Reconstitution of T cell receptor signaling in ZAP-70-deficient cells by retroviral transduction of the ZAP-70 gene.

A variant of severe combined immunodeficiency syndrome (SCID) with a selective inability to produce CD8 single positive T cells and a signal transduction defect in peripheral CD4+ cells has recently been shown to be the result of mutations in the ZAP-70 gene. T cell receptor (TCR) signaling requires the association of the ZAP-70 protein tyrosine kinase with the TCR complex. Human T cell leukemia virus type I-transformed CD4+ T cell lines were established from ZAP-70-deficient patients and normal controls. ZAP-70 was expressed and appropriately phosphorylated in normal T cell lines after TCR engagement, but was not detected in T cell lines from ZAP-70-deficient patients. To determine whether signaling could be reconstituted, wild-type ZAP-70 was introduced into deficient cells with a ZAP-70 retroviral vector. High titer producer clones expressing ZAP-70 were generated in the Gibbon ape leukemia virus packaging line PG13. After transduction, ZAP-70 was detected at levels equivalent to those observed in normal cells, and was appropriately phosphorylated on tyrosine after receptor engagement. The kinase activity of ZAP-70 in the reconstituted cells was also appropriately upregulated by receptor aggregation. Moreover, normal and transduced cells, but not ZAP-70-deficient cells, were able to mobilize calcium after receptor ligation, indicating that proximal TCR signaling was reconstituted. These results indicate that this form of SCID may be corrected by gene therapy

Impact of a Formal Patient Safety and Quality Improvement Curriculum: A Prospective, Controlled Trial

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149337/1/lary27527_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149337/2/lary27527.pd

The interface between silicon and a high-k oxide

The ability to follow Moore's Law has been the basis of the tremendous success of the semiconductor industry in the past decades. To date, the greatest challenge for device scaling is the required replacement of silicon dioxide-based gate oxides by high-k oxides in transistors. Around 2010 high-k oxides are required to have an atomically defined interface with silicon without any interfacial SiO2 layer. The first clean interface between silicon and a high-K oxide has been demonstrated by McKee et al. Nevertheless, the interfacial structure is still under debate. Here we report on first-principles calculations of the formation of the interface between silicon and SrTiO3 and its atomic structure. Based on insights into how the chemical environment affects the interface, a way to engineer seemingly intangible electrical properties to meet technological requirements is outlined. The interface structure and its chemistry provide guidance for the selection process of other high-k gate oxides and for controlling their growth. Our study also shows that atomic control of the interfacial structure can dramatically improve the electronic properties of the interface. The interface presented here serves as a model for a variety of other interfaces between high-k oxides and silicon.Comment: 10 pages, 2 figures (one color

Scanning-probe spectroscopy of semiconductor donor molecules

Semiconductor devices continue to press into the nanoscale regime, and new applications have emerged for which the quantum properties of dopant atoms act as the functional part of the device, underscoring the necessity to probe the quantum structure of small numbers of dopant atoms in semiconductors[1-3]. Although dopant properties are well-understood with respect to bulk semiconductors, new questions arise in nanosystems. For example, the quantum energy levels of dopants will be affected by the proximity of nanometer-scale electrodes. Moreover, because shallow donors and acceptors are analogous to hydrogen atoms, experiments on small numbers of dopants have the potential to be a testing ground for fundamental questions of atomic and molecular physics, such as the maximum negative ionization of a molecule with a given number of positive ions[4,5]. Electron tunneling spectroscopy through isolated dopants has been observed in transport studies[6,7]. In addition, Geim and coworkers identified resonances due to two closely spaced donors, effectively forming donor molecules[8]. Here we present capacitance spectroscopy measurements of silicon donors in a gallium-arsenide heterostructure using a scanning probe technique[9,10]. In contrast to the work of Geim et al., our data show discernible peaks attributed to successive electrons entering the molecules. Hence this work represents the first addition spectrum measurement of dopant molecules. More generally, to the best of our knowledge, this study is the first example of single-electron capacitance spectroscopy performed directly with a scanning probe tip[9].Comment: In press, Nature Physics. Original manuscript posted here; 16 pages, 3 figures, 5 supplementary figure

Challenges and opportunities for implementing integrated mental health care: a district level situation analysis from five low- and middle-income countries.

BACKGROUND: Little is known about how to tailor implementation of mental health services in low- and middle-income countries (LMICs) to the diverse settings encountered within and between countries. In this paper we compare the baseline context, challenges and opportunities in districts in five LMICs (Ethiopia, India, Nepal, South Africa and Uganda) participating in the PRogramme for Improving Mental health carE (PRIME). The purpose was to inform development and implementation of a comprehensive district plan to integrate mental health into primary care. METHODS: A situation analysis tool was developed for the study, drawing on existing tools and expert consensus. Cross-sectional information obtained was largely in the public domain in all five districts. RESULTS: The PRIME study districts face substantial contextual and health system challenges many of which are common across sites. Reliable information on existing treatment coverage for mental disorders was unavailable. Particularly in the low-income countries, many health service organisational requirements for mental health care were absent, including specialist mental health professionals to support the service and reliable supplies of medication. Across all sites, community mental health literacy was low and there were no models of multi-sectoral working or collaborations with traditional or religious healers. Nonetheless health system opportunities were apparent. In each district there was potential to apply existing models of care for tuberculosis and HIV or non-communicable disorders, which have established mechanisms for detection of drop-out from care, outreach and adherence support. The extensive networks of community-based health workers and volunteers in most districts provide further opportunities to expand mental health care. CONCLUSIONS: The low level of baseline health system preparedness across sites underlines that interventions at the levels of health care organisation, health facility and community will all be essential for sustainable delivery of quality mental health care integrated into primary care

Prospective monitoring improves outcomes of primary total hip replacement: a cohort study

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Assessing Adverse Events in Madeira Primary

In last three decades, several epidemiological studies have been developed in order to assess the magnitude, nature and type of adverse events (AEs). Most of these studies focus on hospital settings, where the activities are more standardised, but imultaneously more complex and involving higher risks. However, in the last years, there is a growing movement and strong evidence that point out the importance of studying other healthcare contexts, such as primary care and long-term care. In Portugal, studies on primary care setting are scarce and still in the early stages. In this article, the authors describe the AEs assessment in Portuguese Primary Health Care (PHC) units in Madeira Island/Portugal. This study was quantitative, cross-sectional, observational and analytical, with probability sampling. We quantify and analyse the AEs registered by healthcare providers using the APEAS-PT formulary. A link to the APEAS–PT form was sent to 520 healthcare professionals (111 specialist in Family Medicine, 27 medical students, 382 nurses) who worked in 32 PHC centres. These professionals identified and analysed 85 AEs and 42 incidents, which corresponds to a prevalence of 3.9 AEs per 10,000 visits,with a 95% confidence interval (CI) between 3.7 and 4 AE. Most of the AEs were preventable (96%). The most frequent causal factors of AEs were associated with medication (69%), health care provided to users (54%), communication (41%) and diagnosis (22%). This analysis of AEs in Madeira island PHC contributed to reinforce patient safety culture and to better understand quaternary prevention.info:eu-repo/semantics/publishedVersio

FMRFamide-Like Peptides (FLPs) Enhance Voltage-Gated Calcium Currents to Elicit Muscle Contraction in the Human Parasite Schistosoma mansoni

Schistosomes are amongst the most important and neglected pathogens in the world, and schistosomiasis control relies almost exclusively on a single drug. The neuromuscular system of schistosomes is fertile ground for therapeutic intervention, yet the details of physiological events involved in neuromuscular function remain largely unknown. Short amidated neuropeptides, FMRFamide-like peptides (FLPs), are distributed abundantly throughout the nervous system of every flatworm examined and they produce potent myoexcitation. Our goal here was to determine the mechanism by which FLPs elicit contractions of schistosome muscle fibers. Contraction studies showed that the FLP Tyr-Ile-Arg-Phe-amide (YIRFamide) contracts the muscle fibers through a mechanism that requires Ca2+ influx through sarcolemmal voltage operated Ca2+ channels (VOCCs), as the contractions are inhibited by classical VOCC blockers nicardipine, verapamil and methoxyverapamil. Whole-cell patch-clamp experiments revealed that inward currents through VOCCs are significantly and reversibly enhanced by the application of 1 µM YIRFamide; the sustained inward currents were increased to 190% of controls and the peak currents were increased to 180%. In order to examine the biochemical link between the FLP receptor and the VOCCs, PKC inhibitors calphostin C, RO 31–8220 and chelerythrine were tested and all produced concentration dependent block of the contractions elicited by 1 µM YIRFamide. Taken together, the data show that FLPs elicit contractions by enhancing Ca2+ influx through VOCC currents using a PKC-dependent pathway

Classical kinetic energy, quantum fluctuation terms and kinetic-energy functionals

We employ a recently formulated dequantization procedure to obtain an exact expression for the kinetic energy which is applicable to all kinetic-energy functionals. We express the kinetic energy of an N-electron system as the sum of an N-electron classical kinetic energy and an N-electron purely quantum kinetic energy arising from the quantum fluctuations that turn the classical momentum into the quantum momentum. This leads to an interesting analogy with Nelson's stochastic approach to quantum mechanics, which we use to conceptually clarify the physical nature of part of the kinetic-energy functional in terms of statistical fluctuations and in direct correspondence with Fisher Information Theory. We show that the N-electron purely quantum kinetic energy can be written as the sum of the (one-electron) Weizsacker term and an (N-1)-electron kinetic correlation term. We further show that the Weizsacker term results from local fluctuations while the kinetic correlation term results from the nonlocal fluctuations. For one-electron orbitals (where kinetic correlation is neglected) we obtain an exact (albeit impractical) expression for the noninteracting kinetic energy as the sum of the classical kinetic energy and the Weizsacker term. The classical kinetic energy is seen to be explicitly dependent on the electron phase and this has implications for the development of accurate orbital-free kinetic-energy functionals. Also, there is a direct connection between the classical kinetic energy and the angular momentum and, across a row of the periodic table, the classical kinetic energy component of the noninteracting kinetic energy generally increases as Z increases.Comment: 10 pages, 1 figure. To appear in Theor Chem Ac

Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis

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