The development of tool manufacture in humans: what helps young children make innovative tools?

We know that even young children are proficient tool users, but until recently, little was known about how they make tools. Here, we will explore the concepts underlying tool making, and the kinds of information and putative cognitive abilities required for children to manufacture novel tools. We will review the evidence for novel tool manufacture from the comparative literature and present a growing body of data from children suggesting that innovation of the solution to a problem by making a tool is a much more challenging task than previously thought. Children''s difficulty with these kinds of tasks does not seem to be explained by perseveration with unmodified tools, difficulty with switching to alternative strategies, task pragmatics or issues with permission. Rather, making novel tools (without having seen an example of the required tool within the context of the task) appears to be hard, because it is an example of an ‘ill-structured problem’. In this type of ill-structured problem, the starting conditions and end goal are known, but the transformations and/or actions required to get from one to the other are not specified. We will discuss the implications of these findings for understanding the development of problem-solving in humans and other animals.     

Selection for genetics‐based architecture traits in a native cottonwood negatively affects invasive tamarisk in a restoration field trial

Climate change and competition from invasive species remain two important challenges in restoration. We examined the hypothesis that non‐native tamarisk (Tamarix spp.) reestablishment after aboveground removal is affected by genetics‐based architecture of native Fremont cottonwood (Populus fremontii) used in restoration. As cottonwood architecture (height, canopy width, number of stems, and trunk diameter) is, in part, determined by genetics, we predicted that trees from different provenances would exhibit different architecture, and mean annual maximum temperature transfer distance from the provenances would interact with the architecture to affect tamarisk. In a common garden in Chevelon, AZ, U.S.A. (elevation 1,496 m), with cottonwoods from provenances spanning its elevation distribution, we measured the performance of both cottonwoods and tamarisk. Several key findings emerged. On average, cottonwoods from higher elevations were (1) two times taller and wider, covered approximately 3.5 times more basal area, and were less shrubby in appearance, by exhibiting four times fewer number of stems than cottonwoods from lower elevations; (2) had 50% fewer tamarisk growing underneath, which were two times shorter and covered 6.5 times less basal area than tamarisk growing underneath cottonwoods of smaller stature; and (3) the number of cottonwood stems did not affect tamarisk growth, possibly because the negative relationship between cottonwood stems and basal area. In combination, these findings argue that cottonwood architecture is affected by local conditions that interact with genetics‐based architecture. These interactions can negatively affect the growth of reinvading tamarisk and enhance restoration success. Our study emphasizes the importance of incorporating genetic and environmental interactions of plants used in restoration.     

Clinical Utility of a Coronary Heart Disease Risk Prediction Gene Score in UK Healthy Middle Aged Men and in the Pakistani Population

BackgroundNumerous risk prediction algorithms based on conventional risk factors for Coronary Heart Disease (CHD) are available but provide only modest discrimination. The inclusion of genetic information may improve clinical utility.MethodsWe tested the use of two gene scores (GS) in the prospective second Northwick Park Heart Study (NPHSII) of 2775 healthy UK men (284 cases), and Pakistani case-control studies from Islamabad/Rawalpindi (321 cases/228 controls) and Lahore (414 cases/219 controls). The 19-SNP GS included SNPs in loci identified by GWAS and candidate gene studies, while the 13-SNP GS only included SNPs in loci identified by the CARDIoGRAMplusC4D consortium.ResultsIn NPHSII, the mean of both gene scores was higher in those who went on to develop CHD over 13.5 years of follow-up (19-SNP p=0.01, 13-SNP p=7x10^-3). In combination with the Framingham algorithm the GSs appeared to show improvement in discrimination (increase in area under the ROC curve, 19-SNP p=0.48, 13-SNP p=0.82) and risk classification (net reclassification improvement (NRI), 19-SNP p=0.28, 13-SNP p=0.42) compared to the Framingham algorithm alone, but these were not statistically significant. When considering only individuals who moved up a risk category with inclusion of the GS, the improvement in risk classification was statistically significant (19-SNP p=0.01, 13-SNP p=0.04). In the Pakistani samples, risk allele frequencies were significantly lower compared to NPHSII for 13/19 SNPs. In the Islamabad study, the mean gene score was higher in cases than controls only for the 13-SNP GS (2.24 v 2.34, p=0.04). There was no association with CHD and either score in the Lahore study.ConclusionThe performance of both GSs showed potential clinical utility in European men but much less utility in subjects from Pakistan, suggesting that a different set of risk loci or SNPs may be required for risk prediction in the South Asian population.     

