Unraveling novel mutation patterns and morphological variations in two dalbavancin-resistant MRSA strains in Austria using whole genome sequencing and transmission electron microscopy.

BACKGROUND: The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains resistant to non-beta-lactam antimicrobials poses a significant challenge in treating severe MRSA bloodstream infections. This study explores resistance development and mechanisms in MRSA isolates, especially after the first dalbavancin-resistant MRSA strain in our hospital in 2016. METHODS: This study investigated 55 MRSA bloodstream isolates (02/2015-02/2021) from the University Hospital of the Medical University of Vienna, Austria. The MICs of dalbavancin, linezolid, and daptomycin were assessed. Two isolates (16-33 and 19-362) resistant to dalbavancin were analyzed via whole-genome sequencing, with morphology evaluated using transmission electron microscopy (TEM). RESULTS: S.aureus BSI strain 19-362 had two novel missense mutations (p.I515M and p.A606D) in the pbp2 gene. Isolate 16-33 had a 534 bp deletion in the DHH domain of GdpP and a SNV in pbp2 (p.G146R). Both strains had mutations in the rpoB gene, but at different positions. TEM revealed significantly thicker cell walls in 16-33 (p < 0.05) compared to 19-362 and dalbavancin-susceptible strains. None of the MRSA isolates showed resistance to linezolid or daptomycin. CONCLUSION: In light of increasing vancomycin resistance reports, continuous surveillance is essential to comprehend the molecular mechanisms of resistance in alternative MRSA treatment options. In this work, two novel missense mutations (p.I515M and p.A606D) in the pbp2 gene were newly identified as possible causes of dalbavancin resistance.

Does personality matter? Exploring its moderating role on the relationship between neighbourhood ethnic outgroup-size and preferences for Brexit.

Prior research has examined the relationship between ethnic outgroup-size at the neighbourhood level and Brexit support, yet there is a lack of understanding on the factors that moderate these effects. This paper critically extends prior debate by focusing on how personality traits moderate not only the extent to which the levels (2011) of ethnic outgroup-size in individuals' residential neighbourhoods but also the increase thereof (2001-2011) are associated with individuals' preferences about the 2016 Brexit referendum. Using data from Understanding Society, we find that two personality traits, agreeableness and openness, are key moderators affecting the above-mentioned relationship. High-agreeable and high-open individuals are less likely than low-agreeable and low-open individuals to support Brexit. However, while the gap between low and highly agreeable individuals shrinks as ethnic outgroup-size increases, the gap widens between those higher vs. lower in openness. Our findings highlight the multifaceted role of personality traits as a driver of heterogeneous effects on political behaviour. In sum, this paper shows that analysing the complex and intertwined nature of both contextual and individual factors is fundamental for a better understanding, not only of the Brexit referendum but, more broadly, of anti-immigrant sentiment.

Effects of absolute levels of neighbourhood ethnic diversity vs. changes in neighbourhood diversity on prejudice: Moderation by individual differences in personality.

This paper examines drivers of prejudicial attitudes among adults in the UK, focusing on the interaction between ethnic out-group size and personality traits. Leveraging data from the National Child Development Study (NCDS), we use two survey waves carried out in 2000 and 2008, just before and after the EU enlargement policy that drove a wave of immigration in the UK. We test the extent to which personality traits moderate the relationship between both absolute levels and changes in ethnic diversity at the local level, respectively, and prejudice. Key findings suggest that personality traits, in particular one's agreeableness, are important for conditioning how the proportion of non-white British in one's neighbourhood affects out-group attitudes. We observe a tendency towards polarisation in prejudicial attitudes between low-/high-agreeableness residents as their neighbourhoods become more diverse. These findings have important implications for theorising how contextual and individual characteristics jointly affect intergroup relations.

m6A modulates neuronal functions and sex determination in Drosophila.

N6-methyladenosine RNA (m6A) is a prevalent messenger RNA modification in vertebrates. Although its functions in the regulation of post-transcriptional gene expression are beginning to be unveiled, the precise roles of m6A during development of complex organisms remain unclear. Here we carry out a comprehensive molecular and physiological characterization of the individual components of the methyltransferase complex, as well as of the YTH domain-containing nuclear reader protein in Drosophila melanogaster. We identify the member of the split ends protein family, Spenito, as a novel bona fide subunit of the methyltransferase complex. We further demonstrate important roles of this complex in neuronal functions and sex determination, and implicate the nuclear YT521-B protein as a main m6A effector in these processes. Altogether, our work substantially extends our knowledge of m6A biology, demonstrating the crucial functions of this modification in fundamental processes within the context of the whole animal.

Strategic experimentation with asymmetric players.

