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The PolariX TDS (Polarizable X-Band Transverse Deflection Structure) is an innovative TDS-design operating in the X-band frequency-range. The design gives full control of the streaking plane, which can be tuned in order to characterize the projections of the beam distribution onto arbitrary transverse axes. This novel feature opens up new opportunities for detailed characterization of the electron beam. In this paper we present first measurements of the Polarix TDS at the FLASHForward beamline at DESY, including three-dimensional reconstruction of the charge-density distribution of the bunch and slice emittance measurements in both transverse directions. The experimental results open the path toward novel and more extensive beam characterization in the direction of multi-dimensional-beam-phase-space reconstruction.
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Glycogen synthase kinase-3ß (GSK-3ß) has emerged as a critical factor in several pathways involved in hippocampal neuronal maintenance and function. In Huntington's disease (HD), there are early hippocampal deficits both in patients and transgenic mouse models, which prompted us to investigate whether disease-specific changes in GSK-3ß expression may underlie these abnormalities. Thirty-three postmortem hippocampal samples from HD patients (neuropathological grades 2-4) and age- and sex-matched normal control cases were analyzed using real-time quantitative reverse transcription PCRs (qPCRs) and immunohistochemistry. In vitro and in vivo studies looking at hippocampal pathology and GSK-3ß were also undertaken in transgenic R6/2 and wild-type mice. We identified a disease and stage-dependent upregulation of GSK-3ß mRNA and protein levels in the HD hippocampus, with the active isoform pGSK-3ß-Tyr(216) being strongly expressed in dentate gyrus (DG) neurons and astrocytes at a time when phosphorylation of Tau at the AT8 epitope was also present in these same neurons. This upregulation of pGSK-3ß-Tyr(216) was also found in the R6/2 hippocampus in vivo and linked to the increased vulnerability of primary hippocampal neurons in vitro. In addition, the increased expression of GSK-3ß in the astrocytes of R6/2 mice appeared to be the main driver of Tau phosphorylation and caspase3 activation-induced neuronal death, at least in part via an exacerbated production of major proinflammatory mediators. This stage-dependent overactivation of GSK-3ß in HD-affected hippocampal neurons and astrocytes therefore points to GSK-3ß as being a critical factor in the pathological development of this condition. As such, therapeutic targeting of this pathway may help ameliorate neuronal dysfunction in HD.
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Apoptosis , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hipocampo/metabolismo , Enfermedad de Huntington/patología , Proteínas tau/metabolismo , Adulto , Anciano , Animales , Astrocitos/citología , Astrocitos/metabolismo , Caspasa 3/metabolismo , Células Cultivadas , Citocinas/metabolismo , Giro Dentado/metabolismo , Modelos Animales de Enfermedad , Femenino , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta/genética , Hipocampo/citología , Hipocampo/patología , Humanos , Enfermedad de Huntington/metabolismo , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Neuronas/metabolismo , Estrés Oxidativo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
A pulsed, tunable, narrow band radiation source with frequency in the THz region can be obtained collecting the coherent transition radiation produced by a train of ultra-short electron bunches having picosecond scale inter-distance. In this paper, we review the techniques feasible at the SPARC_LAB test facility to produce and manipulate the requested train of electron bunches and we examine the dynamics of their acceleration and compression. In addition, we show how the performances of the train compression and the radiation intensity and bandwidth can be significantly improved through the insertion of a fourth order harmonic cavity, working in the X-band and acting as a longitudinal phase space linearizer.
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BACKGROUND: In most countries, endoscopes must be disinfected or fully reprocessed before the beginning of each session, even if they were cleaned and disinfected after their last use. Several storage cabinets for heat-sensitive endoscopes (SCHE) are commercially available. They are designed to maintain the microbiological quality of reprocessed endoscopes for a predefined period of time validated by the SCHE manufacturer. Use of an SCHE increases the acceptable storage time before it is necessary to re-disinfect the endoscope. AIM: To evaluate the efficacy of an SCHE (DSC8000, Soluscope, SAS Marseilles, France) in a clinical setting. METHOD: The microbiological quality of endoscopes was assessed after 72 h of storage in an SCHE (Group I), and compared with the microbiological quality of endoscopes stored for 72 h in a clean, dry, dedicated cupboard without morning disinfection (Group II) and the microbiological quality of endoscopes stored for 72 h in a clean, dry, dedicated cupboard with morning disinfection (Group III). Forty-one endoscopes in each group were sampled for microbiological quality. Endoscope contamination levels were analysed according to guidelines published by the National Technical Committee on Nosocomial Infection in 2007. FINDINGS/CONCLUSION: Use of an SCHE helps to maintain the microbiological quality of endoscopes, provided that staff members are well trained and all practices are framed by a proven quality assurance process.