A model for activation of the hexadecameric phosphorylase kinase complex deduced from zero‐length oxidative crosslinking

Phosphorylase kinase (PhK) is a hexadecameric (αβγδ)₄ enzyme complex that upon activation by phosphorylation stimulates glycogenolysis. Due to its large size (1.3 MDa), elucidating the structural changes associated with the activation of PhK has been challenging, although phosphoactivation has been linked with an increased tendency of the enzyme's regulatory β‐subunits to self‐associate. Here we report the effect of a peptide mimetic of the phosphoryltable N‐termini of β on the selective, zero‐length, oxidative crosslinking of these regulatory subunits to form β–β dimers in the nonactivated PhK complex. This peptide stimulated β–β dimer formation when not phosphorylated, but was considerably less effective in its phosphorylated form. Because this peptide mimetic of β competes with its counterpart region in the nonactivated enzyme complex in binding to the catalytic γ‐subunit, we were able to formulate a structural model for the phosphoactivation of PhK. In this model, the nonactivated state of PhK is maintained by the interaction between the nonphosphorylated N‐termini of β and the regulatory C‐terminal domains of the γ‐subunits; phosphorylation of β weakens this interaction, leading to activation of the γ‐subunits.     

A role for LSH in facilitating DNA methylation by DNMT1 through enhancing UHRF1 chromatin association

LSH, a SNF2 family DNA helicase, is a key regulator of DNA methylation in mammals. How LSH facilitates DNA methylation is not well defined. While previous studies with mouse embryonic stem cells (mESc) and fibroblasts (MEFs) derived from Lsh knockout mice have revealed a role of Lsh in de novo DNA methylation by Dnmt3a/3b, here we report that LSH contributes to DNA methylation in various cell lines primarily by promoting DNA methylation by DNMT1. We show that loss of LSH has a much bigger effect in DNA methylation than loss of DNMT3A and DNMT3B. Mechanistically, we demonstrate that LSH interacts with UHRF1 but not DNMT1 and facilitates UHRF1 chromatin association and UHRF1-catalyzed histone H3 ubiquitination in an ATPase activity-dependent manner, which in turn promotes DNMT1 recruitment to replication fork and DNA methylation. Notably, UHRF1 also enhances LSH association with the replication fork. Thus, our study identifies LSH as an essential factor for DNA methylation by DNMT1 and provides novel insight into how a feed-forward loop between LSH and UHRF1 facilitates DNMT1-mediated maintenance of DNA methylation in chromatin.     

Diversity of urea‐degrading microorganisms in open‐ocean and estuarine planktonic communities

Urea is an important and dynamic natural component of marine nitrogen cycling and also a major contributor to anthropogenic eutrophication of coastal ecosystems, yet little is known about the identities or diversity of ureolytic marine microorganisms. Primers targeting the gene encoding urease were used to PCR‐amplify, clone and sequence 709 urease gene fragments from 31 plankton samples collected at both estuarine and open‐ocean locations. Two hundred and eighty‐six amplicons belonged to 22 distinct sequence types that were closely enough related to named organisms to be identified, and included urease sequences both from typical marine planktonic organisms and from bacteria usually associated with terrestrial habitats. The remaining 423 amplicons were not closely enough related to named organisms to be identified, and belonged to 96 distinct sequence types of which 43 types were found in two or more different samples. The distributions of unidentified urease sequence types suggested that some represented truly marine microorganisms while others reflected terrestrial inputs to low‐salinity estuarine areas. The urease primers revealed this great diversity of ureolytic organisms because they were able to amplify many previously unknown, environmentally relevant urease genes, and they will support new approaches for exploring the role of urea in marine ecosystems.     

Meiotic Recombination in Human Oocytes

Studies of human trisomies indicate a remarkable relationship between abnormal meiotic recombination and subsequent nondisjunction at maternal meiosis I or II. Specifically, failure to recombine or recombination events located either too near to or too far from the centromere have been linked to the origin of human trisomies. It should be possible to identify these abnormal crossover configurations by using immunofluorescence methodology to directly examine the meiotic recombination process in the human female. Accordingly, we initiated studies of crossover-associated proteins (e.g., MLH1) in human fetal oocytes to analyze their number and distribution on nondisjunction-prone human chromosomes and, more generally, to characterize genome-wide levels of recombination in the human female. Our analyses indicate that the number of MLH1 foci is lower than predicted from genetic linkage analysis, but its localization pattern conforms to that expected for a crossover-associated protein. In studies of individual chromosomes, our observations provide evidence for the presence of “vulnerable” crossover configurations in the fetal oocyte, consistent with the idea that these are subsequently translated into nondisjunctional events in the adult oocyte.