The T lymphocyte surface protein CD4 is an integral membrane glycoprotein noncovalently associated with the tyrosine protein kinase p56lck. In normal T cells, surface association of CD4 molecules ...with other CD4 molecules or other T-cell surface proteins, such as the T-cell antigen receptor, stimulates the activity of the p56lck tyrosine kinase, resulting in the phosphorylation of various cellular proteins at tyrosine residues. Thus, the signal transduction in T cells generated through the surface engagement of CD4 is similar to that observed for the class of growth factor receptors possessing endogenous tyrosine kinase activity. As CD4 is also the cellular receptor for the human immunodeficiency virus (HIV), binding of the virus or gp120 (the virus surface protein responsible for specific CD4+ T-cell association) could mimic the types of immunological interactions that have previously been found to stimulate p56lck and trigger T-cell activation pathways. We have evaluated this possibility and report here that binding of HIV-1 or the virus glycoprotein gp120 to CD4+ human T cells fails to elicit detectable p56lck-dependent tyrosine kinase activation and signalling, alterations in the composition of cellular phosphotyrosine-containing proteins, or changes in intracellular Ca2+ concentration.
An important challenge in antisense technology remains the adequate delivery of the oligonucleotides (ON) to individual cells. Understanding the subcellular distribution of ONs and their carrier is ...essential to explain the (lack of) biological activity. The ability of several cationic carriers to efficiently deliver anti-ICAM-1 oligonucleotides to their site of action was studied using a cell-based assay. In this assay we evaluated the ability of the ONs to downregulate the expression of the ICAM-1-protein in A549 cells. To understand why some carrier/ONs combinations showed biological activity while others failed, flow cytometry and confocal laser scanning microscopy (CLSM) measurements were used to study cellular uptake and intracellular distribution of the (fluorescently labeled) ONs. We showed that free ONs (both PS-ONs and PO-ONs) and ONs complexed to pEGpEI failed to decrease the ICAM-1 protein level. This was due to the inability of the (free or complexed) ONs to enter the cell, as shown by flow cytometry and CLSM. Flow cytometry and CLSM showed cellular uptake when PO-ONs and PS-ONs were complexed to
graft-pDMAEMA and Lipofectin. However, while the uptake and intracellular localization seemed similar for ONs complexed to, respectively,
graft-pDMAEMA and Lipofectin, the biological activity of the ONs was clearly dependent on their carrier: both PO-ONs and PS-ONs complexed to
graft-pDMAEMA reduced the ICAM-1 expression; however, when complexed to Lipofectin only PS-ONs showed biological activity. Also, PS-ONs complexed to
graft-pDMAEMA were more active than PO-ONs complexed to
graft-pDMAEMA which could not be explained by the results from CLSM and flow cytometry. While the ICAM-1 assay proves whether a certain pharmaceutical carrier successfully delivers ONs or not, it does not answer the important question why one carrier is successful while another one fails. Also, our study shows that flow cytometry and CLSM, although useful techniques, failed to clearly explain the difference in transfection behavior between
graft-pDMAEMA and Lipofectin. As ONs become susceptible to degradation by cytosolic DNase as soon as they are released from their carrier, one could argue that a better understanding of the time and (intracellular) place at which the dissociation of the complexes occurs could be crucial to fully explain our observations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We investigated 4 cases of legionnaires’ disease (LD) reported among workers at an Ohio automotive plant in March 2001. A “confirmed” case of LD was defined as x-ray–confirmed pneumonia and a ...confirmatory laboratory test. A “possible” case of LD was defined as elevated titers of antibody and respiratory symptoms. Legionella pneumophila serogroup 1 (LP1) was isolated from 1 case patient. Legionella was isolated from 18 (9%) of 197 environmental samples; 3 isolates were LP1 but did not match the case isolate. We conducted a case-control study; 17 case patients with confirmed or possible LD and 86 control subjects (workers with low antibody titers and without symptoms) were enrolled. Visiting a specific cleaning line (odds ratio, OR, 7.29; 95% confidence interval CI, 2.31–23.00) and working in the cleaning region of the plant (OR, 3.22; 95% CI, 1.11–9.38) were associated with LD. LD can be transmitted in industrial settings in which aerosols are produced. Clinicians should consider LD when treating persons from these settings for pneumonia
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To study the myosin heavy chain composition of the human extraocular muscles (EOMs) during development.
EOMs from human fetuses of 8 to 22 weeks of gestation were studied with immunocytochemistry and ...gel electrophoresis. Antibodies specific against nine isoforms of myosin heavy chain (MyHC) were used in serial frozen sections.
The developing EOMs had a delayed time course of myotube formation and a unique composition and distribution of MyHCs compared with human limb skeletal muscle. The primary myotubes coexpressed two developmental isoforms of MyHCI from the earliest stages. The third developmental MyHCI delineated the future orbital layer at 10 to 12 weeks of gestation. MyHC-slow tonic also appeared early, whereas MyHC alpha-cardiac and MyHC-extraocular, important components of adult EOM, were never detected at the gestational ages studied.
The developmental features of the EOMs differed significantly from those reported for limb muscles of the corresponding ages. It is clear that the knowledge of limb muscle development does not fully apply to more specialized muscles, such as the eye muscles. The extreme complexity displayed by the EOMs probably reflects their distinct embryonic origin, innervation, and regulatory program of myogenesis.
