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Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele as the principal mechanism for decreased levels of EFEMP1 mRNA. We provide strong clinical and genetic evidence for the haploinsufficiency of EFEMP1 due to nonsense-medicated decay to cause severe kyphoscoliosis, generalized hypermobility of joints, high and narrow arched palate, and potentially severe diverticulosis. To the best of our knowledge, this is the first report of an autosomal dominant EFEMP1-associated hereditary connective tissue disorder and therefore expands the phenotypic spectrum of EFEMP1 related disorders.
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Enfermedades del Tejido Conjuntivo , Proteínas de la Matriz Extracelular , Haploinsuficiencia , Síndrome de Marfan , Fenotipo , Humanos , Haploinsuficiencia/genética , Femenino , Síndrome de Marfan/genética , Síndrome de Marfan/patología , Proteínas de la Matriz Extracelular/genética , Enfermedades del Tejido Conjuntivo/genética , Enfermedades del Tejido Conjuntivo/patología , Linaje , Mutación/genética , Degradación de ARNm Mediada por Codón sin Sentido/genética , Masculino , Adulto , Alelos , Predisposición Genética a la Enfermedad , NiñoRESUMEN
Endothelial cells play an essential role in inflammation through synthesis and secretion of chemoattractant cytokines and expression of adhesion molecules required for inflammatory cell attachment and infiltration. The mechanisms by which endothelial cells control the pro-inflammatory response depend on the type of inflammatory stimuli, endothelial cell origin, and tissue involved. In the present study, we investigated the role of the transcription factor c-Myc in inflammation using a conditional knockout mouse model in which Myc is specifically deleted in the endothelium. At a systemic level, circulating monocytes, the chemokine CCL7, and the extracellular-matrix protein osteopontin were significantly increased in endothelial c-Myc knockout (EC-Myc KO) mice, whereas the cytokine TNFSF11 was downregulated. Using an experimental model of steatohepatitis, we investigated the involvement of endothelial c-Myc in diet-induced inflammation. EC-Myc KO animals displayed enhanced pro-inflammatory response, characterized by increased expression of pro-inflammatory cytokines and leukocyte infiltration, and worsened liver fibrosis. Transcriptome analysis identified enhanced expression of genes associated with inflammation, fibrosis, and hepatocellular carcinoma in EC-Myc KO mice relative to control (CT) animals after short-exposure to high-fat diet. Analysis of a single-cell RNA-sequencing dataset of human cirrhotic livers indicated downregulation of MYC in endothelial cells relative to healthy controls. In summary, our results suggest a protective role of endothelial c-Myc in diet-induced liver inflammation and fibrosis. Targeting c-Myc and its downstream pathways in the endothelium may constitute a potential strategy for the treatment of inflammatory disease.
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Dieta Alta en Grasa/efectos adversos , Endotelio/metabolismo , Hígado Graso , Cirrosis Hepática , Proteínas Proto-Oncogénicas c-myc/deficiencia , Animales , Endotelio/patología , Hígado Graso/inducido químicamente , Hígado Graso/genética , Hígado Graso/metabolismo , Hígado Graso/patología , Femenino , Técnicas de Inactivación de Genes , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
Premature relativistic transparency of ultrathin, laser-irradiated targets is recognized as an obstacle to achieving a stable radiation pressure acceleration in the "light sail" (LS) mode. Experimental data, corroborated by 2D PIC simulations, show that a few-nm thick overcoat surface layer of high Z material significantly improves ion bunching at high energies during the acceleration. This is diagnosed by simultaneous ion and neutron spectroscopy following irradiation of deuterated plastic targets. In particular, copious and directional neutron production (significantly larger than for other in-target schemes) arises, under optimal parameters, as a signature of plasma layer integrity during the acceleration.