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Desinfección/normas , Endoscopios/microbiología , Contaminación de Equipos/prevención & control , Calor , Desinfectantes/farmacología , Francia , Esterilización/métodosRESUMEN
The linac driven coherent THz radiation source at the SPARC-LAB test facility is able to deliver broadband THz pulses with femtosecond shaping. In addition, high peak power, narrow spectral bandwidth THz radiation can be also generated, taking advantage of advanced electron beam manipulation techniques, able to generate an adjustable train of electron bunches with a sub-picosecond length and with sub-picosecond spacing. The paper reports on the manipulation, characterization, and transport of the electron beam in the bending line transporting the beam down to the THz station, where different coherent transition radiation spectra have been measured and studied with the aim to optimize the THz radiation performances.
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Emerging evidence points to reactive glia as a pivotal factor in Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of basal ganglia injury, but whether astrocytes and microglia activation may exacerbate dopaminergic (DAergic) neuron demise and/or contribute to DAergic repair is presently the subject of much debate. Here, we have correlated the loss and recovery of the nigrostriatal DAergic functionality upon acute MPTP exposure with extensive gene expression analysis at the level of the ventral midbrain (VM) and striata (Str) and found a major upregulation of pro-inflammatory chemokines and wingless-type MMTV integration site1 (Wnt1), a key transcript involved in midbrain DAergic neurodevelopment. Wnt signaling components (including Frizzled-1 [Fzd-1] and ß-catenin) were dynamically regulated during MPTP-induced DAergic degeneration and reactive glial activation. Activated astrocytes of the ventral midbrain were identified as candidate source of Wnt1 by in situ hybridization and real-time PCR in vitro. Blocking Wnt/Fzd signaling with Dickkopf-1 (Dkk1) counteracted astrocyte-induced neuroprotection against MPP(+) toxicity in primary mesencephalic astrocyte-neuron cultures, in vitro. Moreover, astroglial-derived factors, including Wnt1, promoted neurogenesis and DAergic neurogenesis from adult midbrain stem/neuroprogenitor cells, in vitro. Conversely, lack of Wnt1 transcription in response to MPTP in middle-aged mice and failure of DAergic neurons to recover were reversed by pharmacological activation of Wnt/ß-catenin signaling, in vivo, thus suggesting MPTP-reactive astrocytes in situ and Wnt1 as candidate components of neuroprotective/neurorescue pathways in MPTP-induced nigrostriatal DAergic plasticity.
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Astrocitos/metabolismo , Astrocitos/patología , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Transducción de Señal/genética , Sustancia Negra/metabolismo , Sustancia Negra/patología , Proteína Wnt1/genética , Animales , Astrocitos/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/genética , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Transducción de Señal/efectos de los fármacos , Sustancia Negra/efectos de los fármacosRESUMEN
In this Letter we report the first experiments aimed at the simultaneous demonstration of the emittance compensation process and velocity bunching in a high brightness electron source, the SPARC photoinjector in INFN-LNF. While a maximum compression ratio up to a factor 14 has been observed, in a particular case of interest a compression factor of 3, yielding a slice current of 120 A with less than 2 microm slice emittance, has been measured. This technique may be crucial in achieving high brightness beams in photoinjectors aiming at optimized performance of short wavelength single-pass free electron lasers or other advanced applications in laser-plasma accelerators.