We examined the expression and activity of Cdk4 and Cdk2 in resting, competent, and proliferating normal human T cells. Expression
of Cdk4 but not of Cdk2 was induced in competent T cells independent ...of an IL-2 signal. This up-regulation of Cdk4 mRNA and
protein was resistant to the immunosuppressant drugs cyclosporin A (CsA) and FK506. A further increase in Cdk4 expression
was seen upon stimulation of competent T cells by IL-2, as was de novo expression of Cdk2. Cyclin D2, a Cdk4 partner, showed
similar patterns of regulation as Cdk4. The increases in Cdk4 and cyclin D2 expression seen in competent T cells were functionally
significant since Cdk4 immunoprecipitates from these cells phosphorylated recombinant RB protein in vitro. Despite the lack
of an increase in the expression of Cdk2, a small pool of pre-existing Cdk2 protein detected in resting T cells could be activated
upon induction of competence. These data demonstrate that 1) the signals that lead to induction of competence in T cells stimulate
an IL-2-independent and CsA-resistant phase of Cdk4 and cyclin D2 expression, Cdk4 kinase activity, and Cdk2 kinase activity,
and 2) IL-2 stimulates a second phase of Cdk4 and cyclin D2 expression and de novo expression of Cdk2 in these cells. The
data show that the expression and activity of these major cell cycle regulatory proteins are controlled differentially by
growth factors and indicate a role for Cdk4 and cyclin D2 in T-cell cycle entry and/or early G1 progression and for Cdk2 in
later G1 progression and G1/S transition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lincoln and Freedom Holzer, Harold; Gabbard, Sara Vaughn; Belz, Herman ...
2007
eBook
Lincoln’s reelection in 1864 was a pivotal moment in the history of the United States. The Emancipation Proclamation had officially gone into effect on January 1, 1863, and the proposed ...Thirteenth Amendment had become a campaign issue. Lincoln and Freedom: Slavery, Emancipation, and the Thirteenth Amendment captures these historic times, profiling the individuals, events, and enactments that led to slavery’s abolition. Fifteen leading Lincoln scholars contribute to this collection, covering slavery from its roots in 1619 Jamestown, through the adoption of the Constitution, to Abraham Lincoln’s presidency.              This comprehensive volume, edited by Harold Holzer and Sara Vaughn Gabbard, presents Abraham Lincoln’s response to the issue of slavery as politician, president, writer, orator, and commander-in-chief. Topics include the history of slavery in North America, the Supreme Court’s Dred Scott decision, the evolution of Lincoln’s view of presidential powers, the influence of religion on Lincoln, and the effects of the Emancipation Proclamation.              This collection effectively explores slavery as a Constitutional issue, both from the viewpoint of the original intent of the nation’s founders as they failed to deal with slavery, and as a study of the Constitutional authority of the commander-in-chief as Lincoln interpreted it. Addressed are the timing of Lincoln’s decision for emancipation and its effect on the public, the military, and the slaves themselves.              Other topics covered include the role of the U.S. Colored Troops, the election campaign of 1864, and the legislative debate over the Thirteenth Amendment. The volume concludes with a heavily illustrated essay on the role that iconography played in forming and informing public opinion about emancipation and the amendments that officially granted freedom and civil rights to African Americans.              Lincoln and Freedom provides a comprehensive political history of slavery in America and offers a rare look at how Lincoln’s views, statements, and actions played a vital role in the story of emancipation.  
PRODH, encoding proline oxidase (POX), has been associated with schizophrenia through linkage, association, and the 22q11 deletion syndrome (Velo-Cardio-Facial syndrome). Here, we show in a ...family-based sample that functional polymorphisms in PRODH are associated with schizophrenia, with protective and risk alleles having opposite effects on POX activity. Using a multimodal imaging genetics approach, we demonstrate that haplotypes constructed from these risk and protective functional polymorphisms have dissociable correlations with structure, function, and connectivity of striatum and prefrontal cortex, impacting critical circuitry implicated in the pathophysiology of schizophrenia. Specifically, the schizophrenia risk haplotype was associated with decreased striatal volume and increased striatal-frontal functional connectivity, while the protective haplotype was associated with decreased striatal-frontal functional connectivity. Our findings suggest a role for functional genetic variation in POX on neostriatal-frontal circuits mediating risk and protection for schizophrenia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pulsar timing arrays (PTAs) are designed to detect low-frequency
gravitational waves (GWs). GWs induce achromatic signals in PTA data, meaning
that the timing delays do not depend on radio-frequency. ...However, pulse arrival
times are also affected by radio-frequency dependent "chromatic" noise from
sources such as dispersion measure (DM) and scattering delay variations.
Furthermore, the characterization of GW signals may be influenced by the choice
of chromatic noise model for each pulsar. To better understand this effect, we
assess if and how different chromatic noise models affect achromatic noise
properties in each pulsar. The models we compare include existing DM models
used by NANOGrav and noise models used for the European PTA Data Release 2
(EPTA DR2). We perform this comparison using a subsample of six pulsars from
the NANOGrav 15 yr data set, selecting the same six pulsars as from the EPTA
DR2 six-pulsar dataset. We find that the choice of chromatic noise model
noticeably affects the achromatic noise properties of several pulsars. This is
most dramatic for PSR J1713+0747, where the amplitude of its achromatic red
noise lowers from $\log_{10}A_{\text{RN}} = -14.1^{+0.1}_{-0.1}$ to
$-14.7^{+0.3}_{-0.5}$, and the spectral index broadens from $\gamma_{\text{RN}}
= 2.6^{+0.5}_{-0.4}$ to $\gamma_{\text{RN}} = 3.5^{+1.2}_{-0.9}$. We also
compare each pulsar's noise properties with those inferred from the EPTA DR2,
using the same models. From the discrepancies, we identify potential areas
where the noise models could be improved. These results highlight the potential
for custom chromatic noise models to improve PTA sensitivity to GWs.
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