Gating mechanism of elongating β-ketoacyl-ACP synthases.

Carbon-carbon bond forming reactions are essential transformations in natural product biosynthesis. During de novo fatty acid and polyketide biosynthesis, β-ketoacyl-acyl carrier protein (ACP) synthases (KS), catalyze this process via a decarboxylative Claisen-like condensation reaction. KSs must recognize multiple chemically distinct ACPs and choreograph a ping-pong mechanism, often in an iterative fashion. Here, we report crystal structures of substrate mimetic bearing ACPs in complex with the elongating KSs from Escherichia coli, FabF and FabB, in order to better understand the stereochemical features governing substrate discrimination by KSs. Complemented by molecular dynamics (MD) simulations and mutagenesis studies, these structures reveal conformational states accessed during KS catalysis. These data taken together support a gating mechanism that regulates acyl-ACP binding and substrate delivery to the KS active site. Two active site loops undergo large conformational excursions during this dynamic gating mechanism and are likely evolutionarily conserved features in elongating KSs

Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-κB pathways.

The NF-κB protein RelB controls dendritic cell (DC) maturation and may be targeted therapeutically to manipulate T cell responses in disease. Here we report that RelB promoted DC activation not as the expected RelB-p52 effector of the noncanonical NF-κB pathway, but as a RelB-p50 dimer regulated by canonical IκBs, IκBα and IκBɛ. IκB control of RelB minimized spontaneous maturation but enabled rapid pathogen-responsive maturation. Computational modeling of the NF-κB signaling module identified control points of this unexpected cell type-specific regulation. Fibroblasts that we engineered accordingly showed DC-like RelB control. Canonical pathway control of RelB regulated pathogen-responsive gene expression programs. This work illustrates the potential utility of systems analyses in guiding the development of combination therapeutics for modulating DC-dependent T cell responses

Accounting for predator species identity reveals variable relationships between nest predation rate and habitat in a temperate forest songbird.

Nest predation is the primary cause of nest failure in most ground-nesting bird species. Investigations of relationships between nest predation rate and habitat usually pool different predator species. However, such relationships likely depend on the specific predator involved, partly because habitat requirements vary among predator species. Pooling may therefore impair our ability to identify conservation-relevant relationships between nest predation rate and habitat. We investigated predator-specific nest predation rates in the forest-dependent, ground-nesting wood warbler Phylloscopus sibilatrix in relation to forest area and forest edge complexity at two spatial scales and to the composition of the adjacent habitat matrix. We used camera traps at 559 nests to identify nest predators in five study regions across Europe. When analyzing predation data pooled across predator species, nest predation rate was positively related to forest area at the local scale (1000 m around nest), and higher where proportion of grassland in the adjacent habitat matrix was high but arable land low. Analyses by each predator species revealed variable relationships between nest predation rates and habitat. At the local scale, nest predation by most predators was higher where forest area was large. At the landscape scale (10,000 m around nest), nest predation by buzzards Buteo buteo was high where forest area was small. Predation by pine martens Martes martes was high where edge complexity at the landscape scale was high. Predation by badgers Meles meles was high where the matrix had much grassland but little arable land. Our results suggest that relationships between nest predation rates and habitat can depend on the predator species involved and may differ from analyses disregarding predator identity. Predator-specific nest predation rates, and their relationships to habitat at different spatial scales, should be considered when assessing the impact of habitat change on avian nesting success

Visualizing the Interface of Biotin and Fatty Acid Biosynthesis through SuFEx Probes

Site-specific covalent conjugation offers a powerful tool to identify and understand protein-protein interactions. In this study, we discover that sulfur fluoride exchange (SuFEx) warheads effectively crosslink the Escherichia coli acyl carrier protein (AcpP) with its partner BioF, a key pyridoxal 5′-phosphate (PLP)-dependent enzyme in the early steps of biotin biosynthesis by targeting a tyrosine residue proximal to the active site. We identify the site of crosslink by MS/MS analysis of the peptide originating from both partners. We further evaluate the BioF-AcpP interface through protein crystallography and mutational studies. Among the AcpP-interacting BioF surface residues, three critical arginine residues appear to be involved in AcpP recognition so that pimeloyl-AcpP can serve as the acyl donor for PLP-mediated catalysis. These findings validate an evolutionary gain-of-function for BioF, allowing the organism to build biotin directly from fatty acid biosynthesis through surface modifications selective for salt bridge formation with acidic AcpP residues.</p

Reproductive success of the wood warbler Phylloscopus sibilatrix varies across Europe

