Targeting lentiviral vectors to antigen-specific immunoglobulins

Gene transfer into B cells by lentivectors can provide an alternative approach to managing B lymphocyte malignancies and autoreactive B cell-mediated autoimmune diseases. These pathogenic B cell Populations can be distinguished by their surface expression of monospecific immunoglobulin. Development of a novel vector system to deliver genes to these specific B cells could improve the safety and efficacy of gene therapy. We have developed an efficient rnethod to target lentivectors to monospecific immunoglobulin-expressing cells in vitro and hi vivo. We were able to incorporate a model antigen CD20 and a fusogenic protein derived from the Sindbis virus as two distinct molecules into the lentiviral Surface. This engineered vector could specifically bind to cells expressing Surface immunoglobulin recognizing CD20 (αCD20), resulting in efficient transduction of target cells in a cognate antigen-dependent manner in vitro, and in vivo in a xenografted tumor model. Tumor suppression was observed in vivo, using the engineered lentivector to deliver a suicide gene to a xenografted tumor expressing αCD20. These results show the feasibility of engineering lentivectors to target immunoglobulin-specific cells to deliver a therapeutic effect. Such targeting lentivectors also Could potentially be used to genetically mark antigen-specific B cells in vivo to study their B cell biology

3D reconstruction of the fundus of a phantom eye through stereo imaging of slit lamp images

In the detection of glaucoma, the second leading cause of blindness worldwide, the alteration of the optic disc's morphology is a key clinical indicator. The current gold standard test, stereo funduscopy using stereo fundus cameras, is subjective. Quantitative devices exist but are prohibitively expensive. Work carried out elsewhere has demonstrated quantitative results from stereo matching fundus camera images. Building on this idea, the slit lamp microscope (a mainstay of eye diagnostics, present in practically all ophthalmology and optometry practices) has the potential to be used as a quantitative device. This study explored the feasibility of uncalibrated 3D reconstructions of retinal structures of a phantom eye's fundus using a slit lamp

ISO Spectroscopy of Young Stellar Objects

Observations of gas-phase and solid-state species toward young stellar objects (YSOs) with the spectrometers on board the Infrared Space Observatory are reviewed. The excitation and abundances of the atoms and molecules are sensitive to the changing physical conditions during star-formation. In the cold outer envelopes around YSOs, interstellar ices contain a significant fraction of the heavy element abundances, in particular oxygen. Different ice phases can be distinguished, and evidence is found for heating and segregation of the ices in more evolved objects. The inner warm envelopes around YSOs are probed through absorption and emission of gas-phase molecules, including CO, CO_2, CH_4 and H_2O. An overview of the wealth of observations on gas-phase H_2O in star-forming regions is presented. Gas/solid ratios are determined, which provide information on the importance of gas-grain chemistry and high temperature gas-phase reactions. The line ratios of molecules such as H_2, CO and H_2O are powerful probes to constrain the physical parameters of the gas. Together with atomic and ionic lines such as [0 I] 63 µm, [S I] 25 µm and (Si II] 35 µm, they can also be used to distinguish between photon- and shock-heated gas. Finally, spectroscopic data on circumstellar disks around young stars are mentioned. The results are discussed in the context of the physical and chemical evolution of YSOs

Comprehensive molecular characterization of urachal adenocarcinoma reveals commonalities with colorectal cancer, including a hypermutable phenotype

Purpose Urachal adenocarcinoma is a rare type of primary bladder adenocarcinoma that comprises less than 1% of all bladder cancers. The low incidence of urachal adenocarcinomas does not allow for an evidence-based approach to therapy. Transcriptome profiling of urachal adenocarcinomas has not been previously reported.Wehypothesized that an in-depth molecular understanding of urachal adenocarcinoma would uncover rational therapeutic strategies. Patients and Methods We performed targeted exon sequencing and global transcriptome profiling of 12 urachal tumors to generate a comprehensive molecular portrait of urachal adenocarcinoma. A single patient with an MSH6 mutation was treated with the anti-programmed death-ligand 1 antibody, atezolizumab. Results Urachal adenocarcinoma closely resembles colorectal cancer at the level of RNA expression, which extends previous observations that urachal tumors harbor genomic alterations that are found in colorectal adenocarcinoma. A subset of tumors was found to have alterations in genes that are associated with microsatellite instability (MSH2 and MSH6) and hypermutation (POLE).Apatient with anMSH6mutation was treated withimmunecheckpoint blockade, which resulted in stable disease. Conclusion Because clinical trials are next to impossible for patients with rare tumors, precision oncology may be an important adjunct for treatment decisions. Our findings demonstrate that urachal adenocarcinomas molecularly resemble colorectal adenocarcinomas at the level ofRNA expression, are the first report, to our knowledge, of MSH2andMSH6mutations in this disease, and support the consideration of immune checkpoint blockade as a rational therapeutic treatment of this exceedingly rare tumor

C-Telopeptide Pyridinoline Cross-Links: Sensitive Indicators of Periodontal Tissue Destruction

