Minireview Trapping Poly(ADP-Ribose) Polymerase

ABSTRACT Recent findings indicate that a major mechanism by which poly (ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they display similar capacity to inhibit PARP catalytic activity, their relative abilities to trap PARP differ by several orders of magnitude, with the ability to trap PARP closely correlating with each drug's ability to kill cancer cells. In this article, we review the available data on molecular interactions between these clinical-stage PARP inhibitors and PARP proteins, and discuss how their biologic differences might be explained by the trapping mechanism. We also discuss how to use the PARP-trapping mechanism to guide the development of PARP inhibitors as a new class of cancer therapy, both for singleagent and combination treatments

Modes of Collective Action in Village Economies:Evidence from Natural and Artefactual Field Experiments in a Developing Country

In a canonical model of collective action, individual contribution to collective action is negatively correlated with group size. Empirical evidence on the group size effect has been mixed, partly due to heterogeneities in group activities. In this paper, we first construct a simple general model of collective action with the free-riding problem, altruism, public goods, and positive externalities of social networks. We then empirically test the theoretical implications of group size effect on individual contribution to four different types of collective action, i.e., monetary or nonmonetary contribution to directly or indirectly productive activities. To achieve this, we collect and employ artefactual field experimental data such as public goods and dictator games conducted in southern Sri Lanka under a natural experimental situation where the majority of farmers were relocated to randomly selected communities based on the government lottery. This unique situation enables us to identify the causal effects of community size on collective action. We find that the levels of collective action can be explained by the social preferences of farmers; we show evidence on the free-riding by self-interested households with no land holdings. The pattern of collective action, however, differs significantly by the mode of activities; the collective action which is directly related to production is less likely to suffer from the free rider problem than from indirectly productive activities. Finally, the monetary contribution is less likely to cause the free riding than the non-monetary contribution

―Evidence from Sri Lanka―

This study uses a unique long panel dataset from Sri Lanka to examine the mechanism of social capital formation in an imperfect credit market. The authors show that households in the face of credit constraints reduce the time allocation for social capital investment, such as participation in community works. The paper also finds that temporal declines in social capital investment persistently reduce the level of trust in the community. These findings imply the existence of a poverty trap, because the absence of a credit market access generates poor social capital which, in turn, leads to poor access to the informal credit market, causing further credit constraints

―Evidence from Sri Lanka―

This study uses a unique long panel dataset from Sri Lanka to examine the mechanism of social capital formation in an imperfect credit market. The authors show that households in the face of credit constraints reduce the time allocation for social capital investment, such as participation in community works. The paper also finds that temporal declines in social capital investment persistently reduce the level of trust in the community. These findings imply the existence of a poverty trap, because the absence of a credit market access generates poor social capital which, in turn, leads to poor access to the informal credit market, causing further credit constraints

Structural basis for endothelial nitric oxide synthase binding to calmodulin

The enzyme nitric oxide synthase (NOS) is exquisitely regulated in vivo by the Ca(2+) sensor protein calmodulin (CaM) to control production of NO, a key signaling molecule and cytotoxin. The differential activation of NOS isozymes by CaM has remained enigmatic, despite extensive research. Here, the crystal lographic structure of Ca(2+)-loaded CaM bound to a 20 residue peptide comprising the endothelial NOS (eNOS) CaM-binding region establishes their individual conformations and intermolecular interactions, and suggests the basis for isozyme-specific differences. The α-helical eNOS peptide binds in an antiparallel orientation to CaM through extensive hydrophobic interactions. Unique NOS interactions occur with: (i) the CaM flexible central linker, explaining its importance in NOS activation; and (ii) the CaM C-terminus, explaining the NOS-specific requirement for a bulky, hydrophobic residue at position 144. This binding mode expands mechanisms for CaM-mediated activation, explains eNOS deactivation by Thr495 phosphorylation, and implicates specific hydrophobic residues in the Ca(2+) independence of inducible NOS

Utilizing ExAC to assess the hidden contribution of variants of unknown significance to Sanfilippo Type B incidence

<div><p>Given the large and expanding quantity of publicly available sequencing data, it should be possible to extract incidence information for monogenic diseases from allele frequencies, provided one knows which mutations are causal. We tested this idea on a rare, monogenic, lysosomal storage disorder, Sanfilippo Type B (Mucopolysaccharidosis type IIIB). Sanfilippo Type B is caused by mutations in the gene encoding <i>α</i>-N-acetylglucosaminidase (NAGLU). There were 189 NAGLU missense variants found in the ExAC dataset that comprises roughly 60,000 individual exomes. Only 24 of the 189 missense variants were known to be pathogenic; the remaining 165 variants were of unknown significance (VUS), and their potential contribution to disease is unknown. To address this problem, we measured enzymatic activities of 164 NAGLU missense VUS in the ExAC dataset and developed a statistical framework for estimating disease incidence with associated confidence intervals. We found that 25% of VUS decreased the activity of NAGLU to levels consistent with Sanfilippo Type B pathogenic alleles. We found that a substantial fraction of Sanfilippo Type B incidence (67%) could be accounted for by novel mutations not previously identified in patients, illustrating the utility of combining functional activity data for VUS with population-wide allele frequency data in estimating disease incidence.</p></div

Effect of EGLN1 Genetic Polymorphisms on Hemoglobin Concentration in Andean Highlanders

The physiological characteristics of Andean natives living at high altitudes have been investigated extensively, with many studies reporting that Andean highlanders have a higher hemoglobin (Hb) concentration than other highlander populations. It has previously been reported that positive natural selection has acted independently on the egl-9 family hypoxia inducible factor 1 (EGLN1) gene in Tibetan and Andean highlanders and is related to Hb concentration in Tibetans. However, no study has yet revealed the genetic determinants of Hb concentration in Andeans even though several single-nucleotide polymorphisms (SNPs) in EGLN1 have previously been examined. Therefore, we explored the relationship between hematological measurements and tag SNPs designed to cover the whole EGLN1 genomic region in Andean highlanders living in Bolivia. Our findings indicated that haplotype frequencies estimated from the EGLN1 SNPs were significantly correlated with Hb concentration in the Bolivian highlanders. Moreover, we found that an Andean-dominant haplotype related to high Hb level may have expanded rapidly in ancestral Andean highlander populations. Analysis of genotype data in an ~436.3 kb genomic region containing EGLN1 using public databases indicated that the population structure based on EGLN1 genetic markers in Andean highlanders was largely different from that in other human populations. This finding may be related to an intrinsic or adaptive physiological characteristic of Andean highlanders. In conclusion, the high Hb concentrations in Andean highlanders can be partly characterized by EGLN1 genetic variants

The enzymatic activity of NAGLU variants.

<p><b>(A)</b> Variants are ordered by average %wt activity. Standard deviation in %wt activity in replicates is represented by vertical bars. Previously identified disease variants are shown in orange. A dashed line shows the 15%wt activity threshold below which variants are considered to be pathogenic. <b>(Insert B)</b> A box plot (y-axis log scale) of the Non-Finnish European allele frequency of variants with ≤15%wt activity (average allele frequency of 3.76 × 10⁻⁵ and those with >15%wt (average allele frequency of 0.0014). The difference in the average allele frequency between the two groups was not statistically significant (p-value = 0.372, t-test).</p