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Objectives Fostering the identification of societal minorities with the larger society is an essential political aim. In this article, we analyze whether minority members' perception of being recognized by society leads to a stronger identification with society, and whether this identification fosters more willingness to recognize other societal subgroups' members as equal members of society. Method Our analysis is based on both a cross-sectional (N = 1,059, 49% female, mean age = 31 years, 78% with migration background, i.e., first- to third-generation) and a longitudinal (N = 159, 57% female, mean age = 30 years, 76% with migration background) sample of Muslims living in Germany. Results Structural equation modeling and path analyses suggested that the perception to be recognized by society as equals yielded stronger identification with Germany. In contrast, the perception that one's needs are recognized had no effect on the identification with Germany, while the perception of achievement recognition even tended to decrease identification with Germany. Identification with Germany, in turn, led to an increased willingness of respondents to extend equality recognition to subgroups' members whose beliefs and/or practices our respondents (on average) disapproved. Conclusions When the societal majority imparts to minorities a sense of being recognized as equals, this equality recognition colors the broader societal framework within which intergroup relations take shape. We further suggest that-if it is desired that subgroups identify with society-the most viable option is a multicultural model of society, which enables minorities to simultaneously retain their subgroup identity. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently1 and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner.

Our own prior research has demonstrated that respect for disapproved others predicts and might foster tolerance toward them. This means that without giving up their disapproval of others’ way of life, people can tolerate others when they respect them as equals (outgroup respect–tolerance hypothesis). Still, there was considerable variation in the study features. Moreover, the studies are part of a larger research project that affords many additional tests of our hypothesis. To achieve integration along with a more robust understanding of the relation between respect and tolerance, we (re)analyzed all existing data from this project, and we synthesized the results with the help of meta-analytic techniques. The average standardized regression coefficient, which describes the relationship between respect and tolerance, was 0.25 (95% confidence interval [CI] = [0.16, 0.34]). In addition to this overall confirmation of our hypothesis, the size of this coefficient varied with a number of variables. It was larger for numerical majorities than for minorities, smaller for high-status than for low-status groups, and larger for religious than for life-style groups. These findings should inspire further theory development and spur growth in the social-psychological literature on tolerance.

Using longitudinal research designs, we examine the role of politicization in the development of polarization. We conducted research in two different political and national contexts. In Study 1, we employ a panel sample of supporters of the Tea Party movement in the United States and examine the relationship between the strength of their politicization and their subsequent feelings towards conservatives versus liberals (affective polarization) as well as their subsequent perceptions of commonalities with conservatives versus liberals (cognitive polarization). In Study 2, we employ a panel sample of members of the lesbian, gay, bisexual, transgender, and intersex (LGBTI) community in Germany and examine the politicization-polarization link with regard to feelings towards, and perceived commonalities with, feminists versus supporters of a populist right-wing political party. We obtained converging evidence suggesting that politicization promotes both affective and cognitive polarization. There was also some, but very limited evidence pointing to reverse causation. The danger of escalating polarization is discussed.

The eukaryotic signal recognition particle (SRP) contains an Alu domain, which docks into the factor binding site of translating ribosomes and confers translation retardation. The canonical Alu domain consists of the SRP9/14 protein heterodimer and a tRNA-like folded Alu RNA that adopts a strictly ‘closed’ conformation involving a loop-loop pseudoknot. Here, we study the structure of the Alu domain from Plasmodium falciparum (PfAlu), a divergent apicomplexan protozoan that causes human malaria. Using NMR, SAXS and cryo-EM analyses, we show that, in contrast to its prokaryotic and eukaryotic counterparts, the PfAlu domain adopts an ‘open’ Y-shaped conformation. We show that cytoplasmic P. falciparum ribosomes are non-discriminative and recognize both the open PfAlu and closed human Alu domains with nanomolar affinity. In contrast, human ribosomes do not provide high affinity binding sites for either of the Alu domains. Our analyses extend the structural database of Alu domains to the protozoan species and reveal species-specific differences in the recognition of SRP Alu domains by ribosomes., The SRP Alu domain is involved in co-translational protein targeting. Soni et al. investigate the Alu domain of Plasmodium falciparum, the agent of malaria, and find that unlike any other it adopts an open conformation.

We employed a longitudinal design to test two hypotheses concerning Muslims' respect for and tolerance towards disapproved outgroups. In support of the outgroup respect-tolerance hypothesis derived from the disapproval-respect model of social tolerance, our results strongly suggest that respect for disapproved outgroups is not just a correlate of tolerance towards those groups, but a causal antecedent. In support of the intergroup respect-reciprocity hypothesis, we identified respect from disapproved outgroups as an effective source of respect for disapproved outgroups and therefore also as a (distal) source of tolerance towards those groups. Normative and political implications are discussed.

Inspired by philosophical reasoning about the connection between equality and freedom, we examined whether experiences of (equality-based) respect increase perceived autonomy. This link was tested with generalized experiences of respect and autonomy people make in their daily lives (Study 1) and with more specific experiences of employees at the workplace (Study 2). In both studies, respect strongly and independently contributed to perceived autonomy over and above other forms of social recognition (need-based care and achievement-based social esteem) and further affected (life/work) satisfaction. Study 3 experimentally confirmed the hypothesized causal influence of respect on perceived autonomy and demonstrated that this effect further translates into social cooperation. The respect–cooperation link was simultaneously mediated by perceived autonomy and superordinate collective identification. We discuss how the recognition approach, which differentiates between respect, care, and social esteem, can enrich research on autonomy.