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OBJECTIVES: To evaluate the use of 0.7 mA as a fixed electrical current to indicate epidural needle placement and to confirm that 0.7 mA is greater than the upper limit of the minimal electrical threshold (MET) for sacrococcygeal epidural needle placement in dogs. STUDY DESIGN: Prospective clinical study. ANIMALS: A group of 20 client-owned dogs. METHODS: During general anesthesia and with standard monitoring, the presence of the patellar reflex was confirmed in all dogs. An insulated needle was inserted through the sacrococcygeal intervertebral junction, and absence of tail movement was confirmed when a fixed electrical current of 0.7 mA was applied. Then, the needle was further advanced toward the epidural space until the expected motor response was obtained - the nerve stimulation test (NST). The NST was considered positive when a motor response of the muscles of the tail was elicited but not the perineal muscles, whereas it was considered negative when no movement of the tail was evoked. The electrical current was turned to 0 mA and then increased by 0.01 mA increments until tail movement was evoked; this was recorded as the MET. In the positive NST cases, 0.05 mL cm-1 occipitococcygeal length of 2% lidocaine or 0.25-0.5% bupivacaine was administered. Epidural blockade was confirmed by the loss of patellar reflex. Descriptive statistics were used to present data. RESULTS: Sacrococcygeal epidural needle placement, corroborated by loss of the patellar reflex, was correctly predicted in 89.5% (95% confidence interval, 68.6-97.1%) of the cases. The MET was 0.22 mA (0.11-0.36). CONCLUSIONS AND CLINICAL RELEVANCE: A current of 0.7 mA is approximately twice the upper limit of the MET for epidural placement. Therefore, this study demonstrates, with a success rate of 89.5%, the adequacy of using 0.7 mA as the fixed electrical current to detect sacrococcygeal epidural needle placement in dogs.
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Anestesia Epidural , Anestesia Epidural/veterinaria , Animales , Perros , Estimulación Eléctrica , Inyecciones Epidurales/veterinaria , Agujas , Estudios ProspectivosRESUMEN
A dual ion species plasma expansion scheme from a novel target structure is introduced, in which a nanometer-thick layer of pure deuterium exists as a buffer species at the target-vacuum interface of a hydrogen plasma. Modeling shows that by controlling the deuterium layer thickness, a composite H^{+}/D^{+} ion beam can be produced by target normal sheath acceleration (TNSA), with an adjustable ratio of ion densities, as high energy proton acceleration is suppressed by the acceleration of a spectrally peaked deuteron beam. Particle in cell modeling shows that a (4.3±0.7) MeV per nucleon deuteron beam is accelerated, in a directional cone of half angle 9°. Experimentally, this was investigated using state of the art cryogenic targetry and a spectrally peaked deuteron beam of (3.4±0.7) MeV per nucleon was measured in a cone of half angle 7°-9°, while maintaining a significant TNSA proton component.
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Ovine interferon tau (IFN-τ) is a unique type I interferon with low toxicity and a broad host range in vivo. We report the generation of a nonreplicative recombinant adenovirus expressing biologically active IFN-τ. Using the B6.A2G-Mx1 mouse model, we showed that single-dose intranasal administration of recombinant Ad5-IFN-τ can effectively prevent lethality and disease induced by highly virulent hv-PR8 influenza virus by activating the interferon response and preventing viral replication.
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Adenoviridae/genética , Vectores Genéticos , Interferón Tipo I/biosíntesis , Infecciones por Orthomyxoviridae/prevención & control , Orthomyxoviridae/inmunología , Proteínas Gestacionales/biosíntesis , Proteínas Recombinantes/biosíntesis , Animales , Modelos Animales de Enfermedad , Terapia Genética/métodos , Interferón Tipo I/genética , Ratones , Infecciones por Orthomyxoviridae/inmunología , Proteínas Gestacionales/genética , Proteínas Recombinantes/genética , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
We report on the first experimental observation of a current-driven instability developing in a quasineutral matter-antimatter beam. Strong magnetic fields (≥1 T) are measured, via means of a proton radiography technique, after the propagation of a neutral electron-positron beam through a background electron-ion plasma. The experimentally determined equipartition parameter of ε_{B}≈10^{-3} is typical of values inferred from models of astrophysical gamma-ray bursts, in which the relativistic flows are also expected to be pair dominated. The data, supported by particle-in-cell simulations and simple analytical estimates, indicate that these magnetic fields persist in the background plasma for thousands of inverse plasma frequencies. The existence of such long-lived magnetic fields can be related to analog astrophysical systems, such as those prevalent in lepton-dominated jets.
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X-ray backscatter imaging can be used for a wide range of imaging applications, in particular for industrial inspection and portal security. Currently, the application of this imaging technique to the detection of landmines is limited due to the surrounding sand or soil strongly attenuating the 10s to 100s of keV X-rays required for backscatter imaging. Here, we introduce a new approach involving a 140 MeV short-pulse (< 100 fs) electron beam generated by laser wakefield acceleration to probe the sample, which produces Bremsstrahlung X-rays within the sample enabling greater depths to be imaged. A variety of detector and scintillator configurations are examined, with the best time response seen from an absorptive coated BaF2 scintillator with a bandpass filter to remove the slow scintillation emission components. An X-ray backscatter image of an array of different density and atomic number items is demonstrated. The use of a compact laser wakefield accelerator to generate the electron source, combined with the rapid development of more compact, efficient and higher repetition rate high power laser systems will make this system feasible for applications in the field. Content includes material subject to Dstl (c) Crown copyright (2014). Licensed under the terms of the Open Government Licence except where otherwise stated. To view this licence, visit http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3 or write to the Information Policy Team, The National Archives, Kew, London TW9 4DU, or email: psi@ nationalarchives.gsi.gov.uk.
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Bombas (Dispositivos Explosivos)/clasificación , Rayos Láser , Intensificación de Imagen Radiográfica/instrumentación , Dispersión de Radiación , Tomografía Computarizada por Rayos X/instrumentación , Guerra , Diseño de Equipo , Análisis de Falla de Equipo , Fantasmas de Imagen , Rayos XRESUMEN
Introduction: Obesity is a major risk factor associated with multiple pathological conditions including diabetes and cardiovascular disease. Endothelial dysfunction is an early predictor of obesity. However, little is known regarding how early endothelial changes trigger obesity. In the present work we report a novel endothelial-mediated mechanism essential for regulation of metabolic homeostasis, driven by c-Myc. Methods: We used conditional knockout (EC-Myc KO) and overexpression (EC-Myc OE) mouse models to investigate the endothelial-specific role of c-Myc in metabolic homeostasis during aging and high-fat diet exposure. Body weight and metabolic parameters were collected over time and tissue samples collected at endpoint for biochemical, pathology and RNA-sequencing analysis. Animals exposed to high-fat diet were also evaluated for cardiac dysfunction. Results: In the present study we demonstrate that EC-Myc KO triggers endothelial dysfunction, which precedes progressive increase in body weight during aging, under normal dietary conditions. At endpoint, EC-Myc KO animals showed significant increase in white adipose tissue mass relative to control littermates, which was associated with sex-specific changes in whole body metabolism and increase in systemic leptin. Overexpression of endothelial c-Myc attenuated diet-induced obesity and visceral fat accumulation and prevented the development of glucose intolerance and cardiac dysfunction. Transcriptome analysis of skeletal muscle suggests that the protective effects promoted by endothelial c-Myc overexpression are associated with the expression of genes known to increase weight loss, energy expenditure and glucose tolerance. Conclusion: Our results show a novel important role for endothelial c-Myc in regulating metabolic homeostasis and suggests its potential targeting in preventing obesity and associated complications such as diabetes type-2 and cardiovascular dysfunction.
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Geleophysic dysplasia-1 (GD1) is an autosomal recessive disorder caused by ADAMTS-like 2 (ADAMTSL2) variants. It is characterized by distinctive facial features, limited joint mobility, short stature, brachydactyly, and life-threatening cardiorespiratory complications. The clinical spectrum spans from perinatal lethality to milder adult phenotypes. We developed and characterized cellular and mouse models, to replicate the genetic profile of a patient who is compound heterozygous for 2 ADAMTSL2 variants, namely p.R61H and p.A165T. The impairment of ADAMTSL2 secretion was observed in both variants, but p.A165T exhibited a more severe impact. Mice carrying different allelic combinations revealed a spectrum of phenotypic severity, from lethality in knockout homozygotes to mild growth impairment observed in adult p.R61H homozygotes. Homozygous and hemizygous p.A165T mice survived but displayed severe respiratory and cardiac dysfunction. The respiratory dysfunction mainly affected the expiration phase, and some of these animals had microscopic post-obstructive pneumonia. Echocardiograms and MRI studies revealed a significant systolic dysfunction, accompanied by a reduction of the aortic root size. Histology verified the presence of hypertrophic cardiomyopathy with myocyte hypertrophy, chondroid metaplasia, and mild interstitial fibrosis. This study revealed a substantial correlation between the degree of impaired ADAMTSL2 secretion and the severity of the observed phenotype in GD1.
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Proteínas ADAMTS , Enfermedades del Desarrollo Óseo , Deformidades Congénitas de las Extremidades , Adulto , Humanos , Animales , Ratones , Proteínas ADAMTS/genética , Enfermedades del Desarrollo Óseo/genética , Mutación , FenotipoRESUMEN
Dependence on Bcl-2 proteins is a common feature of cancer cells and provides a therapeutic opportunity. ABT-737 is an antagonist of antiapoptotic Bcl-2 proteins and therefore is a good predictor of Bcl-x(L)/Bcl-2 dependence. Surprisingly, analysis of Mcl-1-dependent multiple myeloma cell lines revealed codependence on Bcl-2/Bcl-x(L) in half the cells tested. Codependence is not predicted by the expression level of antiapoptotic proteins, rather through interactions with Bim. Consistent with these findings, acquired resistance to ABT-737 results in loss of codependence through redistribution of Bim to Mcl-1. Overall, these results suggest that complex interactions, and not simply expression patterns of Bcl-2 proteins, need to be investigated to understand Bcl-2 dependence and how to better use agents, such as ABT-737.
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Proteínas Reguladoras de la Apoptosis/fisiología , Proteínas de la Membrana/fisiología , Mieloma Múltiple/genética , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , Proteínas Proto-Oncogénicas/fisiología , Proteína bcl-X/fisiología , Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Compuestos de Bifenilo/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas de la Membrana/metabolismo , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Nitrofenoles/farmacología , Piperazinas/farmacología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Interferente Pequeño/farmacología , Sulfonamidas/farmacología , Distribución Tisular , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
Background: Intra-amniotic inflammation (IAI) is associated with increased risk of preterm birth and bronchopulmonary dysplasia (BPD), but the mechanisms by which IAI leads to preterm birth and BPD are poorly understood, and there are no effective therapies for preterm birth and BPD. The transcription factor c-Myc regulates various biological processes like cell growth, apoptosis, and inflammation. We hypothesized that c-Myc modulates inflammation at the maternal-fetal interface, and neonatal lung remodeling. The objectives of our study were 1) to determine the kinetics of c-Myc in the placenta, fetal membranes and neonatal lungs exposed to IAI, and 2) to determine the role of c-Myc in modulating inflammation at the maternal-fetal interface, and neonatal lung remodeling induced by IAI. Methods: Pregnant Sprague-Dawley rats were randomized into three groups: 1) Intra-amniotic saline injections only (control), 2) Intra-amniotic lipopolysaccharide (LPS) injections only, and 3) Intra-amniotic LPS injections with c-Myc inhibitor 10058-F4. c-Myc expression, markers of inflammation, angiogenesis, immunohistochemistry, and transcriptomic analyses were performed on placenta and fetal membranes, and neonatal lungs to determine kinetics of c-Myc expression in response to IAI, and effects of prenatal systemic c-Myc inhibition on lung remodeling at postnatal day 14. Results: c-Myc was upregulated in the placenta, fetal membranes, and neonatal lungs exposed to IAI. IAI caused neutrophil infiltration and neutrophil extracellular trap (NET) formation in the placenta and fetal membranes, and neonatal lung remodeling with pulmonary hypertension consistent with a BPD phenotype. Prenatal inhibition of c-Myc with 10058-F4 in IAI decreased neutrophil infiltration and NET formation, and improved neonatal lung remodeling induced by LPS, with improved alveolarization, increased angiogenesis, and decreased pulmonary vascular remodeling. Discussion: In a rat model of IAI, c-Myc regulates neutrophil recruitment and NET formation in the placenta and fetal membranes. c-Myc also participates in neonatal lung remodeling induced by IAI. Further studies are needed to investigate c-Myc as a potential therapeutic target for IAI and IAI-associated BPD.
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Excitation properties of the isolated C(60) and (C(60))(N) model clusters (N = 2, 3, 4, 6 and 13) are studied using an a priori parameterized and self-consistent Hamiltonian, the Complete Neglect of Differential Overlap considering the l azimuthal quantum number method. This method properly describes electron excitations of the isolated C(60) after the configuration interaction of singles (CIS) procedure, when those are compared with experimental data in n-hexane solution and in a molecular beam. Geometry models of (C(60))(N) clusters to model the effect of aggregation were obtained from the fullerene fcc crystal. Some peaks in the low energy edge of the absorption spectrum appear corresponding to clustering effects, as well as small increases of bandwidths in the strong bands at the UV region. An analysis of the theoretical absorption spectrum for dimer models has been carried out, taking into account the influence of the distance between fullerene centers. The density of states of CIS for fullerene clusters in the range from 2.0 to 6.5 eV shows the possibility of electron transitions as functions of the size of the clusters.