We examine a two-player game with two-armed exponential bandits à la (Keller et al. in Econometrica 73:39-68, 2005), where players operate different technologies for exploring the risky option. We characterise the set of Markov perfect equilibria and show that there always exists an equilibrium in which the player with the inferior technology uses a cut-off strategy. All Markov perfect equilibria imply the same amount of experimentation but differ with respect to the expected speed of the resolution of uncertainty. If and only if the degree of asymmetry between the players is high enough, there exists a Markov perfect equilibrium in which both players use cut-off strategies. Whenever this equilibrium exists, it welfare dominates all other equilibria. This contrasts with the case of symmetric players, where there never exists a Markov perfect equilibrium in cut-off strategies.

Genes Involved in Long-Term Memory Are Expressed in Testis of Cryptorchid Boys and Respond to GnRHa Treatment.

It has been known for many years that boys with unilateral or bilateral undescended testis (cryptorchidism) tend to have a low IQ, and those who belong to the high infertility risk (HIR) group perform less well at school than low infertility risk (LIR) patients. However, the molecular biological processes underlying this phenomenon are not understood. In this study, we report the outcome of testicular RNA profiling for genes involved in long-term memory formation. We analyzed the histology and the transcriptome of testicular biopsies from bilateral HIR cryptorchid boys, comparing those who received GnRHa treatment for 6 months after the first surgery with those who did not receive GnRHa before the second surgery. We found that GnRHa treatment alters the testicular mRNA levels of neuronal genes that are involved in long-term memory and testosterone synthesis. These data highlight a possible molecular link between cryptorchidism, impaired mini-puberty, and diminished cognitive functions. Our results are consistent with the hypothesis that hypogonadotropic hypogonadism in cryptorchid boys with altered mini-puberty may affect neuronal genes important for memory and learning, which could help explaining the negative correlation between cryptorchidism and intellectual abilities.

Alkyne-Functionalized Coumarin Compound for Analytic and Preparative 4-Thiouridine Labeling.

Bioconjugation of RNA is a dynamic field recently reinvigorated by a surge in research on post-transcriptional modification. This work focuses on the bioconjugation of 4-thiouridine, a nucleoside that occurs as a post-transcriptional modification in bacterial RNA and is used as a metabolic label and for cross-linking purposes in eukaryotic RNA. A newly designed coumarin compound named 4-bromomethyl-7-propargyloxycoumarin (PBC) is introduced, which exhibits remarkable selectivity for 4-thiouridine. Bearing a terminal alkyne group, it is conductive to secondary bioconjugation via "click chemistry", thereby offering a wide range of preparative and analytical options. We applied PBC to quantitatively monitor the metabolic incorporation of s4U as a label into RNA and for site-specific introduction of a fluorophore into bacterial tRNA at position 8, allowing the determination of its binding constant to an RNA-modification enzyme.

Analysis of RNA modifications by liquid chromatography-tandem mass spectrometry.

The analysis of RNA modifications is of high importance in order to address a wide range of biological questions. Therefore, a highly sensitive and accurate method such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) has to be available. By using different LC-MS/MS procedures, it is not only possible to quantify very low amounts of RNA modifications, but also to detect probably unknown modified nucleosides. For these cases the dynamic multiple reaction monitoring and the neutral loss scan are the most common techniques. Here, we provide the whole workflow for analyzing RNA samples regarding their modification content. This includes an equipment list, the preparation of required solutions/enzymes and the creation of an internal standard or nucleoside stocks for internal or external calibration. Furthermore, we describe the preparation of RNA samples for the subsequent LC-MS/MS analysis and the corresponding analysis process.

The reverse transcription signature of N-1-methyladenosine in RNA-Seq is sequence dependent.

The combination of Reverse Transcription (RT) and high-throughput sequencing has emerged as a powerful combination to detect modified nucleotides in RNA via analysis of either abortive RT-products or of the incorporation of mismatched dNTPs into cDNA. Here we simultaneously analyze both parameters in detail with respect to the occurrence of N-1-methyladenosine (m(1)A) in the template RNA. This naturally occurring modification is associated with structural effects, but it is also known as a mediator of antibiotic resistance in ribosomal RNA. In structural probing experiments with dimethylsulfate, m(1)A is routinely detected by RT-arrest. A specifically developed RNA-Seq protocol was tailored to the simultaneous analysis of RT-arrest and misincorporation patterns. By application to a variety of native and synthetic RNA preparations, we found a characteristic signature of m(1)A, which, in addition to an arrest rate, features misincorporation as a significant component. Detailed analysis suggests that the signature depends on RNA structure and on the nature of the nucleotide 3' of m(1)A in the template RNA, meaning it is sequence dependent. The RT-signature of m(1)A was used for inspection and confirmation of suspected modification sites and resulted in the identification of hitherto unknown m(1)A residues in trypanosomal tRNA.

Contextual effect of positive intergroup contact on outgroup prejudice.

