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Despite recent controversy, hormone replacement therapy remains the mainstay of treatment of menopausal symptoms. Our Drug review considers the risks and benefits of the current treatment options, followed by sources of further information, an analysis of prescription data and the Datafile. Copyright © 2007 Wiley Interface Ltd

During the last few years, multiple steady states (output multiplicities) have been discovered for reactive distillation processes, for example, for the production of fuel ethers and for some esterification processes. Using the transformation of Ung and Doherty (Chem. Eng. Sci. 1995e, 50 (1), 23−48), a method is presented to predict the existence of output multiplicities based on the reactive vapor−liquid equilibrium for the limiting case of reactive columns of infinite length operated at infinite internal flows. This graphical method rests upon the ∞/∞ analysis for azeotropic distillation columns by Bekiaris et al. (Ind. Eng. Chem. Res. 1993, 32 (9), 2023−2038). It is directly applicable to systems where the reactions take place in the entire column (“nonhybrid” columns). When all possible profiles and products are located through a bifurcation analysis, qualitative and quantitative predictions are obtained. The region of feed compositions leading to multiple steady states can be constructed graphically by applying a necessary and sufficient geometrical condition. The prediction results are shown to carry over to finite columns by application to the methyl tert-butyl ether process and are verified by simulation.

Güttinger and Morari (Ind. Eng. Chem. Res. 1998, 38, 1633−1648) developed graphical methods for the prediction of output multiplicities caused by the reactive vapor−liquid equilibrium in reactive distillation. These methods rest upon the limiting case of reactive columns of infinite length operated at infinite internal flows (∞/∞ analysis) and are directly applicable to systems where the reactions take place in the entire column (“nonhybrid” columns). In this work, the reactive ∞/∞ analysis is extended to columns with a reactive core (“hybrid” columns) by introduction of two new procedures. First, necessary and sufficient feasibility conditions for hybrid column profiles are derived under the assumption that each of the reactive and nonreactive column sections has infinite length. Using these conditions, an “exact” method is formulated where all possible products of such an ∞/∞ hybrid column can be located in the composition space (by a continuation of solutions). The existence of multiple steady states and the feed region leading to output multiplicities can be predicted. Second, an “approximate” procedure is proposed to obtain an estimate of the product locations of a hybrid column with finite nonreactive sections. The exact method was applied to an “ideal” reactive system, and a new type of multiplicity, which is purely caused by the hybrid nature of the system, is shown. Moreover, the methyl tert-butyl ether (MTBE) reactive distillation process is analyzed using both methods, and the physical causes of the MTBE multiplicities are studied in detail. All analytical results are verified by simulation.

Physiological concentrations of urokinase plasminogen activator (uPA) stimulated a chemotactic response in human monocytic THP‐1 through binding to the urokinase receptor (uPAR). The effect did not require the protease moiety of uPA, as stimulation was achieved also with the N‐terminal fragment (ATF), while the 33 kDa low molecular weight uPA was ineffective. Co‐immunoprecipitation experiments showed association of uPAR with intracellular kinase(s), as demonstrated by in vitro kinase assays. Use of specific antibodies identified p56/p59hck as a kinase associated with uPAR in THP‐1 cell extracts. Upon addition of ATF, p56/p59hck activity was stimulated within 2 min and returned to normal after 30 min. Since uPAR lacks an intracellular domain capable of interacting with intracellular kinase, activation of p56/p59hck must require a transmembrane adaptor. Evidence for this was strongly supported by the finding that a soluble form of uPAR (suPAR) was capable of inducing chemotaxis not only in THP‐1 cells but also in cells lacking endogenous uPAR (IC50, 5 pM). However, activity of suPAR require chymotrypsin cleavage between the N‐terminal domain D1 and D2 + D3. Chymotrypsin‐cleaved suPAR also induced activation of p56/p59hck in THP‐1 cells, with a time course comparable with ATF. Our data show that uPA‐induced signal transduction takes place via uPAR, involves activation of intracellular tyrosine kinase(s) and requires an as yet undefined adaptor capable of connecting the extracellular ligand binding uPAR to intracellular transducer(s).

In order to characterize T cell epitopes in the Plasmodium falciparum circumsporozoite (CS) protein sequence, we isolated T cell clones, from non‐immune donors, which reacted with synthetic peptides corresponding to two predicted CS protein T cell epitopes. Peptide CS.T3 (corresponding to a non‐polymorphic region of the CS protein, residues 378‐398) was recognized in association with either DR2 or DRw9 restriction elements. T cell clones recognizing CS.T3 also reacted with the sporozoite‐derived CS protein. Peptide CS.T2 corresponds to a polymorphic region (residues 325‐341) of the CS protein. Unlike the CS.T3‐specific clones, the CS.T2‐specific clones did not recognize the CS protein. Since the CS.T2 peptide includes residues which are polymorphic in different P. falciparum isolates, we investigated whether these residues were critical for recognition of the peptide. We show here that a single amino acid substitution at a position of the CS protein which shows genetic polymorphism affects recognition of the sequence by human T cells. The implications of these data for malaria vaccine development are discussed.

