relatively few repeated doses produced in advanced cases a marked and rapid diminution of the cells of the spinal fluid and were associated with definite improvement of mental and nervous symptoms. The occurrence of visual disturbances in certain advanced cases was the only untoward effect detected during the course of the work, and was apparently related to a too frequent administration of the drug. The condition was transitory in the majority of instances and resumption of treatment was not followed by a recurrence of this symptom. The general beneficial effect of the drug was a noticeable feature of its action in both early and advanced cases as shown by the disappearance of subjective symptoms, by the return of the pulse and temperature to

  8. Bridging in vitro and in vivo metabolism and transport of faldaprevir in human using a novel cocultured human hepatocyte system, HepatoPac.

    PubMed

    Ramsden, Diane; Tweedie, Donald J; Chan, Tom S; Taub, Mitchell E; Li, Yongmei

    2014-03-01

    An increased appreciation of the importance of transporter and enzyme interplay in drug clearance and a desire to delineate these mechanisms necessitates the utilization of models that contain a full complement of enzymes and transporters at physiologically relevant activities. Additionally, the development of drugs with longer half-lives requires in vitro systems with extended incubation times that allow characterization of metabolic pathways for low-clearance drugs. A recently developed coculture hepatocyte model, HepatoPac, has been applied to meet these challenges. Faldaprevir is a drug in late-stage development for the treatment of hepatitis C. Faldaprevir is a low-clearance drug with the somewhat unique characteristic of being slowly metabolized, producing two abundant hydroxylated metabolites (M2a and M2b) in feces (∼40% of the dose) without exhibiting significant levels of circulating metabolites in humans. The human HepatoPac model was investigated to characterize the metabolism and transport of faldaprevir. In human HepatoPac cultures, M2a and M2b were the predominant metabolites formed, with extents of formation comparable to in vivo. Direct glucuronidation of faldaprevir was shown to be a minor metabolic pathway. HepatoPac studies also demonstrated that faldaprevir is concentrated in liver with active uptake by multiple transporters (including OATP1B1 and Na(+)-dependent transporters). Overall, human HepatoPac cultures provided valuable insights into the metabolism and disposition of faldaprevir in humans and demonstrated the importance of enzyme and transporter interplay in the clearance of the drug. PMID:24366904

  9. Human disease and drug pharmacology, complex as real life.

    PubMed

    Viayna, E; Sola, I; Di Pietro, O; Muñoz-Torrero, D

    2013-01-01

    In the past decades drug discovery practice has escaped from the complexity of the formerly used phenotypic screening in animals to focus on assessing drug effects on isolated protein targets in the search for drugs that exclusively and potently hit one selected target, thought to be critical for a given disease, while not affecting at all any other target to avoid the occurrence of side-effects. However, reality does not conform to these expectations, and, conversely, this approach has been concurrent with increased attrition figures in late-stage clinical trials, precisely due to lack of efficacy and safety. In this context, a network biology perspective of human disease and treatment has burst into the drug discovery scenario to bring it back to the consideration of the complexity of living organisms and particularly of the (patho)physiological environment where protein targets are (mal)functioning and where drugs have to exert their restoring action. Under this perspective, it has been found that usually there is not one but several disease-causing genes and, therefore, not one but several relevant protein targets to be hit, which do not work on isolation but in a highly interconnected manner, and that most known drugs are inherently promiscuous. In this light, the rationale behind the currently prevailing single-target-based drug discovery approach might even seem a Utopia, while, conversely, the notion that the complexity of human disease must be tackled with complex polypharmacological therapeutic interventions constitutes a difficult-to-refuse argument that is spurring the development of multitarget therapies. PMID:23410162

  10. Human disease and drug pharmacology, complex as real life.

    PubMed

    Viayna, E; Sola, I; Di Pietro, O; Muñoz-Torrero, D

    2013-01-01

    In the past decades drug discovery practice has escaped from the complexity of the formerly used phenotypic screening in animals to focus on assessing drug effects on isolated protein targets in the search for drugs that exclusively and potently hit one selected target, thought to be critical for a given disease, while not affecting at all any other target to avoid the occurrence of side-effects. However, reality does not conform to these expectations, and, conversely, this approach has been concurrent with increased attrition figures in late-stage clinical trials, precisely due to lack of efficacy and safety. In this context, a network biology perspective of human disease and treatment has burst into the drug discovery scenario to bring it back to the consideration of the complexity of living organisms and particularly of the (patho)physiological environment where protein targets are (mal)functioning and where drugs have to exert their restoring action. Under this perspective, it has been found that usually there is not one but several disease-causing genes and, therefore, not one but several relevant protein targets to be hit, which do not work on isolation but in a highly interconnected manner, and that most known drugs are inherently promiscuous. In this light, the rationale behind the currently prevailing single-target-based drug discovery approach might even seem a Utopia, while, conversely, the notion that the complexity of human disease must be tackled with complex polypharmacological therapeutic interventions constitutes a difficult-to-refuse argument that is spurring the development of multitarget therapies.

  11. Arachidonic acid and docosahexaenoic acid suppress osteoclast formation and activity in human CD14+ monocytes, in vitro.

    PubMed

    Kasonga, Abe E; Deepak, Vishwa; Kruger, Marlena C; Coetzee, Magdalena

    2015-01-01

    An unbalanced diet can have adverse effects on health. Long chain polyunsaturated fatty acids (LCPUFAs) have been the focus of research owing to their necessity of inclusion in a healthy diet. However, the effects of LCPUFAs on human osteoclast formation and function have not been explored before. A human CD14+ monocyte differentiation model was used to elucidate the effects of an ω-3 LCPUFA, docosahexaenoic acid (DHA), and an ω-6 LCPUFA, arachidonic acid (AA), on osteoclast formation and activity. CD14+ monocytes were isolated from peripheral blood of healthy donors and stimulated with macrophage colony stimulating factor and receptor activator of nuclear factor kappa-B ligand to generate osteoclasts. Data from this study revealed that both the LCPUFAs decreased osteoclast formation potential of CD14+ monocytes in a dose-dependent manner when treated at an early stage of differentiation. Moreover, when exposed at a late stage of osteoclast differentiation AA and DHA impaired the bone resorptive potential of mature osteoclasts without affecting osteoclast numbers. AA and DHA abrogated vitronectin receptor expression in differentiating as well as mature osteoclasts. In contrast, the degree of inhibition for calcitonin receptor expression varied between the LCPUFAs with only AA causing inhibition during osteoclast differentiation. Furthermore, AA and DHA down regulated the expression of key osteoclast-specific genes in differentiating as well as mature osteoclasts. This study demonstrates for the first time that LCPUFAs can modulate osteoclast formation and function in a human primary osteoclast cell line.

  12. Human See, Human Do.

    ERIC Educational Resources Information Center

    Tomasello, Michael

    1997-01-01

    A human demonstrator showed human children and captive chimpanzees how to drag food or toys closer using a rakelike tool. One side of the rake was less efficient than the other for dragging. Chimps tried to reproduce results rather than methods while children imitated and used the more efficient rake side. Concludes that imitation leads to…

  13. Specialized proresolving mediators enhance human B cell differentiation to antibody secreting cells1

    PubMed Central

    Ramon, Sesquile; Gao, Fei; Serhan, Charles N.; Phipps, Richard P.

    2012-01-01

    The resolution of inflammation is an active and dynamic process critical in maintaining homeostasis. Newly identified lipid mediators have been recognized as key players during the resolution phase. These specialized proresolving mediators (SPM) constitute separate families that include lipoxins, resolvins, protectins and maresins each derived from essential polyunsaturated fatty acids. New results demonstrate that SPM regulate aspects of the immune response, including reduction of neutrophil infiltration, decreased T cell cytokine production and stimulation of macrophage phagocytic activity. The actions of SPM on B lymphocytes remain unknown. Our study shows for the first time that the novel SPM 17-hydroxydosahexaenoic acid (17-HDHA), resolvin D1 (RvD1) and protectin D1 (PD1) are present in the spleen. Interestingly, 17-HDHA, RvD1 but not PD1, strongly increase activated human B cell IgM and IgG production. Furthermore, increased antibody production by 17-HDHA is due to augmented B cell differentiation towards a CD27+CD38+ antibody-secreting cell phenotype. 17-HDHA did not affect proliferation and was non-toxic to cells. Increase of plasma cell differentiation and antibody production supports the involvement of SPM during the late stages of inflammation and pathogen clearance. The present study provides new evidence for SPM activity in the humoral response. These new findings highlight the potential applications of SPM as endogenous and non-toxic adjuvants, and as anti-inflammatory therapeutic molecules. PMID:22711890

  14. Slower evolution of human immunodeficiency virus type 1 quasispecies during progression to AIDS.

    PubMed Central

    Delwart, E L; Pan, H; Sheppard, H W; Wolpert, D; Neumann, A U; Korber, B; Mullins, J I

    1997-01-01

    The evolution of human immunodeficiency virus type 1 (HIV-1) quasispecies at the envelope gene was studied from the time of infection in 11 men who experienced different rates of CD4+ cell count decline and 6 men with unknown dates of infection by using DNA heteroduplex mobility assays. Quasispecies were genetically homogeneous near the time of seroconversion. Subsequently, slower proviral genetic diversification and higher plasma viremia correlated with rapid CD4+ cell count decline. Except for the fastest progressors to AIDS, highly diverse quasispecies developed in all subjects within 3 to 4 years. High quasispecies diversity was then maintained for years until again becoming more homogeneous in a subset of late-stage AIDS patients. Individuals who maintained high CD4+ cell counts showed continuous genetic turnover of their complex proviral quasispecies, while more closely related sets of variants were found in longitudinal samples of severely immunocompromised patients. The limited number of variants that grew out in short-term PBMC cocultures were rare in the uncultured proviral quasispecies of healthy, long-term infected individuals but more common in vivo in patients with low CD4+ cell counts. The slower evolution of HIV-1 observed during rapid progression to AIDS and in advanced patients may reflect ineffective host-mediated selection pressures on replicating quasispecies. PMID:9311829

  15. Erythropoietin critically regulates the terminal maturation of murine and human primitive erythroblasts

    PubMed Central

    Malik, Jeffrey; Kim, Ah Ram; Tyre, Kaitlin A.; Cherukuri, Anjuli R.; Palis, James

    2013-01-01

    Primitive erythroid cells, the first red blood cells produced in the mammalian embryo, are necessary for embryonic survival. Erythropoietin and its receptor EpoR, are absolutely required for survival of late-stage definitive erythroid progenitors in the fetal liver and adult bone marrow. Epo- and Epor-null mice die at E13.5 with a lack of definitive erythrocytes. However, the persistence of circulating primitive erythroblasts raises questions about the role of erythropoietin/EpoR in primitive erythropoiesis. Using Epor-null mice and a novel primitive erythroid 2-step culture we found that erythropoietin is not necessary for specification of primitive erythroid progenitors. However, Epor-null embryos develop a progressive, profound anemia by E12.5 as primitive erythroblasts mature as a synchronous cohort. This anemia results from reduced primitive erythroblast proliferation associated with increased p27 expression, from advanced cellular maturation, and from markedly elevated rates of apoptosis associated with an imbalance in pro- and anti-apoptotic gene expression. Both mouse and human primitive erythroblasts cultured without erythropoietin also undergo accelerated maturation and apoptosis at later stages of maturation. We conclude that erythropoietin plays an evolutionarily conserved role in promoting the proliferation, survival, and appropriate timing of terminal maturation of primitive erythroid precursors. PMID:23894012

  16. Synthesis of Eupalinilide E, a Promoter of Human Hematopoietic Stem and Progenitor Cell Expansion.

    PubMed

    Johnson, Trevor C; Chin, Matthew R; Han, Tianxu; Shen, John Paul; Rana, Tariq; Siegel, Dionicio