Von Willebrand factor (VWF) is a key player in the regulation of hemostasis by promoting recruitment of platelets to sites of vascular injury. An array of 6 C domains forms the dimeric C-terminal VWF stem. Upon shear force activation, the stem adopts an open conformation allowing the adhesion of VWF to platelets and the vessel wall. To understand the underlying molecular mechanism and associated functional perturbations in disease-related variants, knowledge of high-resolution structures and dynamics of C domains is of paramount interest. Here, we present the solution structure of the VWF C4 domain, which binds to the platelet integrin and is therefore crucial for the VWF function. In the structure, we observed 5 intra- and inter-subdomain disulfide bridges, of which 1 is unique in the C4 domain. The structure further revealed an unusually hinged 2-subdomain arrangement. The hinge is confined to a very short segment around V2547 connecting the 2 subdomains. Together with 2 nearby inter-subdomain disulfide bridges, this hinge induces slow conformational changes and positional alternations of both subdomains with respect to each other. Furthermore, the structure demonstrates that a clinical gain-of-function VWF variant (Y2561) is more likely to have an effect on the arrangement of the C4 domain with neighboring domains rather than impairing platelet integrin binding.

Past research indicates that in political debates the same arguments are judged very differently depending on the perceiver’s own position on the issue, because positions on controversial issues are often tied to collective identities. In this article, we test the assumption that equality-based respect from an opposing opinion-based group can reduce such biases. Results confirmed that identification as an opponent or proponent of a contested issue was negatively related to evaluations of outgroup arguments (Study 1) and that this negative link was no longer significant when intergroup respect was experimentally induced (Study 2). Results support the notion that disagreements over political issues are intergroup conflicts, in which different socio-political groups struggle for recognition, and that approaches that protect collective identities and improve intergroup relations should be employed to de-escalate them.

The succession of molecular events leading to eukaryotic translation reinitiation—whereby ribosomes terminate translation of a short open reading frame (ORF), resume scanning, and then translate a second ORF on the same mRNA—is not well understood. Density-regulated reinitiation and release factor (DENR) and multiple copies in T-cell lymphoma-1 (MCTS1) are implicated in promoting translation reinitiation both in vitro in translation extracts and in vivo. We present here the crystal structure of MCTS1 bound to a fragment of DENR. Based on this structure, we identify and experimentally validate that DENR residues Glu42, Tyr43, and Tyr46 are important for MCTS1 binding and that MCTS1 residue Phe104 is important for tRNA binding. Mutation of these residues reveals that DENR-MCTS1 dimerization and tRNA binding are both necessary for DENR and MCTS1 to promote translation reinitiation in human cells. These findings thereby link individual residues of DENR and MCTS1 to specific molecular functions of the complex. Since DENR–MCTS1 can bind tRNA in the absence of the ribosome, this suggests the DENR–MCTS1 complex could recruit tRNA to the ribosome during reinitiation analogously to the eukaryotic initiation factor 2 (eIF2) complex in cap-dependent translation., Author summary Usually, eukaryotic ribosomes translate only a single open reading frame (ORF) on an mRNA and then dissociate from the mRNA. In some cases, when there is a short upstream open reading frame (uORF) that precedes the main ORF, ribosomes can translate the uORF, terminate translation, and then undergo a poorly understood process called “translation reinitiation” whereby they resume scanning for another AUG initiation codon and then translate the main ORF. The molecular functions required for translation reinitiation are not known. We previously showed that two noncanonical initiation factors, density-regulated reinitiation and release factor (DENR) and multiple copies in T-cell lymphoma-1 (MCTS1), are involved in this process. We show here, based on a structure of MCTS1 bound to a fragment of DENR, that in order to successfully promote translation reinitiation, DENR and MCTS1 need to dimerize, and they need to bind tRNA. We thereby identify two molecular functions needed for translation reinitiation.

Two laboratory experiments tested the hypothesis that (equality-based) respect from outgroup members facilitates recategorization of the original ingroup and outgroup as a common group. In Experiment 1, we varied respect from outgroup members (low vs. medium vs. high) and measured recipients' willingness to recategorize. As predicted, high respect from an outgroup source increased willingness to recategorize as a common group relative to low respect. In Experiment 2, we orthogonally varied respect (low vs. medium vs. high) and its source (ingroup members vs. outgroup members) and employed a more differentiated recategorization measure including an intermediate or nested-group option (i.e., two subgroups of a common group). While the recategorization effect of high versus low respect from outgroup members was replicated, no such effect was observed for respect from ingroup members. Instead, there was some indication that, when it comes from ingroup members, a medium level of respect may be optimal for inducing a shift towards recategorization as a common group. Implications of the present research for the conceptualization of respect are discussed.

International audience; Multi-domain proteins play critical roles in fine-tuning essential processes in cellular signaling and gene regulation. Typically, multiple globular domains that are connected by flexible linkers undergo dynamic re-arrangements upon binding to protein, DNA or RNA ligands. RNA binding proteins (RBPs) represent an important class of multi-domain proteins, which regulate gene expression by recognizing linear or structured RNA sequence motifs. Here, we employ segmental perdeuteration of the three RNA recognition motif (RRM) domains in the RBP TIA-1 using Sortase A-mediated protein ligation. We show that domain-selective perdeuteration combined with contrast-matched small-angle neutron scattering (SANS), SAXS and computational modelling provides valuable information to precisely define relative domain arrangements. The approach is generally applicable to study conformational arrangements of individual domains in multi-domain proteins and changes induced by ligand binding.