In this article, multiple steady states are studied in sequences of interlinked columns commonly used to separate azeotropes in ternary homogeneous distillation. More specifically, two major separation schemes were concerned:  the intermediate entrainer scheme and the “boundary separation” scheme. On the basis of the results on multiplicities in single columns for the case of infinite reflux and infinite column length (infinite number of trays) similar criteria for separation sequences were developed. It is shown how to construct bifurcation diagrams on physical grounds with one product flow rate as the bifurcation parameter and how the product paths of a sequence can be located. Moreover, a necessary and sufficient condition for the existence of multiple steady states in column sequences is derived on the basis of the geometry of the product paths. The overall feed compositions that lead to multiple steady states in the composition space are also located. For the intermediate entrainer scheme multiplicities occur for all feed compositions. For the boundary separation scheme multiplicities may disappear when a single column is integrated into a sequence. By use of examples of the two separation schemes, it is shown that the prediction of the existence of multiple steady states in the ∞/∞ case has relevant implications for columns with finite length (finite number of trays) operated at finite reflux.

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Bekiaris et al. (Ind. Eng. Chem. Res. 1993, 32 (9), 2023) explained the existence of multiple steady states in homogeneous azeotropic distillation on the basis of the analysis of columns with infinite reflux and infinite length (infinite number of trays). They showed that the predictions of multiple steady states for such infinite columns have relevant implications for columns of finite length operated at finite reflux. The first experimental verification of the existence of such multiple steady states was published by Güttinger et al. (Ind. Eng. Chem. Res. 1997, 36 (3), 794). Using an industrial pilot column without an automatic control system, they confirmed the existence of two stable steady states for the ternary homogeneous system methanol−methyl butyrate−toluene. That is, two different column profiles occurred for the same operating parameters, feed flow rate, and feed composition. In this paper, experiments for the same ternary system are described which show the existence of a third unstable steady state. The unstable steady state is stabilized with PI control. Furthermore, the transition from an unstable to a stable operating point is demonstrated when the control action is removed.

The binding of several peptides derived from the Plasmodium falciparum circumsporozoite protein (CS protein) to the human major histocompatibility complex class II proteins HLA-DR5 and -DRw6 was examined in a competition assay. Fixed antigen-presenting cells (APCs) were incubated with various concentrations of each peptide and suboptimal concentrations of stimulator peptides. The binding of the CS peptides to DR5 or DRw6 proteins was then determined in a proliferation assay using two established DR5 or DRw6-restricted T-cell clones with specificity for the stimulator peptides as responder cells. One of five CS peptides, comprising together about 50% of the CS protein sequence, was found to compete with the binding of the stimulator peptides to DR5 and DRw6. The CS peptide CS-(378-398), binding to DR5 and DRw6, was then shown to be able to induce primary in vitro responses of T cells from donors with DR5 and DRw6 haplotypes. CS-(378-398)-induced T-cell clones responded not only to the homologous peptide but also to the native CS protein in the presence of appropriate APCs. The strategy we have applied is of considerable general interest for the engineering of vaccines against any pathogen, since it greatly facilitates the selection of appropriate T-cell epitopes to be incorporated in the vaccine.

We assessed the temporal and functional relationship of myelin maturation and of neuronal development in the telencephalic song motor centres of the canary at different developmental stages. Brain differentiation was modulated by exogenous testosterone, its effects on song quality were also monitored. Myelin maturation was studied by using computer aided analysis of silver impregnated brain sections, whereas the differentiation of neurones was determined by measuring neuronal soma sizes. At an early developmental stage, testosterone triggers growth of neurones but does not affect myelination. At a later developmental stage, both neurone soma sizes and myelination are enhanced by testosterone.

Adhesive mechanisms are considered to be of crucial importance for blastocyst adherence to the uterine wall, as well as for the interactions between embryonal and decidual tissues during hemochorial placenta formation. Epithelial V-like Antigen (Eva) is a novel homophilic adhesion molecule of the immunoglobulin superfamily, which during mouse embryonic development is expressed by various differentiating epithelia. In the present paper we describe Eva expression during mouse trophoblast invasion and placental morphogenesis, analysing day 5.5 to 18.5 postcoitum (p.c.) placentas and deciduomas by in situ hybridization. Eva transcripts were detected in spongiotrophoblast cells from 7.5 to 18.5 days p.c. Expression was uniform at early stages, but after day 11.5, p.c. became limited to the invasive subpopulation of spongiotrophoblasts (known as glycogen cells). Trophoblast giant cells did not express Eva in any of the stages analysed. Besides trophoblasts, also early postimplantation decidua was positive for Eva transcripts. In decidual tissue, Eva expression was present at day 5.5 p.c., peaked at day 7.5 p.c., and declined on successive days. The expression pattern of Eva transcripts suggests that during mouse placenta formation, its protein product may play a role in the processes of trophoblast invasion, decidual response, and trophoblast–decidual interaction. Dev. Genet. 23:317–323, 1998. © 1998 Wiley-Liss, Inc.

