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Genome-wide association studies have discovered numerous genomic loci associated with Alzheimer’s disease (AD); yet the causal genes and variants are incompletely identified. We performed an updated genome-wide AD meta-analysis, which identified 37 risk loci, including new associations near CCDC6 , TSPAN14 , NCK2 and SPRED2 . Using three SNP-level fine-mapping methods, we identified 21 SNPs with >50% probability each of being causally involved in AD risk and others strongly suggested by functional annotation. We followed this with colocalization analyses across 109 gene expression quantitative trait loci datasets and prioritization of genes by using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we found that evidence converged on likely causal genes, including the above four genes, and those at previously discovered AD loci, including BIN1 , APH1B , PTK2B , PILRA and CASS4 . Genome-wide meta-analysis, fine-mapping and integrative prioritization using expression quantitative trait loci, protein interaction networks and tissue-specific expression implicate new candidate susceptibility genes for Alzheimer’s disease.

Empirical studies of quantitative genetic variation have revealed robust patterns that are observed both across traits and across species. However, these patterns have no compelling explanation, and some of the observations even appear to be mutually incompatible. We review and extend a major class of theoretical models, 'mutation-selection models', that have been proposed to explain quantitative genetic variation. We also briefly review an alternative class of 'balancing selection models'. We consider to what extent the models are compatible with the general observations, and argue that a key issue is understanding and modelling pleiotropy. We discuss some of the thorny issues that arise when formulating models that describe many traits simultaneously.

Key Points To date, there have been at least 76 genome-wide association studies and a large number of candidate gene studies of drug efficacy. From these, there are at least 12 drugs with high-confidence genetic predictors of drug efficacy. Genetic predictors of drug efficacy are mostly common variants with a range of effect sizes; most have been discovered through studies of sensitive quantitative measures of drug response, and all but one were discovered following drug approval. Less than 20% of drugs are estimated to have common genetic predictors of efficacy that are large enough to inform clinical decision making. There are limited scenarios in which genetics can 'rescue' a trial that fails owing to lack of efficacy. However, advances in genetic technologies can allow for cost-effective screening for genetic predictors with potential clinical utility during the course of clinical development. Pharmaceutical and academic researchers should combine resources to study the efficacy pharmacogenetics of marketed drugs. In this Review, the authors highlight the potential for efficacy genetics to drive drug development and guide treatment options. They argue for the integration of routine pharmacogenetic screening into clinical development and propose strategies for identifying efficacy loci for marketed drugs. Lack of sufficient efficacy is the most common cause of attrition in late-phase drug development. It has long been envisioned that genetics could drive stratified drug development by identifying those patient subgroups that are most likely to respond. However, this vision has not been realized as only a small proportion of drugs have been found to have germline genetic predictors of efficacy with clinically meaningful effects, and so far all but one were found after drug approval. With the exception of oncology, systematic application of efficacy pharmacogenetics has not been integrated into drug discovery and development across the industry. Here, we argue for routine, early and cumulative screening for genetic predictors of efficacy, as an integrated component of clinical trial analysis. Such a strategy would identify clinically relevant predictors that may exist at the earliest possible opportunity, allow these predictors to be integrated into subsequent clinical development and provide mechanistic insights into drug disposition and patient-specific factors that influence response, therefore paving the way towards more personalized medicine.

Stereogenic sp3-hybridized carbon centres are fundamental building blocks of chiral molecules. Unlike dynamic stereogenic motifs, such as sp3-nitrogen centres or atropisomeric biaryls, sp3-carbon centres are usually fixed, requiring intermolecular reactions to undergo configurational changes. Here we report the internal enantiomerization of fluxional carbon cages and the consequences of their adaptive configurations for the transmission of stereochemical information. The sp3-carbon stereochemistry of the rigid tricyclic cages is inverted through strain-assisted Cope rearrangements, emulating the low-barrier configurational dynamics typical for sp3-nitrogen inversion or conformational isomerism. This dynamic enantiomerization can be stopped, restarted or slowed by external reagents, while the configuration of the cage is controlled by neighbouring, fixed stereogenic centres. As part of a phosphoramidite–olefin ligand, the fluxional cage acts as a conduit to transmit stereochemical information from the ligand while also transferring its dynamic properties to chiral-at-metal coordination environments, influencing catalysis, ion pairing and ligand exchange energetics.Stereogenic sp3-hybridized carbon centres are the principal building blocks of chiral organic molecules. Usually, these centres are configurationally fixed. Now, low-energy pericyclic rearrangements have been used to create rigid cage molecules with fluxional sp3-stereochemistry, influencing chiral information transfer. The sp3-carbon stereochemistry of the cages is inverted through strain-assisted Cope rearrangements.