NMR spectroscopy is a key method for studying the structure and dynamics of (large) multidomain proteins and complexes in solution. It plays a unique role in integrated structural biology approaches as especially information about conformational dynamics can be readily obtained at residue resolution. Here, we review NMR techniques for such studies focusing on state-of-the-art tools and practical aspects. An efficient approach for determining the quaternary structure of multidomain complexes starts from the structures of individual domains or subunits. The arrangement of the domains/subunits within the complex is then defined based on NMR measurements that provide information about the domain interfaces combined with (long-range) distance and orientational restraints. Aspects discussed include sample preparation, specific isotope labeling and spin labeling; determination of binding interfaces and domain/subunit arrangements from chemical shift perturbations (CSP), nuclear Overhauser effects (NOEs), isotope editing/filtering, cross-saturation, and differential line broadening; and based on paramagnetic relaxation enhancements (PRE) using covalent and soluble spin labels. Finally, the utility of complementary methods such as small-angle X-ray or neutron scattering (SAXS, SANS), electron paramagnetic resonance (EPR) or fluorescence spectroscopy techniques is discussed. The applications of NMR techniques are illustrated with studies of challenging (high molecular weight) protein complexes.

Summary The condensin protein complex plays a key role in the structural organization of genomes. How the ATPase activity of its SMC subunits drives large-scale changes in chromosome topology has remained unknown. Here we reconstruct, at near-atomic resolution, the sequence of events that take place during the condensin ATPase cycle. We show that ATP binding induces a conformational switch in the Smc4 head domain that releases its hitherto undescribed interaction with the Ycs4 HEAT-repeat subunit and promotes its engagement with the Smc2 head into an asymmetric heterodimer. SMC head dimerization subsequently enables nucleotide binding at the second active site and disengages the Brn1 kleisin subunit from the Smc2 coiled coil to open the condensin ring. These large-scale transitions in the condensin architecture lay out a mechanistic path for its ability to extrude DNA helices into large loop structures., Graphical Abstract, Highlights • Smc4 and Smc2 ATPase head structures reorganize upon ATP binding and dimerization • A Q-loop-mediated switch releases the Ycs4 HEAT-repeat subunit from the Smc4 head • The Smc2 head engages with the ATP-bound Smc4 head into an asymmetric heterodimer • Head dimerization releases the Brn1 kleisin from Smc2 via coiled-coil rotation, Hassler et al. report structural and functional insights into the enzymatic core of the condensin protein complex that reveal large-scale conformational changes upon ATP binding by and subsequent dimerization of its catalytic SMC head domains. These movements presumably power the condensin-mediated extrusion of DNA loops during mitotic chromosome formation.

Building on theorizing in social and political philosophy the article illuminates the phenomenology of respect and examines its role in intergroup relations. The particular focus is on members of the gay and lesbian community in Germany, their respect experiences, and how these experiences relate to their attitudes towards Muslims. We predicted and found that the experience of being respected in society primarily reflected perceived recognition of gays and lesbians as equal members of society. In addition, we predicted and found that perceived respect from the Muslim community was negatively related to anti-Muslim attitude among gays and lesbians. The same was true for perceived respect from society at large. More specifically, respondents who felt respected by the majority of society showed lower levels of anti-Muslim attitude and, in line with the dominant status of perceived equality recognition in the experience of being respected, this decrease was fully mediated via an increase in perceived equality recognition.

Past research has demonstrated that equality-based respect is an important antecedent of positive social interaction and group-serving behavior. In the present research we tested whether intragroup equality-based respect affects perceptions of being treated as a human as well as self-dehumanization. In Experiment 1, we found that high respect received from fellow work group members heightens group members' sense of being treated as a human being, while low respect diminishes it. In Experiment 2, we secured evidence that (dis)respect also affected recipients' self-views in terms of self-dehumanization. More specifically, if respect was withheld by other ingroup members, fewer human nature and human uniqueness traits, as well as secondary positive emotions, were attributed to the self. This increase in self-infrahumanization was further related to higher endorsement of unethical behavior. We discuss the importance of equality-based respect for (de-)humanization processes in social groups.

Different domains of a protein can interact dynamically to recognize a ligand, but the coordination of binding by multiple domains is not well understood. Michael Sattler and colleagues have investigated binding of a polypurine tract RNA by tandem RNA recognition motifs (RRMs) of a splicing factor. The domains exist in equilibrium between two distinct conformations, which shifts based on the affinity of the tract for the RRMs. This work highlights the role that cooperative multi-domain conformational selection can have when sequence specificity is not strict. Many cellular functions involve multi-domain proteins, which are composed of structurally independent modules connected by flexible linkers. Although it is often well understood how a given domain recognizes a cognate oligonucleotide or peptide motif, the dynamic interaction of multiple domains in the recognition of these ligands remains to be characterized. Here we have studied the molecular mechanisms of the recognition of the 3′-splice-site-associated polypyrimidine tract RNA by the large subunit of the human U2 snRNP auxiliary factor (U2AF65)1,2,3 as a key early step in pre-mRNA splicing4. We show that the tandem RNA recognition motif domains of U2AF65 adopt two remarkably distinct domain arrangements in the absence or presence of a strong (that is, high affinity) polypyrimidine tract. Recognition of sequence variations in the polypyrimidine tract RNA involves a population shift between these closed and open conformations. The equilibrium between the two conformations functions as a molecular rheostat that quantitatively correlates the natural variations in polypyrimidine tract nucleotide composition, length and functional strength to the efficiency to recruit U2 snRNP to the intron during spliceosome assembly1,5,6,7,8. Mutations that shift the conformational equilibrium without directly affecting RNA binding modulate splicing activity accordingly. Similar mechanisms of cooperative multi-domain conformational selection may operate more generally in the recognition of degenerate nucleotide or amino acid motifs by multi-domain proteins9,10.

