Cis-4-hydroxypipecolic acid and 2,4-cis-4,5-trans-4,5-dihydroxypipecolic acid from Calliandra

cis-4-Hydroxypipecolic acid and 2,4-cis-4,5-trans-4,5-dihydroxypipecolic acid were isolated from leaves of Calliandra pittieri. A system for resolving the eight imino acids isolated from Calliandra is described.     

Crystal structure of a type II dehydroquinate dehydratase-like protein from Bifidobacterium longum

Dehydroquinate dehydratase (DHQD) catalyzes the third step in the biosynthetic shikimate pathway. Here we identify a Bifidobacterium longum protein with high sequence homology to type II DHQDs but no detectable DHQD activity under standard assay conditions. A crystal structure reveals that the B. longum protein adopts a DHQD-like tertiary structure but a distinct quaternary state. Apparently forming a dimer, the B. longum protein lacks the active site aspartic acid contributed from a neighboring protomer in the type II DHQD dodecamer. Relating to the absence of protein–protein interactions established in the type II DHQD dodecameric assembly, substantial conformational changes distinguish the would-be active site of the B. longum protein. As B. longum possess no other genes with homology to known DHQDs, these findings imply a unique DHQD activity within B. longum.     

Hasty generalisation and exaggerated certainties: reporting genetic findings in health disparities research

Abstract

In the United States, research that examines potential genetic contributions to health disparities often relies on racial categories. Some see benefit in this research especially for conditions where disparities in health status seem strongly associated with racial identity, such as heart disease and prostate cancer. But this research calls for close scrutiny. First, despite common optimism about genetic research, it may not be the most productive way to examine health disparities. And second, this research has the potential to contribute to racial stereotypes, arguably a prime cause of the health disparities the genetic research actually seeks to ameliorate. Two articles reporting results about genetics and heart disease are used to illustrate these concerns. Both report strong correlations between increased vulnerability to heart disease and black racial identity. Despite serious sampling and analysis problems in these articles, the findings rapidly entered the scientific and popular literature. A possible reason for their ready acceptance is their congruence with stereotypes that attribute poor health and genetic inferiority to minority US populations.     

Ultrasensitivity in Phosphorylation-Dephosphorylation Cycles with Little Substrate

Cellular decision-making is driven by dynamic behaviours, such as the preparations for sunrise enabled by circadian rhythms and the choice of cell fates enabled by positive feedback. Such behaviours are often built upon ultrasensitive responses where a linear change in input generates a sigmoidal change in output. Phosphorylation-dephosphorylation cycles are one means to generate ultrasensitivity. Using bioinformatics, we show that in vivo levels of kinases and phosphatases frequently exceed the levels of their corresponding substrates in budding yeast. This result is in contrast to the conditions often required by zero-order ultrasensitivity, perhaps the most well known means for how such cycles become ultrasensitive. We therefore introduce a mechanism to generate ultrasensitivity when numbers of enzymes are higher than numbers of substrates. Our model combines distributive and non-distributive actions of the enzymes with two-stage binding and concerted allosteric transitions of the substrate. We use analytical and numerical methods to calculate the Hill number of the response. For a substrate with phosphosites, we find an upper bound of the Hill number of , and so even systems with a single phosphosite can be ultrasensitive. Two-stage binding, where an enzyme must first bind to a binding site on the substrate before it can access the substrate''s phosphosites, allows the enzymes to sequester the substrate. Such sequestration combined with competition for each phosphosite provides an intuitive explanation for the sigmoidal shifts in levels of phosphorylated substrate. Additionally, we find cases for which the response is not monotonic, but shows instead a peak at intermediate levels of input. Given its generality, we expect the mechanism described by our model to often underlay decision-making circuits in eukaryotic cells.

Authors Summary

Dose-response curves are said to be ultrasensitive when they are sigmoidal rather than hyperbolic and often underlay cellular decision-making circuits. Zero-order ultrasensitivity is a well-known mechanism to generate sigmoidal curves in phosphorylation cycles, but one of its assumptions often implies that the substrate is more abundant than the modifying enzymes. We show that this assumption is unlikely to always hold in vivo, and we present a general model that generates ultrasensitivity when the enzymes are in excess of their substrate. The model combines conformational allosteric transitions of the substrate with two-stage binding of the enzymes: the enzymes bind first to a docking site on the substrate and then to the substrate''s phosphosites. Ultrasensitivity is generated because the kinase can bind to the fully phosphorylated form of the substrate (at its docking site) and sequester the substrate away from the phosphatase and, similarly, the phosphatase can bind to the fully dephosphorylated form of the substrate and sequester the substrate away from the kinase. The number of kinase-phosphatase competitions for the substrate determines the degree of ultrasensitivity. Finally, we show that this model can generate non-monotonic responses that peak at intermediate levels of input.     