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Dolor en el Pecho/etiología , Enfermedades Renales/diagnóstico , Enfermedades Pulmonares/diagnóstico , Malacoplasia/diagnóstico , Anciano , Antibacterianos/uso terapéutico , Drenaje , Infecciones por Escherichia coli/diagnóstico , Infecciones por Escherichia coli/tratamiento farmacológico , Femenino , Humanos , Enfermedades Renales/cirugía , Enfermedades Pulmonares/terapia , Malacoplasia/terapiaRESUMEN
Bovine papillomavirus type 1 (BPV-1) and, less commonly, BPV-2 are associated with the pathogenesis of common equine skin tumors termed sarcoids. In an attempt to understand the mechanisms by which BPV-1 induces sarcoids, we used gene expression profiling as a screening tool to identify candidate genes implicated in disease pathogenesis. Gene expression profiles of equine fibroblasts transformed by BPV-1 experimentally or from explanted tumors were compared with those of control equine fibroblasts to identify genes associated with expression of BPV-1. Analysis of the microarray data identified 81 probe sets that were significantly (P < 0.01) differentially expressed between the BPV-1-transformed and control cell lines. Expression of several deregulated genes, including MMP-1, CXCL5, FRA-1, NKG7, TLR4, and the gene encoding the major histocompatibility complex class I (MHC-I) protein, was confirmed using other BPV-1-transformed cell lines. Furthermore, expression of these genes was examined using a panel of 10 sarcoids. Increased expression of MMP-1, CXCL5, FRA-1, and NKG7 was detected in a subset of tumors, and TLR4 and MHC I showed robust down-regulation in all tumors. Deregulated expression was confirmed at the protein level for MMP-1 and MHC-I. The present report identifies genes modulated by BPV-1 transformation and will help identify the molecular mechanisms involved in disease pathogenesis.
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Papillomavirus Bovino 1 , Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica , Enfermedades de los Caballos/virología , Infecciones por Papillomavirus/metabolismo , Animales , Línea Celular Transformada , Cartilla de ADN/genética , Fibroblastos/virología , Citometría de Flujo , Perfilación de la Expresión Génica , Caballos , Complejo Mayor de Histocompatibilidad/genética , Microscopía Fluorescente , Análisis de Secuencia por Matrices de Oligonucleótidos , Infecciones por Papillomavirus/virología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Following a French circular published in 2001, the use of glutaraldehyde for the disinfection of reusable medical devices was abandoned in favour of non-fixative disinfectants such as peracetic-acid-based solutions. Data published regarding the fixative properties of alternative disinfectants remain contradictory. We compared the effect of repetitive treatments of polytetrafluoroethylene (PTFE) tubes, contaminated by a liquid medium inoculated with Pseudomonas aeruginosa, using five different disinfectant solutions: two peracetic acid solutions (with and without an activator), glutaraldehyde, ortho-phthaldehyde and succine dialdehyde. The results confirmed that repeated treatments of a PTFE tube with a 2% glutaraldehyde solution induce an important accumulation and/or fixation of protein, compared to peracetic-acid-based disinfectants, for which the accumulation and/or fixation of proteins remain low and vary from one formulation to another.
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Aldehídos/farmacología , Desinfectantes/farmacología , Glutaral/farmacología , Ácido Peracético/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , o-Ftalaldehído/farmacología , Contaminación de Equipos/prevención & control , Fijadores/farmacología , Polímeros de FluorocarbonoRESUMEN
Inadequate drying of endoscope channels is a possible cause of microbial proliferation during storage. This risk could be reduced by any procedure or process used to dry endoscope channels and control storage conditions. The efficacy of a drying and storage cabinet (Hysis Medical) was tested on three different endoscopes: a colonoscope (Olympus); duodenoscope (Fujinon) and an enteroscope (Pentax), all of which had been artificially contaminated with a suspension of Pseudomonas aeruginosa CIP 103467. Changes to the residual internal contamination level of these endoscopes when stored inside or outside the drying cabinet for 12, 24, 48 or 72 h were compared. When stored in the drying and storage cabinet, microbial contamination levels on endoscopes were lower than the number of bacteria initially introduced and could decrease considerably thereafter. For endoscopes stored outside the drying storage cabinet, microbial numbers were stable or even increased. These data demonstrate the advantages of such endoscope drying/storage cabinets that limit the risk of bacterial proliferation in the internal channels of endoscopes during storage, and which ensure that the disinfection level reached at the end of the reprocessing procedure is maintained.
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Desinfección/instrumentación , Endoscopios Gastrointestinales/microbiología , Ambiente Controlado , Contaminación de Equipos/prevención & control , Control de Infecciones/métodos , Movimientos del Aire , Recuento de Colonia Microbiana , Infección Hospitalaria/prevención & control , Desinfección/métodos , Equipo Reutilizado , Filtración , HumanosRESUMEN
The major histocompatibility complex (MHC) class I region in mammals contains both classical and non-classical MHC class I genes. Classical MHC class I molecules present antigenic peptides to cytotoxic T lymphocytes, whereas non-classical MHC class I molecules have a variety of functions. Both classical and non-classical MHC molecules interact with natural killer cell receptors and may under some circumstances prevent cell death by natural killer cytotoxicity. The E5 oncoprotein of BPV-4 down-regulates the expression of classical MHC class I on the cell surface and retains the complex in the Golgi apparatus. The inhibition of classical MHC class I to the cell surface results from both the impaired acidification of the Golgi, due to the interaction of E5 with subunit c of the H+ V-ATPase, and to the physical binding of E5 to the heavy chain of MHC class I. Despite the profound effect of E5 on classical MHC class I, E5 does not retain a non-classical MHC class I in the Golgi, does not inhibit its transport to the cell surface and does not bind its heavy chain. We conclude that, as is the case for HPV-16 E5, BPV-4 E5 does not down-regulate certain non-classical MHC class I, potentially providing a mechanism for the escape of the infected cell from attack by both cytotoxic T lymphocytes and NK cells.
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Papillomavirus Bovino 1/fisiología , Antígenos de Histocompatibilidad Clase I/metabolismo , Proteínas Oncogénicas Virales/fisiología , Animales , Papillomavirus Bovino 1/clasificación , Papillomavirus Bovino 4 , Bovinos , Línea Celular Tumoral , Mastocitoma/patología , RatonesRESUMEN
Although many failed surrogate markers are provided in the literature, inflammation may contribute to the outcome of ischemic stroke. In 50 consecutive patients with acute ischemic stroke, in the absence of symptoms and signs of concomitant infection, we evaluated a panel of biomarkers reported to be variably associated with brain ischemia, and correlate their serum level with the brain lesion volume and clinical outcome. Infarct size was calculated on computed tomography (CT) scans by means of the Cavalieri's method. Neurological impairment was scored by using the Glasgow Coma Scale, Glasgow Outcome Scale and National Institutes of Health (NIH) scales at stroke onset and 3-month follow-up. Some markers showed a direct significant correlation with both initial and final NIH scale and with infarct size, particularly tumor necrosis factor alpha (TNF-alpha) (P=0.002), intercellular adhesion molecule-1 (P<0.01) and matrix metalloproteinase-2/9 (P=0.001). In contrast to previous reports, interleukin-6 (IL-6) serum level showed a significant inverse correlation with both final neurological impairment and infarct size (P<0.001). This novel finding allows us suggesting that IL-6, in the context of a complex pro-inflammatory network occurring during stroke, is associated with neuroprotection rather than neurotoxicity in patients with ischemic brain injury.