Lansoprazole (AG 1749) is a novel substituted benzimidazole which inhibits gastric acid secretion by blocking H+,K(+)-ATPase. This randomized, double-blind multicentre trial studied the dose-response relationship of lansoprazole on ulcer healing and compared it with ranitidine in 314 out-patients with endoscopically assessed, symptomatic duodenal ulcer. Cumulative healing rates with Lansoprazole 7.5, 15, and 30 mg o.m. were 48, 59, and 74% at 2 weeks and 75, 84, and 95% at 4 weeks, respectively (intention-to-treat); the difference of the healing rates between 7.5 and 30 mg groups was significant (P less than 0.001). Corresponding healing rates for 300 mg ranitidine nocte were 51 and 89%. Pain relief was similar in all treatment groups. Lansoprazole was well tolerated. During a follow-up of 6 months relapse rates after lansoprazole 7.5, 15, and 30 mg were 21, 29, and 22%, respectively; the relapse rate after ranitidine 300 mg was 20%. In conclusion, lansoprazole provides faster healing of duodenal ulcer than ranitidine and a similar relapse pattern. For further trials in peptic ulcer disease a daily dose of lansoprazole 30 mg o.m. is recommended.

SUMMARY There are two major principles of ulcer therapy. Today, the most widely accepted drugs are those which substantially reduce aggressive factors (i.e. acid and pepsin), namely histamine H2-receptor antagonists, antimuscarinics and antacids. Less frequently applied are mucoprotective agents like colloidal bismuth compounds and sucralfate. Prostaglandins both reduce acid secretion substantially and are believed to enhance mucosal resistance. Their anti-ulcer efficacy, however, is solely explicable by their antisecretory activity. Although mucosa-strengthening agents and H2-receptor blockers have nearly identical healing rates, mucosa-strengthening agents have inconvenient dosage regimens (four times or twice daily) and are probably less effective in relieving pain. The same holds true for antacids. Prostaglandins, antimuscarinics and antacids have dose related side effects. In contrast, H2-receptor blockers are characterized by a clear mechanism of action, convenient dosage regimes, good tolerance and a low incidence of side-effects. H2-receptor antagonists are the most effective anti-ulcer drugs presently available.

The article assesses a disapproval-respect model of tolerance according to which tolerance is made possible when disapproval of others' beliefs, preferences, or practices is balanced by respect for them as equal fellow citizens. Employing a sample of Muslims living in Germany, we predicted and found that such respect was more predictive of outgroup toleration when respondents disapproved rather than approved of the outgroups' beliefs, preferences, or practices. Moreover, respondents who displayed the critical combination of extreme disapproval and full respect indeed showed outgroup toleration. A parallel pattern of results was observed for willingness to engage in intergroup cooperation. Practical implications are discussed.

Biological activity in the cell is predominantly mediated by large multiprotein and protein-nucleic acid complexes that act together to ensure functional fidelity. Nuclear magnetic resonance (NMR) spectroscopy is the only method that can provide information for high-resolution three-dimensional structures and the conformational dynamics of these complexes in solution. Mapping of binding interfaces and molecular interactions along with the characterization of conformational dynamics is possible for very large protein complexes. In contrast, de novo structure determination by NMR becomes very time consuming and difficult for protein complexes larger than 30 kDa as data are noisy and sparse. Fortunately, high-resolution structures are often available for individual domains or subunits of a protein complex and thus sparse data can be used to define their arrangement and dynamics within the assembled complex. In these cases, NMR can therefore be efficiently combined with complementary solution techniques, such as small-angle X-ray or neutron scattering, to provide a comprehensive description of the structure and dynamics of protein complexes in solution. Particularly useful are NMR-derived paramagnetic relaxation enhancements (PREs), which provide long-range distance restraints (ca. 20Å) for structural analysis of large complexes and also report on conformational dynamics in solution. Here, we describe the use of PREs from sample production to structure calculation, focusing on protein-RNA complexes. On the basis of recent examples from our own research, we demonstrate the utility, present protocols, and discuss potential pitfalls when using PREs for studying the structure and dynamic features of protein-RNA complexes.

SummaryTitin is a gigantic elastic filament that determines sarcomere ultrastructure and stretch response in vertebrate muscle. It folds into numerous Ig and FnIII domains connected in tandem. Data on interdomain arrangements and dynamics are essential for understanding the function of this filament. Here, we report a mechanistic analysis of the conformational dynamics of two Ig domains from the N terminus of titin, Z1Z2, by using X-ray crystallography, SAXS, NMR relaxation data, and residual dipolar couplings in combination. Z1Z2 preferentially adopts semiextended conformations in solution, with close-hinge arrangements representing low-probability states. Although interdomain contacts are not observed, the linker appears to acquire moderate rigidity via small, local hydrophobic interactions. Thus, Z1Z2 constitutes an adaptable modular system with restricted dynamics. We speculate that its preexistent conformation contributes to the selective recruitment of the binding partner telethonin onto the repetitive surface of the filament. The structural interconversion of four Z1Z2 conformers is analyzed.

The experiment (N = 80) tested whether the effectiveness of intragroup respect is moderated by structural (in)equality between the self and the rest of one's group. Equality (restricted vs. full rights) and respect (disrespect vs. respect) were manipulated as independent variables, while collective identification and willingness to engage in group-serving behaviour were the main dependent variables. Moderation was confirmed such that the positive effects of respect were more pronounced among group members with restricted rights than among group members with full rights. Moreover, respect fully compensated for the initial deficit in self-perception as a fully fledged group member. However, there was also some indication that, when money is at stake, formal guarantees of equality may be necessary for respect to have a facilitative effect on individual sacrifices for the sake of the group. The practical and political implications of the results are discussed.

The authors conducted a panel study with two points of measurement throughout a 12-month interval in the context of the German gay movement to test the predictive power of collective identification in subsequent actual social movement participation. Regression analyses including cross-lagged panel analyses clearly confirmed the hypothesized unique predictive value of identification with a formal social movement organization above and beyond the role the collective, normative, and reward motives traditionally considered in social movement research. Of the three motives, the normative motive was particularly predictive. Moreover, data from an additional telephone follow-up (3 years after the initial measurement) suggests that when the conflict with political opponents becomes particularly fierce, identification with the broader recruitment category, which was previously ineffective as a unique predictor, can politicize to such an extent that it also becomes a strong predictor of participation.

