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PubMed2003

Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1.

The transcription factor X-box binding protein 1 (XBP-1) is essential for the differentiation of plasma cells and the unfolded protein response (UPR). Here we show that UPR-induced splicing of XBP-1 by the transmembrane endonuclease IRE1 is required to restore production of immunoglobulin in XBP-1-/- mouse B cells, providing an integral link between XBP-1, the UPR and plasma cell differentiation. Signals involved in plasma cell differentiation, specifically interleukin-4, control the transcription of XBP-1, whereas its post-transcriptional processing is dependent on synthesis of immunoglobulins during B cell differentiation. We also show that XBP-1 is involved in controlling the production of interleukin-6, a cytokine that is essential for plasma cell survival. Thus, signals upstream and downstream of XBP-1 integrate plasma cell differentiation with the UPR.

Animals↗
PubMed2004

Neurogenomics: at the intersection of neurobiology and genome sciences.

Neurogenomics is the study of how the genome as a whole contributes to the evolution, development, structure and function of the nervous system. It includes investigations of how genome products (transcriptomes and proteomes) vary in time and space. Neurogenomics differs markedly from the application of genome sciences to other systems, particularly in the spatial category, because anatomy and connectivity are paramount to our understanding of function in the nervous system. We focus here on some of the influences of genomics and its associated technologies on neuroscience. We discuss comparative genomics, gene expression atlases of the brain, network genetics and applications to behavioral phenotypes, and consider the culture, organization and funding of genome-scale projects.

Animals↗
PubMed2006

Fragile X syndrome and autism at the intersection of genetic and neural networks.

Autism, an entirely behavioral diagnosis with no largely understood etiologies and no population-wide biomarkers, contrasts with fragile X syndrome (FXS), a single-gene disorder with definite alterations of gene expression and neuronal morphology. Nevertheless, the behavioral overlap between autism and FXS suggests some overlapping mechanisms. Understanding how the single-gene alteration in FXS plays out within complex genetic and neural network processes may suggest targets for autism research and illustrate strategies for relating autism to more singular genetic syndromes.

Animals↗
PubMed2001

Mitogenesis and endocytosis: What's at the INTERSECTIoN?

Endocytosis is a regulated physiological process by which cell surface proteins are internalized along with extracellular factors such as nutrients, pathogens, peptides, toxins, etc. The process begins with the invagination of small regions of the plasma membrane which ultimately form intracellullar vesicles. These internalized vesicles may shuttle back to the plasma membrane to recycle the membrane components or they may be targeted for degradation. One role for endocytosis is in the attenuation of receptor signaling. For example, desensitization of activated membrane bound receptors such as G-protein coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs) occurs, in part, through endocytosis of the activated receptor. However, accumulating evidence suggests that endocytosis also mediates intracellular signaling. In this review, we discuss the experimental data that implicate endocytosis as a critical component in cellular signal transduction, both in the initiation of a signal as well as in the termination of a signal. Furthermore, we focus our attention on a recently described adaptor protein, intersectin (ITSN), which provides a link to both the endocytic and the mitogenic machinery of a cell. Thus, ITSN functions at a crossroad in the biochemical regulation of cell function.

Adaptor Proteins, Vesicular Transport↗
PubMed2004

Identification of a negative regulatory cis-element in the enhancer core region of the prostate-specific antigen promoter: implications for intersection of androgen receptor and nuclear factor-kappaB signalling in prostate cancer cells.