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Biomarcadores/sangre , Encéfalo/patología , Infarto Cerebral/sangre , Inflamación/sangre , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Infarto Cerebral/diagnóstico , Infarto Cerebral/diagnóstico por imagen , Personas con Discapacidad , Femenino , Humanos , Interleucinas/sangre , Masculino , Metaloproteinasas de la Matriz/sangre , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , Molécula 1 de Adhesión Celular Vascular/sangreRESUMEN
Post-menopausal estrogen deficiency is recognized to play a pivotal role in the pathogenesis of a number of age-related diseases in women, such as osteoporosis, coronary heart disease and Alzheimer's disease. There are also sexual differences in the progression of diseases associated with the nigrostriatal dopaminergic system, such as Parkinson's disease, a chronic progressive degenerative disorder characterized by the selective degeneration of mesencephalic dopaminergic neurons in the substancia nigra pars compacta. The mechanism(s) responsible for dopaminergic neuron degeneration in Parkinson's disease are still unknown, but oxidative stress and neuroinflammation are believed to play a key role in nigrostriatal dopaminergic neuron demise. Estrogen neuroprotective effects have been widely reported in a number of neuronal cell systems including the nigrostriatal dopaminergic neurons, via both genomic and non-genomic effects, however, little is known on estrogen modulation of astrocyte and microglia function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. We here highlight estrogen modulation of glial neuroinflammatory reaction in the protection of mesencephalic dopaminergic neurons and emphasize the cardinal role of glia-neuron crosstalk in directing neuroprotection vs neurodegeneration. In particular, the specific role of astroglia and its pro-/anti-inflammatory mechanisms in estrogen neuroprotection are presented. This study shows that astrocyte and microglia response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injury vary according to the estrogenic status with direct consequences for dopaminergic neuron survival, recovery and repair. These findings provide a new insight into the protective action of estrogen that may possibly contribute to the development of novel therapeutic treatment strategies for Parkinson's disease.
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Estrógenos/fisiología , Degeneración Nerviosa/fisiopatología , Neuroglía/fisiología , Enfermedad de Parkinson/fisiopatología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Modelos Animales de Enfermedad , Humanos , Inflamación/fisiopatología , Modelos Neurológicos , Degeneración Nerviosa/prevención & control , Sistema Nervioso/fisiopatología , Neuronas/patología , Neuronas/fisiología , Estrés OxidativoRESUMEN
BPV-4 E5 inhibits transcription of the bovine MHC class I heavy chain (HC) gene, increases degradation of HC and downregulates surface expression of MHC class I by retaining the complex in the Golgi apparatus (GA). Here we report that transcription inhibition can be alleviated by interferon treatment and the degradation of HC can be reversed by treatment with inhibitors of proteasomes and lysosomes. However, the inhibition of transport of MHC class I to the cell surface is irreversible. We show that E5 is capable of physically interacting with HC. Together with the inhibition of the vacuolar ATPase (due to the interaction between E5 and 16k subunit c), the interaction between E5 and HC is likely to be responsible for retention of MHC class I in the GA. C-terminus deletion mutants of E5 are incapable of either downregulating surface MHC class I or interacting with HC, establishing that the C-terminus domain of E5 is important in the inhibition of MHC class I.
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Aparato de Golgi/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Proteínas Oncogénicas Virales/metabolismo , Animales , Antivirales/farmacología , Papillomavirus Bovino 1/patogenicidad , Papillomavirus Bovino 4 , Bovinos , Transformación Celular Viral , Inhibidores de Cisteína Proteinasa/farmacología , Regulación hacia Abajo , Inhibidores Enzimáticos/farmacología , Feto , Inmunoprecipitación , Interferón beta/farmacología , Interferón gamma/farmacología , Leupeptinas/farmacología , Macrólidos/farmacología , Proteínas Oncogénicas Virales/genética , Biosíntesis de Proteínas , Proteínas Tirosina Quinasas/metabolismo , Eliminación de Secuencia , Transcripción Genética , ATPasas de Translocación de Protón Vacuolares/antagonistas & inhibidores , ATPasas de Translocación de Protón Vacuolares/metabolismoRESUMEN
Bovine papillomavirus (BPV) induces papillomas in cattle; in the great majority of cases, these regress due to the host immune response, but they can persist and progress to malignancy. Even in the absence of malignant transformation, BPV infection persists for a significant period of time before activation of the host immune system, suggesting that the host immune system is unaware of, or disabled by, BPV. E5 is the major oncoprotein of BPV, which, in addition to its transforming properties, downregulates the expression and transport to the cell surface of major histocompatibility complex class I (MHC I). Here, it is shown that co-expression of MHC I and E5 in papillomas caused by BPV-4 infection is mutually exclusive, in agreement with the inhibition of surface MHC I expression by E5 that is observed in vitro. The inhibition of MHC expression in E5-expressing papilloma cells could explain the long period that is required for activation of the immune response and has implications for the progression of papillomas to the malignant stage; absence of peptide presentation by MHC I to cytotoxic T lymphocytes would allow the infected cells to evade the host cellular immune response and allow the lesions to persist.