Aim To compare the effect of pantoprazole and esomeprazole on intra-oesophageal pH and investigate their pharmacokinetics in patients with symptomatic gastro-oesophageal reflux disease (GORD). Methods Double-blind, randomized, two-period crossover study. Caucasian men with symptomatic GORD (n = 48) were selected on the basis of clinical records of typical GORD symptoms, confirmed by a pathological reflux time (oesophageal pH < for ≥ 6% of the time). They received oral pantoprazole 40 mg once daily (od) or esomeprazole 40 mg od for seven days. Continuous 24 h oesophageal pH-metry was performed at baseline and day 7. Evaluations included: pre- and post-treatment differences in the percentage of time with pH < 4.0 and < 3.0 between baseline and day 7; area under the curve (AUC), C max , and T; point estimates and 90% confidence intervals (Cl) on days 1 and 7, calculated for ratios of the AUC and C max . Results Both drugs decreased the mean total number of reflux episodes and reduced the percentage of reflux time within 24 h to < 3%. No pathological reflux was detectable after repeated administration of either drug. The 90% CI were within the predefined range at all time points; thus, equivalence of pantoprazole and esomeprazole was concluded. For pantoprazole, C max and AUC were unchanged on day 7 vs day 1, confirming its high and constant bioavailability. For esomeprazole, C max and AUC were increased on day 7 vs day 1 by 80% and 50%, respectively, indicating low initial bioavailability. No clinically relevant side effects were seen for either drug. Conclusion Pantoprazole and esomeprazole have equivalent effect on oesophageal pH, since no pathological reflux was detected after treatment with either drug. For esomeprazole, the C max and AUC increased after multiple dosing; for pantoprazole the pharmacokinetics were predictable and independent of the number of administered doses.

This experiment examined how (disrespectful vs. respectful) treatment and (negative vs. positive) performance evaluation, both received from the same fellow group members, affects collective identification and willingness to engage in group-serving behavior. It was predicted and found that respectful as opposed to disrespectful intragroup treatment increased collective identification and willingness to engage in group-serving behavior in the immediate group situation, irrespective of whether intragroup evaluation was positive or negative. There was also evidence of a mediating role of collective identification. Regression analyses based on the measurement of perceived intragroup treatment and perceived intragroup evaluation as continuous variables corroborated these findings but also pointed to limits of the positive effects of respectful intragroup treatment. Finally, the interrelation of treatment and evaluation by fellow group members as two possible components of intragroup respect are discussed as well as the political dimension of research on intragroup respect.

This article develops a social psychological model of politicized collective identity that revolves around 3 conceptual triads. The 1st triad consists of collective identity, the struggle between groups for power, and the wider societal context. It is proposed that people evince politicized collective identity to the extent that they engage as self-conscious group members in a power struggle on behalf of their group knowing that it is the more inclusive societal context in which this struggle has to be fought out. Next, 3 antecedent stages leading to politicized collective identity are distinguished: awareness of shared grievances, adversarial attributions, and involvement of society at large. This sequence culminates in the final triad because the intergroup power struggle is eventually triangulated by involving society at large or representatives thereof. Consequences of politicized collective identity are discussed.

The authors examined the interactive influence of accessibility of the individual self and relative in-group size on group-level as opposed to individual-level information processing. In Expt 1, the authors predicted and found that, when accessibility of the individual self was low, minority members tended more towards group-level information processing than did majority members. This was not true when accessibility of the individual self was high. Contrary to the authors' hypothesis, however, the disappearance of the minority-majority effect in the high-accessibility condition did not result from a decrease in group-level information processing among minority members, but from an increase among majority members. Experiment 2 replicated this unexpected effect using two different measures of group level information processing. It also provided additional data on the dynamic interplay of the individual self and the collective self which seems to be responsible for the observed effects.

FKBP38 regulates apoptosis through unique interactions with multiple regulators including Bcl-2. Interestingly, the peptidylprolyl isomerase activity of FKBP38 is only detectable when it binds to calcium-saturated calmodulin (CaM/Ca2+). This, in turn, permits the formation of a complex with Bcl-2. FKBP38 thereby provides an important link between isomerase activity and apoptotic pathways. Here, we show that the N-terminal extension (residues 1-32) preceding the catalytic domain of FKBP38 has an autoinhibitory activity. The core isomerase activity of FKBP38 is inhibited by transient interactions involving the flexible N-terminal extension that precedes the catalytic domain. Notably, CaM/Ca2+ binds to this N-terminal extension and thereby releases the autoinhibitory contacts between the N-terminal extension and the catalytic domain, thus potentiating the isomerase activity of FKBP38. Our data demonstrate how CaM/Ca2+ modulates the catalytic activity of FKBP38. Published version

This article examines the role of dual identity in political radicalism among migrants. Dual identity is defined as identification with both one’s ethnocultural minority in-group and one’s society of residence. We employed a longitudinal research design using members of the two largest migrant groups in Germany (Turkish migrants and Russian migrants) as participants. We reasoned that when dual identity is burdened with incompatibility between component identifications, it may foster controversial or even destructive forms of political mobilization, such as radicalism. Multiple regression analysis controlling for other influences confirmed the hypothesized moderated relationship between dual identification and sympathy for radical action. When accompanied by high, as opposed to low, perceived identity incompatibility, dual identification predicted increases in sympathy for radical action among both Turkish migrants and Russian migrants. The implications for public life in ethnically and culturally heterogeneous societies are discussed.