Macrocyclic peptides have drawn considerable interest as modalities for drug discovery. Graspetides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) that harbor one or more macrocycles. These macrocycles are built via side chain-side chain linkages that are installed by ATP-grasp enzymes, giving the peptide family their name. We recently reported on the discovery, structure, and biosynthesis of the graspetide pre-fuscimiditide which is comprised of a stem covalently linked by two ester moieties and a 10 aa loop. Here we probe the substrate tolerance of the fuscimiditide ATP-grasp enzyme, ThfB, and show that it is highly promiscuous. ThfB can cyclize substrates with substitutions to or extensions of the stem region as well as generate multivalent cyclic structures. ThfB also shows remarkable tolerance to substitutions in the loop of pre-fuscimiditide. Loops comprised of flexible glycine-serine sequences ranging from 4 aa to 72 aa were efficiently cyclized by ThfB. Even substrates in which full-length proteins were swapped for the 10 aa loop of pre-fuscimiditide could be cyclized by ThfB. We also show that ThfB can covalently cross-link supramolecularly assembled protein chains. These data show that ThfB is a highly generalizable biocatalyst for both peptide and protein macrocyclization as well for intermolecular protein cross-linking.

The purpose of this research is to ascertain how occupational attitudes and background characteristics shape police recruit perceptions of policing people from diverse communities categorized by variations in racial, ethnic, religious, sexual, and gender identities. Applying an ordinary least squares (OLS) regression model, data categorized into two groups (occupational attitudes and background characteristics) were collected from police recruits (N = 946). Results suggest police recruits are significantly influenced by superior officers, the level of pride they have in their job, and their awareness of temperament and are cognizant of rule breaking when policing diverse community members, and ethnic minority self-identified recruits are significantly more likely to be aware of negative influences on proper conduct (such as lack of pride in their work, negativity of senior officers toward policing diverse people, and likelihood of rule breaking) when policing members of diverse groups than other recruits. The lessons learnt from this Australian research offer new insight into how police recruit perceptions of policing members of diverse groups are shaped.

Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.

Many Australian police organisations embed mental health response training (MHRT) into their recruit training packages. Yet critics argue police officers are under-trained and ill-equipped to engage with persons with mental illness (PWMI) in crisis, and officers frequently police PWMI using discretional techniques that are procedurally unfair and unjust. Applying a procedural justice lens, this research sought to better understand whether MHRT offered by one Australian state police organisation (de-identified as part of the ethics agreement) equips its recruits to engage appropriately with PWMI in future practice, and whether the MHRT effectively prepares recruits to use procedurally fair policing techniques when responding to PWMI in crisis. Conducting semi-structured interviews with recruits upon completion of the MHRT, this research determines that recruits are aware of their lack of knowledge regarding policing PWMI in crisis and are concerned that they may engage in differential policing because the MHRT has under-prepared them for future policing practice.

Across the globe, there is little research that examines the impact of diversity on police practice, particularly whether it increases or decreases the competency of the police organization or whether police officers perceive diversity within the organization and the addition of diverse officers as positive or negative. Contributing new findings to the extant policing literature, this research analyzes data collected from interviews with forty-six constables working in one of the largest Australian state police organizations. Contributing five key findings regarding diversity and inclusion in policing, this research suggests that lack of acceptance of diversity broadly, and bias towards diverse identified officers, results in the exclusion of officers, and a workforce that is fragmented. The lack of unification constables in this research have with diverse colleagues is concerning given that a cohesive police team increases the safety of all officers, improves the effectiveness of police response, strengthens the communication between police and citizens (as well as communication within the organization), increases the morale of officers, and will support the legitimacy of the organization. Whilst constables in this study were not asked questions about their own implicit or explicit levels of bias towards members of diverse groups, the unsolicited responses from many of the constables, as well as the recognition of Whiteness in terms of the racial identity of many officers within the organization, suggests that constables in this study are biased towards officers that are not part of the majority group.

LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations. We used genome-wide association data from up to 11 685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290 140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations. In our initial scan, we found two SNPs (rs599839 [p=1·7×10 −15] and rs4970834 [p=3·0×10 −11]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4·3×10 −9]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1·2×10 −33) and rs646776 (p=4·8×10 −20) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L. We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease.