Darwinian transformation of a 'scarcely nutritious fluid' into milk

In an early challenge to an aspect of Darwin’s theory of natural selection, Jackson Mivart contended that milk could not have evolved ‘from a scarcely nutritious fluid from an accidentally hypertrophied cutaneous gland’. The evolutionary change from a gland secretion to milk involves an increase in calcium and protein concentrations by up to 100- and 1000-fold, respectively. Even so, the challenge, we suggest, is not just a problem of scale. An increase in the concentrations of calcium and phosphate brings an increased risk of calcification of the secretory gland because calcium phosphate is highly insoluble. In addition, two of the four constituent milk casein proteins (κ and αS2) aggregate to produce toxic amyloid fibrils. It is proposed that both problems were solved through the cosecretion of ancestral β- and κ-caseins to form a stable amorphous aggregate of both proteins with sequestered amorphous calcium phosphate, that is, a primordial casein micelle. Evolutionarily, a gradual increase in the concentration of casein micelles could therefore produce progressively more nutritious fluids for the neonate without endangering the reproductive potential of the mother

Structure/function studies of dogfish α-crystallin, comparison with bovine α-crystallin

Purpose: α-Crystallin is the major protein of the mammalian lens where it contributes to the refractive properties needed for vision and possibly to the stability of the tissue. The aim of this study was to determine whether the properties of α-crystallin have changed during the course of evolution. Methods: Dogfish α-crystallin, which appeared over 420 million years ago, has been contrasted with bovine α-crystallin, which emerged around 160 million years later, by comparing their sizes, the microenvironments of their cysteine and tryptophan residues, their chaperone-like activities and the flexibility of their COOH-terminal extensions. Results: Dogfish α-crystallin consists of α A- and α B-polypeptides, in a 1: 5 ratio, and has a molecular mass of around 400 kDa. By contrast, the bovine protein is around 600-800 kDa in mass and has a 3: 1 subunit ratio. Cysteine residues in the proteins were equally accessible to reaction with 5,5'-dithiobis-(2-nitrobenzoic acid). Quenching of fluorescence with acrylamide indicated tryptophan residues in the two proteins were in similar environments. The chaperone activity of dogfish α-crystallin was comparable to that of bovine α-crystallin in preventing the heat-induced precipitation of β(L)-crystallin but the dogfish protein was three times more effective at preventing insulin precipitation after reduction at 37 degrees C. H-1 nuclear magnetic resonance spectroscopic studies showed that the last 17 amino acids of the dogfish α B polypeptide (V162-K178) have great conformational flexibility, are highly exposed to solvent and adopt little ordered conformation. This is comparable to, but slightly longer in length, than the COOH-terminal extension observed in mammalian alpha-crystallins. Conclusions: The structure and properties of α-crystallin have changed relatively little during the evolutionary period from the emergence of sharks and mammals. © US National Library of Medicine National Institutes of Healt

Invited review: Modeling milk stability

Novel insights into the stability of milk and milk products during storage and processing result from describing caseins near neutral pH as hydrophilic, intrinsically disordered, proteins. Casein solubility is strongly influenced by pH and multivalent ion binding. Solubility is high at neutral pH or above but decreases as casein net charge approaches zero, allowing a condensed casein phase or gel to form then increases at lower pH. Of particular importance for casein micelle stability near neutral pH is the proportion of free caseins in the micelle (i.e., caseins not bound directly to nanoclusters of calcium phosphate). Free caseins are more soluble and better able to act as molecular chaperones (to prevent casein and whey protein aggregation) than bound caseins. Some free caseins are highly phosphorylated and can also act as mineral chaperones to inhibit the growth of calcium phosphate phases and prevent mineralized deposits from forming on membranes or heat exchangers. Thus, casein micelle stability is reduced when free caseins bind to amyloid fibrils, destabilized whey proteins or calcium phosphate. The multivalent-binding model of the casein micelle quantitatively describes these and other factors affecting the stability of milk and milk protein products during manufacture and storage

NOx and O3 above a tropical rainforest: an analysis with a global and box model

A cross-platform field campaign, OP3, was conducted in the state of Sabah in Malaysian Borneo between April and July of 2008. Among the suite of observations recorded, the campaign included measurements of NOx and O3 – crucial outputs of any model chemistry mechanism. We describe the measurements of these species made from both the ground site and aircraft. We then use the output from two resolutions of the chemistry transport model p-TOMCAT to illustrate the ability of a global model chemical mechanism to capture the chemistry at the rainforest site. The basic model performance is good for NOx and poor for ozone. A box model containing the same chemical mechanism is used to explore the results of the global model in more depth and make comparisons between the two. Without some parameterization of the nighttime boundary layer – free troposphere mixing (i.e. the use of a dilution parameter), the box model does not reproduce the observations, pointing to the importance of adequately representing physical processes for comparisons with surface measurements. We conclude with a discussion of box model budget calculations of chemical reaction fluxes, deposition and mixing, and compare these results to output from p-TOMCAT. These show the same chemical mechanism behaves similarly in both models, but that emissions and advection play particularly strong roles in influencing the comparison to surface measurements

