Perceived Work Ability: A Constant Comparative Analysis of Workers' Perspectives.

Perceived work ability, or one's perceived ability to continue working in their current job, is important to understand in order to inform efforts to retain talent and promote worker well-being. The current study offers a unique contribution by taking an inductive approach, giving participants voice to describe their own work ability experiences. Participants ( = 301) who were working at least 30 h a week in the U.

Evolution of island lizards remains a mystery.

Lizards that live in the Greater Antilles exploit a large range of skeletal variations to adapt to similar habitats, in defiance of the theory of plasticity-led evolution.

Evidence of five digits in embryonic horses and developmental stabilization of tetrapod digit number.

Previous work comparing the developmental mechanisms involved in digit reduction in horses with other mammals reported that horses have only a 'single digit', with two flanking metapodials identified as remnants of digit II and IV. Here we show that early embryos go through a stage with five digit condensations, and that the flanking splint metapodials result from fusions of the two anterior digits I and II and the two posterior digits IV and V, in a striking parallel between ontogeny and phylogeny. Given that even this most extreme case of digit reduction exhibits primary pentadactyly, we re-examined the initial stages of digit condensation of all digit-reduced tetrapods where data are available and found that in all cases, five or four digits initiate (four with digit I missing).

Developmental plasticity associated with early structural integration and evolutionary patterns: Examples of developmental bias and developmental facilitation in the skeletal system.

The relation of developmental plasticity to evolutionary diversification is a key component of evolutionary theory involving developmental bias, but the basis of the relationship varies among traits and among taxa. Here I review some scenarios of how structural integration during early organogenesis could influence this relationship. When condensations are highly integrated and dependent on each other during early organogenesis, both plasticity and evolution are restricted, for example size proportions in molar tooth rows and phalanges within a digit.

A Parsimonious Mechanism of Sugar Dehydration by Human GDP-Mannose-4,6-dehydratase.

Biosynthesis of 6-deoxy sugars, including l-fucose, involves a mechanistically complex, enzymatic 4,6-dehydration of hexose nucleotide precursors as the first committed step. Here, we determined pre- and postcatalytic complex structures of the human GDP-mannose 4,6-dehydratase at atomic resolution. These structures together with results of molecular dynamics simulation and biochemical characterization of wildtype and mutant enzymes reveal elusive mechanistic details of water elimination from GDP-mannose C5″ and C6″, coupled to NADP-mediated hydride transfer from C4″ to C6″.

Mechanical constraint from growing jaw facilitates mammalian dental diversity.

Much of the basic information about individual organ development comes from studies using model species. Whereas conservation of gene regulatory networks across higher taxa supports generalizations made from a limited number of species, generality of mechanistic inferences remains to be tested in tissue culture systems. Here, using mammalian tooth explants cultured in isolation, we investigate self-regulation of patterning by comparing developing molars of the mouse, the model species of mammalian research, and the bank vole.

A randomized, controlled trial of the family check-up model in public secondary schools: Examining links between parent engagement and substance use progressions from early adolescence to adulthood.

Objective: Substance use in adulthood compromises work, relationships, and health. Prevention strategies in early adolescence are designed to reduce substance use and progressions to problematic use by adulthood. This report examines the long-term effects of offering Family Check-up (FCU) at multiple time points in secondary education on the progression of substance use from age 11 to 23 years.

The inhibition of human farnesyl pyrophosphate synthase by nitrogen-containing bisphosphonates. Elucidating the role of active site threonine 201 and tyrosine 204 residues using enzyme mutants.

Farnesyl pyrophosphate synthase (FPPS) is the major molecular target of nitrogen-containing bisphosphonates (N-BPs), used clinically as bone resorption inhibitors. We investigated the role of threonine 201 (Thr201) and tyrosine 204 (Tyr204) residues in substrate binding, catalysis and inhibition by N-BPs, employing kinetic and crystallographic studies of mutated FPPS proteins. Mutants of Thr201 illustrated the importance of the methyl group in aiding the formation of the Isopentenyl pyrophosphate (IPP) binding site, while Tyr204 mutations revealed the unknown role of this residue in both catalysis and IPP binding.