Excited state intramolecular proton transfer in 3-hydroxychromone: a DFT-based computational study

Potential energy (PE) curves for intramolecular proton transfer in the ground (GSIPT) and intramolecular proton transfer in the excited (ESIPT) states of 3-hydroxychromone (3HC) have been studied using DFT-B3LYP/6-31G(d,p) and TD-DFT/6-31G(d,p) level of theory, respectively. Our calculations suggest the non-viability of GSIPT in 3HC. Excited states PE calculations show the existence of ESIPT process in 3HC. ESIPT in 3HC has also been explained in terms of HOMO and LUMO electron densities of the enol and keto tautomers of 3HC.     

Incest versus abstinence: reproductive trade‐offs between mate limitation and progeny fitness in a self‐incompatible invasive plant

Plant mating systems represent an evolutionary and ecological trade‐off between reproductive assurance through selfing and maximizing progeny fitness through outbreeding. However, many plants with sporophytic self‐incompatibility systems exhibit dominance interactions at the S‐locus that allow biparental inbreeding, thereby facilitating mating between individuals that share alleles at the S‐locus. We investigated this trade‐off by estimating mate availability and biparental inbreeding depression in wild radish from five different populations across Australia. We found dominance interactions among S‐alleles increased mate availability relative to estimates based on individuals that did not share S‐alleles. Twelve of the sixteen fitness variables were significantly reduced by inbreeding. For all the three life‐history phases evaluated, self‐fertilized offspring suffered a greater than 50% reduction in fitness, while full‐sib and half‐sib offspring suffered a less than 50% reduction in fitness. Theory indicates that fitness costs greater than 50% can result in an evolutionary trajectory toward a stable state of self‐incompatibility (SI). This study suggests that dominance interactions at the S‐locus provide a possible third stable state between SI and SC where biparental inbreeding increases mate availability with relatively minor fitness costs. This strategy allows weeds to establish in new environments while maintaining a functional SI system.     

Interactions of allelic variance of PNPLA3 with nongenetic factors in predicting nonalcoholic steatohepatitis and nonhepatic complications of severe obesity

Objective : Allelic variation (rs738409C→G) in adiponutrin (patatin‐like phospholipase domain‐containing protein 3, PNPLA3) has been associated with hepatic steatosis and liver fibrosis. The physiologic impact of the PNPLA3 G allele may be exacerbated in patients with severe obesity. In this study, we investigated the interactions of PNPLA3 rs738409 with a broad panel of metabolic and histologic characteristics of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) in patients with medically complicated obesity. Design and Methods : Consecutive patients undergoing bariatric surgery were selected for a prospective study. They underwent extensive laboratory and histologic (liver biopsy) assessment, as well as evaluation of rs738409 polymorphism by TaqMan assay. Results : Only 12 (8.3%) of the 144 patients had normal liver histology, with 72 (50%) NASH, of whom 15 (10.4% of total patients) had fibrosis stage 2‐3. PNPLA3 GG genotype correlated positively (P < 0.05) with serum levels of alanine aminotransferase (ALT), asparate aminotransferase (AST), glucose, fibrinogen, and insulin‐dependent diabetes mellitus, homeostasis model assessment—insulin resistance, and presence of NASH. Multivariate analysis indicated that PNPLA3 rs738409 G versus C allele remained an (independent) risk factor for NASH, in addition to CK‐18 >145 IU/l, glucose >100 mg/dl, and C‐reactive protein (CRP) >0.8 mg/dl. The probability of NASH increased from 9% (no risk factor) to 82% if all four risk factors were present. Conclusions : In this cohort of patients with medically complicated obesity, PNPLA3 rs738409 G allelic expression is associated with hepatic (NASH) and nonhepatic complications of obesity, such as insulin resistance. These novel findings may be related to a greater impact of PNPLA3 variant in magnitude and scope in patients with severe obesity than in less obese populations. Further studies are needed to characterize the nature of these associations.     

Impact of chromate and dichromate on lysozyme stability: A spectroscopic and molecular docking investigation

A comparative study of interaction between chicken egg white lysozyme (Lyz) with two hexavalent chromate ions; chromate and dichromate; which are prevalently known for their toxicity, was investigated using different spectroscopic techniques along with a molecular docking study. Both steady-state and time-resolved studies revealed that the addition of chromate/dichromate is responsible for strong quenching of intrinsic fluorescence in Lyz and the quenching is caused by both static and dynamic quenching mechanisms. Different binding and thermodynamic parameters were also calculated at different temperatures from the intrinsic fluorescence of Lyz. The conformational change in Lyz and thermodynamic parameters obtained during the course of interaction with chromate/dichromate were well-supported by the molecular docking results.     

Regulation of the generation and maintenance of T-cell memory: a direct,default pathway from effectors to memory cells

Memory T cells are derived directly from effector cells without need for additional antigen, TcR triggering or induced cytokines. A large fraction of effectors can become memory cells without division, supporting a default pathway with little further differentiation. This suggests that the same signals during infection/vaccination determine the extent and nature of both effector and memory cell development.