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Multiple Sclerosis (MS) is a chronic CNS autoimmune disease characterized by immune-mediated demyelination, axon loss, and disability. Dysregulation of transglutaminase-2 (TG2) has been implicated in disease initiation and progression. Herein, TG2 expression in post-mortem human brain tissue from Relapsing Remitting MS (RRMS) or Progressive MS (PMS) individuals were examined and correlated with the presence of TG2 binding partners and effectors implicated in the processes of inflammation, scar formation, and the antagonism of repair. Tissues from Relapsing-Remitting Multiple Sclerosis (RRMS; n = 6), Progressive Multiple Sclerosis (PMS; n = 5), and non-MS control (n = 6) patients underwent immunohistochemistry for TG2, PLA2, COX-2, FN, CSPG, and HSPG. TG2 was strongly upregulated in active RRMS and PMS lesions, within blood vessels and the perivascular tissue of sclerotic plaques. TG2 colocalization was observed with GFAP+ astrocytes and ECM, including FN, HSPG, and CSPG, which also increased in either RRMS or PMS lesions. Although TG2 was not colocalized with inflammatory mediators COX-2 and PLA2, or the macrophage-microglia marker Iba1, its increased expression correlated with their elevation in active RRMS and PMS lesions. In summary, the correlation of strong TG2 induction in either RRMS or PMS with some of its binding partners but not others implicates potentially different roles for TG2 in disparate MS forms that may warrant further investigation.
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The response of the BAS-TR image plate (IP) was absolutely calibrated using a CR-39 track detector for high linear energy transfer Au ions up to â¼1.6 GeV (8.2 MeV/nucleon), accelerated by high-power lasers. The calibration was carried out by employing a high-resolution Thomson parabola spectrometer, which allowed resolving Au ions with closely spaced ionization states up to 58+. A response function was obtained by fitting the photo-stimulated luminescence per Au ion for different ion energies, which is broadly in agreement with that expected from ion stopping in the active layer of the IP. This calibration would allow quantifying the ion energy spectra for high energy Au ions, which is important for further investigation of the laser-based acceleration of heavy ion beams.
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Image plates (IPs) are a popular detector in the field of laser driven ion acceleration, owing to their high dynamic range and reusability. An absolute calibration of these detectors to laser-driven protons in the routinely produced tens of MeV energy range is, therefore, essential. In this paper, the response of Fujifilm BAS-TR IPs to 1-40 MeV protons is calibrated by employing the detectors in high resolution Thomson parabola spectrometers in conjunction with a CR-39 nuclear track detector to determine absolute proton numbers. While CR-39 was placed in front of the image plate for lower energy protons, it was placed behind the image plate for energies above 10 MeV using suitable metal filters sandwiched between the image plate and CR-39 to select specific energies. The measured response agrees well with previously reported calibrations as well as standard models of IP response, providing, for the first time, an absolute calibration over a large range of proton energies of relevance to current experiments.
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Polysialic acid (PolySia) is a critical post-translational modification on the neural cell adhesion molecule (NCAM, a.k.a., CD56), important for cell migration and axon growth during nervous system development, plasticity and repair. PolySia induction on Schwann cells (SCs) enhances their migration, axon growth support and ability to improve functional recovery after spinal cord injury (SCI) transplantation. In the current investigation two methods of PolySia induction on SCs, lentiviral vector transduction of the mouse polysialytransferase gene ST8SIA4 (LV-PST) or enzymatic engineering with a recombinant bacterial PST (PSTNm), were examined comparatively for their effects on PolySia induction, SC migration, the innate immune response and axon growth after acute SCI. PSTNm produced significant PolySia induction and a greater diversity of surface molecule polysialylation on SCs as evidenced by immunoblot. In the scratch wound assay, PSTNm was superior to LV-PST in the promotion of SC migration and gap closure. At 24 h after SCI transplantation, PolySia induction on SCs was most pronounced with LV-PST. Co-delivery of PSTNm with SCs, but not transient cell exposure, led to broader induction of PolySia within the injured spinal cord due to polysialylation upon both host cells and transplanted SCs. The innate immune response after SCI, measured by CD68 immunoreactivity, was similar among PolySia induction methods. LV-PST or PSTNm co-delivery with SCs provided a similar enhancement of SC migration and axon growth support above that of unmodified SCs. These studies demonstrate that LV-PST and PSTNm provide comparable acute effects on SC polysialation, the immune response and neurorepair after SCI.