Phosphotyrosine binding domains (PTB) are protein-protein interaction domains that play important roles in various cellular signal transduction pathways. The second phosphotyrosine binding domain (PTB2) of the human scaffolding protein FE65 interacts with the C-terminal part of the Amyloid Precursor Protein (APP) involved in Alzheimer's disease. The structure of PTB2 in complex with a 32 amino acid fragment of APP has been solved previously by X-ray crystallography. Here, we report the NMR spectral assignments of the free FE65 PTB2. This provides the basis for further investigation of the interactions of PTB2 with peptides and small organic ligands with the aim of disrupting the PTB2-APP interaction.

Neuronal Fe65 is a central adapter for the intracellular protein network of Alzheimer’s disease related amyloid precursor protein (APP). It contains a unique tandem array of phosphotyrosine-binding (PTB) domains that recognize NPXY internalization motifs present in the intracellular domains of APP (AICD) and the low-density lipoprotein receptor-related protein LRP1 (LICD). The ternary APP/Fe65/LRP1 complex is an important mediator of APP processing and affects β-amyloid peptide production. Here we dissect by biochemical and biophysical methods the direct interactions within the ternary complex and reveal a phosphorylation-dependent insulin receptor substrate (IRS-) like interaction of the distal NPVY 4507 motif of LICD with Fe65-PTB1. Structured summary of protein interactions APP-AICD and FE65 bind by nuclear magnetic resonance ( View interaction ) Src phosphorylates LRP1-LICD by protein kinase assay ( View interaction ) LRP1-LICD physically interacts with FE65 and APP-AICD by pull down ( View interaction ) FE65-PTB1 and LRP1-LICD bind by nuclear magnetic resonance ( View interaction ) LRP1-LICD binds to FE65-PTB1 by pull down ( View interaction ) APP-AICD binds to FE65-PTB2 by pull down ( View interaction )

Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin ( TTN ) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin protein to the transitional junction at intercalated disks. Methods and Results— All 312 titin exons known to be expressed in human cardiac titin and the complete 3′ untranslated region were sequenced in 38 ARVC families. Eight unique TTN variants were detected in 7 families, including a prominent Thr2896Ile mutation that showed complete segregation with the ARVC phenotype in 1 large family. The Thr2896IIe mutation maps within a highly conserved immunoglobulin-like fold (Ig10 domain) located in the spring region of titin. Native gel electrophoresis, nuclear magnetic resonance, intrinsic fluorescence, and proteolysis assays of wild-type and mutant Ig10 domains revealed that the Thr2896IIe exchange reduces the structural stability and increases the propensity for degradation of the Ig10 domain. The phenotype of TTN variant carriers was characterized by a history of sudden death (5 of 7 families), progressive myocardial dysfunction causing death or heart transplantation (8 of 14 cases), frequent conduction disease (11 of 14), and incomplete penetrance (86%). Conclusions— Our data provide evidence that titin mutations can cause ARVC, a finding that further expands the origin of the disease beyond desmosomal proteins. Structural impairment of the titin spring is a likely cause of ARVC and constitutes a novel mechanism underlying myocardial remodeling and sudden cardiac death.

The EMBO journal 28, 745-754 (2009). doi:10.1038/emboj.2009.7, Protein import into peroxisomes depends on a complex and dynamic network of protein–protein interactions. Pex14 is a central component of the peroxisomal import machinery and binds the soluble receptors Pex5 and Pex19, which have important function in the assembly of peroxisome matrix and membrane, respectively. We show that the N‐terminal domain of Pex14, Pex14(N), adopts a three‐helical fold. Pex5 and Pex19 ligand helices bind competitively to the same surface in Pex14(N) albeit with opposite directionality. The molecular recognition involves conserved aromatic side chains in the Pex5 WxxxF/Y motif and a newly identified F/YFxxxF sequence in Pex19. The Pex14–Pex5 complex structure reveals molecular details for a critical interaction in docking Pex5 to the peroxisomal membrane. We show that mutations of Pex14 residues located in the Pex5/Pex19 binding region disrupt Pex5 and/or Pex19 binding in vitro. The corresponding full‐length Pex14 variants are impaired in peroxisomal membrane localisation in vivo, showing that the molecular interactions mediated by the N‐terminal domain modulate peroxisomal targeting of Pex14., Published by Wiley, Hoboken, NJ [u.a.]

The article examines the role of collective identification processes in the politicization of Turkish migrants in Germany. Building on the suggestion that politicized collective identity is a dual identity, the authors predicted and found that dual identification as both Turkish and German was positively related to politicization among members of the Turkish minority in Germany. This relationship was found in both cross-sectional and longitudinal analyses and held up even when the influence of sociodemographic variables, past political activity, and other forms of collective identification were statistically controlled, suggesting a unique and causal role of dual identification. However, there was no evidence that dual identification fosters radicalization or even political violence. The implications for social integration of politicization driven by dual identification are discussed, as is the interplay of dual identification and separatist identification that could underlie the shift from involvement in normative politics to radicalization.

Cleavage of the amyloid precursor protein (APP) is a crucial event in Alzheimer disease pathogenesis that creates the amyloid-beta peptide (Abeta) and liberates the carboxy-terminal APP intracellular domain (AICD) into the cytosol. The interaction of the APP C terminus with the adaptor protein Fe65 mediates APP trafficking and signalling, and is thought to regulate APP processing and Abeta generation. We determined the crystal structure of the AICD in complex with the C-terminal phosphotyrosine-binding (PTB) domain of Fe65. The unique interface involves the NPxY PTB-binding motif and two alpha helices. The amino-terminal helix of the AICD is capped by threonine T(668), an Alzheimer disease-relevant phosphorylation site involved in Fe65-binding regulation. The structure together with mutational studies, isothermal titration calorimetry and nuclear magnetic resonance experiments sets the stage for understanding T(668) phosphorylation-dependent complex regulation at a molecular level. A molecular switch model is proposed.