Bekiaris et al. (1993) explained the existence of multiple steady states in homogeneous ternary azeotropic distillation, on the basis of the analysis of the case of infinite reflux and infinite column length (infinite number of trays). They showed that the predictions of multiple steady states for such infinite columns have relevant implications for columns of finite length operated at finite reflux. In this article, experiments are described for the ternary homogeneous system methanol−methyl butyrate−toluene which demonstrate the existence of multiple steady states (output multiplicities) caused by the vapor−liquid−equilibrium. The experiments on an industrial pilot column show two stable steady states for the same feed flow rate and composition and the same set of operating parameters. The measurements are in excellent agreement with the predictions obtained for infinite columns using the ∞/∞ analysis tools as well as with stage-by-stage simulation results. These experiments represent the first published study reporting evidence for the predictions and simulations by various researchers showing that type of output multiplicities in distillation.

During antigen recognition by T cells, CD4 and the T-cell receptor (TCR)/CD3/zeta complex are thought to interact with the same major histocompatibility complex II molecule in a stable ternary complex. Evidence has suggested that the association of CD4 with TCR/CD3/zeta requires the interaction of the protein tyrosine kinase p56lck with CD4. We have taken a biochemical approach to understand the mechanism by which p56lck and, in particular, its src homology (SH) 2 domain contributes to the association of CD4 with TCR/CD3/zeta during activation. We have previously shown that the p56lck SH2 domain binds directly to tyrosine-phosphorylated ZAP-70. Here we formally demonstrate the in vivo association of p56lck with the homologous protein tyrosine kinases Syk and ZAP-70 after CD3 stimulation of Jurkat cells. A tyrosine-phosphorylated peptide containing the sequence predicted to be optimal for binding to the SH2 domain of src family kinases specifically competes for this association, indicating that tyrosine-phosphorylated ZAP-70 and Syk bind to p56lck by an SH2-mediated interaction. We also show that the same peptide is able to compete for the activation-dependent TCR/CD4 association in Jurkat cells. Moreover, ZAP-70 and CD4 cocap only after CD3 stimulation in human T lymphoblasts. We propose that the interaction of the p56lck SH2 domain with zeta-associated tyrosine-phosphorylated ZAP-70 and/or Syk enables CD4 to associate with antigen-stimulated TCR/CD3/zeta complexes.

RNA is central to the COVID-19 pandemic—it shapes how the SARS Coronavirus 2 (SARS-CoV-2) behaves, and how researchers investigate and fight it. However, RNA has received relatively little attention in the history and philosophy of the life sciences. By analysing RNA biology in more detail, philosophers and historians of science could gain new and powerful tools to assess the current pandemic, and the biological sciences more generally.

Discussions about a replicability crisis in science have been driven by the normative claim that all of science should be replicable and the empirical claim that most of it isn’t. Recently, such crisis talk has been challenged by a new localism, which argues a) that serious problems with replicability are not a general occurrence in science and b) that replicability itself should not be treated as a universal standard. The goal of this article is to introduce this emerging strand of the debate and to discuss some of its implications and limitations. I will in particular highlight the issue of demarcation that localist accounts have to address, i.e. the question of how we can distinguish replicable science from disciplines where replicability does not apply.

An ideal vaccine should elicit a long lasting immune response against the natural parasite, both at the T- and B-cell level. The immune response should occur in all individuals and be directed against determinants that do not vary in the natural parasite population. A major problem in designing synthetic peptide vaccines is that T cells generally recognize peptide antigens only in association with one or a few of the many variants of major histocompatibility complex (MHC) antigens1,2. During the characterization of epitopes of the malaria parasite Plasmodium falciparum that are recognized by human T cells, we analysed a sequence of the circumsporozoite protein, and found that synthetic peptides corresponding to this sequence are recognized by T cells in association with many different MHC class II molecules, both in mouse and in man. This region of the circumsporozoite protein is invariant in different parasite isolates3,4. Peptides derived from this region should be capable of inducing T-cell responses in individuals of most HLA-DR types, and may represent good candidates for inclusion in an effective anti-malaria peptide vaccine.