Differences in population trends across a species’ breeding range are ultimately linked to variation in demographic rates. In small songbirds, demographic rates related to fecundity typically have strong effects on population trends. Populations of a forest songbird, the wood warbler Phylloscopus sibilatrix, have been declining in many but not all regions of the European breeding range. We investigated if clutch size, hatching rate, nest survival and number of fledglings vary across Europe, and if nest survival is related to differences in the regionally dominant nest predator class (birds versus mammals). From 2009 to 2020, we monitored 1896 nests and used cameras at a subsample of 645 nests in six study regions: the United Kingdom (mid-Wales, Dartmoor, the New Forest), Germany (Hessen), Switzerland (Jura mountains) and Poland (Białowieża National Park). Number of fledglings was lowest in the New Forest (1.43 ± CI 0.23), intermediate in Jura (2.41 ± 0.31) and Białowieża (2.26 ± 0.24) and highest in mid-Wales (3.02 ± 0.48) and Dartmoor (2.92 ± 0.32). The reason for low reproductive success in the New Forest, Jura and Białowieża was low nest survival, and large clutch sizes in Białowieża did not compensate for high nest losses. High reproductive success in mid-Wales and Dartmoor was due to high nest survival and large clutch sizes. Overall predation rates were similar everywhere despite variation between the regions in the dominant nest predator class. Unsuccessful nests in mid-Wales were mainly predated by birds; in Dartmoor, the New Forest, Hessen and Jura similarly by birds and mammals; and in Białowieża exclusively by mammals. Regional reproductive success does not match the population trends recently reported for the wood warbler in the six study regions (i.e. high reproduction ≠ positive trend). Annual survival may be a decisive factor, but it is difficult to quantify for a nomadic species such as the wood warbler that rarely returns to the same breeding locations

Quenching of Star Formation in Molecular Outflow Host NGC 1266

We detail the rich molecular story of NGC 1266, its serendipitous discovery within the ATLAS3D survey (Cappellari et al. 2011) and how it plays host to an AGN-driven molecular outflow, potentially quenching all of its star formation (SF) within the next 100 Myr. While major mergers appear to play a role in instigating outflows in other systems, deep imaging of NGC 1266 as well as stellar kinematic observations from SAURON, have failed to provide evidence that NGC 1266 has recently been involved in a major interaction. The molecular gas and the instantaneous SF tracers indicate that the current sites of star formation are located in a hypercompact disk within 200 pc of the nucleus (Fig. 1; SF rate ~ 2 Msuns/yr). On the other hand, tracers of recent star formation, such as the H{\beta} absorption map from SAURON and stellar population analysis show that the young stars are distributed throughout a larger area of the galaxy than current star formation. As the AGN at the center of NGC 1266 continues to drive cold gas out of the galaxy, we expect star formation rates to decline as the star formation is ultimately quenched. Thus, NGC 1266 is in the midst of a key portion of its evolution and continued studies of this unique galaxy may help improve our understanding of how galaxies transition from the blue to the red sequence (Alatalo et al. 2011).Comment: 1 page, Proceedings IAU symposium No. 292: Molecular gas, dust and star formation in galaxies, ed. by Tony Wong and Juergen Ot

Evolutionary and biomedical insights from the rhesus macaque genome

The rhesus macaque (Macaca mulatta) is an abundant primate species that diverged from the ancestors of Homo sapiens about 25 million years ago. Because they are genetically and physiologically similar to humans, rhesus monkeys are the most widely used nonhuman primate in basic and applied biomedical research. We determined the genome sequence of an Indian-origin Macaca mulatta female and compared the data with chimpanzees and humans to reveal the structure of ancestral primate genomes and to identify evidence for positive selection and lineage-specific expansions and contractions of gene families. A comparison of sequences from individual animals was used to investigate their underlying genetic diversity. The complete description of the macaque genome blueprint enhances the utility of this animal model for biomedical research and improves our understanding of the basic biology of the species

Effects of childhood socioeconomic position on subjective health and health behaviours in adulthood: how much is mediated by adult socioeconomic position?

<p>Abstract</p> <p>Background</p> <p>Adult socioeconomic position (SEP) is one of the most frequently hypothesised indirect pathways between childhood SEP and adult health. However, few studies that explore the indirect associations between childhood SEP and adult health systematically investigate the mediating role of multiple individual measures of adult SEP for different health outcomes. We examine the potential mediating role of individual measures of adult SEP in the associations of childhood SEP with self-rated health, self-reported mental health, current smoking status and binge drinking in adulthood.</p> <p>Methods</p> <p>Data came from 10,010 adults aged 25-64 years at Wave 3 of the Survey of Family, Income and Employment in New Zealand. The associations between childhood SEP (assessed using retrospective information on parental occupation) and self-rated health, self-reported psychological distress, current smoking status and binge drinking were determined using logistic regression. Models were adjusted individually for the mediating effects of education, household income, labour market activity and area deprivation.</p> <p>Results</p> <p>Respondents from a lower childhood SEP had a greater odds of being a current smoker (OR 1.70 95% CI 1.42-2.03), reporting poorer health (OR 1.82 95% CI 1.39-2.38) or higher psychological distress (OR 1.60 95% CI 1.20-2.14) compared to those from a higher childhood SEP. Two-thirds to three quarters of the association of childhood SEP with current smoking (78%), and psychological distress (66%) and over half the association with poor self-rated health (55%) was explained by educational attainment. Other adult socioeconomic measures had much smaller mediating effects.</p> <p>Conclusions</p> <p>This study suggests that the association between childhood SEP and self-rated health, psychological distress and current smoking in adulthood is largely explained through an indirect socioeconomic pathway involving education. However, household income, area deprivation and labour market activity are still likely to be important as they are intermediaries in turn, in the socioeconomic pathway between education and health.</p