    2016-05-11

    Improving the ex vivo and in vivo production of hematopoietic stem and progenitor cells (HSPCs) has the potential to address the short supply of these cells that are used in the treatment of various blood diseases and disorders. Eupalinilide E promotes the expansion of human HSPCs and inhibits subsequent differentiation, leading to increased numbers of clinically useful cells. This natural product represents an important tool to uncover new methods to drive expansion while inhibiting differentiation. However, in the process of examining these effects, which occur through a novel mechanism, the natural product was consumed, which limited additional investigation. To provide renewed and improved access to eupalinilide E, a laboratory synthesis has been developed and is reported herein. The synthetic route can access >400 mg in a single batch, employing reactions conducted on useful scales in a single vessel. Key transformations enabling the approach include a diastereoselective borylative enyne cyclization and a late-stage double allylic C-H oxidation as well as adapted Luche reduction and aluminum-mediated epoxidation reactions to maximize the synthetic efficiency. Retesting of the synthetic eupalinilide E confirmed the compound's ability to expand HSPCs and inhibit differentiation. PMID:27096704

  17. Human behavioural research applied to the leprosy control programme of Sarawak, Malaysia.

    PubMed

    Chen, P C

    1986-09-01

    In 1984, in Sarawak, there were a total of 1,099 recorded cases of leprosy for a population of 1.3 million. However, for each case recorded, it is estimated that two others remain undiagnosed as a consequence of the stigmatization associated with leprosy. For the five year period, 1979-1983, an average of 29 new cases were detected each year of which 8.6 (30%) were deformed due to the late stages at which it was being reported. To increase the case-finding rate, human behavioural research was applied to the leprosy control programme so as to develop culture-specific health education packages aimed at self diagnosis and self referral in order to detect the large pool of undiagnosed cases hidden behind the veil of aversion, fear and ignorance. This was achieved through anthropological studies to identify how the various major ethnic groups perceived leprosy and their attitudes towards leprosy. Taking into account these findings, health education packages aimed at adults as well as children were developed for the Chinese as well as the non-Chinese, and consisted of newspaper articles, cartoon tape-slides, cartoon story books and posters.

  18. The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma.

    PubMed

    Ma, Kai; Cao, Baoping; Guo, Mingzhou

    2016-01-01

    Esophageal cancer is one of the most common malignancies in the world. Squamous cell carcinoma accounts for approximately 90 % of esophageal cancer cases. Genetic and epigenetic changes have been found to accumulate during the development of various cancers, including esophageal squamous carcinoma (ESCC). Tobacco smoking and alcohol consumption are two major risk factors for ESCC, and both tobacco and alcohol were found to induce methylation changes in ESCC. Growing evidence demonstrates that aberrant epigenetic changes play important roles in the multiple-step processes of carcinogenesis and tumor progression. DNA methylation may occur in the key components of cancer-related signaling pathways. Aberrant DNA methylation affects genes involved in cell cycle, DNA damage repair, Wnt, TGF-β, and NF-κB signaling pathways, including P16, MGMT, SFRP2, DACH1, and ZNF382. Certain genes methylated in precursor lesions of the esophagus demonstrate that DNA methylation may serve as esophageal cancer early detection marker, such as methylation of HIN1, TFPI-2, DACH1, and SOX17. CHFR methylation is a late stage event in ESCC and is a sensitive marker for taxanes in human ESCC. FHIT methylation is associated with poor prognosis in ESCC. Aberrant DNA methylation changes may serve as diagnostic, prognostic, and chemo-sensitive markers. Characterization of the DNA methylome in ESCC will help to better understand its mechanisms and develop improved therapies. PMID:27110300

  19. Monocytes in Kaposi's sarcoma lesions are productively infected by human herpesvirus 8.

    PubMed Central

    Blasig, C; Zietz, C; Haar, B; Neipel, F; Esser, S; Brockmeyer, N H; Tschachler, E; Colombini, S; Ensoli, B; Stürzl, M

    1997-01-01

    PCR analysis and serological studies demonstrated a close association between Kaposi's sarcoma (KS)-associated herpesvirus, or human herpesvirus 8 (HHV-8), and the development of Kaposi's sarcoma (KS). The majority of the KS cells were shown to be latently infected by the virus. In this study we investigated which type of cell is productively infected in KS lesions. In situ hybridization was performed with strand-specific RNA probes complementary to the sequences coding for the minor capsid protein (VP23) of HHV-8. The VP23 gene is specifically expressed during the lytic or replicative period of the virus life cycle, and therefore it is a useful marker to detect productively infected cells. By in situ hybridization of KS lesions, a strong hybridization signal was detected only in a small subset of the KS cells of the lesions. Simultaneous application of immunohistochemical staining and in situ hybridization identified the virus-replicating cells to be of monocytic origin. Productively infected monocytes may be an important reservoir for transmission of the virus and for the increase and maintenance of the high load of HHV-8 generally observed in nodular KS lesions during late stages of infection. PMID:9311888

  20. The treatment pathways followed by cases of human African trypanosomiasis in western Kenya and eastern Uganda.

    PubMed

    Bukachi, S A; Wandibba, S; Nyamongo, I K

    2009-04-01

    Although early diagnosis and treatment are key factors in the effective control of human African trypanosomiasis (HAT), many cases of the disease delay taking appropriate action, leading to untold suffering. As a better understanding of treatment-seeking behaviour should help in identifying the obstacles to early diagnosis and effective treatment, the treatment pathways followed by 203 former HAT cases in western Kenya and eastern Uganda have recently been explored. About 86% of the HAT cases had utilized more than two different healthcare options before being correctly diagnosed for HAT, with about 70% each using more than three different health facilities. Only about 8% of the cases reported that they had been correctly diagnosed the first time they sought treatment. Just over half (51%) of the HAT cases had been symptomatic for >2 months before being correctly diagnosed for HAT, and such time lags in diagnosis contributed to 72% of the cases receiving their first appropriate treatment only in the late stage of the disease. The likelihood of a correct diagnosis increased with the time the case had been symptomatic. These observations indicate an urgent need to build the diagnostic capacity of the primary healthcare facilities in the study area, so that all HAT cases can be identified and treated in the early stage of the disease.

  1. Human macrophages can express the Hodgkin's cell-associated antigen Ki-1 (CD30).

    PubMed Central

    Andreesen, R.; Brugger, W.; Löhr, G. W.; Bross, K. J.

    1989-01-01

    The normal precursor of the neoplastic cell in Hodgkin's lymphoma is still unknown. Previous reports on the expression of the Hodgkin's cell-associated antigen Ki-1, CD30, on normal cells have been limited to activated lymphocytes. This study demonstrates, however, that cells of the macrophage lineage also are able to express the Ki-1 antigen. The Ki-1 antigen is absent from normal blood monocytes but expressed on up to 85% of macrophage-type cells developed during subsequent in vitro differentiation on Teflon membranes. Unlike other maturation-associated antigens, Ki-1 is found only at late stages of the macrophage primary cultures. Its expression can be enhanced by human interferon-gamma in a fashion similar to that of HLA-DR molecules. In addition, freshly explanted tumor cells from three patients with histopathologic and clinical features consistent with the diagnosis of true histiocytic lymphoma or malignant histiocytosis as well as the permanent cell line SU-DHL-1 could be demonstrated to express the Ki-1 antigen. The phenotype of histiocytic malignancy was further evaluated to be HLA-DR+MAX.26+CD25+-EMA+OKT9+Ki-1+. The results could indicate either that Hodgkin's lymphoma may arise not only from the lymphocyte but also from the macrophage lineage or may emphasize a macrophage involvement in the pathogenesis of this disease. Images Figure 3 PMID:2536522

  2. Knowledge Gaps in Rodent Pancreas Biology: Taking Human Pluripotent Stem Cell-Derived Pancreatic Beta Cells into Our Own Hands

    PubMed Central

    Santosa, Munirah Mohamad; Low, Blaise Su Jun; Pek, Nicole Min Qian; Teo, Adrian Kee Keong

    2016-01-01

    In the field of stem cell biology and diabetes, we and others seek to derive mature and functional human pancreatic β cells for disease modeling and cell replacement therapy. Traditionally, knowledge gathered from rodents is extended to human pancreas developmental biology research involving human pluripotent stem cells (hPSCs). While much has been learnt from rodent pancreas biology in the early steps toward Pdx1+ pancreatic progenitors, much less is known about the transition toward Ngn3+ pancreatic endocrine progenitors. Essentially, the later steps of pancreatic β cell development and maturation remain elusive to date. As a result, the most recent advances in the stem cell and diabetes field have relied upon combinatorial testing of numerous growth factors and chemical compounds in an arbitrary trial-and-error fashion to derive mature and functional human pancreatic β cells from hPSCs. Although this hit-or-miss approach appears to have made some headway in maturing human pancreatic β cells in vitro, its underlying biology is vaguely understood. Therefore, in this mini-review, we discuss some of these late-stage signaling pathways that are involved in human pancreatic β cell differentiation and highlight our current understanding of their relevance in rodent pancreas biology. Our efforts here unravel several novel signaling pathways that can be further studied to shed light on unexplored aspects of rodent pancreas biology. New investigations into these signaling pathways are expected to advance our knowledge in human pancreas developmental biology and to aid in the translation of stem cell biology in the context of diabetes treatments. PMID:26834702

  3. Histopathological Study of the Lungs of Mice Receiving Human Secretory IgA and Challenged with Mycobacterium tuberculosis

    PubMed Central

    ALVAREZ, Nadine; INFANTE, Juan Francisco; BORRERO, Reinier; MATA, Dulce; PAYAN, JORGE BARRIOS-; HOSSAIN, Md. Murad; MOHD NOR, Norazmi; SARMIENTO, María Elena; HERNANDEZ-PANDO, Rogelio; ACOSTA, Armando

    2014-01-01

    Background: Humoral and cellular immune responses are associated with protection against extracellular and intracellular pathogens, respectively. In the present study, we evaluated the effect of receiving human secretory immunoglobulin A (hsIgA) on the histopathology of the lungs of mice challenged with virulent Mycobacterium tuberculosis. Methods: The hsIgA was purified from human colostrum and administered to Balb/c mice by the intranasal route prior to infection with M. tuberculosis or in a pre-incubated formulation with mycobacteria, with the principal aim to study its effect on qualitative pulmonary histopathology. Results: The intranasal administration of hsIgA and the pre-incubation of mycobacteria with this preparation was associated with the presence of organised granulomas with signs of immune activation and histological features related to efficient disease control. This effect was highly evident during the late stage of infection (60 days), as demonstrated by numerous organised granulomas with numerous activated macrophages in the lungs of treated mice. Conclusion: The administration of hsIgA to mice before intratracheal infection with M. tuberculosis or the pre-incubation of the bacteria with the antibody formulation induced the formation of well-organised granulomas and inflammatory lesions in lungs compared with non-treated animals which correlates with the protective effect already demonstrated by these antibody formulations. PMID:25246833

  4. Indian Hedgehog in Synovial Fluid Is a Novel Marker for Early Cartilage Lesions in Human Knee Joint

    PubMed Central

    Zhang, Congming; Wei, Xiaochun; Chen, Chongwei; Cao, Kun; Li, Yongping; Jiao, Qiang; Ding, Juan; Zhou, Jingming; Fleming, Braden C.; Chen, Qian; Shang, Xianwen; Wei, Lei

    2014-01-01

    To determine whether there is a correlation between the concentration of Indian hedgehog (Ihh) in synovial fluid (SF) and the severity of cartilage damage in the human knee joints, the knee cartilages from patients were classified using the Outer-bridge scoring system and graded using the Modified Mankin score. Expression of Ihh in cartilage and SF samples were analyzed with immunohistochemistry (IHC), western blot, and enzyme-linked immunosorbent assay (ELISA). Furthermore, we detected and compared Ihh protein levels in rat and mice cartilages between normal control and surgery-induced osteoarthritis (OA) group by IHC and fluorescence molecular tomography in vivo respectively. Ihh expression was increased 5.2-fold in OA cartilage, 3.1-fold in relative normal OA cartilage, and 1.71-fold in OA SF compared to normal control samples. The concentrations of Ihh in cartilage and SF samples was significantly increased in early-stage OA samples when compared to normal samples (r = 0.556; p < 0.001); however, there were no significant differences between normal samples and late-stage OA samples. Up-regulation of Ihh protein was also an early event in the surgery-induced OA models. Increased Ihh is associated with the severity of OA cartilage damage. Elevated Ihh content in human knee joint synovial fluid correlates with early cartilage lesions. PMID:24786088

  5. Human T-Lymphotropic Virus Type 1 Oncoprotein Tax Promotes S-Phase Entry but Blocks Mitosis

    PubMed Central

    Liang, Min-Hui; Geisbert, Thomas; Yao, Yao; Hinrichs, Steven H.; Giam, Chou-Zen

    2002-01-01

    Human T-lymphotropic virus type 1 (HTLV-1) Tax exerts pleiotropic effects on multiple cellular regulatory processes to bring about NF-κB activation, aberrant cell cycle progression, and cell transformation. Here we report that Tax stimulates cellular G1/S entry but blocks mitosis. Tax expression in naive cells transduced with a retroviral vector, pBabe-Tax, leads to a significant increase in the number of cells in the S phase, with an accompanying rise in the population of cells with a DNA content of 4N or more. In all cell types tested, including BHK-21, mouse NIH 3T3, and human diploid fibroblast WI-38, Tax causes an uncoupling of DNA synthesis from cell division, resulting in the formation of multinucleated giant cells and cells with decondensed, highly convoluted and lobulated nuclei that are reminiscent of the large lymphocytes with cleaved or cerebriform nuclei seen in HTLV-1-positive individuals. This contrasts with the Tax-transformed cell lines, PX1 (fibroblast) and MT4 (lymphocyte), which produce Tax at high levels, but without the accompanying late-stage cell cycle abnormalities. PX1 and MT4 may have been selected to harbor somatic mutations that allow a bypass of the Tax-induced block in mitosis. PMID:11907241

  6. LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans

    PubMed Central

    Tu, Ho-Chou; Schwitalla, Sarah; Qian, Zhirong; LaPier, Grace S.; Yermalovich, Alena; Ku, Yuan-Chieh; Chen, Shann-Ching; Viswanathan, Srinivas R.; Zhu, Hao; Nishihara, Reiko; Inamura, Kentaro; Kim, Sun A.; Morikawa, Teppei; Mima, Kosuke; Sukawa, Yasutaka; Yang, Juhong; Meredith, Gavin; Fuchs, Charles S.; Ogino, Shuji

    2015-01-01

    Colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding protein paralogs that regulate biogenesis of let-7 microRNAs and influence development, metabolism, tissue regeneration, and oncogenesis. Here we demonstrate that overexpression of either LIN28 paralog cooperates with the Wnt pathway to promote invasive intestinal adenocarcinoma in murine models. When LIN28 alone is induced genetically, half of the resulting tumors harbor Ctnnb1 (β-catenin) mutation. When overexpressed in ApcMin/+ mice, LIN28 accelerates tumor formation and enhances proliferation and invasiveness. In conditional genetic models, enforced expression of a LIN28-resistant form of the let-7 microRNA reduces LIN28-induced tumor burden, while silencing of LIN28 expression reduces tumor volume and increases tumor differentiation, indicating that LIN28 contributes to tumor maintenance. We detected aberrant expression of LIN28A and/or LIN28B in 38% of a large series of human CRC samples (n = 595), where LIN28 expression levels were associated with invasive tumor growth. Our late-stage CRC murine models and analysis of primary human tumors demonstrate prominent roles for both LIN28 paralogs in promoting CRC growth and progression and implicate the LIN28/let-7 pathway as a therapeutic target. PMID:25956904

  7. Retinal Remodeling and Metabolic Alterations in Human AMD

    PubMed Central

    Jones, Bryan W.; Pfeiffer, Rebecca L.; Ferrell, William D.; Watt, Carl B.; Tucker, James; Marc, Robert E.

    2016-01-01

    Age-related macular degeneration (AMD) is a progressive retinal degeneration resulting in central visual field loss, ultimately causing debilitating blindness. AMD affects 18% of Americans from 65 to 74, 30% older than 74 years of age and is the leading cause of severe vision loss and blindness in Western populations. While many genetic and environmental risk factors are known for AMD, we currently know less about the mechanisms mediating disease progression. The pathways and mechanisms through which genetic and non-genetic risk factors modulate development of AMD pathogenesis remain largely unexplored. Moreover, current treatment for AMD is palliative and limited to wet/exudative forms. Retina is a complex, heterocellular tissue and most retinal cell classes are impacted or altered in AMD. Defining disease and stage-specific cytoarchitectural and metabolic responses in AMD is critical for highlighting targets for intervention. The goal of this article is to illustrate cell types impacted in AMD and demonstrate the implications of those changes, likely beginning in the retinal pigment epithelium (RPE), for remodeling of the the neural retina. Tracking heterocellular responses in disease progression is best achieved with computational molecular phenotyping (CMP), a tool that enables acquisition of a small molecule fingerprint for every cell in the retina. CMP uncovered critical cellular and molecular pathologies (remodeling and reprogramming) in progressive retinal degenerations such as retinitis pigmentosa (RP). We now applied these approaches to normal human and AMD tissues mapping progression of cellular and molecular changes in AMD retinas, including late-stage forms of the disease. PMID:27199657

  8. Human Development, Human Evolution.

    ERIC Educational Resources Information Center

    Smillie, David

    One of the truly remarkable events in human evolution is the unprecedented increase in the size of the brain of "Homo" over a brief span of 2 million years. It would appear that some significant selective pressure or opportunity presented itself to this branch of the hominid line and caused a rapid increase in the brain, introducing a wholly new…

  9. A 4.2 kb upstream region of the human corneodesmosin gene directs site-specific expression in hair follicles and hyperkeratotic epidermis of transgenic mice.

    PubMed

    Gallinaro, Hélène; Jonca, Nathalie; Langbein, Lutz; Vincent, Christian; Simon, Michel; Serre, Guy; Guerrin, Marina

    2004-03-01

    Corneodesmosin (CDSN) is a desmosomal protein expressed in the epidermis during the late stages of differentiation and in the inner root sheath of hair follicles. The homophilic adhesive properties of the protein suggest that it reinforces keratinocyte cohesion in the upper layers of the epidermis (stratum granulosum and stratum corneum). In this study, we analyzed the expression of the CDSN gene in 16 human tissues. We confirmed the closely restricted expression pattern of CSDN. Indeed, apart from the skin, the mRNA was significantly detected only in the placenta and the thymus. As a step in elucidating the mechanisms of tissue-specific expression, transgenic mice bearing a 4.2 kb fragment of the human CSDN gene promoter linked to the LacZ gene were generated. The reporter-gene expression was detected in special areas of the inner root sheath of the hair follicles and the hair medulla but not in the epidermis. Induction of epidermis hyperproliferation however either by pharmacological agents or by wounding led to strong expression of the reporter gene in the keratinocytes of the stratum granulosum and the parakeratotic corneocytes of the stratum corneum. The data suggest that the genomic sequences and/or regulating factors responsible for the cell-specific expression of the human CDSN gene in the normal hair follicle as well as in the hyperproliferative epidermis are different from those necessary for expression in the normal epidermis.

  10. Dysfunctional Patterns of Gamma-Band Activity in Response to Human Faces Compared to Non-Facial Stimuli in Patients with Schizophrenia

    PubMed Central

    Lee, Seung-Hwan; Kim, Sangrae; Shim, Mi-Seon; Kim, Do-Won

    2016-01-01

    Objective Healthy individuals show stronger gamma-band activities (GBAs) for socially relevant stimuli (human faces) than for non-relevant ones. This study aimed to examine whether this gamma-band preference occurs in patients with schizophrenia. Methods EEG was recorded for 24 patients with schizophrenia and 23 healthy controls while they viewed pictures of human faces, chairs, and nature scenes. The spectral powers of high-beta (20–30 Hz) and gamma (30–80 Hz) frequencies were analyzed along 3 midline cortical regions, and phase synchronization was calculated. Results Compared to the response to non-facial stimuli, higher event related deactivation to facial stimuli was observed for the high-beta frequency across groups. For the gamma frequency, early-stage GBA was increased and late-stage GBA was decreased for all 3 stimuli in patients with schizophrenia compared to healthy controls. Preferential GBA patterns (100–200 and 200–300 ms) were found in healthy controls, but not in patients with schizophrenia. Significant correlation existed between negative symptoms and GBA in the frontal region for chair and scene stimuli. There was no significant intergroup difference in phase synchronization pattern. Conclusion Our results suggest that patients with schizophrenia have deficits in the preferential pattern of GBA for human faces and the deficits in the preferential pattern were mainly influenced by over-response to socially non-relevant stimuli. PMID:27247603

  11. Human Health

    MedlinePlus

    ... effects of climate change Video not supported Human Health Climate change threatens human health and well-being ... Copy link to clipboard Key Message: Wide-ranging Health Impacts Climate change threatens human health and well- ...

  12. RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development.

    PubMed

    Verma, Rakesh; Su, Su; McCrann, Donald J; Green, Jennifer M; Leu, Karen; Young, Peter R; Schatz, Peter J; Silva, Jeffrey C; Stokes, Matthew P; Wojchowski, Don M

    2014-08-25

    Ligation of erythropoietin (EPO) receptor (EPOR) JAK2 kinase complexes propagates signals within erythroid progenitor cells (EPCs) that are essential for red blood cell production. To reveal hypothesized novel EPOR/JAK2 targets, a phosphotyrosine (PY) phosphoproteomics approach was applied. Beyond known signal transduction factors, 32 new targets of EPO-modulated tyrosine phosphorylation were defined. Molecular adaptors comprised one major set including growth factor receptor-bound protein 2 (GRB2)-associated binding proteins 1-3 (GAB1-3), insulin receptor substrate 2 (IRS2), docking protein 1 (DOK1), Src homology 2 domain containing transforming protein 1 (SHC1), and sprouty homologue 1 (SPRY1) as validating targets, and SPRY2, SH2 domain containing 2A (SH2D2A), and signal transducing adaptor molecule 2 (STAM2) as novel candidate adaptors together with an ORF factor designated as regulator of human erythroid cell expansion (RHEX). RHEX is well conserved in Homo sapiens and primates but absent from mouse, rat, and lower vertebrate genomes. Among tissues and lineages, RHEX was elevated in EPCs, occurred as a plasma membrane protein, was rapidly PY-phosphorylated >20-fold upon EPO exposure, and coimmunoprecipitated with the EPOR. In UT7epo cells, knockdown of RHEX inhibited EPO-dependent growth. This was associated with extracellular signal-regulated kinase 1,2 (ERK1,2) modulation, and RHEX coupling to GRB2. In primary human EPCs, shRNA knockdown studies confirmed RHEX regulation of erythroid progenitor expansion and further revealed roles in promoting the formation of hemoglobinizing erythroblasts. RHEX therefore comprises a new EPO/EPOR target and regulator of human erythroid cell expansion that additionally acts to support late-stage erythroblast development.

  13. Mapping the Homodimer Interface of an Optimized, Artificial, Transmembrane Protein Activator of the Human Erythropoietin Receptor

    PubMed Central

    Bears, Zachary; Barrera, Francisco N.; Alonso, Miriam; Engelman, Donald M.; DiMaio, Daniel

    2014-01-01

    Transmembrane proteins constitute a large fraction of cellular proteins, and specific interactions involving membrane-spanning protein segments play an important role in protein oligomerization, folding, and function. We previously isolated an artificial, dimeric, 44-amino acid transmembrane protein that activates the human erythropoietin receptor (hEPOR) in trans. This artificial protein supports limited erythroid differentiation of primary human hematopoietic progenitor cells in vitro, even though it does not resemble erythropoietin, the natural ligand of this receptor. Here, we used a directed-evolution approach to explore the structural basis for the ability of transmembrane proteins to activate the hEPOR. A library that expresses thousands of mutants of the transmembrane activator was screened for variants that were more active than the original isolate at inducing growth factor independence in mouse cells expressing the hEPOR. The most active mutant, EBC5-16, supports erythroid differentiation in human cells with activity approaching that of EPO, as assessed by cell-surface expression of glycophorin A, a late-stage marker of erythroid differentiation. EBC5-16 contains a single isoleucine to serine substitution at position 25, which increases its ability to form dimers. Genetic studies confirmed the importance of dimerization for activity and identified the residues constituting the homodimer interface of EBC5-16. The interface requires a GxxxG dimer packing motif and a small amino acid at position 25 for maximal activity, implying that tight packing of the EBC5-16 dimer is a crucial determinant of activity. These experiments identified an artificial protein that causes robust activation of its target in a natural host cell, demonstrated the importance of dimerization of this protein for engagement of the hEPOR, and provided the framework for future structure-function studies of this novel mechanism of receptor activation. PMID:24788775

  14. RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development.

    PubMed

    Verma, Rakesh; Su, Su; McCrann, Donald J; Green, Jennifer M; Leu, Karen; Young, Peter R; Schatz, Peter J; Silva, Jeffrey C; Stokes, Matthew P; Wojchowski, Don M

    2014-08-25

    Ligation of erythropoietin (EPO) receptor (EPOR) JAK2 kinase complexes propagates signals within erythroid progenitor cells (EPCs) that are essential for red blood cell production. To reveal hypothesized novel EPOR/JAK2 targets, a phosphotyrosine (PY) phosphoproteomics approach was applied. Beyond known signal transduction factors, 32 new targets of EPO-modulated tyrosine phosphorylation were defined. Molecular adaptors comprised one major set including growth factor receptor-bound protein 2 (GRB2)-associated binding proteins 1-3 (GAB1-3), insulin receptor substrate 2 (IRS2), docking protein 1 (DOK1), Src homology 2 domain containing transforming protein 1 (SHC1), and sprouty homologue 1 (SPRY1) as validating targets, and SPRY2, SH2 domain containing 2A (SH2D2A), and signal transducing adaptor molecule 2 (STAM2) as novel candidate adaptors together with an ORF factor designated as regulator of human erythroid cell expansion (RHEX). RHEX is well conserved in Homo sapiens and primates but absent from mouse, rat, and lower vertebrate genomes. Among tissues and lineages, RHEX was elevated in EPCs, occurred as a plasma membrane protein, was rapidly PY-phosphorylated >20-fold upon EPO exposure, and coimmunoprecipitated with the EPOR. In UT7epo cells, knockdown of RHEX inhibited EPO-dependent growth. This was associated with extracellular signal-regulated kinase 1,2 (ERK1,2) modulation, and RHEX coupling to GRB2. In primary human EPCs, shRNA knockdown studies confirmed RHEX regulation of erythroid progenitor expansion and further revealed roles in promoting the formation of hemoglobinizing erythroblasts. RHEX therefore comprises a new EPO/EPOR target and regulator of human erythroid cell expansion that additionally acts to support late-stage erythroblast development. PMID:25092874

  15. Regulation of CCAAT/enhancer-binding protein (C/EBP) α in human-cytomegalovirus-infected fibroblasts.

    PubMed

    Lee, Junsub; Kim, Sunyoung

    2016-05-01

    CCAAT/enhancer-binding protein (C/EBP) α, a member of the C/EBP family of transcription factors, is known to be involved in gene expression and DNA replication of human cytomegalovirus (HCMV). This study aimed to understand the regulation of endogenous C/EBPα during HCMV infection using an in vitro infection model. The expression and localization of C/EBPα were investigated in fibroblasts infected with HCMV. The overexpression of C/EBP homologous protein (CHOP), the endogenous inhibitor of C/EBP, was also employed to test the involvement of C/EBPα during HCMV infection. Our data showed that HCMV infection increases the expression of the full-length C/EBPα isoform (p42) especially during the late stage of infection at the transcriptional and post-translational levels. The increased p42 accumulated in the viral DNA replication compartment. p42 expression was not induced in cells treated with UV-irradiated virus or in cells infected with normal virus in the presence of ganciclovir. CHOP-mediated inhibition of C/EBP activity suppressed viral gene expression and DNA replication, which lowered the level of viral production. Together, our data suggest that HCMV-mediated C/EBPα regulation might play a beneficial role in the lytic cycle of HCMV. PMID:26831934

  16. Andrographolide inhibits intracellular Chlamydia trachomatis multiplication and reduces secretion of proinflammatory mediators produced by human epithelial cells

    PubMed Central

    Hua, Ziyu; Frohlich, Kyla M.; Zhang, Yan; Feng, Xiaogeng; Zhang, Jiaxing; Shen, Li

    2014-01-01

    Chlamydia trachomatis is the most common sexually transmitted bacterial disease worldwide. Untreated C. trachomatis infections may cause inflammation and ultimately damage tissues. Here, we evaluated the ability of Andrographolide (Andro), a natural diterpenoid lactone component of Andrographis paniculata, to inhibit C. trachomatis infection in cultured human cervical epithelial cells. We found that Andro exposure inhibited C. trachomatis growth in a dose- and time-dependent manner. The greatest inhibitory effect was observed when exponentially growing C. trachomatis was exposed to Andro. Electron micrographs demonstrated the accumulation of unusual, structurally deficient chlamydial organisms, correlated with a decrease in levels of OmcB expressed at the late stage of infection. Additionally, Andro significantly reduced the secretion of interleukin6, CXCL8 and interferon-γ-induced protein10 produced by host cells infected with C. trachomatis. These results indicate the efficacy of Andro to perturb C. trachomatis transition from the metabolically active reticulate body to the infectious elementary body and concurrently reduce the production of a proinflammatory mediator by epithelial cells in vitro. Further dissection of Andro's anti-Chlamydia action may provide identification of novel therapeutic targets. PMID:25854005

  17. Increases in c-Yes expression level and activity promote motility but not proliferation of human colorectal carcinoma cells.

    PubMed

    Barraclough, Jane; Hodgkinson, Cassandra; Hogg, Alison; Dive, Caroline; Welman, Arkadiusz

    2007-09-01

    Increases in the levels and/or activity of nonreceptor tyrosine kinases c-Src and c-Yes are often associated with colorectal carcinogenesis. The physiological consequences of increased c-Yes activity during the early and late stages of tumorigenesis, in addition to the degree of redundancy between c-Yes and c-Src in colorectal cancer cells, remain elusive. To study the consequences of increases in c-Yes levels and activity in later stages of colorectal carcinogenesis, we developed human colorectal cancer cell lines in which c-Yes levels and activity can be inducibly increased by a tightly controlled expression of wild-type c-Yes or by constitutively active mutants of c-Yes, c-YesY537F, and c-Yes Delta t6aa. c-Yes induction resulted in increased cell motility but did not promote proliferation either in vitro or in vivo. These results suggest that in later stages of colorectal carcinogenesis, elevations in c-Yes levels/activity may promote cancer spread and metastasis rather than tumor growth.

  18. Filamin A Protein Interacts with Human Immunodeficiency Virus Type 1 Gag Protein and Contributes to Productive Particle Assembly*

    PubMed Central

    Cooper, JoAnn; Liu, Ling; Woodruff, Elvin A.; Taylor, Harry E.; Goodwin, J. Shawn; D'Aquila, Richard T.; Spearman, Paul; Hildreth, James E. K.; Dong, Xinhong

    2011-01-01

    HIV-1 Gag precursor directs virus particle assembly and release. In a search for Gag-interacting proteins that are involved in late stages of the HIV-1 replication cycle, we performed yeast two-hybrid screening against a human cDNA library and identified the non-muscle actin filament cross-linking protein filamin A as a novel Gag binding partner. The 280-kDa filamin A regulates cortical actin network dynamics and participates in the anchoring of membrane proteins to the actin cytoskeleton. Recent studies have shown that filamin A facilitates HIV-1 cell-to-cell transmission by binding to HIV receptors and coreceptors and regulating their clustering on the target cell surface. Here we report a novel role for filamin A in HIV-1 Gag intracellular trafficking. We demonstrate that filamin A interacts with the capsid domain of HIV-1 Gag and that this interaction is involved in particle release in a productive manner. Disruption of this interaction eliminated Gag localization at the plasma membrane and induced Gag accumulation within internal compartments. Moreover, blocking clathrin-dependent endocytic pathways did not relieve the restriction to particle release induced by filamin A depletion. These results suggest that filamin A is involved in the distinct step of the Gag trafficking pathway. The discovery of the Gag-filamin A interaction may provide a new therapeutic target for the treatment of HIV infection. PMID:21705339

  19. Shape of the intercondylar notch of the human femur: a comparison of osteoarthritic and non-osteoarthritic bones from a skeletal sample

    PubMed Central

    Shepstone, L; Rogers, J; Kirwan, J; Silverman, B

    2001-01-01

    OBJECTIVES—To compare objectively the shape of the intercondylar notch in human osteoarthritic and non-osteoarthritic femora.
METHODS—A sample of 96 human femora from a large skeletal population were selected for study. These femora included subjects with evidence of late stage osteoarthritis (that is, with eburnation present) and subjects with no such evidence. The distal end of the femur, viewed axially, was recorded with a video camera, and digitised computer images were produced. The outline of the intercondylar notch was extracted and represented mathematically as two functions. A functional principal components analysis was used to identify important modes of shape variation. These variations in shape were compared between eburnated and non-eburnated femora.
RESULTS—A statistically significant difference in the shape of the intercondylar notch was found between the two groups. The difference related mostly to the shape of the edge of the medial condyle: in the non-osteoarthritic group this tended to exhibit a concavity; in the osteoarthritic group it tended to be straight.
CONCLUSIONS—This observed difference may be a predisposing factor to the development of osteoarthritis. The morphology of the intercondylar notch is related to the functioning of and possible damage to the cruciate ligaments, and damage to the cruciate ligaments is a known risk factor for osteoarthritis. Alternatively, this difference may be due to bony remodelling secondary to the onset of osteoarthritis, perhaps in response to altered biomechanics.

 PMID:11557655

  20. Autophagy in human skin fibroblasts: Comparison between young and aged cells and evaluation of its cellular rhythm and response to Ultraviolet A radiation.

    PubMed

    Pernodet, Nadine; Dong, Kelly; Pelle, Edward

    2016-01-01

    Autophagic mechanisms play critical roles in cell maintenance. Damaged organelles that are not removed by autophagosomes, which act by engulfing and degrading these cellular components, have been linked to various pathologies. Recently, the progression of aging has also been correlated to a compromised autophagic response. Here, we report for the first time a significant reduction in autophagic levels in synchronized aged normal human skin fibroblasts as compared to young fibroblasts. We measured a 77.9% reduction in autophagy as determined by reverse transcription-polymerase chain reaction for LC3B expression, a microtubule-associated protein correlated to late stage autophagosome formation. In addition, we visualized these same changes by immunocytofluorescence with antibodies directed against LC3B. By harvesting synchronized, as well as unsynchronized cells over time, we were also able to measure for the first time a nighttime peak in autophagy that was present in young but absent in aged fibroblasts. Finally, since human skin is constantly subjected to environmentally induced oxidative stress from sunlight, we exposed fibroblasts to 10 J/cm2 ultraviolet A and found, in good agreement with current literature, not only that irradiation could partially reactivate autophagy in the aged cells, but also that this increase was phase shifted earlier from its endogenous temporal pattern because of its loss of synchronization with circadian rhythm.

  1. Novel region within the V kappa gene promoter is responsible for tissue and stage-specific expression of immunoglobulin genes in human lymphoid neoplasms.

    PubMed

    Kossakowska, A E; Urbanski, S J

    1989-03-01

    Immunoglobulin gene-specific transacting factors have been shown to play a role in lymphoid tissue-specific expression of immunoglobulin genes. The role of these factors in B-cell differentiation and stage-specific expression of these genes is, however, not fully understood. We have used a model of human lymphoid neoplasia to address this question. Different fragments of unrearranged human variable region of immunoglobulin kappa gene (V kappa) were used for cell-free in vitro transcription and DNA mobility shift assays. Previously described enhancement of in vitro transcription that was only seen with nuclear extracts derived from B-cell neoplasms corresponding to the late stages of B-cell differentiation was shown to be dependent on the actions of these factor(s) on the DNA region within the V kappa gene promoter. This region is located within the 920 bp fragment located 210 bp upstream from the coding region and this fragment represents a possible novel DNA region, which plays a role in the stage- and tissue-specific expression of immunoglobulin genes.

  2. Enhanced production of the chemotactic cytokines interleukin-8 and monocyte chemoattractant protein-1 in human abdominal aortic aneurysms.

    PubMed Central

    Koch, A. E.; Kunkel, S. L.; Pearce, W. H.; Shah, M. R.; Parikh, D.; Evanoff, H. L.; Haines, G. K.; Burdick, M. D.; Strieter, R. M.

    1993-01-01

    Inflammatory leukocytes play a central role in the pathogenesis of human atherosclerotic disease, from early atherogenesis to the late stages of atherosclerosis, such as aneurysm formation. We have shown previously that human abdominal aortic aneurysms are characterized by the presence of numerous chronic inflammatory cells throughout the vessel wall (Am J Pathol 1990, 137: 1199-1213). The signals that attract lymphocytes and monocytes into the aortic wall in aneurysmal disease remain to be precisely defined. We have studied the production of the chemotactic cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) by aortic tissues obtained from 47 subjects. We compared the antigenic production of these cytokines by explants of: 1) human abdominal aneurysmal tissue, 2) occlusive (atherosclerotic) aortas, and 3) normal aortas. IL-8, which is chemotactic for neutrophils, lymphocytes, and endothelial cells was liberated in greater quantities by abdominal aortic aneurysms than by occlusive or normal aortas. Using immunohistochemistry, macrophages, and to a lesser degree endothelial cells, were found to be positive for the expression of antigenic IL-8. Similarly, MCP-1, a potent chemotactic cytokine for monocytes/macrophages, was released by explants from abdominal aortic aneurysms in greater quantities than by explants from occlusive or normal aortas. Using immunohistochemistry, the predominant MCP-1 antigen-positive cells were macrophages and to a lesser extent smooth muscle cells. Our results indicate that human abdominal aortic aneurysms produce IL-8 and MCP-1, both of which may serve to recruit additional inflammatory cells into the abdominal aortic wall, hence perpetuating the inflammatory reaction that may result in the pathology of vessel wall destruction and aortic aneurysm formation. Images Figure 2 Figure 3 Figure 4 Figure 5 PMID:8494046

  3. BMP15 suppresses progesterone production by down-regulating StAR via ALK3 in human granulosa cells.

    PubMed

    Chang, Hsun-Ming; Cheng, Jung-Chien; Klausen, Christian; Leung, Peter C K

    2013-12-01

    In addition to somatic cell-derived growth factors, oocyte-derived growth differentiation factor (GDF)9 and bone morphogenetic protein (BMP)15 play essential roles in female fertility. However, few studies have investigated their effects on human ovarian steroidogenesis, and fewer still have examined their differential effects or underlying molecular determinants. In the present study, we used immortalized human granulosa cells (SVOG) and human granulosa cell tumor cells (KGN) to compare the effects of GDF9 and BMP15 on steroidogenic enzyme expression and investigate potential mechanisms of action. In SVOG cells, neither GDF9 nor BMP15 affects the mRNA levels of P450 side-chain cleavage enzyme or 3β-hydroxysteroid dehydrogenase. However, treatment with BMP15, but not GDF9, significantly decreases steroidogenic acute regulatory protein (StAR) mRNA and protein levels as well as progesterone production. These suppressive effects, along with the induction of Sma and Mad-related protein (SMAD)1/5/8 phosphorylation, are attenuated by cotreatment with 2 different BMP type I receptor inhibitors (dorsomorphin and DMH-1). Furthermore, depletion of activin receptor-like kinase (ALK)3 using small interfering RNA reverses the effects of BMP15 on SMAD1/5/8 phosphorylation and StAR expression. Similarly, knockdown of ALK3 abolishes BMP15-induced SMAD1/5/8 phosphorylation in KGN cells. These results provide evidence that oocyte-derived BMP15 down-regulates StAR expression and decreases progesterone production in human granulosa cells, likely via ALK3-mediated SMAD1/5/8 signaling. Our findings suggest that oocyte may play a critical role in the regulation of progesterone to prevent premature luteinization during the late stage of follicle development.

  4. The pisiform growth plate is lost in humans and supports a role for Hox in growth plate formation

    PubMed Central

    Kjosness, Kelsey M; Hines, Jasmine E; Lovejoy, C Owen; Reno, Philip L

    2014-01-01

    The human pisiform is a small, nodular, although functionally significant, bone of the wrist. In most other mammals, including apes and Australopithecus afarensis, pisiforms are elongate. An underappreciated fact is that the typical mammalian pisiform forms from two ossification centers. We hypothesize that: (i) the presence of a secondary ossification center in mammalian pisiforms indicates the existence of a growth plate; and (ii) human pisiform reduction results from growth plate loss. To address these hypotheses, we surveyed African ape pisiform ossification and confirmed the presence of a late-forming secondary ossification center in chimpanzees and gorillas. Identification of the initial ossification center occurs substantially earlier in apes relative to humans, raising questions concerning the homology of the human pisiform and the two mammalian ossification centers. Second, we conducted histological and immunohistochemical analyses of pisiform ossification in mice. We confirm the presence of two ossification centers separated by organized columnar and hypertrophic chondrocyte zones. Flattened chondrocytes were highly mitotic, indicating the presence of a growth plate. Hox genes have been proposed to play a fundamental role in growth plate patterning. The existence of a pisiform growth plate presents an interesting test case for the association between Hox expression and growth plate formation, and could explain the severe effects on the pisiform observed in Hoxa11 and Hoxd11 knockout mice. Consistent with this hypothesis, we show that Hoxd11 is expressed adjacent to the pisiform in late-stage embryonic mouse limbs supporting a role for Hox genes in growth plate specification. This raises questions concerning the mechanisms regulating Hox expression in the developing carpus. PMID:25279687

  5. Human Trafficking

    MedlinePlus

    ... TRAFFICKING (English) Listen < Back to Search FACT SHEET: HUMAN TRAFFICKING (English) Published: August 2, 2012 Topics: Public Awareness , ... organizations that protect and serve trafficking victims. National Human Trafficking Resource Center at 1.888.373.7888 Last ...

  6. Human Rights/Human Needs.

    ERIC Educational Resources Information Center

    Canning, Cynthia

    1978-01-01

    The faculty of Holy Names High School developed an interdisciplinary human rights program with school-wide activities focusing on three selected themes: the United Nations Universal Declaration of Human Rights, in conjunction with Human Rights Week; Food; and Women. This article outlines major program activities. (SJL)

  7. Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

    PubMed Central

    Pizzuto, Matteo S.; Silic-Benussi, Micol; Pavone, Silvia; Ciminale, Vincenzo; Capua, Ilaria

    2014-01-01

    ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of human cancer, with dismal survival rates due to late-stage diagnoses and a lack of efficacious therapies. Building on the observation that avian influenza A viruses (IAVs) have a tropism for the pancreas in vivo, the present study was aimed at testing the efficacy of IAVs as oncolytic agents for killing human PDA cell lines. Receptor characterization confirmed that human PDA cell lines express the alpha-2,3- and the alpha-2,6-linked glycan receptor for avian and human IAVs, respectively. PDA cell lines were sensitive to infection by human and avian IAV isolates, which is consistent with this finding. Growth kinetic experiments showed preferential virus replication in PDA cells over that in a nontransformed pancreatic ductal cell line. Finally, at early time points posttreatment, infection with IAVs caused higher levels of apoptosis in PDA cells than gemcitabine and cisplatin, which are the cornerstone of current therapies for PDA. In the BxPC-3 PDA cell line, apoptosis resulted from the engagement of the intrinsic mitochondrial pathway. Importantly, IAVs did not induce apoptosis in nontransformed pancreatic ductal HPDE6 cells. Using a model based on the growth of a PDA cell line as a xenograft in SCID mice, we also show that a slightly pathogenic avian IAV significantly inhibited tumor growth following intratumoral injection. Taken together, these results are the first to suggest that IAVs may hold promise as future agents of oncolytic virotherapy against pancreatic ductal adenocarcinomas. IMPORTANCE Despite intensive studies aimed at designing new therapeutic approaches, PDA still retains the most dismal prognosis among human cancers. In the present study, we provide the first evidence indicating that avian IAVs of low pathogenicity display a tropism for human PDA cells, resulting in viral RNA replication and a potent induction of apoptosis in vitro and antitumor effects in vivo. These

  8. Late stage Imbrium volcanism on the Moon: Evidence for two source regions and implications for the thermal history of Mare Imbrium

    NASA Astrophysics Data System (ADS)

    Zhang, F.; Zhu, M.-H.; Zou, Y. L.

    2016-07-01

    Large open fissures or volcanic rifts can form in volcanic terrain and they are also conduits for magma ascending through the lunar crust. On the Moon, we investigated two volcanic source regions within Mare Imbrium by tracking surface morphologic features and compositional information. The Euler source region is situated at the southwest edge of the basin, while the Lambert source region lies off the south margin of the Imbrium mascon. Survey of dike surface manifestations in Euler source site suggest that dikes are the possible source of the local upper basaltic flows and the last lava phases with well developed scarps near the Euler crater, which extend northeast to the basin center. The Euler dike swarm are radial to the basin and reveal possible dike-to-conduit transition mechanism. They reveal radial subsurface fractures which may be tensional cracks preceding to the emplacement of the last stage of the mare fill. Of these, the largest dike has a more than 100 km length. The spatial arrangement of tectonic and volcanic features in Lambert source site is directly or indirectly controlled by the regional compression and extension stresses associated with flexure in response to mascon and basalt loading. In addition, compositional variation trends show a general southwest-to-northeast flooding direction of the exposed high-Ti basalts. This will have important implications for both the Imbrium basin's mare volcanism and for the thermal evolution of Mare Imbrium and the Moon.

  9. Experimental oral transmission of chronic wasting disease to red deer (Cervus elaphus elaphus): Early detection and late stage distribution of protease-resistant prion protein

    PubMed Central

    Balachandran, Aru; Harrington, Noel P.; Algire, James; Soutyrine, Andrei; Spraker, Terry R.; Jeffrey, Martin; González, Lorenzo; O’Rourke, Katherine I.

    2010-01-01

    Chronic wasting disease (CWD), an important emerging prion disease of cervids, is readily transmitted by intracerebral or oral inoculation from deer-to-deer and elk-to-elk, suggesting the latter is a natural route of exposure. Studies of host range susceptibility to oral infection, particularly of those species found in habitats where CWD currently exists are imperative. This report describes the experimental transmission of CWD to red deer following oral inoculation with infectious CWD material of elk origin. At 18 to 20 months post-inoculation, mild to moderate neurological signs and weight loss were observed and animals were euthanized and tested using 3 conventional immunological assays. The data indicate that red deer are susceptible to oral challenge and that tissues currently used for CWD diagnosis show strong abnormal prion (PrPCWD) accumulation. Widespread peripheral PrPCWD deposition involves lymphoreticular tissues, endocrine tissues, and cardiac muscle and suggests a potential source of prion infectivity, a means of horizontal transmission and carrier state. PMID:20436863

  10. Geological and 40Ar/39Ar age constraints on late-stage Deccan rhyolitic volcanism, inter-volcanic sedimentation, and the Panvel flexure from the Dongri area, Mumbai

    NASA Astrophysics Data System (ADS)

    Sheth, Hetu C.; Pande, Kanchan

    2014-04-01

    Post-K-Pg Boundary Deccan magmatism is well known from the Mumbai area in the Panvel flexure zone. Represented by the Salsette Subgroup, it shows characters atypical of much of the Deccan Traps, including rhyolite lavas and tuffs, mafic tuffs and breccias, spilitic pillow basalts, and "intertrappean" sedimentary or volcanosedimentary deposits, with mafic intrusions as well as trachyte intrusions containing basaltic enclaves. The intertrappean deposits have been interpreted as formed in shallow marine or lagoonal environments in small fault-bounded basins due to syn-volcanic subsidence. We report a previously unknown sedimentary deposit underlying the Dongri rhyolite flow from the upper part of the Salsette Subgroup, with a westerly tectonic dip due to the Panvel flexure. We have obtained concordant 40Ar/39Ar ages of 62.6 ± 0.6 Ma (2σ) and 62.9 ± 0.2 Ma (2σ) for samples taken from two separate outcrops of this rhyolite. The results are significant in showing that (i) Danian inter-volcanic sedimentary deposits formed throughout Mumbai, (ii) the rock units are consistent with the stratigraphy postulated earlier for Mumbai, (iii) shale fragments known in some Dongri tuffs were likely derived from the sedimentary deposit under the Dongri rhyolite, (iv) the total duration of extrusive and intrusive Deccan magmatism was at least 8-9 million years, and (v) Panvel flexure formed, or continued to form, after 63 Ma, possibly even 62 Ma, and could not have formed by 65-64 Ma as concluded in a recent study.

  11. Stable Isotope Variability of Altered Sanidine Feldspars within the Bear Lodge Alkaline Intrusive Complex, Wyoming: Implications for Mineral Exploration Near a Late-Stage Carbonatite Ore Body

    NASA Astrophysics Data System (ADS)

    Mulvaney-Norris, J. L.; Larson, P. B.

    2015-12-01

    In a brecciated intrusive complex, mineral assemblages from non-ore-stage hydrothermal alteration may be mistakenly associated with ore body emplacement during exploration. The ability to differentiate mineralizing from non-mineralizing alteration by stable isotope analysis, and to map the fluid pathways, is a useful tool for future exploration. The Bull Hill diatreme, central Bear Lodge Mountains, contains porphyritic alkaline clasts and cross-cutting megacrystic sanidine trachyte dikes. The K feldspar (Kfs) phenocrysts reacted with and recorded the passage of hydrothermal fluids, likely derived from post-diatreme carbonatite intrusions. A study of the δ18O values of Kfs in the complex can assist mineralization mapping by revealing the late hydrothermal fluid pathways and provenance. Dike and breccia samples were split from three drill holes at regular distances, moving away from carbonatite dikes and large veins. Eighteen samples were prepared for oxygen isotope analysis by physical separation of megacrysts, or by crushing and hand-picking Kfs fragments from the breccia. A carbonatite Kfs sample was prepared by partial HCl digestion. Oxygen isotope ratios were measured at the Washington State University GeoAnalytical Laboratory using a Finnegan Delta S Mass Spectrometer. Kfs δ18O values range between 7.69‰ and 9.09‰ in the diatreme breccia xenocrysts, 5.28‰ to 8.12‰ in the megacrystic dike phenocrysts, and 7.15‰ in the carbonatite phenocrysts. Results suggest no clear relationship between the δ18O values in Kfs and the different phases of intrusion. This may be due to δ18O variability introduced by zoned and multi-crystal samples, limited variations of δ18O values among intrusion fluids, or that the final carbonatite intrusion pervasively altered all samples within the study area. Therefore, this method may not be particularly useful for identifying potential ore-bearing units in the Bear Lodge Intrusive Complex.

  12. Altered cellular infiltration and cytokine levels during early Mycobacterium tuberculosis sigC mutant infection are associated with late-stage disease attenuation and milder immunopathology in mice

    PubMed Central

    Abdul-Majid, Khairul-Bariah; Ly, Lan H; Converse, Paul J; Geiman, Deborah E; McMurray, David N; Bishai, William R

    2008-01-01

    Background Mouse virulence assessments of certain Mycobacterium tuberculosis mutants have revealed an immunopathology defect in which high tissue CFU counts are observed but the tissue pathology and lethality are reduced. M. tuberculosis mutants which grow and persist in the mouse lungs, but have attenuated disease progression, have the immunopathology (imp) phenotype. The antigenic properties of these strains may alter the progression of disease due to a reduction in host immune cell recruitment to the lungs resulting in disease attenuation and prolonged host survival. Results In this study we focused on the mouse immune response to one such mutant; the M. tuberculosis ΔsigC mutant. Aerosol infection of DBA/2 and SCID mice with the M. tuberculosis ΔsigC mutant, complemented mutant and wild type strain showed proliferation of mutant bacilli in mouse lungs, but with decreased inflammation and mortality in DBA/2 mice. SCID mice shared the same phenotype as the DBA/2 mice in response to the ΔsigC mutant, however, they succumbed to the infection faster. Bronchoalveolar lavage (BAL) fluid analysis revealed elevated numbers of infiltrating neutrophils in the lungs of mice infected with wild type and complemented ΔsigC mutant strains but not in mice infected with the ΔsigC mutant. In addition, DBA/2 mice infected with the ΔsigC mutant had reduced levels of TNF-α, IL-1β, IL-6 and IFN-γ in the lungs. Similarly, there was a reduction in proinflammatory cytokines in the lungs of SCID mice. In contrast to the mouse model, the ΔsigC mutant had reduced initial growth in guinea pig lungs. A possible mechanism of attenuation in the ΔsigC mutant may be a reduction in neutrophilic-influx in the alveolar spaces of the lungs, and decreased proinflammatory cytokine secretion. In contrast to mouse data, the M. tuberculosis ΔsigC mutant proliferates slowly in guinea pig lungs, a setting characterized by caseating necrosis. Conclusion Our observations suggest that the immunopathology phenotype is associated with the inability to trigger a strong early immune response, resulting in disease attenuation. While macrophages and T cells have been shown to be important in containing M. tuberculosis disease our study has shown that neutrophils may also play an important role in the containment of this organism. PMID:18798983

  13. Nuclear substructure reorganization during late-stage erythropoiesis is selective and does not involve caspase cleavage of major nuclear substructural proteins.

    PubMed

    Krauss, Sharon Wald; Lo, Annie J; Short, Sarah A; Koury, Mark J; Mohandas, Narla; Chasis, Joel Anne

    2005-09-15

    Enucleation, a rare feature of mammalian differentiation, occurs in 3 cell types: erythroblasts, lens epithelium, and keratinocytes. Previous investigations suggest that caspase activation functions in lens epithelial and keratinocyte enucleation, as well as in early erythropoiesis encompassing erythroid burst-forming unit (BFU-E) differentiation to proerythroblast. To determine whether caspase activation contributes to later erythropoiesis and whether nuclear substructures other than chromatin reorganize, we analyzed distributions of nuclear subcompartment proteins and assayed for caspase-induced cleavage of subcompartmental target proteins in mouse erythroblasts. We found that patterns of lamin B in the filamentous network interacting with both the nuclear envelope and DNA, nuclear matrix protein NuMA (Nuclear mitotic apparatus), and splicing factors Sm and SC35 persisted during nuclear condensation, consistent with effective transcription of genes expressed late in differentiation. Thus, nuclear reorganization prior to enucleation is selective, allowing maintenance of critical transcriptional processes independent of extensive chromosomal reorganization. Consistent with these data, we found no evidence for caspase-induced cleavage of major nuclear subcompartment proteins during late erythropoiesis, in contrast to what has been observed in early erythropoiesis and in lens epithelial and keratinocyte differentiation. These findings imply that nuclear condensation and extrusion during terminal erythroid differentiation involve novel mechanisms that do not entail major activation of apoptotic machinery.

  14. The late stages of the Pampean Orogeny, Córdoba (Argentina): Evidence of postcollisional Early Cambrian slab break-off magmatism

    NASA Astrophysics Data System (ADS)

    Ramos, Victor A.; Escayola, Mónica; Leal, Pablo; Pimentel, Marcio M.; Santos, João O. S.

    2015-12-01

    Widespread rhyolitic and mafic volcanism in the northern and southern sectors respectively of Eastern Sierras Pampeanas, central western Argentina, are associated with an important phase of extension and uplift linked to slab break-off on latest stages of the Pampean Orogeny. The main orogenic deformation took place between 540 and 535 Ma based on new ages available for this region. New U-Pb ages in zircons from the Oncán Rhyolite and new and old recalculated zircons from Los Burros Rhyodacite in the northern sector of Sierras de Córdoba, together with new U-Pb ages of the southern sector, indicate that volcanic and subvolcanic rocks of both sectors are partially coeval and unconformably overlying and/or intruding the basement rocks during a period of exhumation and subsequent cooling at 530-520 Ma. These data are in agreement with previous estimates for the final uplift of the Sierras de Córdoba based on the K-Ar cooling ages. The southern sector of Eastern Sierras Pampeanas may represent deeper structural levels within the crust and is characterized by the occurrence of small mafic bodies with OIB-like signature. New and reinterpreted U-Pb SHRIMP and TIMS ages on zircons and monazites in the metamorphic associated rocks date this episode, which is related to a rapid slab break-off event at 519-515 Ma. This episode is also associated with the emplacement of peraluminous granitoids, and with the extension, cooling and final uplift of the rocks affected by the Pampean Orogeny all along the Eastern Sierras Pampeanas.

  15. A young Moon-forming giant impact at 70-110 million years accompanied by late-stage mixing, core formation and degassing of the Earth.

    PubMed

    Halliday, Alex N

    2008-11-28

    New W isotope data for lunar metals demonstrate that the Moon formed late in isotopic equilibrium with the bulk silicate Earth (BSE). On this basis, lunar Sr isotope data are used to define the former composition of the Earth and hence the Rb-Sr age of the Moon, which is 4.48+/-0.02Ga, or 70-110Ma (million years) after the start of the Solar System. This age is significantly later than had been deduced from W isotopes based on model assumptions or isotopic effects now known to be cosmogenic. The Sr age is in excellent agreement with earlier estimates based on the time of lunar Pb loss and the age of the early lunar crust (4.46+/-0.04Ga). Similar ages for the BSE are recorded by xenon and lead-lead, providing evidence of catastrophic terrestrial degassing, atmospheric blow-off and significant late core formation accompanying the ca 100Ma giant impact. Agreement between the age of the Moon based on the Earth's Rb/Sr and the lead-lead age of the Moon is consistent with no major losses of moderately volatile elements from the Earth during the giant impact. The W isotopic composition of the BSE can be explained by end member models of (i) gradual accretion with a mean life of roughly 35Ma or (ii) rapid growth with a mean life of roughly 10Ma, followed by a significant hiatus prior to the giant impact. The former assumes that approximately 60 per cent of the incoming metal from impactors is added directly to the core during accretion. The latter includes complete mixing of all the impactor material into the BSE during accretion. The identical W isotopic composition of the Moon and the BSE limits the amount of material that can be added as a late veneer to the Earth after the giant impact to less than 0.3+/-0.3 per cent of ordinary chondrite or less than 0.5+/-0.6 per cent CI carbonaceous chondrite based on their known W isotopic compositions. Neither of these on their own is sufficient to explain the inventories of both refractory siderophiles such as platinum group elements and rhenium, and volatiles such as sulphur, carbon and water. PMID:18826916

  16. Developmental exposure of aflatoxin B1 reversibly affects hippocampal neurogenesis targeting late-stage neural progenitor cells through suppression of cholinergic signaling in rats.

    PubMed

    Tanaka, Takeshi; Mizukami, Sayaka; Hasegawa-Baba, Yasuko; Onda, Nobuhiko; Sugita-Konishi, Yoshiko; Yoshida, Toshinori; Shibutani, Makoto

    2015-10-01

    To elucidate the maternal exposure effects of aflatoxin B1 (AFB1) and its metabolite aflatoxin M1, which is transferred into milk, on postnatal hippocampal neurogenesis, pregnant Sprague-Dawley rats were provided a diet containing AFB1 at 0, 0.1, 0.3, or 1.0 ppm from gestational day 6 to day 21 after delivery on weaning. Offspring were maintained through postnatal day (PND) 77 without AFB1 exposure. Following exposure to 1.0 ppm AFB1, offspring showed no apparent systemic toxicity at weaning, whereas dams showed increased liver weight and DNA repair gene upregulation in the liver. In the hippocampal dentate gyrus of male PND 21 offspring, the number of doublecortin(+) progenitor cells were decreased, which was associated with decreased proliferative cell population in the subgranular zone at ≥ 0.3 ppm, although T-box brain 2(+) cells, tubulin beta III(+) cells, gamma-H2A histone family, member X(+) cells, and cyclin-dependent kinase inhibitor 1A(+) cells did not fluctuate in number. AFB1 exposure examined at 1.0 ppm also resulted in transcript downregulation of the cholinergic receptor subunit Chrna7 and dopaminergic receptor Drd2 in the dentate gyrus, although there was no change in transcript levels of DNA repair genes. In the hippocampal dentate hilus, interneurons expressing CHRNA7 or phosphorylated tropomyosin receptor kinase B (TRKB) decreased at ≥ 0.3 ppm. On PND 77, there were no changes in neurogenesis-related parameters. These results suggested that maternal AFB1 exposure reversibly affects hippocampal neurogenesis targeting type-3 progenitor cells. This mechanism likely involves suppression of cholinergic signals on hilar GABAergic interneurons and brain-derived neurotrophic factor-TRKB signaling from granule cells. The no-observed-adverse-effect level for offspring neurogenesis was determined to be 0.1 ppm (7.1-13.6 mg/kg body weight/day).

  17. A young Moon-forming giant impact at 70-110 million years accompanied by late-stage mixing, core formation and degassing of the Earth.

    PubMed

    Halliday, Alex N

    2008-11-28

    New W isotope data for lunar metals demonstrate that the Moon formed late in isotopic equilibrium with the bulk silicate Earth (BSE). On this basis, lunar Sr isotope data are used to define the former composition of the Earth and hence the Rb-Sr age of the Moon, which is 4.48+/-0.02Ga, or 70-110Ma (million years) after the start of the Solar System. This age is significantly later than had been deduced from W isotopes based on model assumptions or isotopic effects now known to be cosmogenic. The Sr age is in excellent agreement with earlier estimates based on the time of lunar Pb loss and the age of the early lunar crust (4.46+/-0.04Ga). Similar ages for the BSE are recorded by xenon and lead-lead, providing evidence of catastrophic terrestrial degassing, atmospheric blow-off and significant late core formation accompanying the ca 100Ma giant impact. Agreement between the age of the Moon based on the Earth's Rb/Sr and the lead-lead age of the Moon is consistent with no major losses of moderately volatile elements from the Earth during the giant impact. The W isotopic composition of the BSE can be explained by end member models of (i) gradual accretion with a mean life of roughly 35Ma or (ii) rapid growth with a mean life of roughly 10Ma, followed by a significant hiatus prior to the giant impact. The former assumes that approximately 60 per cent of the incoming metal from impactors is added directly to the core during accretion. The latter includes complete mixing of all the impactor material into the BSE during accretion. The identical W isotopic composition of the Moon and the BSE limits the amount of material that can be added as a late veneer to the Earth after the giant impact to less than 0.3+/-0.3 per cent of ordinary chondrite or less than 0.5+/-0.6 per cent CI carbonaceous chondrite based on their known W isotopic compositions. Neither of these on their own is sufficient to explain the inventories of both refractory siderophiles such as platinum group elements and rhenium, and volatiles such as sulphur, carbon and water.

  18. Treatment of late stage disease in a model of arenaviral hemorrhagic fever: T-705 efficacy and reduced toxicity suggests an alternative to ribavirin.

    PubMed

    Gowen, Brian B; Smee, Donald F; Wong, Min-Hui; Hall, Jeffery O; Jung, Kie-Hoon; Bailey, Kevin W; Stevens, John R; Furuta, Yousuke; Morrey, John D

    2008-01-01

    A growing number of arenaviruses are known to cause viral hemorrhagic fever (HF), a severe and life-threatening syndrome characterized by fever, malaise, and increased vascular permeability. Ribavirin, the only licensed antiviral indicated for the treatment of certain arenaviral HFs, has had mixed success and significant toxicity. Since severe arenaviral infections initially do not present with distinguishing symptoms and are difficult to clinically diagnose at early stages, it is of utmost importance to identify antiviral therapies effective at later stages of infection. We have previously reported that T-705, a substituted pyrazine derivative currently under development as an anti-influenza drug, is highly active in hamsters infected with Pichinde virus when the drug is administered orally early during the course of infection. Here we demonstrate that T-705 offers significant protection against this lethal arenaviral infection in hamsters when treatment is begun after the animals are ill and the day before the animals begin to succumb to disease. Importantly, this coincides with the time when peak viral loads are present in most organs and considerable tissue damage is evident. We also show that T-705 is as effective as, and less toxic than, ribavirin, as infected T-705-treated hamsters on average maintain their weight better and recover more rapidly than animals treated with ribavirin. Further, there was no added benefit to combination therapy with T-705 and ribavirin. Finally, pharmacokinetic data indicate that plasma T-705 levels following oral administration are markedly reduced during the latter stages of disease, and may contribute to the reduced efficacy seen when treatment is withheld until day 7 of infection. Our findings support further pre-clinical development of T-705 for the treatment of severe arenaviral infections.

  19. A role for histamine in cardiovascular regulation in late stage embryos of the red-footed tortoise, Chelonoidis carbonaria Spix, 1824.

    PubMed

    Crossley, Dane A; Sartori, Marina R; Abe, Augusto S; Taylor, Edwin W

    2013-08-01

    A chorioallantoic membrane artery in embryos of the red-footed tortoise, Chelonoidis carbonaria was occlusively cannulated for measurement of blood pressure and injection of drugs. Two age groups of embryos in the final 10 % of incubation were categorized by the ratio of embryonic body to yolk mass. All embryos first received cholinergic and β-adrenergic blockade. This revealed that β-adrenergic control was established in both groups whereas cholinergic control was only established in the older group immediately prior to hatching. The study then progressed as two series. Series one was conducted in a subset of embryos treated with histamine before or after injection of ranitidine, the antagonist of H2 receptors. Injection of histamine caused an initial phasic hypertension which recovered, followed by a longer lasting hypertensive response accompanied by a tachycardia. Injection of the H2 receptor antagonist ranitidine itself caused a hypotensive tachycardia with subsequent recovery of heart rate. Ranitidine also abolished the cardiac effects of histamine injection while leaving the initial hypertensive response intact. In series, two embryos were injected with histamine after injection of diphenhydramine, the antagonist to H1 receptors. This abolished the whole of the pressor response to histamine injection but left the tachycardic response intact. These data indicate that histamine acts as a non-adrenergic, non-cholinergic factor, regulating the cardiovascular system of developing reptilian embryos and that its overall effects are mediated via both H1 and H2 receptor types.

  20. Use of the novel Plk1 inhibitor ZK-thiazolidinone to elucidate functions of Plk1 in early and late stages of mitosis.

    PubMed

    Santamaria, Anna; Neef, Rüdiger; Eberspächer, Uwe; Eis, Knut; Husemann, Manfred; Mumberg, Dominik; Prechtl, Stefan; Schulze, Volker; Siemeister, Gerhard; Wortmann, Lars; Barr, Francis A; Nigg, Erich A

    2007-10-01

    Polo-like kinase 1 (Plk1) is a key regulator of mitotic progression and cell division in eukaryotes. It is highly expressed in tumor cells and considered a potential target for cancer therapy. Here, we report the discovery and application of a novel potent small-molecule inhibitor of mammalian Plk1, ZK-Thiazolidinone (TAL). We have extensively characterized TAL in vitro and addressed TAL specificity within cells by studying Plk1 functions in sister chromatid separation, centrosome maturation, and spindle assembly. Moreover, we have used TAL for a detailed analysis of Plk1 in relation to PICH and PRC1, two prominent interaction partners implicated in spindle assembly checkpoint function and cytokinesis, respectively. Specifically, we show that Plk1, when inactivated by TAL, spreads over the arms of chromosomes, resembling the localization of its binding partner PICH, and that both proteins are mutually dependent on each other for correct localization. Finally, we show that Plk1 activity is essential for cleavage furrow formation and ingression, leading to successful cytokinesis.

  1. Changes during late-stage embryonic development from egg-juvenile to free-living hatchling in Chinese freshwater crab Sinopotamon yangtsekiense (Decapoda, Brachyura, Potamidae)

    NASA Astrophysics Data System (ADS)

    Xue, Junzeng; Liu, Yan; Cumberlidge, Neil; Wu, Huixian

    2013-05-01

    This study expands on recent reports that direct development in the Chinese potamid freshwater crab Sinopotamon yangtsekiense involves the completion of all brachyuran larval stages (nauplius, zoea, and megalopa) inside the egg case during embryonic development. Detailed studies of embryonic development in this species revealed the presence of an additional larval stage (the egg-juvenile) between the megalopa and the free-living hatchling crab. We described and compared the appendages of the head, thorax, and abdomen of the egg-juvenile with those of the hatchling crab in S. yangtsekiense. Significant differences were found between most of the appendages of these two stages with a soft exoskeleton in the egg-juvenile, no joint articulation, a slimmer appearance, and a lack of setae when compared with the newly emerged free-living hatchling crab. These modifications of the appendages are related to the confinement within the egg case of the egg-megalopa and egg-juvenile during direct development, and the need for the free-living hatchling freshwater crab to move, feed, and respire. In marine crabs, the megalopa gives rise to the first crab stage whereas in freshwater crabs the egg-juvenile follows the megalopa and immediately precedes the free-living first crab stage.

  2. FK506 binding protein 8 peptidylprolyl isomerase activity manages a late stage of cystic fibrosis transmembrane conductance regulator (CFTR) folding and stability.

    PubMed

    Hutt, Darren M; Roth, Daniela Martino; Chalfant, Monica A; Youker, Robert T; Matteson, Jeanne; Brodsky, Jeffrey L; Balch, William E

    2012-06-22

    Cystic fibrosis (CF) is caused by mutations in the apical chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) with 90% of patients carrying at least one deletion of the F508 (ΔF508) allele. This mutant form of CFTR is characterized by a folding and trafficking defect that prevents exit from the endoplasmic reticulum. We previously reported that ΔF508 CFTR can be recovered in a complex with Hsp90 and its co-chaperones as an on-pathway folding intermediate, suggesting that Δ508 CF disease arises due to a failure of the proteostasis network (PN), which manages protein folding and degradation in the cell. We have now examined the role of FK506-binding protein 8 (FKBP8), a component of the CFTR interactome, during the biogenesis of wild-type and ΔF508 CFTR. FKBP8 is a member of the peptidylprolyl isomerase family that mediates the cis/trans interconversion of peptidyl prolyl bonds. Our results suggest that FKBP8 is a key PN factor required at a post-Hsp90 step in CFTR biogenesis. In addition, changes in its expression level or alteration of its activity by a peptidylprolyl isomerase inhibitor alter CFTR stability and transport. We propose that CF is caused by the sequential failure of the prevailing PN pathway to stabilize ΔF508-CFTR for endoplasmic reticulum export, a pathway that can be therapeutically managed.

  3. Experimental oral transmission of chronic wasting disease to red deer (Cervus elaphus elaphus): Early detection and late stage distribution of protease-resistant prion protein

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic wasting disease CWD is the transmissible spongiform encephalopathy or prion disease of wild and farmed cervid ruminants, including Rocky Mountain elk (Cervus elaphus nelsoni), white tailed deer (Odocoileus virginianus), mule deer (Odocoileus hemionus), or moose (Alces alces). Reliable data ...

  4. Yersinia pestis requires the 2-component regulatory system OmpR-EnvZ to resist innate immunity during the early and late stages of plague.

    PubMed

    Reboul, Angéline; Lemaître, Nadine; Titecat, Marie; Merchez, Maud; Deloison, Gaspard; Ricard, Isabelle; Pradel, Elizabeth; Marceau, Michaël; Sebbane, Florent

    2014-11-01

    Plague is transmitted by fleas or contaminated aerosols. To successfully produce disease, the causal agent (Yersinia pestis) must rapidly sense and respond to rapid variations in its environment. Here, we investigated the role of 2-component regulatory systems (2CSs) in plague because the latter are known to be key players in bacterial adaptation to environmental change. Along with the previously studied PhoP-PhoQ system, OmpR-EnvZ was the only one of Y. pestis' 23 other 2CSs required for production of bubonic, septicemic, and pneumonic plague. In vitro, OmpR-EnvZ was needed to counter serum complement and leukocytes but was not required for the secretion of antiphagocyte exotoxins. In vivo, Y. pestis lacking OmpR-EnvZ did not induce an early immune response in the skin and was fully virulent in neutropenic mice. We conclude that, throughout the course of Y. pestis infection, OmpR-EnvZ is required to counter toxic effectors secreted by polymorphonuclear leukocytes in the tissues.

  5. Differential roles of MMP-9 in early and late stages of dystrophic muscles in a mouse model of Duchenne muscular dystrophy.

    PubMed

    Shiba, Naoko; Miyazaki, Daigo; Yoshizawa, Takahiro; Fukushima, Kazuhiro; Shiba, Yuji; Inaba, Yuji; Imamura, Michihiro; Takeda, Shin'ichi; Koike, Kenichi; Nakamura, Akinori

    2015-10-01

    Matrix metalloprotease (MMP)-9 is an endopeptidase associated with the pathogenesis of Duchenne muscular dystrophy (DMD). The precise function of MMP-9 in DMD has not been elucidated to date. We investigated the effect of genetic ablation of MMP-9 in the mdx mouse model (mdx/Mmp9(-/-)). At the early disease stage, the muscles of mdx/Mmp9(-/-) mice showed reduced necrosis and neutrophil invasion, accompanied by down-regulation of chemokine MIP-2. In addition, muscle regeneration was enhanced, which coincided with increased macrophage infiltration and upregulation of MCP-1, and resulted in increased muscle strength. The mdx/Mmp9(-/-) mice also displayed accelerated upregulation of osteopontin expression in skeletal muscle at the acute onset phase of dystrophy. However, at a later disease stage, the mice exhibited muscle growth impairment through altered expression of myogenic factors, and increased fibroadipose tissue. These results showed that MMP-9 might have multiple functions during disease progression. Therapy targeting MMP-9 may improve muscle pathology and function at the early disease stage, but continuous inhibition of this protein may result in the accumulation of fibroadipose tissues and reduced muscle strength at the late disease stage.

  6. The formation and evolution of youthful gullies on Mars: Gullies as the late-stage phase of Mars’ most recent ice age

    NASA Astrophysics Data System (ADS)

    Dickson, James L.; Head, James W.

    2009-11-01

    Gullies are extremely young erosional/depositional systems on Mars that have been carved by an agent that was likely to have been comprised in part by liquid water [Malin, M.C., Edgett, K.S., 2000. Evidence for recent groundwater seepage and surface runoff on Mars. Science 288, 2330-2335; McEwen, A.S. et al., 2007. A closer look at water-related geologic activity on Mars. Science 317, 1706-1709]. The strong latitude and orientation dependencies that have been documented for gullies require (1) a volatile near the surface, and (2) that insolation is an important factor for forming gullies. These constraints have led to two categories of interpretations for the source of the volatiles: (1) liquid water at depth beneath the melting isotherm that erupts suddenly ("groundwater"), and (2) ice at the surface or within the uppermost layer of soil that melts during optimal insolation conditions ("surface/near-surface melting"). In this contribution we synthesize global, hemispheric, regional and local studies of gullies across Mars and outline the criteria that must be met by any successful explanation for the formation of gullies. We further document trends in both hemispheres that emphasize the importance of top-down melting of recent ice-rich deposits and the cold-trapping of atmospherically-derived H 2O frost/snow as important components in the formation of gullies. This provides context for the incorporation of high-resolution multi-spectral and hyper-spectral data from the Mars Reconnaissance Orbiter that show that (1) cold-trapping of seasonal H 2O frost occurs at the alcove/channel-level on contemporary Mars; (2) gullies are episodically active systems; (3) gullies preferentially form in the presence of deposits plausibly interpreted as remnants of the Late Amazonian emplacement of ice-rich material; and (4) gully channels frequently emanate from the crest of alcoves instead of the base, showing that alcove generation is not necessarily a product of undermining and collapse at these locations, a prediction of the groundwater model. We interpret these various lines of evidence to mean that the majority of gullies on Mars are explained by the episodic melting of atmospherically emplaced snow/ice under spin-axis/orbital conditions characteristic of the last several Myr.

  7. Influence of 2,2',4,4',5,5'-hexachlorobiphenyl on the placental blood flow in Guinea pigs at a late stage of gestation

    SciTech Connect

    Hedman, C.; Bjellin, L.; Martensson, L.

    1985-12-01

    Three groups of primaparous pregnant guinea pigs were fed once daily with a total of either 0 (control group, n = 9), 3 (n = 8), or 30 mg (n = 9) of 2,2',4,4',5,5'-hexachlorobiphenyl (HCB) starting at Day 45 of gestation to evaluate the effects of HCB on placental perfusion. The guinea pigs were separated into their groups randomly. At Day 63 of gestation the organ blood flow was determined with microsphere technique in the awake animal. The results show a statistically significant decrease in the placental blood flow and an increase in the pulmonary blood flow in the animals fed with 30 mg HCB compared to the control groups. A higher incidence of resorptions in fetuses is shown in both treatment groups compared to the control group. It is concluded that ecologically relevant doses of polychlorinated biphenyls might cause a deterioration in the placental function by reducing its blood flow.

  8. Potent efficacy of metronomic topotecan and pazopanib combination therapy in preclinical models of primary or late stage metastatic triple-negative breast cancer

    PubMed Central

    Man, Shan; Bocci, Guido; Kerbel, Robert S.

    2015-01-01

    Metronomic chemotherapy has shown promising activity in numerous preclinical studies and also some phase II clinical studies involving various tumor types, and is currently undergoing phase III trial evaluation. Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Herein, we evaluated the potential therapeutic impact and molecular mechanisms of topotecan administered in a continuous low-dose metronomic (LDM) manner, alone or in concurrent combination with pazopanib, an antiangiogenic tyrosine kinase inhibitor (TKI), in a triple-negative, primary and metastatic breast cancer orthotopic model; potential molecular mechanisms of efficacy were also studied, especially the impact of hypoxic conditions. The combination of metronomic topotecan and pazopanib significantly enhanced antitumor activity compared to monotherapy with either drug and prolonged survival, even in the advanced metastatic survival setting, with a marked decrease in tumor vascularity, proliferative index, and the induction of apoptosis. Significant changes in tumor angiogenesis, cancer cell proliferation, apoptosis, HIF1α levels, HIF-1 target genes and ABCG2 were found both in vitro and in tumor tissue. Notably, the pazopanib and metronomic topotecan combination treatment inhibited expression of HIF1α and ABCG2 genes in cells grown under hypoxic conditions, and this was associated with an increased intracellular concentration of the active form of topotecan. Our results suggest a potential novel therapeutic option for the treatment of metastatic triple-negative breast cancer patients. PMID:26623560

  9. Infection of Mouse Macrophages by Seasonal Influenza Viruses Can Be Restricted at the Level of Virus Entry and at a Late Stage in the Virus Life Cycle

    PubMed Central

    Londrigan, Sarah L.; Short, Kirsty R.; Ma, Joel; Gillespie, Leah; Rockman, Steven P.; Brooks, Andrew G.

    2015-01-01

    ABSTRACT Airway epithelial cells are susceptible to infection with seasonal influenza A viruses (IAV), resulting in productive virus replication and release. Macrophages (MΦ) are also permissive to IAV infection; however, virus replication is abortive. Currently, it is unclear how productive infection of MΦ is impaired or the extent to which seasonal IAV replicate in MΦ. Herein, we compared mouse MΦ and epithelial cells for their ability to support genomic replication and transcription, synthesis of viral proteins, assembly of virions, and release of infectious progeny following exposure to genetically defined IAV. We confirm that seasonal IAV differ in their ability to utilize cell surface receptors for infectious entry and that this represents one level of virus restriction. Following virus entry, we demonstrate synthesis of all eight segments of genomic viral RNA (vRNA) and mRNA, as well as seven distinct IAV proteins, in IAV-infected mouse MΦ. Although newly synthesized hemagglutinin (HA) and neuraminidase (NA) glycoproteins are incorporated into the plasma membrane and expressed at the cell surface, electron microscopy confirmed that virus assembly was defective in IAV-infected MΦ, defining a second level of restriction late in the virus life cycle. IMPORTANCE Seasonal influenza A viruses (IAV) and highly pathogenic avian influenza viruses (HPAI) infect macrophages, but only HPAI replicate productively in these cells. Herein, we demonstrate that impaired virus uptake into macrophages represents one level of restriction limiting infection by seasonal IAV. Following uptake, seasonal IAV do not complete productive replication in macrophages, representing a second level of restriction. Using murine macrophages, we demonstrate that productive infection is blocked late in the virus life cycle, such that virus assembly is defective and newly synthesized virions are not released. These studies represent an important step toward identifying host-encoded factors that block replication of seasonal IAV, but not HPAI, in macrophages. PMID:26423941

  10. Phase 3 Study of Bavituximab Plus Docetaxel Versus Docetaxel Alone in Patients With Late-stage Non-squamous Non-small-cell Lung Cancer

    ClinicalTrials.gov

    2016-02-01

    Non-Small-Cell Lung Cancer Stage IIIB; Non-Small-Cell Lung Cancer Stage IV; Non-Small-Cell Lung Cancer Metastatic; Carcinoma, Non-Small-Cell Lung; Non-Small Cell Lung Cancer; Non-Small-Cell Lung Carcinoma; Nonsmall Cell Lung Cancer

  11. Specific Antibody Production by Blood B Cells is Retained in Late Stage Drug-naïve HIV-infected Africans