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The levitated sensor detector (LSD) is a compact resonant gravitational-wave (GW) detector based on optically trapped dielectric particles that is under construction. The LSD sensitivity has more favorable frequency scaling at high frequencies compared to laser interferometer detectors such as LIGO and VIRGO. We propose a method to substantially improve the sensitivity by optically levitating a multilayered stack of dielectric discs. These stacks allow the use of a more massive levitated object while exhibiting minimal photon recoil heating due to light scattering. Over an order of magnitude of unexplored frequency space for GWs above 10 kHz is accessible with an instrument 10 to 100 meters in size. Particularly motivated sources in this frequency range are gravitationally bound states of the axion from quantum chromodynamics with decay constant near the grand unified theory scale that form through black hole superradiance and annihilate to GWs. The LSD is also sensitive to GWs from binary coalescence of sub-solar-mass primordial black holes and as-yet unexplored new physics in the high-frequency GW window.
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We present experimental results on optical trapping of Yb-doped ß-NaYF subwavelength-thickness high-aspect-ratio hexagonal prisms with a micron-scale radius. The prisms are trapped in vacuum using an optical standing wave, with the normal vector to their face oriented along the beam propagation direction, yielding much higher trapping frequencies than those typically achieved with microspheres of similar mass. This platelike geometry simultaneously enables trapping with low photon-recoil-heating, high mass, and high trap frequency, potentially leading to advances in high frequency gravitational wave searches in the Levitated Sensor Detector, currently under construction. The material used here has previously been shown to exhibit internal cooling via laser refrigeration when optically trapped and illuminated with light of suitable wavelength. Employing such laser refrigeration methods in the context of our work may enable higher trapping intensity and thus higher trap frequencies for gravitational wave searches approaching the several hundred kilohertz range.
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We explore the formation of double-compact-object binaries in Milky Way (MW) globular clusters (GCs) that may be detectable by the Laser Interferometer Space Antenna (LISA). We use a set of 137 fully evolved GC models that, overall, effectively match the properties of the observed GCs in the MW. We estimate that, in total, the MW GCs contain â¼21 sources that will be detectable by LISA. These detectable sources contain all combinations of black hole (BH), neutron star, and white dwarf components. We predict â¼7 of these sources will be BH-BH binaries. Furthermore, we show that some of these BH-BH binaries can have signal-to-noise ratios large enough to be detectable at the distance of the Andromeda galaxy or even the Virgo cluster.
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Immunotherapeutic herpes simplex virus 2 (HSV-2) vaccine efficacy depends upon the promotion of antigen-specific immune responses that inhibit reactivation or reactivated virus, thus controlling both recurrent lesions and viral shedding. In the present study, a candidate subunit vaccine, GEN-003/MM-2, was evaluated for its ability to induce a broad-spectrum immune response in mice and therapeutic efficacy in HSV-2-infected guinea pigs. GEN-003 is comprised of HSV-2 glycoprotein D2 (gD2ΔTMR340-363) and a truncated form of infected cell polypeptide 4 (ICP4383-766), formulated with Matrix M-2 (MM-2) adjuvant (GEN-003/MM-2). In addition to eliciting humoral immune responses, CD4(+) and CD8(+) T cells characterized by the secretion of multiple cytokines and cytolytic antigen-specific T cell responses that were able to be recalled at least 44 days after the last immunization were induced in immunized mice. Furthermore, vaccination with either GEN-003 or GEN-003/MM-2 led to significant reductions in both the prevalence and severity of lesions in HSV-2-infected guinea pigs compared to those of phosphate-buffered saline (PBS) control-vaccinated animals. While vaccination with MM-2 adjuvant alone decreased recurrent disease symptoms compared to the PBS control group, the difference was not statistically significant. Importantly, the frequency of recurrent viral shedding was considerably reduced in GEN-003/MM-2-vaccinated animals but not in GEN-003- or MM-2-vaccinated animals. These findings suggest a possible role for immunotherapeutic GEN-003/MM-2 vaccination as a viable alternative to chronic antiviral drugs in the treatment and control of genital herpes disease.
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Adjuvantes Imunológicos/farmacologia , Herpes Genital/imunologia , Herpesvirus Humano 2/imunologia , Imunoterapia/métodos , Linfócitos T/imunologia , Vacinas Virais/imunologia , Análise de Variância , Animais , Baculoviridae , Western Blotting , Chlorocebus aethiops , Clonagem Molecular , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , ELISPOT , Cobaias , Herpes Genital/terapia , Camundongos , Testes de Neutralização , Células Vero , Proteínas do Envelope Viral/imunologia , Vacinas Virais/farmacologia , Eliminação de Partículas Virais/imunologiaRESUMO
We review the tests of general relativity that will become possible with space-based gravitational-wave detectors operating in the â¼ 10-5 - 1 Hz low-frequency band. The fundamental aspects of gravitation that can be tested include the presence of additional gravitational fields other than the metric; the number and tensorial nature of gravitational-wave polarization states; the velocity of propagation of gravitational waves; the binding energy and gravitational-wave radiation of binaries, and therefore the time evolution of binary inspirals; the strength and shape of the waves emitted from binary mergers and ringdowns; the true nature of astrophysical black holes; and much more. The strength of this science alone calls for the swift implementation of a space-based detector; the remarkable richness of astrophysics, astronomy, and cosmology in the low-frequency gravitational-wave band make the case even stronger.
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The compatibility of superficially porous (SP) resin for label-free intact protein analysis with online capillary LC/MS is demonstrated to give improved chromatographic resolution, sensitivity, and reproducibility. The robustness of the platform was measured against several samples of varying complexity and sample loading amount. The results indicate that capillary SP columns provide high loading capacities and that â¼6 s chromatographic peak widths are typical for standard proteins in simple mixtures and proteins isolated from cell and tissue lysates. Subfemtomole detection limits for standard proteins were consistently observed, with the lowest levels at 12 amol for ubiquitin. The analysis of total heart homogenates shows that capillary SP columns provide theoretical peak capacity of 106 protein forms with 30 min total analysis time and enabled detection of proteins from complex mixtures with a single high-resolution scan. The SPLC/MS platform also detected 343 protein forms from two HeLa acid extract replicate analyses that consumed 5 × 10(4) cells and 30 min analysis time, each. Comparison of all the species observed in each HeLa replicate showed 90% overlap (309 forms) with a Pearson correlation coefficient of 89.9% for the common forms observed in the replicates. Efficient acid extract of 1 × 10(4) HeLa cells allowed reproducible detection of common modification states and members from all five of the histone families and demonstrated that capillary SPLC/MS supports reproducible label-free profiling of histones in <15 min total analysis time. The data presented demonstrate that a capillary LC/MS platform utilizing superficially porous stationary phase and a LTQ-Orbitrap FT-MS is fast, sensitive, and reproducible for intact protein profiling from small tissue and cell amounts.
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Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Espectrometria de Massas , Proteínas/análise , Células HeLa , Histonas/análise , Humanos , Peso Molecular , Ubiquitina/análiseRESUMO
Measurement of neutralizing antibodies against herpes simplex virus (HSV) is important for evaluation of candidate vaccines. The established plaque-reduction neutralization assay is time consuming, labor intensive, and difficult to validate and transfer. Here, we describe the characterization of a HSV-neutralization assay based on the expression of a reporter gene, ß-galactosidase (ß-Gal). Using previously constructed HSV-ß-Gal recombinant viruses, HSV-2/Gal and HSV-1/tk12, we developed a colorimetric ß-Gal-based neutralization assay that is sensitive and highly reproducible, and performed in less than 48h. HSV-1 and HSV-2 neutralizing titers measured by the ß-Gal-based neutralization assay were equivalent to those obtained by a plaque reduction neutralization assay. Intra- and inter-assay precision studies demonstrated that the ß-Gal-based assay was repeatable and yielded low and acceptable variation. In addition, comparison of HSV-2 neutralizing antibody (NAb) titers measured in two independent laboratories by two unique ß-Gal-based assays showed a highly significant correlation (r=0.9499, p<0.0001) between the two assays. The new assay will serve as an important tool both for preclinical and clinical trials of new HSV vaccines.
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Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Herpes Simples/imunologia , Testes de Neutralização , Animais , Chlorocebus aethiops , Genes Reporter , Herpes Simples/sangue , Herpesvirus Humano 1 , Herpesvirus Humano 2 , Ensaios de Triagem em Larga Escala , Humanos , Reprodutibilidade dos Testes , Células Vero , beta-Galactosidase/genéticaRESUMO
PURPOSE: GEN-003 is a candidate therapeutic HSV-2 vaccine containing a fragment of infected cell protein 4 (ICP4.2), a deletion mutant of glycoprotein D2 (gD2ΔTMR), and Matrix-M2 adjuvant. In a dose-ranging phase 1/2a clinical trial, immunization with GEN-003 reduced viral shedding and the percentage of reported herpetic lesion days. Here we examine the immune responses in the same trial, to characterize vaccine-related changes in antibody and cell-mediated immunity. METHODS: Participants with genital HSV-2 infection were randomized to 1 of 3 doses of GEN-003, antigens without adjuvant, or placebo. Subjects received 3 intramuscular doses, three weeks apart, and were monitored for viral shedding, lesions and immunogenicity. Antibody titers were measured by ELISA and neutralization assay in serum samples collected at baseline and 3weeks post each dose. T cell responses were assessed pre-immunization and 1week post each dose by IFN-γ ELISpot and intracellular cytokine staining. Blood was also collected at 6 and 12months to monitor durability of immune responses. RESULTS: Antibody and T cell responses increased with vaccination and were potentiated by adjuvant. Among the doses tested, the rank order of reduction in viral shedding follows the ranking of fold change from baseline in T cell responses. Some immune responses persisted up to 12months. CONCLUSION: All measures of immunity are increased by vaccination with GEN-003; however, a correlate of protection is yet to be defined.
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Herpes Genital/imunologia , Herpes Genital/terapia , Vacinas contra o Vírus do Herpes Simples/imunologia , Vacinas contra o Vírus do Herpes Simples/uso terapêutico , Herpesvirus Humano 2/imunologia , Adjuvantes Imunológicos , Adolescente , Adulto , Anticorpos Antivirais/sangue , Relação Dose-Resposta Imunológica , ELISPOT , Feminino , Vacinas contra o Vírus do Herpes Simples/administração & dosagem , Humanos , Imunidade Celular , Imunoterapia , Interferon gama/biossíntese , Masculino , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Linfócitos T/imunologia , Proteínas da Matriz Viral/administração & dosagem , Proteínas da Matriz Viral/imunologia , Eliminação de Partículas Virais , Adulto JovemRESUMO
INTRODUCTION: Exertional rhabdomyolysis is a clinical entity of significant muscle breakdown in the setting of exercise. However, clinical course and discharge criteria, once hospitalized, are poorly described. We describe 30 cases of exertional rhabdomyolysis and their hospital course. METHODS: Thirty hospitalized cases with ICD-9 code of 722.88 (rhabdomyolysis) as the primary diagnosis were reviewed from 2010 to 2012. We excluded those with associated trauma, toxin, and heat illnesses. RESULTS: The average length of stay was 3.6 days (range: 1-8 days). Length of stay correlated significantly with peak creatine kinase (CK) levels. The mean admission CK was 61,391 U/L (range 697-233,180 U/L). The mean discharge CK was 23,865 U/L with a wide range (1,410-94,665 U/L). Six cases (20%) had evidence of acute kidney injury, but most had serum creatinine (Cr) <1.7 mg/dL. One had a peak Cr of 4.8 mg/dL. Higher serum Cr levels correlated significantly with lower CK levels. Twenty-nine out of 30 patients were discharged when CKs downtrended. CONCLUSION: Higher peak CK levels predicted longer length of stay. Higher serum Cr significantly correlated with lower CK levels. There did not appear to be any threshold CK for admission or discharge, however, all but one patient were discharged after CK downtrended.
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Exercício Físico/fisiologia , Hospitalização , Militares , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Adulto , Creatina Quinase/análise , Creatina Quinase/sangue , Feminino , Havaí , Humanos , Masculino , Rabdomiólise/sangue , EnsinoRESUMO
Reactivation of latent herpes simplex virus 2 (HSV-2) infections can be characterized by episodic recurrent genital lesions and/or viral shedding. We hypothesize that infected (HSV-2(pos)) asymptomatic individuals have acquired T cell responses to specific HSV-2 antigen(s) that may be an important factor in controlling their recurrent disease symptoms. Our proteomic screening technology, ATLAS, was used to characterize the antigenic repertoire of T cell responses in infected (HSV-2(pos)) and virus-exposed seronegative (HSV-2(neg)) subjects. T cell responses, determined by IFN-γ secretion, were generated to gL, UL2, UL11, UL21, ICP4, ICP0, ICP47 and UL40 with greater magnitude and/or frequency among cohorts of exposed HSV-2(neg) or asymptomatic HSV-2(pos) individuals, compared to symptomatic recurrent HSV-2(pos) subjects. T cell antigens recognized preferentially among individuals who are resistant to infection or who are infected and have mild or no clinical disease may provide new targets for the design of vaccines aimed at treating and/or preventing HSV-2 infection.
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Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Herpes Genital/imunologia , Herpesvirus Humano 2/imunologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , Linfócitos T CD8-Positivos/imunologia , Estudos de Coortes , Epitopos de Linfócito T/genética , Feminino , Herpes Genital/genética , Herpes Genital/virologia , Herpesvirus Humano 2/genética , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The therapeutic mechanism of mesenchymal stromal/stem cells (MSC) for the treatment of acute myocardial infarction is not well understood. Our goal was to get insights into this mechanism by analyzing the survival kinetics of allogeneic and syngeneic cell transplants under different tissue conditions. Two MSC cell banks, stably and equally expressing the luciferase reporter construct, were developed for these studies and injected directly to the myocardium of Lewis rat recipients under syngeneic or allogeneic transplantation conditions. Cell survival was monitored by real-time fashion for up to 2 weeks, using optical imaging device (IVIS, Xenogen Corp.). We found that both syngeneic and allogeneic grafts reduced significantly in size during the first week of transplantation, either in the normal or in the late infarcted heart (5 days after MI) and allotransplants became always smaller than syngeneic grafts during this period. Low dose of cyclosporine A treatment had a benefit on both allo- and syngeneic graft sizes, suggesting that multiple mechanisms play a role in early graft reduction. The MSC characteristic factors IL-6, IL-8, MCP-1, and VEGF were well above the control level in the heart tissue at 4 days after cell injection, suggesting that the peak therapeutic effect of MSC can be expected during the first week of the administration. Although allogeneic cells induced immunoglobulin production, their biological effects (cell survival, factor productions) are very similar to the syngeneic transplants and therefore they could deliver the same therapeutic effect as the syngeneic cells. Finally, freshly infarcted tissue (30 min) supported better the survival of MSC than late postischemic tissue (5 days) but only "off the shelf" allogeneic cell transplants fits with this treatment strategy.