Shared rules of development predict patterns of evolution in vertebrate segmentation.

Phenotypic diversity is not uniformly distributed, but how biased patterns of evolutionary variation are generated and whether common developmental mechanisms are responsible remains debatable. High-level 'rules' of self-organization and assembly are increasingly used to model organismal development, even when the underlying cellular or molecular players are unknown. One such rule, the inhibitory cascade, predicts that proportions of segmental series derive from the relative strengths of activating and inhibitory interactions acting on both local and global scales.

Towards a systematic analysis of human short-chain dehydrogenases/reductases (SDR): Ligand identification and structure-activity relationships.

Short-chain dehydrogenases/reductases (SDRs) constitute a large, functionally diverse branch of enzymes within the class of NAD(P)(H) dependent oxidoreductases. In humans, over 80 genes have been identified with distinct metabolic roles in carbohydrate, amino acid, lipid, retinoid and steroid hormone metabolism, frequently associated with inherited genetic defects. Besides metabolic functions, a subset of atypical SDR proteins appears to play critical roles in adapting to redox status or RNA processing, and thereby controlling metabolic pathways.

Ribosomal oxygenases are structurally conserved from prokaryotes to humans.

2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components and in the hydroxylation of transcription factors and splicing factor proteins. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA and ribosomal proteins have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans raises questions as to their structural and evolutionary relationships.

Developmental bias in the evolution of phalanges.

Evolutionary theory has long argued that the entrenched rules of development constrain the range of variations in a given form, but few empirical examples are known. Here we provide evidence for a very deeply conserved skeletal module constraining the morphology of the phalanges within a digit. We measured the sizes of phalanges within populations of two bird species and found that successive phalanges within a digit exhibit predictable relative proportions, whether those phalanges are nearly equal in size or exhibit a more striking gradient in size from large to small.

Response to comment on "Evolutionary trade-offs, Pareto optimality, and the geometry of phenotype space".

Edelaar raises concerns about the way we tested our theory. Our mathematical theorem predicts that despite the high dimensionality of trait space, trade-offs between tasks leads to phenotypes in low-dimensional regions in trait space, such as lines and triangles. We address Edelaar's questions with statistical tests that eliminate pseudoreplication concerns, finding that our predictions remain convincingly supported.

Structure and mechanism of human UDP-xylose synthase: evidence for a promoting role of sugar ring distortion in a three-step catalytic conversion of UDP-glucuronic acid.

UDP-xylose synthase (UXS) catalyzes decarboxylation of UDP-D-glucuronic acid to UDP-xylose. In mammals, UDP-xylose serves to initiate glycosaminoglycan synthesis on the protein core of extracellular matrix proteoglycans. Lack of UXS activity leads to a defective extracellular matrix, resulting in strong interference with cell signaling pathways.

Structure of human aspartyl aminopeptidase complexed with substrate analogue: insight into catalytic mechanism, substrate specificity and M18 peptidase family.

Background: Aspartyl aminopeptidase (DNPEP), with specificity towards an acidic amino acid at the N-terminus, is the only mammalian member among the poorly understood M18 peptidases. DNPEP has implicated roles in protein and peptide metabolism, as well as the renin-angiotensin system in blood pressure regulation. Despite previous enzyme and substrate characterization, structural details of DNPEP regarding ligand recognition and catalytic mechanism remain to be delineated.

Structural and kinetic evidence that catalytic reaction of human UDP-glucose 6-dehydrogenase involves covalent thiohemiacetal and thioester enzyme intermediates.

Biosynthesis of UDP-glucuronic acid by UDP-glucose 6-dehydrogenase (UGDH) occurs through the four-electron oxidation of the UDP-glucose C6 primary alcohol in two NAD(+)-dependent steps. The catalytic reaction of UGDH is thought to involve a Cys nucleophile that promotes formation of a thiohemiacetal enzyme intermediate in the course of the first oxidation step. The thiohemiacetal undergoes further oxidation into a thioester, and hydrolysis of the thioester completes the catalytic cycle.

Structure of Candida albicans methionine synthase determined by employing surface residue mutagenesis.

Fungal methionine synthase, Met6p, transfers a methyl group from 5-methyl-tetrahydrofolate to homocysteine to generate methionine. The enzyme is essential to fungal growth and is a potential anti-fungal drug design target. We have characterized the enzyme from the pathogen Candida albicans but were unable to crystallize it in native form.

Crystal structure of PHYHD1A, a 2OG oxygenase related to phytanoyl-CoA hydroxylase.

Phytanoyl-CoA hydroxylase (PAHX) catalyzes an important step in the metabolism of the fatty acid side chain of chlorophyll. PHYHD1 exists in three isoforms and is the closest human homologue of PAHX. We show that like PAHX, the PHYHD1A but likely not the PHYHD1B/C isoforms, is a functional Fe(II) and 2-oxoglutarate (2OG) dependent oxygenase.

Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming.

Endoplasmatic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme involved in trimming of peptides to an optimal length for presentation by major histocompatibility complex (MHC) class I molecules. Polymorphisms in ERAP1 have been associated with chronic inflammatory diseases, including ankylosing spondylitis (AS) and psoriasis, and subsequent in vitro enzyme studies suggest distinct catalytic properties of ERAP1 variants. To understand structure-activity relationships of this enzyme we determined crystal structures in open and closed states of human ERAP1, which provide the first snapshots along a catalytic path.

Structure and mechanism of human UDP-glucose 6-dehydrogenase.

Elevated production of the matrix glycosaminoglycan hyaluronan is strongly implicated in epithelial tumor progression. Inhibition of synthesis of the hyaluronan precursor UDP-glucuronic acid (UDP-GlcUA) therefore presents an emerging target for cancer therapy. Human UDP-glucose 6-dehydrogenase (hUGDH) catalyzes, in two NAD(+)-dependent steps without release of intermediate aldehyde, the biosynthetic oxidation of UDP-glucose (UDP-Glc) to UDP-GlcUA.

Structural basis of fumarate hydratase deficiency.

Fumarate hydratase catalyzes the stereospecific hydration across the olefinic double bond in fumarate leading to L-malate. The enzyme is expressed in mitochondrial and cytosolic compartments, and participates in the Krebs cycle in mitochondria, as well as in regulation of cytosolic fumarate levels. Fumarate hydratase deficiency is an autosomal recessive trait presenting as metabolic disorder with severe encephalopathy, seizures and poor neurological outcome.

An ecological approach to promoting early adolescent mental health and social adaptation: family-centered intervention in public middle schools.

This study examined the impact of the Family Check-Up (FCU) and linked intervention services on reducing health-risk behaviors and promoting social adaptation among middle school youth. A total of 593 students and their families were randomly assigned to receive either the intervention or middle school services as usual. Forty-two percent of intervention families engaged in the service and received the FCU.

Contemporary temperature-driven divergence in a Nordic freshwater fish under conditions commonly thought to hinder adaptation.

Background: Evaluating the limits of adaptation to temperature is important given the IPCC-predicted rise in global temperatures. The rate and scope of evolutionary adaptation can be limited by low genetic diversity, gene flow, and costs associated with adaptive change. Freshwater organisms are physically confined to lakes and rivers, and must therefore deal directly with climate variation and change.

The crystal structure of human GLRX5: iron-sulfur cluster co-ordination, tetrameric assembly and monomer activity.

Human GLRX5 (glutaredoxin 5) is an evolutionarily conserved thiol-disulfide oxidoreductase that has a direct role in the maintenance of normal cytosolic and mitochondrial iron homoeostasis, and its expression affects haem biosynthesis and erythropoiesis. We have crystallized the human GLRX5 bound to two [2Fe-2S] clusters and four GSH molecules. The crystal structure revealed a tetrameric organization with the [2Fe-2S] clusters buried in the interior and shielded from the solvent by the conserved β1-α2 loop, Phe⁶⁹ and the GSH molecules.