Ribosomal association of the yeast SAL4 (SUP45) gene product: implications for its role in translation fidelity and termination

The SAL4 gene of the yeast Saccharomyces cerevisiae encodes a novel translation factor (Sal4p) involved in maintaining translational fidelity. Using a polyclonal antibody raised against a Sal4p-beta-galactosidase fusion protein, Sal4p was shown to be almost exclusively associated with the ribosomal fraction. Even when the ribosomes were treated with 0.8 M KCl, only low levels of Sal4p were detected in the post-ribosomal supernatant, suggesting a very strong affinity between Sal4p and the ribosome. Analysis of the distribution of Sal4p in the ribosomal population revealed that it was principally associated with 40S subunits, monosomes and polysomes. Incubation in high salt concentrations (0.8 M KCl) suggested that the affinity of Sal4p for the 40S subunit was lower than that for monosomes or polysomes. The Sal4p:ribosome association was only maintained when ribosomes were prepared in the presence of the translation elongation inhibitor cycloheximide; in uninhibited cells much lower levels of Sal4p were detectable in the 'run-off' polysomes. In view of these data, and given the stoichiometry of Sal4p to individual ribosomal proteins (estimated at less than 1:20), we suggest that Sal4p plays an ancillary role in translation termination.     

There is an obstetrical dilemma: Misconceptions about the evolution of human childbirth and pelvic form

Compared to other primates, modern humans face high rates of maternal and neonatal morbidity and mortality during childbirth. Since the early 20th century, this “difficulty” of human parturition has prompted numerous evolutionary explanations, typically assuming antagonistic selective forces acting on maternal and fetal traits, which has been termed the “obstetrical dilemma.” Recently, there has been a growing tendency among some anthropologists to question the difficulty of human childbirth and its evolutionary origin in an antagonistic selective regime. Partly, this stems from the motivation to combat increasing pathologization and overmedicalization of childbirth in industrialized countries. Some authors have argued that there is no obstetrical dilemma at all, and that the difficulty of childbirth mainly results from modern lifestyles and inappropriate and patriarchal obstetric practices. The failure of some studies to identify biomechanical and metabolic constraints on pelvic dimensions is sometimes interpreted as empirical support for discarding an obstetrical dilemma. Here we explain why these points are important but do not invalidate evolutionary explanations of human childbirth. We present robust empirical evidence and solid evolutionary theory supporting an obstetrical dilemma, yet one that is much more complex than originally conceived in the 20th century. We argue that evolutionary research does not hinder appropriate midwifery and obstetric care, nor does it promote negative views of female bodies. Understanding the evolutionary entanglement of biological and sociocultural factors underlying human childbirth can help us to understand individual variation in the risk factors of obstructed labor, and thus can contribute to more individualized maternal care.     

Hydrographic influences on the summer dive behaviour of Weddell seals (Leptonychotes weddellii) in Atka Bay, Antarctica

In order to gain insights into species-level behavioural responses to the physical environment, it is necessary to obtain information from various populations and at all times of year. We analysed the influences of physical environmental parameters on the mid-summer dive behaviour of Weddell seals (Leptonychotes weddellii) from a little-known population at Atka Bay, Antarctica. Dive depth distributions followed a typical bimodal pattern also exhibited by seals from other populations and seals targeted both shallow water layers of <50 m and depths near the seafloor. Increased stratification of temperature layers within the water column resulted in increased forage efforts by the seals through relatively high numbers of dives to the seafloor, as well as forage effort associated with shallow dives. We interpret these behavioural responses to be due to increased water temperature stratification resulting in the concentration of prey species in particular depth layers.     

A Novel Objective Method of Estimating the Age of Mandibles from African Elephants (Loxodonta africana Africana)

The importance of assigning an accurate estimate of age and sex to elephant carcasses found in the wild has increased in recent years with the escalation in levels of poaching throughout Africa. Irregularities identified in current ageing techniques prompted the development of a new method to describe molar progression throughout life. Elephant mandibles (n = 323) were studied and a point near the distal dental alveolus was identified as being most useful in ranking each jaw according to molar progression. These ‘Age Reference Lines’ were then associated with an age scale based on previous studies and Zimbabwean mandibles of known age. The new ranking produced a single age scale that proved useful for both male and female mandibles up to the maximum lifespan age of 70–75 years. Methods to aid in molar identification and the sexing of found jaws were also identified.     