C-telopeptides and related pyridinoline cross-links of bone Type I collagen are sensitive markers of bone resorption in osteolytic diseases such as osteoporosis and osteoarthritis. We have studied the release of C-telopeptide pyridinoline crosslinks of Type I collagen as measures of bone destruction in periodontal disease. Studies in preclinical animal models and humans have demonstrated the relationship between radiographic bone loss and crevicular fluid C-telopeptide levels. We have recently found that C-telopeptide levels correlate strongly with microbial pathogens associated with periodontitis and around endosseous dental implants. Host-modulation of bone-related collagen breakdown has been shown by studies in humans demonstrating that MMP inhibition blocks tissue destruction and release of C-telopeptides in patients with active periodontal disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72598/1/j.1749-6632.1999.tb07698.x.pd

Clumped isotope thermometry in earthworm carbonates

Earthworm-secreted calcium carbonate can store carbon derived from the soil-atmosphere interface on geological timescales [1]. The mechanism of calcification [2,3,4] is well understood based on multiple years of research conducted both under controlled and natural conditions. We analysed carbonate granules produced by the earthworm Lumbricus terrestris cultured in variable pH and temperature for δ18O to establish thermometry [2]. The governing equation proposed for the thermometry differed from the inorganic calcite precipitation relationship, capturing the signature of kinetic processes during carbonate growth. We have now analysed the granules for clumped isotope thermometry. This provides an opportunity to understand the role of kinetic processes in governing the relationship of clumped isotope in the carbonate system. The clumped isotopic composition of these carbonates yields the following relationship with varying temperature: The linear regression relationship obtained in this study has a similar slope as seen in case of inorganic calcite [5] and otolith carbonate [6]. However, the intercept of the governing equation varied significantly denoting carbonate growth rate. The study presented here provides the first experimental results of clumped isotope composition on carbonates precipitated under monitored disequilibrium conditions and thus, enables quantification of growth rate dependency on clumping. The intercept of the linear regression relationship differs from the line proposed for inorganic calcite precipitation and thus introduces a new parameter to quantify the kinetic process. In this study replicate experiments were performed on carbonate granules generated at controlled temperature and with a knowledge of water isotopic compositio

Using smart meters to estimate low voltage losses

Losses on low voltage networks are often substantial. For example, in the UK they have been estimated as being 4% of the energy supplied by low voltage networks. However, the breakdown of the losses to individual conductors and their split over time are poorly understood as generally only the peak demands and average loads over several months have been recorded. The introduction of domestic smart meters has the potential to change this. How domestic smart meter readings can be used to estimate the actual losses is analysed. In particular, the accuracy of using 30 minute readings compared with 1 minute readings, and how this accuracy could be improved, were investigated. This was achieved by assigning the data recorded by 100 smart meters with a time resolution of 1 minute to three test networks. Smart meter data from three sources were used in the investigation. It was found that 30 minute resolution data underestimated the losses by between 9% and 24%. By fitting an appropriate model to the data, it was possible to reduce the inaccuracy by approximately 50%. Having a smart meter time resolution of 10 minutes rather than 30 gave little improvement to the accuracy

Electron Dephasing in Mesoscopic Metal Wires

The low-temperature behavior of the electron phase coherence time, $\tau_{\phi}$, in mesoscopic metal wires has been a subject of controversy recently. Whereas theory predicts that $\tau_{\phi}(T)$ in narrow wires should increase as $T^{-2/3}$ as the temperature $T$ is lowered, many samples exhibit a saturation of $\tau_{\phi}$ below about 1 K. We review here the experiments we have performed recently to address this issue. In particular we emphasize that in sufficiently pure Ag and Au samples we observe no saturation of $\tau_{\phi}$ down to our base temperature of 40 mK. In addition, the measured magnitude of $\tau_{\phi}$ is in excellent quantitative agreement with the prediction of the perturbative theory of Altshuler, Aronov and Khmelnitskii. We discuss possible explanations why saturation of $\tau_{\phi}$ is observed in many other samples measured in our laboratory and elsewhere, and answer the criticisms raised recently by Mohanty and Webb regarding our work.Comment: 14 pages, 3 figures; to appear in proceedings of conference "Fundamental Problems of Mesoscopic Physics", Granada, Spain, 6-11 September, 200

Does It Really Work? Re-Assessing the Impact of Pre-Departure Cross-Cultural Training on Expatriate Adjustment

Cultural adjustment is considered to be a prerequisite for expatriate success abroad. One way to enhance adjustment is to provide employees with knowledge and awareness of appropriate norms and behaviors of the host country through cross-cultural training (CCT). This article analyzes the impact of pre-departure CCT on expatriate adjustment and focuses on variations in participation, length and the comprehensiveness of training. Unlike previous research, the study focuses on the effectiveness of pre-departure CCT for non-US employees expatriated to a broad range of host country settings. Employing data from 339 expatriates from 20 German Multinational Corporations (MNCs) the study finds CCT has little if any effect on general, interactional or work setting expatriate adjustment. However, a significant impact of foreign language competence was found for all three dimensions of expatriate adjustment. We used interviews with 20 expatriates to supplement our discussion and provide further implications for practice