The selective cyclooxygenase-2 inhibitor lumiracoxib has been shown to reduce endoscopically detected ulcers and ulcer complications in the upper gastrointestinal tract compared with nonselective nonsteroidal anti-inflammatory drugs. We investigated whether lumiracoxib would reduce small-bowel injury compared with naproxen plus omeprazole.Healthy volunteers were randomized to receive lumiracoxib 100 mg once daily, naproxen 500 mg twice daily plus omeprazole 20 mg once daily, or placebo in a 16-day double-blind, parallel-group study. Small-bowel mucosal injury and inflammation were assessed by video capsule endoscopy, the lactulose:L-rhamnose permeability assessment, and the fecal calprotectin test.Of 152 randomized subjects, 139 completed the study with valid video capsule endoscopies (lumiracoxib, n = 47; naproxen plus omeprazole, n = 45; placebo, n = 47). Compared with placebo, an increased number of subjects on naproxen plus omeprazole had small-bowel mucosal breaks (77.8% vs 40.4%, P.001), with increased permeability (P = .023) and increased fecal calprotectin (increase, 96.8 vs 14.5 mg/kg for placebo; P.001). With lumiracoxib, 27.7% of subjects had small-bowel mucosal breaks (P = .196 vs placebo; P.001 vs naproxen), there was no increase in permeability (P = .157 vs placebo; P = .364 vs naproxen), and no increase in fecal calprotectin (-5.7 mg/kg; P = .377 vs placebo; P.001 vs naproxen).As assessed by 3 different measures, acute small-bowel injury on lumiracoxib treatment is less frequent than with naproxen plus omeprazole and similar to placebo.

Mutations in the autoimmune regulator protein AIRE1 cause a monogenic autosomal recessively inherited disease: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE1 is a multidomain protein that harbors two plant homeodomain (PHD)-type zinc fingers. The first PHD finger of AIRE1 is a mutational hot spot, to which several pathological point mutations have been mapped. Using heteronuclear NMR spectroscopy, we determined the solution structure of the first PHD finger of AIRE1 (AIRE1-PHD1), and characterized the peptide backbone mobility of the domain. We performed a conformational analysis of pathological AIRE1-PHD1 mutants that allowed us to rationalize the structural impact of APECED-causing mutations and to identify an interaction site with putative protein ligands of the AIRE1-PHD1 domain. The structure unequivocally exhibits the canonical PHD finger fold, with a highly conserved tryptophan buried inside the structure. The PHD finger is stabilized by two zinc ions coordinated in an interleaved (cross-brace) scheme. This zinc coordination resembles RING finger domains, which can function as E3 ligases in the ubiquitination pathway. Based on this fold similarity, it has been suggested that PHD fingers might also function as E3 ligases, although this hypothesis is controversial. At variance to a previous report, we could not find any evidence that AIRE1-PHD1 has an intrinsic E3 ubiquitin ligase activity, nor detect any direct interaction between AIRE1-PHD1 and its putative cognate E2. Consistently, we show that the AIRE1-PHD1 structure is clearly distinct from the RING finger fold. Our results point to a function of the AIRE1-PHD1 domain in protein-protein interactions, which is impaired in some APECED mutations.

Pleckstrin1 is a major substrate for protein kinase C in platelets and leukocytes, and comprises a central DEP (disheveled, Egl-10, pleckstrin) domain, which is flanked by two PH (pleckstrin homology) domains. DEP domains display a unique alpha/beta fold and have been implicated in membrane binding utilizing different mechanisms. Using multiple sequence alignments and phylogenetic tree reconstructions, we find that 6 subfamilies of the DEP domain exist, of which pleckstrin represents a novel and distinct subfamily. To clarify structural determinants of the DEP fold and to gain further insight into the role of the DEP domain, we determined the three-dimensional structure of the pleckstrin DEP domain using heteronuclear NMR spectroscopy. Pleckstrin DEP shares main structural features with the DEP domains of disheveled and Epac, which belong to different DEP subfamilies. However, the pleckstrin DEP fold is distinct from these structures and contains an additional, short helix alpha4 inserted in the beta4-beta5 loop that exhibits increased backbone mobility as judged by NMR relaxation measurements. Based on sequence conservation, the helix alpha4 may also be present in the DEP domains of regulator of G-protein signaling (RGS) proteins, which are members of the same DEP subfamily. In pleckstrin, the DEP domain is surrounded by two PH domains. Structural analysis and charge complementarity suggest that the DEP domain may interact with the N-terminal PH domain in pleckstrin. Phosphorylation of the PH-DEP linker, which is required for pleckstrin function, could regulate such an intramolecular interaction. This suggests a role of the pleckstrin DEP domain in intramolecular domain interactions, which is distinct from the functions of other DEP domain subfamilies found so far.

Structural genomics requires the application of a standardised process for overexpression of soluble proteins that allows high-throughput purification and analysis of protein products. We have developed a highly parallel approach to protein expression, including the simultaneous expression screening of a large number of cDNA clones in an appropriate vector system and the use of a protease-deficient host strain. A set of 221 human genes coding for proteins of various sizes with unknown structures was selected to evaluate the system. We transferred the cDNAs from an E. coli vector to the yeast expression vector by recombinational cloning, avoiding time-consuming recloning steps and the use of restriction enzymes in the cloning process. The subcloning yield was 95%, provided that a PCR fragment of the correct size could be obtained. Sixty percent of these proteins were expressed as soluble products at detectable levels and 48% were successfully purified under native conditions using the His6 tag fusion. The advantages of the developed yeast-based expression system are the ease of manipulation and cultivation of S. cerevisiae in the same way as with prokaryotic hosts and the ability to introduce post-translational modifications of proteins if required, thus being an attractive system for heterologous expression of mammalian proteins. The expression clones selected in this screening process are passed on to the fermentation process in order to provide milligram amounts of proteins for structure analysis within the 'Berlin Protein Structure Factory'. All data generated is stored in a relational database and is available on our website (http://www.proteinstrukturfabrik.de).