The NF-kappaB (nuclear factor-kappaB) transcription factors mediate activation of a large number of gene promoters containing diverse kappaB-site sequences. Here, PSA (prostate-specific antigen) was used as an AR (androgen receptor)-responsive gene to examine the underlying mechanism by which the NF-kappaB p65 transcription factor down-regulates the transcriptional activity of AR in cells. We observed that activation of NF-kappaB by TNFalpha (tumour necrosis factor alpha) inhibited both basal and androgen-stimulated PSA expression, and that this down-regulation occurred at the promoter level, as confirmed by the super-repressor IkappaBalpha (S32A/S36A), a dominant negative inhibitor of NF-kappaB. Using a linker-scanning mutagenesis approach, we identified a cis -element, designated XBE (X-factor-binding element), in the AREc (androgen response element enhancer core) of the PSA promoter, which negatively regulated several AR-responsive promoters, including that of PSA. When three copies of XBE in tandem were juxtaposed to GRE4 (glucocorticoid response element 4), a 4-6-fold reduction of inducible GRE4 activity was detected in three different cell lines, LNCaP, ARCaP-AR and PC3-AR. Bioinformatics and molecular biochemical studies indicated that XBE is a kappaB-like element that binds specifically to the NF-kappaB p65 subunit; consistent with these observations, only NF-kappaB p65, but not the NF-kappaB p50 subunit, was capable of inhibiting AR-mediated PSA promoter transactivation in LNCaP cells. In addition, our data also showed that AR binds to XBE, as well as to the kappaB consensus site, and that the transfection of AR inhibits the kappaB-responsive promoter in transient co-transfection assays. Collectively, these data indicate that cross-modulation between AR and NF-kappaB p65 transcription factors may occur by a novel mechanism involving binding to a common cis -DNA element.

Animals↗
PubMed2004

The intersection of the development of gestures and intentionality.

This study examined the development of deictic and representational gestures in 12 typically developing children from 6 to 24 months of age. Gestures were categorized into J. Bruner's (1981) 3 broad (and 8 specific) communicative functions: behavior regulation (i.e., requesting objects, requesting actions, protesting), joint attention (i.e., commenting, requesting information), and social interaction (i.e., representational gestures, attention seeking, social games). Ongoing parental completion of researcher-created gesture recording forms and monthly researcher observational confirmation were used to capture the emergence and consistent use of targeted gestures. Within each specific functional category, a hierarchy of development was documented for the gestures and behaviors used to signal that intent. This study provides rich detail as to the order of emergence of common deictic and representational gestures and their relationship to other preceding and concomitant behaviors that children use to signal their intentions. Furthermore, the results document younger ages of emergence, in comparison with previous studies, for most of the targeted gestures and provide insight into the controversy in the literature regarding the relative emergence of declarative and imperative gestures.

Adult↗
PubMed2000

Knowledge management in the NHS: positioning the healthcare librarian at the knowledge intersection.

This paper defines what is meant by Knowledge Management, investigates how it interlinks with new ways of delivering health care and gives a synopsis of a study that investigated issues around implementation of Knowledge Management across a sample of healthcare librarians. Areas of investigation that are related to Knowledge Management include: HSG(97)47, evidence-based medicine, clinical governance, information and communication technologies, and the changing role of the healthcare librarian. A diagram is included in this paper which illustrates how the healthcare librarian interacts with resources, staff and practices, so contributing to the knowledge base of health care. The paper concludes that Government policy, new technologies and the push towards the practice of information age medicine are forcing changes throughout the NHS. Recognition of Knowledge Management is still in its infancy in the NHS--it calls for major change in organizational thinking and acceptance by the librarian that their service must also be subject to continuous improvement.

Humans↗
PubMed2002

The nature of psychiatric nursing: the intersection of paradigm, evolution, and history.

Psychiatric nursing, while vibrant and applicable once, is predicated on an approach to care and an understanding of mental illness that reflects an older time. Psychiatric nursing is in the precarious position of having an aging paradigm of practice, rooted in older knowledge and beliefs and recalcitrant to new knowledge and new realities of clinical practice. This article highlights paradigmatic assumptions and identifies the two dominant knowledge structures that struggle to coexist within that paradigm. Practical consequences of practicing psychiatric nursing with an aging paradigm are reviewed and a beginning point for the development of a new paradigm is presented.