Making things happen : a model of proactive motivation

Being proactive is about making things happen, anticipating and preventing problems, and seizing opportunities. It involves self-initiated efforts to bring about change in the work environment and/or oneself to achieve a different future. The authors develop existing perspectives on this topic by identifying proactivity as a goal-driven process involving both the setting of a proactive goal (proactive goal generation) and striving to achieve that proactive goal (proactive goal striving). The authors identify a range of proactive goals that individuals can pursue in organizations. These vary on two dimensions: the future they aim to bring about (achieving a better personal fit within one’s work environment, improving the organization’s internal functioning, or enhancing the organization’s strategic fit with its environment) and whether the self or situation is being changed. The authors then identify “can do,” “reason to,” and “energized to” motivational states that prompt proactive goal generation and sustain goal striving. Can do motivation arises from perceptions of self-efficacy, control, and (low) cost. Reason to motivation relates to why someone is proactive, including reasons flowing from intrinsic, integrated, and identified motivation. Energized to motivation refers to activated positive affective states that prompt proactive goal processes. The authors suggest more distal antecedents, including individual differences (e.g., personality, values, knowledge and ability) as well as contextual variations in leadership, work design, and interpersonal climate, that influence the proactive motivational states and thereby boost or inhibit proactive goal processes. Finally, the authors summarize priorities for future researc

Terminal regions confer plasticity to the tetrameric assembly of human HspB2 and HspB3

Heterogeneity in small heat shock proteins (sHsps) spans multiple spatiotemporal regimes – from fast fluctuations of part of the protein, to conformational variability of tertiary structure, plasticity of the interfaces, and polydispersity of the inter-converting, and co-assembling oligomers. This heterogeneity and dynamic nature of sHsps has significantly hindered their structural characterisation. Atomic-coordinates are particularly lacking for vertebrate sHsps, where most available structures are of extensively truncated homomers. sHsps play important roles in maintaining protein levels in the cell and therefore in organismal health and disease. HspB2 and HspB3 are vertebrate sHsps that are found co-assembled in neuromuscular cells, and variants thereof are associated with disease. Here, we present the structure of human HspB2/B3, which crystallised as a hetero-tetramer in a 3:1 ratio. In the HspB2/B3 tetramer, the four a-crystallin domains (ACDs) assemble into a flattened tetrahedron which is pierced by two non-intersecting approximate dyads. Assembly is mediated by flexible “nuts and bolts” involving IXI/V motifs from terminal regions filling ACD pockets. Parts of the N-terminal region bind in an unfolded conformation into the anti-parallel shared ACD dimer grooves. Tracts of the terminal regions are not resolved, most likely due to their disorder in the crystal lattice. This first structure of a full-length human sHsp heteromer reveals the heterogeneous interactions of the terminal regions and suggests a plasticity that is important for the cytoprotective functions of sHsps

Developmental trajectories of infants with multiplex family risk for Autism: a Baby Siblings Research Consortium Study

Importance: Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with different genetic etiologies. Prospective examination of familial-risk infants informs understanding of developmental trajectories preceding ASD diagnosis, potentially improving early detection. Objective: Compare outcomes and trajectories associated with varying familial risk for ASD across first 3 years of life. Design and Setting: Longitudinal, prospective observational study. Data from 11 sites in Baby Siblings Research Consortium (BSRC) database included. Data collected between 2003-2015. Infants followed for 3 years. Analyses conducted in 2018. Participants: Of initial 1,008 infants from BSRC database, 573 removed due to missing necessary data, diagnostic discrepancies, or only one older sibling. 435 younger siblings of children with ASD included; 355 from single-incidence families (1 sibling with ASD and 1+ sibling without ASD) and 80 from multiplex families (2+ siblings with ASD). No group differences in major demographics. Exposure: Number of ASD-siblings. Main Outcomes and Measures: Outcomes included ASD symptoms, cognitive abilities, and adaptive skills. Diagnosis (ASD/no-ASD) given at 36-month outcome. No-ASD group classified as atypical (developmental delays and/or social-communication concerns) or typical for some analyses. Generalized linear mixed models examined developmental trajectories by ASD outcome and familial-risk group. Results: In the 435 analyzed participants (age range at outcome: 32-43 months; 57% male), children from multiplex families were more likely than those from single-incidence families to 5 be classified as ASD (36% vs. 16%, p<.001) and less likely as typical (33% vs. 57%, p<.001), with similar rates of atypical classifications (31% vs. 27%, p=.49). No differences in ASD symptoms between multiplex and single-incidence groups, after controlling for ASD outcome (p=.18). During infancy, differences in cognitive and adaptive abilities observed based upon ASD outcome in single-incidence group only (ps<.001-.04). At 36 months, multiplex/no-ASD group had lower cognitive abilities than single-incidence/no-ASD group (p=.02), and multiplex had lower adaptive abilities than single-incidence, after controlling for ASD outcome (p=.02). Conclusions and Relevance: Infants with a multiplex family history of ASD should be monitored early and often and referred for early intervention at the first sign of concern. Direct examination of genetic contributions to neurodevelopmental phenotypes in infants with familial risk for ASD is needed

Search for leptophobic Z ' bosons decaying into four-lepton final states in proton-proton collisions at root s=8 TeV

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