Definition of a platform continuous capture scale down model and link to scale-up for monoclonal antibody clinical manufacturing

Definition and scale-up of a batch chromatography process is based on a few main variables such as linear velocity, column loading, and bed height, which are scaled proportionally to column volume. Continuous chromatography consists of multiple columns with column loading and washes/elution/regeneration occurring simultaneously. The definition of a small scale method for continuous chromatography can be extremely complex due to the extensive number of method variables. Limited knowledge exists for development of a scale down and up strategy for continuous chromatography. This abstract should provide some insight into case studies on integration of continuous operations and scale-up, which is one of the themes of the integrated continuous biomanufacturing (ICB) conference. This presentation will describe a strategy for definition of a platform continuous capture scale down model and scale-up pathway. The platform continuous capture step utilizes periodic counter-current chromatography (PCC) for operation of affinity chromatography in a semi-continuous manner. A scale down model for the PCC step was defined and simplified to the following three ranges of harvested cell culture fluid (HCCF) titers: ≤ 2 g/L, 2.5-8 g/L, and 8.5-13 g/L. For each of the three titer ranges, the following variable setpoints are changed based on the specific HCCF titer range: step linear velocity, number of columns, column size, and ΔUV. After these setpoints are inputted into the algorithm, PCC method variables, such as sample loading flowrate, loop time, number of loops and cycles, throughput (g/L/hr), and time cycle, will populate to finish the method design. This PCC scale down model was utilized to scale-up to a bioreactor range of 500-2000L. Quality results showed a good correlation between scale down model and scale-up data. Additional parameters for the 2000L scale-up run included assessment of cleaning and drug substance stability. The cleaning results of the continuous chromatography skid showed passing bioburden, endotoxin, and conductivity. Drug substance stability was also maintained for a year, which was the study duration. This data set proves the PCC small scale model data is representative of the scale-up quality results. In addition, targets such as skid cleanability and DS stability met specifications, which supports the scale-up package for implementation of a platform continuous capture step into a purification process for clinical mAb manufacturing

Searches for continuous gravitational waves from nine young supernova remnants

We describe directed searches for continuous gravitational waves in data from the sixth LIGO science data run. The targets were nine young supernova remnants not associated with pulsars; eight of the remnants are associated with non-pulsing suspected neutron stars. One target's parameters are uncertain enough to warrant two searches, for a total of ten. Each search covered a broad band of frequencies and first and second frequency derivatives for a fixed sky direction. The searches coherently integrated data from the two LIGO interferometers over time spans from 5.3-25.3 days using the matched-filtering F-statistic. We found no credible gravitational-wave signals. We set 95% confidence upper limits as strong (low) as $4\times10^{-25}$ on intrinsic strain, $2\times10^{-7}$ on fiducial ellipticity, and $4\times10^{-5}$ on r-mode amplitude. These beat the indirect limits from energy conservation and are within the range of theoretical predictions for neutron-star ellipticities and r-mode amplitudes.Comment: Science summary available at http://www.ligo.org/science/Publication-S6DirectedSNR/index.ph

Methods and results of a search for gravitational waves associated with gamma-ray bursts using the GEO 600, LIGO, and Virgo detectors

Paper producido por "The LIGO Scientific Collaboration and the Virgo Collaboration". (En el registro se mencionan solo algunos autores de las decenas de personas que participan).In this paper we report on a search for short-duration gravitational wave bursts in the frequency range 64 Hz–1792 Hz associated with gamma-ray bursts (GRBs), using data from GEO 600 and one of the LIGO or Virgo detectors. We introduce the method of a linear search grid to analyze GRB events with large sky localization uncertainties, for example the localizations provided by the Fermi Gamma-ray Burst Monitor (GBM). Coherent searches for gravitational waves (GWs) can be computationally intensive when the GRB sky position is not well localized, due to the corrections required for the difference in arrival time between detectors. Using a linear search grid we are able to reduce the computational cost of the analysis by a factor of Oð10Þfor GBM events. Furthermore, we demonstrate that our analysis pipeline can improve upon the sky localization of GRBs detected by the GBM, if a high-frequency GW signal is observed in coincidence. We use the method of the linear grid in a search for GWs associated with 129 GRBs observed satellite-based gamma-ray experiments between 2006 and 2011. The GRBs in our sample had not been previously analyzed for GW counterparts. A fraction of our GRB events are analyzed using data from GEO 600 while the detector was using squeezed-light states to improve its sensitivity; this is the first search for GWs using data from a squeezed-light interferometric observatory. We find no evidence for GW signals, either with any individual GRB in this sample or with the population as a whole. For each GRB we place lower bounds on the distance to the progenitor, under an assumption of a fixed GWemission energy of 10−2M⊙c2, with a median exclusion distance of 0.8 Mpc for emission at 500 Hz and 0.3 Mpc at 1 kHz. The reduced computational cost associated with a linear search grid will enable rapid searches for GWs associated with Fermi GBM events once the advanced LIGO and Virgo detectors begin operation.http://journals.aps.org/prd/abstract/10.1103/PhysRevD.89.122004publishedVersionFil: Aasi, J. LIGO. California Institute of Technology; Estados Unidos de América.Fil: Domínguez, E. Argentinian Gravitational Wave Group; Argentina.Fil: Maglione, C. Argentinian Gravitational Wave Group; Argentina.Fil: Reula, O. Argentinian Gravitational Wave Group; Argentina.Fil: Ortega, W. Argentinian Gravitational Wave Group; Argentina.Fil: Wolovick, N. Argentinian Gravitational Wave Group; Argentina.Fil: Schilman, M. Argentinian Gravitational Wave Group; Argentina.Física de Partículas y Campo