Forecasting↗
PubMed2003

[Health services research: subject matter and objectives of a field at the intersection of economics, medicine and ethics].

In analogy to the famous saying that war is too serious to leave it to the generals, one could say that the provision of medical care is too serious and too costly to leave it to doctors. This, however.would give the impression of an incongruity which does not exist as an actual factor or as a standpoint in research on the healthcare system. Having said that, there are differences in the methods of observation used: doctors always base their observations on their experiences at the doctor/patient level. In these situations, they are influenced by the therapeutic imperative of wanting to help and their convictions do not allow them to take into account competing requirements or to feel dependent on the higher-level conditions; and the realm of research on the health care system bases its observations more or less on findings derived by means of analysing what is often highly aggregated data, be it of a medical, economic or epidemiological nature. Even though the insights gained at the macrolevel ultimately have to be applied at the microlevel of the doctor/patient relationship, there remains an internal distance from the problems of care which is conducive to proper judgement. From this distant vantage point, researchers attempt to prove the relationship between effort and yield, to indicate weak spots which individual doctors cannot recognise and to define capacity, structure and incentive conditions which guarantee maxi-mum medical care quality. There is, for instance, evidence of astonishing dependence between the medical care provided and incentives for the number of doctor/patient contacts, use of medicines, surgery rates and number of diagnoses. This evidence can be used to draw up recommendations for self-governing bodies in the health care sector and for the political sphere as to how the health care system could be enhanced to achieve a high level of efficiency and quality.

Adolescent↗
PubMed1994

Intersecting epidemics--crack cocaine use and HIV infection among inner-city young adults. Multicenter Crack Cocaine and HIV Infection Study Team.

BACKGROUND AND METHODS: The smoking of "crack" cocaine is thought to be associated with high-risk sexual practices that accelerate the spread of infection with the human immunodeficiency virus (HIV). We studied 2323 young adults, 18 to 29 years of age, who smoked crack regularly or who had never smoked crack. The study participants, recruited from the streets of inner-city neighborhoods in New York, Miami, and San Francisco, were interviewed and tested for HIV. This report presents the findings for the 1967 participants (85 percent) who had never injected drugs. RESULTS: Of the 1137 crack smokers, 15.7 percent were positive for HIV antibody, as compared with 5.2 percent of the 830 nonsmokers (prevalence ratio adjusted for the city, 2.4; 99 percent confidence interval, 1.7 to 3.6). The prevalence of HIV was highest among the crack-smoking women in New York (29.6 percent) and Miami (23.0 percent). Of the 283 women who had sex in exchange for money or drugs, 30.4 percent were infected with HIV as compared with 9.1 percent of the 286 other women (prevalence ratio, 3.1; 99 percent confidence interval, 1.9 to 5.1); of the 91 men who had anal sex with other men, 42.9 percent were infected with HIV as compared with 9.3 percent of the 582 men who did not have anal sex with other men (prevalence ratio, 4.7; 99 percent confidence interval, 3.0 to 7.4). In multivariable analyses, these high-risk sexual practices accounted for the higher prevalence of HIV infection among the crack smokers, as compared with those who did not smoke crack. Women who had recently had unprotected sex in exchange for money or drugs were as likely to be infected as men who had had sex with men (40.9 percent vs. 42.9 percent). CONCLUSIONS: In poor, inner-city communities young smokers of crack cocaine, particularly women who have sex in exchange for money or drugs, are at high risk for HIV infection. Crack use promotes the heterosexual transmission of HIV.

Adolescent↗
PubMed2004

Cyclic-N3. I. An accurate potential energy surface for the ground doublet electronic state up to the energy of the 2A2/2B1 conical intersection.

A sophisticated adiabatic ground electronic state potential energy surface for a pure nitrogen ring (cyclic-N3) molecule is constructed based on extensive high-level ab initio calculations and accurate three-dimensional spline representation. Most of the important features of the potential energy surface are presented using various reduced dimensionality slices in internal hyperspherical coordinates as well as full dimensional isoenergy surfaces. Very significant geometric phase effects are predicted in the spectra of rotational-vibrational states of cyclic-N3.

