Understanding the variability in clinical and biological response to B-cell depletion therapy in rheumatoid arthritis and systemic lupus erythematosus

Factors including pharmacokinetics, B-cell internalisation of anti-CD20 monoclonal antibodies (mAbs) and disease-associated defects in complement system, NK cells and macrophages may influence the efficiency of rituximab, a Type I anti-CD20 mAb disposed to internalisation by B cells, and contribute to variable clinical and biological response in patients with Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). The work presented in this thesis investigated the potential of Obinutuzumab, a commercially available, mechanistically different Type II anti-CD20 mAb with an afucosylated Fc portion not disposed to internalisation, as an alternative B-cell depleting agent in RA and SLE. In patients with SLE, the duration of B-cell depletion was shorter and serum rituximab levels were significantly lower compared to RA. Hypogammaglobulinemia in the SLE cohort was mostly limited to the IgM isotype and was associated with lower baseline IgM levels, sequential therapy with mycophenolate mofetil and lower frequency of IgD+CD27+ unswitched memory B cells. Anti-dsDNA antibodies in those with high pretreatment levels remained elevated in the long-term, a potential mechanism of poor response to rituximab. Obinutuzumab was at least two-fold more efficient than rituximab at inducing cytotoxicity in B cells from patients with RA and SLE in whole blood assays. B cells from patients with RA and SLE internalised obinutuzumab to a significantly lower extent than rituximab, which was significantly more efficient than obinutuzumab at evoking complement-dependent cellular cytotoxicity of isolated B cells. In contrast, obinutuzumab was significantly more efficient at inducing NK cell activation, an indirect measure of antibody-dependent cell cytotoxicity, in RA and SLE; and also activated neutrophils, an indirect measure of antibody-dependent cell phagocytosis, more efficiently than rituximab in SLE. Obinutuzumab was also more efficient at inducing direct cell death in CD19+ B-cells and switched (IgD-CD27+) memory B cells specifically, a higher frequency of which is associated with poor clinical response to rituximab. Thus, increased clearance and/or internalisation of rituximab may impair its efficiency in RA and SLE. Regardless, obinutuzumab was more efficient than rituximab at inducing B-cell cytotoxicity in vitro in both RA and SLE samples mediated by superior FcγR-dependent and -independent effector mechanisms with greater ability to remain at the cell surface following CD20 engagement despite inferior ability to evoke complement-dependent cellular cytotoxicity. These data provide compelling mechanistic reasons for expecting better outcomes with obinutuzumab as an alternative B-cell depleting agent in RA and SLE

Analysis of the influence of natural wear and tear in gates and runners on the filling of a balanced multi-cavity injection mold

Design of injection molds is outmost important in the manufacture of parts. Its components runners and gates significantly influence the mold filling. Using a simulation package for injection molding a balanced multi-cavity mold was designed. Wear in the gates of runner was simulated by varying the cross-sectional area of the components. Influence of wear of tear in gates of runners on mold filling was measured in terms of flow rate of time of fill. Detailed analysis is done on four different models using four different materials Polycarbonate, Polypropylene, Nylon6 and Polybutylene terephthalate. Graphical display of result is presented and analyzed in terms of deviation in time of fill and flow rate from their original values. Remedies suggested for reducing the affects of wear and tear and replacement of the equipment

Inductive Approach to Assessing Consumer Reactions to Institutional Advertising

The paper represents an attempt to study inductively the effects of institutional advertising on the consumer. A sample of thirty institutional advertisements were selected and shown to 267 respondents. The respondents rated the advertisements on fifteen seperate dependent variables. The responses were factor analyzed, resulting in two factors--a content and physical appearence factor. The scores were then submitted to cluster analysis, and six clusters of advertisements were obtained. The variables making up each factor were summed in each cluster to obtain a mean favorability score for the cluster. Analysis of variance CANOVA) was then utilized to determine if any signiftcant differences existed between the clusters on each factor. The ANOVA analysis revealed that a significant difference existed between clusters on both factors. An examination of the clusters revealed that 1. the variables of the content factor, such as intelligence, trustworthiness, and influence, were strongly related to the written content of the advertisements. An advertisement that presented an innovative product or pictured a product in an innovative way was highly favored. Advertisements which were written such that they posed negative implications for consumers were poorly received by respondents 2. the variables of the physical factor, such as attraction, interest, and complexity, were strongly related to the physical dimensions of an advertisement. Advertisements were perceived most favorably on these variables if the advertisement. possessed only one page, had medium sized print, utilized a lot of pictures, had few lines per 6olumn, and had a few columns per page.Business Administratio

Fabrication of Cost Effective Microbolometer using front end bulk Micromachining

Frontend bulk micro machining is one of the proven techniques of making suspended microstructures and is highly adapted due to its simple and cost effective way of fabricating the devices. In this thesis we propose a low-cost un-cooled infrared micro-bolometer detector, where the Si itself is used as the infrared sensitive material. The process does not required any diffusion or electrochemical etch-stop technique as is required in traditional CMOS line micro-bolometer fabrication. Rather we are reporting two ways of fabricating the device. The first method is done by frontend bulk micromachining using wet etching which helps us realize the device with relatively low cost as compared to other proposed method of fabricating the device. The second uses both dry and wet etching which reduces the area per pixel. In this work we adapt the geometric mask design such that the openings are aligned at 45º to wafer prime flat of silicon (100) wafer and act as etch openings for frontend bulk micromachining. The fabrication process was simulated using Intellisuite FABSIM based physical simulator. The proposed concept was experimented and verified by fabricating micro bridges/ cantilevers. Further the same concept was applied to fabricate micro-bolometer (IR sensor)

Abrupt Stoppage of Turbine Rotor, Running on Barring after Major Overhauling

Case StudyCase Study 15: This case study is about a typical experience where a steam turbine, which was running at 100 RPM on barring (turning) after overhaul, stopped abruptly and the rotor was found to be seized. The case study is about this incident and the external factors influencing the turbine rotor seizure, from 100 RPM to zero RPM in less than 5 seconds, its root cause and the rectification activities

Bogidiella indica, A New Species of Subterranean Amphipod Crustacean (Bogidiellidae) from Wells in Southeastern India, with Remarks on the Biogeographic Importance of Recently Discovered Bogidiellids on the Indian Subcontinent

Bogidiella indica, new species, is described from three water wells in southeastern India, including a bore-well on the campus of Acharya Nagarjuna University in Nagarjunanagar, a water well in Guntur town, and an agricultural well in the Godavari and Krishna Basin, all in the state of Andhra Pradesh, India. The new species is assigned to the genus Bogidiella Hertzog and to a newly designated species group within the genus. Despite the near circum-global distribution of the family Bogidiellidae, only a single, partially intact specimen of a bogidiellid had been collected from the Indian subcontinent prior to the discovery of specimens from the well in Nagarjunanagar. Including the new taxon described in this paper, the family Bogidiellidae contains 35 genera and 106 species. Although B. indica is closely similar to other species presently assigned to the genus Bogidiella, it is easily distinguished by a proportionately shorter and relatively heavily spinose pereopod 5. The sexes are generally similar except that the male bears a large, distally modified apical spine on the inner ramus of uropod 1. The location of the well sites within 45 to 50 km of the eastern coast of India strongly suggest that they lie in an area that was submerged under shallow marine water within the last 1 million years

X-RAY TIME AND SPECTRAL VARIABILITY AS PROBES OF ULTRALUMINOUS X-RAY SOURCES

A long-standing debate in the field of ultraluminous X-ray sources (ULXs: luminosities > 3×1039 ergs s-1) is whether these objects are powered by stellar-mass black holes (mass range of 3-25 solar masses) undergoing hyper-accretion/emission or if they host the long-sought after class of intermediate-mass black holes (mass range of a few 100-1000 solar masses) accreting material at sub-Eddington rates. We present X-ray time and energy spectral variability studies of ULXs in order to understand their physical environments and accurately weigh their compact objects. A sample of ULXs exhibit quasi-periodic oscillations (QPOs) with centroid frequencies in the range of 10-200 mHz. The nature of the power density spectra (PDS) of these sources is qualitatively similar to stellar-mass black holes when they exhibit the so-called type-C low-frequency QPOs (frequency range of 0.2-15 Hz). However, the crucial difference is that the characteristic frequencies within the PDS of ULXs, viz., the break frequencies and the centroid frequencies of the QPOs, are scaled down by a factor of approximately 10-100 compared to stellar-mass black holes. It has thus been argued that the ULX mHz QPOs are the type-C low-frequency QPO analogs of stellar-mass black holes and that the observed difference in the frequencies (a few×0.01 Hz compared with a few Hz) is due to the presence of intermediate-mass black holes (MULX = (QPOstellar-mass black hole}/QPOULX)×Mstellar-mass black hole, where M and QPO are the mass and the QPO frequency, respectively) within these ULXs. We analyzed all the archival XMM-Newton X-ray data of ULXs NGC 5408 X-1 and M82 X-1 in order to test the hypothesis that the ULX mHz QPOs are the type-C analogs by searching for a correlation between the mHz QPO frequency and the energy spectral power-law index as type-C QPOs show such a dependence. From our multi-epoch timing and spectral analysis of ULXs NGC 5408 X-1 and M82 X-1, we found that the mHz QPOs of these sources vary in frequency by factors of approximately 4 and 6, respectively. However, we did not find evidence for changes in their energy-spectral indices. The apparent lack of a correlation--unlike the type-C QPOs--implies that either the ULX mHz QPOs are fundamentally different compared to the stellar-mass black hole low-frequency QPOs or they are indeed analogous to the low-frequency QPOs but with the observed dependence corresponding to the saturated portion of the correlation seen in stellar-mass black holes. We analyzed all the archival Swift data of ULX NGC 5408 X-1 and found evidence for a 243±23 day X-ray period. Based on its variation profile, energy dependence and transient nature, we argue that this period represents the orbital period of the black hole binary. We revisit the previously reported 62 day X-ray period of M82 X-1 and found evidence that the accretion disk's flux varies with this period's phase and also noted that the period's phase changed unusually fast during a certain epoch. Based on this we argue that this period might not be orbital but instead be due to a precessing accretion disk. By combining and averaging all the archival RXTE/PCA data of M82 we detect stable, 3:2 frequency ratio QPOs (>4.7 σ statistical significance) which we argue represent the high-frequency QPO analogs of stellar-mass black holes. Unlike the low-frequency QPOs, the high-frequency QPOs of stellar-mass black holes are stable, often occur in frequency ratios of 3:2 and scale inversely with black hole mass. Using the most recent mass estimates of stellar-mass black holes which show high-frequency QPOs and the detected 3:2 pair frequencies of 3.32±0.06 and 5.07±0.06 Hz from M82 X-1, we were able to accurately weigh its black hole to 428±105 solar masses. This detection presents a unique technique to weigh the black holes in variable ULXs. Similar oscillations in other ULXs should be detectable with future X-ray observatories. Finally, we conclude by discussing our preliminary results from the first X-ray -- optical reverberation mapping of a ULX and also describe future prospects of detecting intermediate-mass black holes using tidal disruption flares and by searching for high-frequency QPOs in ULXs

GSU Connects Us.

“GSU Connects US” is a posting based student communication website. Today on the internet there are lots of social sites available but most of them are for the technical purpose only. On the current market analysis the most popular site for posting is “Facebook” and the “Google+” but both contains mix categories of technical and non – technical, so a normal person surfing on the internet to find the event for his or her interested find it difficult to choose proper category for the event. It covers Events, Connect to the students, Q & A forum Resale of used books, Upload and share files like photo, videos etc. It Provides you with the proper guidance by the experts and it will help the slow learners also has messaging capabilities to keep in touch simply, quickly and cheaply. So as a reason for need of the Project is to make the process of discovery for events and activities easier, faster, and better

Design of a 2X2 Reading and Writing Array for Programmable Metallization Cell

A transistor level 2X2 reading and writing array for non-volatile memory cell has been designed. This circuit is an innovative reading and writing circuit designed specifically for Programmable Metallization Cells (PMC). The write circuitry is designed to provide appropriate positive and negative voltage bias to an individual PMC memory cell in order to program it to high resistance state (write '0') or low resistance state (write '1'). A terminal switching mechanism is constructed using two pairs of complimentary MOS transistors in writing circuit