We assessed evidence for a contextual effect of positive intergroup contact, whereby the effect of intergroup contact between social contexts (the between-level effect) on outgroup prejudice is greater than the effect of individual-level contact within contexts (the within-level effect). Across seven large-scale surveys (five cross-sectional and two longitudinal), using multilevel analyses, we found a reliable contextual effect. This effect was found in multiple countries, operationalizing context at multiple levels (regions, districts, and neighborhoods), and with and without controlling for a range of demographic and context variables. In four studies (three cross-sectional and one longitudinal) we showed that the association between context-level contact and prejudice was largely mediated by more tolerant norms. In social contexts where positive contact with outgroups was more commonplace, norms supported such positive interactions between members of different groups. Thus, positive contact reduces prejudice on a macrolevel, whereby people are influenced by the behavior of others in their social context, not merely on a microscale, via individuals' direct experience of positive contact with outgroup members. These findings reinforce the view that contact has a significant role to play in prejudice reduction, and has great policy potential as a means to improve intergroup relations, because it can simultaneously impact large numbers of people.

Easy mammalian expression and crystallography of maltose-binding protein-fused human proteins.

We present a strategy to obtain milligrams of highly post-translationally modified eukaryotic proteins, transiently expressed in mammalian cells as rigid or cleavable fusions with a mammalianized version of bacterial maltose-binding protein (mMBP). This variant was engineered to combine mutations that enhance MBP solubility and affinity purification, as well as provide crystal-packing interactions for increased crystallizability. Using this cell type-independent approach, we could increase the expression of secreted and intracellular human proteins up to 200-fold. By molecular replacement with MBP, we readily determined five novel high-resolution structures of rigid fusions of targets that otherwise defied crystallization.

Developmental Dynamics of Intergroup Contact and Intergroup Attitudes: Long-Term Effects in Adolescence and Early Adulthood.

Intergroup contact represents a powerful way to improve intergroup attitudes and to overcome prejudice and discrimination. However, long-term effects of intergroup contact that consider social network dynamics have rarely been studied at a young age. Study 1 validated an optimized social network approach to investigate intergroup contact (N = 6,457; Mage  = 14.91 years). Study 2 explored the developmental trajectories of intergroup contact by applying this validated network approach in a cross-sequential design (four-cohort-four-wave; N = 3,815; 13-26 years). Accelerated growth curve models showed that contact predicts the development of attitudes in adolescence, whereas acquired attitudes buffer against decreasing contact in adulthood. Findings highlight the potential of social network analysis and the developmental importance of early intergroup contact experiences.

Neighborhood ethnic diversity and trust: the role of intergroup contact and perceived threat.

This research reported here speaks to a contentious debate concerning the potential negative consequences of diversity for trust. We tested the relationship between neighborhood diversity and out-group, in-group, and neighborhood trust, taking into consideration previously untested indirect effects via intergroup contact and perceived intergroup threat. A large-scale national survey in England sampled White British majority (N = 868) and ethnic minority (N = 798) respondents from neighborhoods of varying degrees of diversity. Multilevel path analyses showed some negative direct effects of diversity for the majority group but also confirmed predictions that diversity was associated indirectly with increased trust via positive contact and lower threat. These indirect effects had positive implications for total effects of diversity, cancelling out most negative direct effects. Our findings have relevance for a growing body of research seeking to disentangle effects of diversity on trust that has so far largely ignored the key role of intergroup contact.

Reducing aggressive intergroup action tendencies: effects of intergroup contact via perceived intergroup threat.

Two studies tested the prediction that more positive intergroup contact would be associated with reduced aggressive intergroup action tendencies, an effect predicted to occur indirectly via reduced intergroup threat perceptions, and over and above well-established effects of contact on intergroup attitudes. Study 1, using data based on a cross-section of the general population of eight European countries (France, Germany, Hungary, Italy, the Netherlands, Poland, Portugal, and the UK; N = 7,042), examined this hypothesis in the context of aggressive action tendencies towards immigrants. Study 2, using longitudinal data obtained from a general population sample in Northern Ireland, considered effects on aggressive action tendencies between ethno-religious groups in conflict. Both studies confirmed our predictions, showing that while perceived threat was associated with greater intergroup aggressive tendencies, positive intergroup contact was indirectly associated with reduced aggressive action tendencies, via reduced intergroup threat. Findings are discussed in terms of the theoretical contributions of this research for understanding the relationship between intergroup contact and intergroup aggression.

Rationally blind? Rationality polarizes policy support for colour blindness versus multiculturalism.