The identification of a selective dopamine D2 partial agonist,D3 antagonist displaying high levels of brain exposure

The identification of a highly selective D₂ partial agonist, D₃ antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.     

Potent, orally active inhibitors of lipoprotein-associated phospholipase A(2): 1-(biphenylmethylamidoalkyl)-pyrimidones.

A series of 1-(biphenylmethylamidoalkyl)-pyrimidones has been designed as nanomolar inhibitors of recombinant lipoprotein-associated phospholipase A(2) with high potency in whole human plasma. 5-(Pyrazolylmethyl) derivative 16 and 5-(methoxypyrimidinylmethyl) derivative 27 demonstrated excellent pharmacodynamic profiles which correlated well with their pharmacokinetic effects.     

Tetracyclic indole inhibitors of hepatitis C virus NS5B-polymerase

We report the evolutionary path from an open-chain series to conformationally constrained tetracyclic indole inhibitors of HCV NS5B-polymerase, where the C2 aromatic is tethered to the indole nitrogen. SAR studies led to the discovery of zwitterionic compounds endowed with good intrinsic enzyme affinity and cell-based potency, as well as superior DMPK profiles to their acyclic counterparts, and ultimately to the identification of a pre-clinical candidate with an excellent predicted human pharmacokinetic profile.     

BDNF and Huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity

High levels of manganese (Mn) exposure decrease striatal medium spiny neuron (MSN) dendritic length and spine density, but the mechanism(s) are not known. The Huntingtin (HTT) gene has been functionally linked to cortical brain‐derived neurotrophic factor (BDNF) support of striatal MSNs via phosphorylation at serine 421. In Huntington's disease, pathogenic CAG repeat expansions of HTT decrease synthesis and disrupt transport of cortical–striatal BDNF, which may contribute to disease, and Mn is a putative environmental modifier of Huntington's disease pathology. Thus, we tested the hypothesis that changes in MSN dendritic morphology Mn due to exposure are associated with decreased BDNF levels and alterations in Htt protein. We report that BDNF levels are decreased in the striatum of Mn‐exposed non‐human primates and in the cerebral cortex and striatum of mice exposed to Mn. Furthermore, proBDNF and mature BDNF concentrations in primary cortical and hippocampal neuron cultures were decreased by exposure to Mn confirming the in vivo findings. Mn exposure decreased serine 421 phosphorylation of Htt in cortical and hippocampal neurons and increased total Htt levels. These data strongly support the hypothesis that Mn‐exposure‐related MSN pathology is associated with decreased BDNF trophic support via alterations in Htt.

     

Unique residues involved in activation of the multitasking protease/chaperone HtrA from Chlamydia trachomatis

DegP, a member of the HtrA family of proteins, conducts critical bacterial protein quality control by both chaperone and proteolysis activities. The regulatory mechanisms controlling these two distinct activities, however, are unknown. DegP activation is known to involve a unique mechanism of allosteric binding, conformational changes and oligomer formation. We have uncovered a novel role for the residues at the PDZ1:protease interface in oligomer formation specifically for chaperone substrates of Chlamydia trachomatis HtrA (DegP homolog). We have demonstrated that CtHtrA proteolysis could be activated by allosteric binding and oligomer formation. The PDZ1 activator cleft was required for the activation and oligomer formation. However, unique to CtHtrA was the critical role for residues at the PDZ1:protease interface in oligomer formation when the activator was an in vitro chaperone substrate. Furthermore, a potential in vivo chaperone substrate, the major outer membrane protein (MOMP) from Chlamydia, was able to activate CtHtrA and induce oligomer formation. Therefore, we have revealed novel residues involved in the activation of CtHtrA which are likely to have important in vivo implications for outer membrane protein assembly.