Multimessenger Search for Sources of Gravitational Waves and High-Energy Neutrinos: Results for Initial LIGO-Virgo and IceCube

We report the results of a multimessenger search for coincident signals from the LIGO and Virgo gravitational-wave observatories and the partially completed IceCube high-energy neutrino detector, including periods of joint operation between 2007-2010. These include parts of the 2005-2007 run and the 2009-2010 run for LIGO-Virgo, and IceCube's observation periods with 22, 59 and 79 strings. We find no significant coincident events, and use the search results to derive upper limits on the rate of joint sources for a range of source emission parameters. For the optimistic assumption of gravitational-wave emission energy of $10^{-2}$\,M$_\odot$c$^2$ at $\sim 150$\,Hz with $\sim 60$\,ms duration, and high-energy neutrino emission of $10^{51}$\,erg comparable to the isotropic gamma-ray energy of gamma-ray bursts, we limit the source rate below $1.6 \times 10^{-2}$\,Mpc$^{-3}$yr$^{-1}$. We also examine how combining information from gravitational waves and neutrinos will aid discovery in the advanced gravitational-wave detector era

A directed search for gravitational waves from Scorpius X-1 with initial LIGO

19 pages, 8 figuresInternational audienceWe present results of a search for continuously-emitted gravitational radiation, directed at the brightest low-mass X-ray binary, Scorpius X-1. Our semi-coherent analysis covers 10 days of LIGO S5 data ranging from 50-550 Hz, and performs an incoherent sum of coherent $\mathcal{F}$-statistic power distributed amongst frequency-modulated orbital sidebands. All candidates not removed at the veto stage were found to be consistent with noise at a 1% false alarm rate. We present Bayesian 95% confidence upper limits on gravitational-wave strain amplitude using two different prior distributions: a standard one, with no a priori assumptions about the orientation of Scorpius X-1; and an angle-restricted one, using a prior derived from electromagnetic observations. Median strain upper limits of 1.3e-24 and 8e-25 are reported at 150 Hz for the standard and angle-restricted searches respectively. This proof of principle analysis was limited to a short observation time by unknown effects of accretion on the intrinsic spin frequency of the neutron star, but improves upon previous upper limits by factors of ~1.4 for the standard, and 2.3 for the angle-restricted search at the sensitive region of the detector

C1q and tumor necrosis factor superfamily: modularity and versatility.

C1q is the target recognition protein of the classical complement pathway and a major connecting link between innate and acquired immunity. As a charge pattern recognition molecule of innate immunity, C1q can engage a broad range of ligands via its globular (gC1q) domain and modulate immune cells, probably via its collagen region. The gC1q signature domain, also found in many non-complement proteins, has a compact jelly-roll beta-sandwich fold similar to that of the multifunctional tumor necrosis factor (TNF) ligand family. The members of this newly designated 'C1q and TNF superfamily' are involved in processes as diverse as host defense, inflammation, apoptosis, autoimmunity, cell differentiation, organogenesis, hibernation and insulin-resistant obesity. This review is an attempt to draw structural and functional parallels between the members of the C1q and TNF superfamily

Effect of different contraceptive methods on the oxidative stress status in women aged 40-48 years from the ELAN study in the province of Liege, Belgium

Oxidative stress is associated with the development of several disorders including cardiovascular disease and cancer. Among conditions known to influence oxidative stress, the use of oral contraception (OC) in women has been a matter of ongoing discussion. METHODS: A total of 897 eligible and healthy volunteers were recruited from among the patients of 50 general practitioners participating in the ELAN study (Etude Liegeoise sur les ANtioxydants). A subsample consisting of 209 women aged 40-48 years was studied for a comprehensive oxidative stress status (OSS), including the analysis of antioxidants, trace elements and three markers of oxidative damage to lipids. Among 209 subsample, 49 (23%) were OC users (OCU), 119 (57%) non-contraception users (NCU) and 41 (20%) were intrauterine (hormonal and copper) devices users (IUD). RESULTS: After adjustment for smoking, systolic and diastolic blood pressure and BMI (or waist circumference), a marked and significant increase in lipid peroxides was observed among OCU women when compared with NCU and IUD users. A cut-off value of 660 mu M in lipid peroxides allowed the discrimination of OCU from the two other groups. In contrast, no difference was observed in the plasma concentration of both oxidized low-density lipoprotein (LDL) and their related antibodies. The increased level in lipid peroxides was strongly related to higher concentrations of copper (r < 0.84; P < 0.0001, cut-off value 1.2 mg/1). When compared with NCU and IUD users, plasma antioxidant defences were significantly altered in OCU women as shown by lower levels of beta-carotene (decrease of 39%; P < 0.01) andytocopherol (decrease by 22%; P < 0.01). In contrast, higher concentrations of selenium (increased by 11.8%; P < 0.01) were observed in OCU women. Blood concentrations of vitamin C, alpha-tocopherol and zinc were unaffected by OC use. CONCLUSIONS: The intake of OC significantly increases the lipid peroxidation in women aged 40-48 years. This may represent a potential cardiovascular risk factor for these women