Do White Americans prefer society to be 'colour-blind' by rising above racial identities, or 'multicultural' by openly discussing and considering them? We developed an ideology-rationality model to understand support for these diversity perspectives. Specifically, since people endorse a diversity perspective in line with their ideological values, we hypothesized that conservatism is related to a relative preference for colour blindness over multiculturalism. However, since colour blindness and multiculturalism are complex and multi-layered ideologies, we further hypothesized that the relationship between conservatism and a preference for colour blindness over multiculturalism is especially pronounced under higher levels of rationality. Results confirmed the hypotheses, either when rationality was operationalized within a dual process theory (Study 1, N = 496) or experimentally induced within a tripartite model of cognition (Study 2, N = 497). Higher levels of rationality guided White Americans high in conservatism towards a stronger preference for colour-blindness, but those low in conservatism towards a stronger preference for multiculturalism. These results suggest that among White Americans the endorsement of colour blindness versus multiculturalism stems from the interplay between ideological orientation and rationality and that rational considerations about racial policies may further divide rather than unify along ideological lines.

The association between political orientation and political knowledge in 45 nations.

Political knowledge is crucial for well-functioning democracies, with most scholars assuming that people at the political extremes are more knowledgeable than those at the center. Here, we adopt a data-driven approach to examine the relationship between political orientation and political knowledge by testing a series of polynomial curves in 45 countries (N = 63,544), spread over 6 continents. Contrary to the dominant perspective, we found no evidence that people at the political extremes are the most knowledgeable about politics. Rather, the most common pattern was a fourth-degree polynomial association in which those who are moderately left-wing and right-wing are more knowledgeable than people at the extremes and center of the political spectrum. This pattern was especially, though not exclusively, prevalent in Western countries. We conclude that the relationship between political orientation and political knowledge is more context-dependent and complex than assumed, and caution against (implicit) universal conclusions in social sciences.

Selective exposure bias predicts views on diversity over time.

Despite growing diversity, many individuals do not support it, posing a challenge to the successful functioning of societies, institutions, and organizations. We investigated the role of the selective exposure bias on diversity beliefs. In a large-scale nationally representative Spanish sample (N = 2,297), we conducted a time-lagged experiment with two time points 5 months apart in which we offered participants a monetary incentive to (allegedly) read attitude contradictory versus conforming information about societal support for refugees. The selective exposure bias asymmetrically predicted future diversity beliefs. Among individuals with a positive intergroup orientation, the selective exposure bias did not predict future diversity beliefs. However, among individuals with a negative intergroup orientation, the selective exposure bias predicted lower pro-diversity beliefs over time, over and above initial pro-diversity beliefs and ideological dispositions. These findings suggest that the absence of pro-diversity beliefs partly originates from a cognitive bias, holding critical implications for policymakers seeking to improve intergroup relations.

epiAneufinder identifies copy number alterations from single-cell ATAC-seq data.

Single-cell open chromatin profiling via scATAC-seq has become a mainstream measurement of open chromatin in single-cells. Here we present epiAneufinder, an algorithm that exploits the read count information from scATAC-seq data to extract genome-wide copy number alterations (CNAs) for individual cells, allowing the study of CNA heterogeneity present in a sample at the single-cell level. Using different cancer scATAC-seq datasets, we show that epiAneufinder can identify intratumor clonal heterogeneity in populations of single cells based on their CNA profiles. We demonstrate that these profiles are concordant with the ones inferred from single-cell whole genome sequencing data for the same samples. EpiAneufinder allows the inference of single-cell CNA information from scATAC-seq data, without the need of additional experiments, unlocking a layer of genomic variation which is otherwise unexplored.

Intergroup contact is reliably associated with reduced prejudice, even in the face of group threat and discrimination.

Intergroup contact provides a reliable means of reducing prejudice. Yet, critics suggested that its efficacy is undermined, even eliminated, under certain conditions. Specifically, contact may be ineffective in the face of threat, especially to (historically) advantaged groups, and discrimination, experienced especially by (historically) disadvantaged groups. We considered perceived intergroup threat and perceived discrimination as potential moderators of the effect of contact on prejudice. Two meta-analyses of correlational data from 34 studies (totaling 63,945 respondents-drawn from 67 subsamples across 19 countries) showed that contact was associated with decreased prejudice and increased out-group positivity, in cross-sectional and longitudinal designs, among advantaged and disadvantaged group members, and in both Western, Educated, Industrialized, Rich, and Democratic (WEIRD) and non-WEIRD contexts. Both perceived threat and perceived discrimination moderated the contact-attitude association, but in an unanticipated direction. Indeed, contact's beneficial effects were at least as strong among individuals high (r = .19) as among individuals low (r = .18) in perceived threat. Similarly, the effects of contact were at least as strong among those high (r = .23) as among those low (r = .20) in perceived discrimination. We conclude that contact is effective for promoting tolerant societies because it is effective even among subpopulations where achieving that goal might be most challenging. (PsycInfo Database Record (c) 2023 APA, all rights reserved).