Journal Article↗
PubMed2005

Computation of conical intersections by using perturbation techniques.

Multiconfigurational second-order perturbation theory, both in its single-state multiconfigurational second-order perturbation theory (CASPT2) and multistate (MS-CASPT2) formulations, is used to search for minima on the crossing seams between different potential energy hypersurfaces of electronic states in several molecular systems. The performance of the procedures is tested and discussed, focusing on the problem of the nonorthogonality of the single-state perturbative solutions. In different cases the obtained structures and energy differences are compared with available complete active space self-consistent field and multireference configuration interaction solutions. Calculations on different state crossings in LiF, formaldehyde, the ethene dimer, and the penta-2,4-dieniminium cation illustrate the discussions. Practical procedures to validate the CASPT2 solutions in polyatomic systems are explored, while it is shown that the application of the MS-CASPT2 procedure is not straightforward and requires a careful analysis of the stability of the results with the quality of the reference wave functions, that is, the size of the active space.

Journal Article↗
PubMed2005

Exploring the Jahn-Teller and pseudo-Jahn-Teller conical intersections in the ethane radical cation.

We report a theoretical account on the static and dynamic aspects of the Jahn-Teller (JT) and pseudo-Jahn-Teller (PJT) interactions in the ground and first excited electronic states of the ethane radical cation. The findings are compared with the experimental photoionization spectrum of ethane. The present theoretical approach is based on a model diabatic Hamiltonian and with the parameters derived from ab initio calculations. The optimized geometry of ethane in its electronic ground state (1A1g) revealed an equilibrium staggered conformation belonging to the D3d symmetry point group. At the vertical configuration, the ethane radical cation belongs to this symmetry point group. The ground and low-lying electronic states of this radical cation are of 2Eg, 2A1g, 2Eu, and 2A2u symmetries. Elementary symmetry selection rule suggests that the degenerate electronic states of the radical cation are prone to the JT distortion when perturbed along the degenerate vibrational modes of eg symmetry. The 2A1g state is estimated to be approximately 0.345 eV above the 2Eg state and approximately 2.405 eV below the 2Eu state at the vertical configuration. The symmetry selection rule also suggests PJT crossings of the 2A1g and the 2Eg electronic states of the radical cation along the vibrational modes of eg symmetry and such crossings appear to be energetically favorable also. The irregular vibrational progressions, with numerous shoulders and small peaks, observed below 12.55 eV in the experimental recording are manifestations of the dynamic (E x e)-JT effect. Our findings revealed that the PJT activity of the degenerate vibrational modes is particularly strong in the 2Eg-2A1g electronic manifold which leads to a broad and diffuse structure of the observed photoelectron band.

Journal Article↗
PubMed2006

Ab initio nonadiabatic dynamics study of ultrafast radiationless decay over conical intersections illustrated on the Na3F cluster.

We present a theoretical approach for the ultrafast nonadiabatic dynamics based on the ab initio molecular dynamics carried out "on the fly" in the framework of the configuration interaction method combined with Tully's surface hopping algorithm for nonadiabatic transitions. This approach combined with our Wigner distribution approach allows us to perform accurate simulations of femtosecond pump-probe spectra in the systems where radiationless transitions among electronic states take place. In this paper we illustrate this by theoretical simulation of ultrafast processes and nonradiative relaxation in the Na(3)F cluster, involving three excited states and the ground electronic state. Furthermore, we show that our accurate simulation of the photoionization pump-probe spectrum is in full agreement with the experimental signal. Based on the nonadiabatic dynamics at high level of accuracy and taking into account all degrees of freedom, the nonradiative lifetime for the 1 (1)B(1) excited state of Na(3)F has been determined to be approximately 900 fs.

Journal Article↗