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Movimiento Celular/efectos de los fármacos , Células de Schwann/efectos de los fármacos , Ácidos Siálicos/farmacología , Sialiltransferasas/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Movimiento Celular/fisiología , Modelos Animales de Enfermedad , Ratones , Moléculas de Adhesión de Célula Nerviosa , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Células de Schwann/metabolismo , Sialiltransferasas/genética , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
The use of arsenic trioxide (ATO) to treat multiple myeloma (MM) is supported by preclinical studies as well as several phase 2 studies, but the precise mechanism(s) of action of ATO has not been completely elucidated. We used gene expression profiling to determine the regulation of apoptosis-related genes by ATO in 4 MM cell lines and then focused on Bcl-2 family genes. ATO induced up-regulation of 3 proapoptotic BH3-only proteins (Noxa, Bmf, and Puma) and down-regulation of 2 antiapoptotic proteins Mcl-1 and Bcl-X(L). Coimmunoprecipitation demonstrated that Noxa and Puma bind Mcl-1 to release Bak and Bim within 6 hours of ATO addition. Bak and Bim are also released from Bcl-X(L). Silencing of Bmf, Noxa, and Bim significantly protected cells from ATO-induced apoptosis, while Puma silencing had no effect. Consistent with a role for Noxa inhibition of Mcl-1, the Bad-mimetic ABT-737 synergized with ATO in the killing of 2 MM lines. Finally, Noxa expression was enhanced by GSH depletion and inhibited by increasing GSH levels in the cells. Understanding the pattern of BH3-only protein response should aid in the rational design of arsenic-containing regimens.
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Proteínas Reguladoras de la Apoptosis/genética , Apoptosis/efectos de los fármacos , Arsenicales/farmacología , Mieloma Múltiple/tratamiento farmacológico , Óxidos/farmacología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/fisiología , Proteínas Reguladoras de la Apoptosis/fisiología , Trióxido de Arsénico , Proteína 11 Similar a Bcl2 , Muerte Celular , Línea Celular Tumoral , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/fisiología , Mieloma Múltiple/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/fisiologíaRESUMEN
We demonstrate through experiments and numerical simulations that low-density, low-loss, meter-scale plasma channels can be generated by employing a conditioning laser pulse to ionize the neutral gas collar surrounding a hydrodynamic optical-field-ionized (HOFI) plasma channel. We use particle-in-cell simulations to show that the leading edge of the conditioning pulse ionizes the neutral gas collar to generate a deep, low-loss plasma channel which guides the bulk of the conditioning pulse itself as well as any subsequently injected pulses. In proof-of-principle experiments, we generate conditioned HOFI (CHOFI) waveguides with axial electron densities of n_{e0}≈1×10^{17}cm^{-3} and a matched spot size of 26µm. The power attenuation length of these CHOFI channels was calculated to be L_{att}=(21±3)m, more than two orders of magnitude longer than achieved by HOFI channels. Hydrodynamic and particle-in-cell simulations demonstrate that meter-scale CHOFI waveguides with attenuation lengths exceeding 1 m could be generated with a total laser pulse energy of only 1.2 J per meter of channel. The properties of CHOFI channels are ideally suited to many applications in high-intensity light-matter interactions, including multi-GeV plasma accelerator stages operating at high pulse repetition rates.
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The Time-of-Flight (TOF) technique coupled with semiconductorlike detectors, as silicon carbide and diamond, is one of the most promising diagnostic methods for high-energy, high repetition rate, laser-accelerated ions allowing a full on-line beam spectral characterization. A new analysis method for reconstructing the energy spectrum of high-energy laser-driven ion beams from TOF signals is hereby presented and discussed. The proposed method takes into account the detector's working principle, through the accurate calculation of the energy loss in the detector active layer, using Monte Carlo simulations. The analysis method was validated against well-established diagnostics, such as the Thomson parabola spectrometer, during an experimental campaign carried out at the Rutherford Appleton Laboratory (UK) with the high-energy laser-driven protons accelerated by the VULCAN Petawatt laser.