This research examined the interplay of group formation and individualization processes with a particular emphasis on minority and majority groups. First, a 2-component theory of individuality that distinguishes between individuality as independence and as differentiation from other people was presented, tested, and cross-validated in 2 questionnaire studies. Next, a pilot experiment provided first support for the working assumption that the salience of the differentiation or independence components of individuality differentially affect minority and majority group formation. Finally, the main experiment demonstrated that these individuality effects on minority and majority group formation are due largely to a differential orientation toward either intergroup or intragroup comparisons. This experiment also uncovered a unique effect of relative in-group size, but this effect was limited to similarity-based group formation.

SUMMARY One hundred and twenty-five patients with duodenal ulcer disease were given continuous ranitidine therapy after initial acute healing. Cumulative remission rates indicated that 95 % of patients were ulcer-free after 1 year, 89% at 2 years, 81% at 3 years, 70% at 4 years and 60% at 5 and 6 years. Nine patients had a second recurrence after healing of the first. No patient developed an ulcer complication. These results support the view that long-term continuous ranitidine therapy prevents ulcer recurrence and complications.

SUMMARY The effects of the H+, K+-ATPase inhibitor BY 1023/SK&F 96022 on pentagastrin-stimulated acid secretion have been studied in healthy male volunteers (n= 12). The gastric acid response to submaximal pentagastrin-stimulation (0.6 μg/h/kg b.w.) was dose-dependently inhibited. A single dose of 5 mg decreased acid output by 22% while after 60 mg and 80 mg secretion was almost completely abolished. A good dose linearity was observed for AUC (0, >) and Cmax over the dose range from 5 to 80 mg. Elimination half-life, total clearance and volume of distribution of the parent compound were independent of the dose. The drug was well tolerated up to the highest dose of 80 mg. No clinically relevant influence was found on either laboratory screen or cardiovascular parameters.

In an attempt to characterize the adenylate cyclase-coupled alpha-adrenoceptors of human fat cells the effects of various alpha-adrenergic agonists and antagonists were examined in the presence of 0.05 mmol/l of propranolol. The order of agonist potencies with respect to alpha-adrenergic inhibition was (-)-adrenaline greater than alpha-methyl-(-)-noradrenaline greater than (-)-phenylephrine with half-maximal inhibition occurring at 2 mumol/l of (-)-adrenaline and 7 mumol/l of alpha-methyl-(-)-noradrenaline respectively. The inhibition of adenylate cyclase induced by 0.05 mmol/l of (-)-adrenaline was reversed by the alpha-blocking agents yohimbine and prazosin, with the alpha 2-site-directed antagonist yohimbine being more than 100-times more potent than prazosin which is more active at alpha 1-sites. The results show that the cyclase-coupled alpha-adrenoceptors of human fat cells, which probably represent the physiologically relevant target of antilipolytic catecholamine effects, display characteristic features of the alpha 2-adrenoceptor subtype.

Adenylate cyclase of human fat cell ghosts shows a biphasic response towards prostaglandin E2 with inhibition occurring at nanomolar concentrations of the hormone and stimulation at concentrations beyond 10(-6) mol/liter. The expression of the inhibitory effect is critically dependent on GTP. Under the conditions employed (1 mmol/liter ATP, 5 mmol/liter Mg2+, 30 degrees C) the inhibitory component of prostaglandin E2 became apparent at GTP concentrations exceeding 10(-6) mol/liter. The prostaglandin E2-induced inhibition displayed characteristic features of prostaglandin action in intact fat cells with respect to the effective concentrations and degree of inhibition. It is concluded that prostaglandin E2 is capable of inducing antagonistic effects upon lipolysis via interaction with the membrane-bound adenylate cyclase.

In a randomized, double-bind, parallel, multi-clinic study, the safety and efficacy of enprostil (35 micrograms twice daily) and ranitidine (150 mg twice daily) were compared in the treatment of active gastric ulcer in 93 outpatients (47 enprostil-treated patients and 46 ranitidine). The two treatment groups were well matched for demographic characteristics. The healing rates in the enprostil group were 22, 58, 80, and 86 percent at two, four, six, and eight weeks, respectively. The corresponding rates in the ranitidine group were 22, 66, 84, and 89 percent. None of these differences was statistically significant. The area of the ulcer at baseline and smoking status did not appear to influence healing rates. There were no significant differences between treatment groups in time to relief of ulcer symptoms, frequency of daytime or nighttime ulcer pain, or antacid use. Side effects attributable to enprostil treatment were diarrhea (10 percent versus 6 percent with ranitidine), gastrointestinal pain, and vomiting. These side effects, however, did not influence the patients' assessments of their overall response to enprostil and ranitidine therapy. Six enprostil-treated patients and one ranitidine-treated patient withdrew from the trial prematurely because of adverse experiences. Monitoring of clinical laboratory test results showed no significant changes in the two treatment groups. This study demonstrates that a prostaglandin E2 analogue, enprostil, in a dose of 35 micrograms twice daily, is similarly safe and effective as ranitidine in the treatment of active gastric ulcer.

The effects of guanine nucleotides on basal and parathyroid hormone-stimulated adenylate cyclase of human fat cell ghosts were studied. GTP (10(-7)-10(-3) M) caused a dose-dependent inhibition of basal enzyme activity, but it had no significant effect on PTH-stimulated rates of cAMP-formation. The guanine nucleotide analogue 5'-guanylyl-imidodiphosphate GMP (PNP) when applied in the same concentration range, stimulated basal as well as PTH-activated adenylate cyclase activity up to 300%. GMP (PNP) activation was non-linear with time. PTH-activated the human fat cell adenylate cyclase via an individual receptor distinct from beta-adrenergic receptor sites.