Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease

High-resolution crystal structures are described for seven macrocycles complexed with HIV-1 protease (HIVPR). The macrocycles possess two amides and an aromatic group within 15-17 membered rings designed to replace N- or C-terminal tripeptides from peptidic inhibitors of HIVPR. Appended to each macrocycle is a transition state isostere and either an acyclic peptide, nonpeptide, or another macrocycle. These cyclic analogues are potent inhibitors of HIVPR, and the crystal structures show them to be structural mimics of acyclic peptides, binding in the active site of HIVPR via the same interactions. Each macrocycle is restrained to adopt a P-strand conformation which is preorganized for protease binding. An unusual feature of the binding of C-terminal macrocyclic inhibitors is the interaction between a positively charged secondary amine and a catalytic aspartate of HIVPR. A bicyclic inhibitor binds similarly through its secondary amine that lies between its component N-terminal and C-terminal macrocycles. In contrast, the corresponding tertiary amine of the N-terminal macrocycles does not interact with the catalytic aspartates. The amine-aspartate interaction induces a 1.5 Angstrom N-terminal translation of the inhibitors in the active site and is accompanied by weakened interactions with a water molecule that bridges the ligand to the enzyme, as well as static disorder in enzyme flap residues. This flexibility may facilitate peptide cleavage and product dissociation during catalysis. Proteases [Aba(67,95)]HIVPR and [Lys(7),Ile(33),Aba(67,95)]- HIVPR used in this work were shown to have very similar crystal structures.

Is there an association between normal cognitive functioning and trinucleotide repeat expansion at loci involved in neurodegenerative disorders?

Recent reports have shown neurodegenerative disorders to be associated with abnormal expansions of a CAG trinucleotide repeat allele at various autosomal loci. While normal chromosomes have 14 to 44 repeats, disease chromosomes may have 60 to 84 repeats. The number of CAG repeats on mutant chromosomes correlates with increasing severity of disease or decreasing age at onset of symptoms. Since we are interested in identifying the many quantitative trait loci (QTL) influencing brain functioning, we examined the possibility that the number of CAG repeats in the normal size range at these loci are relevant to "normal" neural functioning. We have used 150 pairs of adolescent (aged 16 years) twins and their parents to examine allele size at the MJD, SCA1, and DRPLA loci in heterozygous normal individuals. These are part of a large ongoing project using cognitive and physiological measures to investigate the genetie influences on cognition, and an extensive protocol of tests is employed to assess some of the key components of intellectual functioning. This study selected to examine full-scale psychometric IQ (FSIQ) and a measure of information processing (choice reaction time) and working memory (slow wave amplitude). CAG repeat size was determined on an ABI Genescan system following multiplex PCR amplification. Quantitative genetic analyses were performed to determine QTL effects of MJD, SCA1, and DRPLA on cognitive functioning. Analyses are in progress and will be discussed.

The current status of psychological debriefing - It may do more harm than good

Despite the widespread use of psychological debriefing, serious concerns have been raised about its effectiveness and potential to do harm. 1 2 Psychological debriefing is broadly defined as a set of procedures including counselling and the giving of information aimed at preventing psychological morbidity and aiding recovery after a traumatic event. In 1995 Raphael and colleagues emphasised that there was an urgent need for reliable evidence from randomised controlled trials on the impact and worth of debriefing.3 Unfortunately, the news has not been good for debriefing. Debriefing is generally applied within the first few days after a traumatic event, lasts one to three hours, and usually includes procedures that encourage and normalise emotional expression. Debriefing can also be more narrowly defined in terms of the procedures used, the information provided and the target population. One example of this type of debriefing is known as critical incident stress debriefing.4

Adolescent depressive symptomatology: Improve schools or help students?

Despite the increasing interest in programs designed to improve the social ecology of schools, surprisingly little is known about whether differences between schools influence student mental health. This 3-year prospective, naturalistic study examines the school effect on adolescent depressive symptomatology (measured by the Center for Epidemiological Studies Depression Scale, CES-D) among 2,489 students from 25 Australian high schools. Multilevel modelling techniques (HLM) formed the basis of the statistical analyses, There were statistically significant school effects on students' depressive symptomatology; however, these were much smaller than expected. Nearly all of the variation in CES-D depression scores was found to be at the student level, indicating that the potential mental health gains from reducing risk factors in school social environments may be extremely limited and have little effect on student depressive symptomatology.

The polar ionosphere at Zhongshan Station on May 11, 1999, the day the solar wind almost disappeared

The solar wind almost disappeared on May 11,1999: the solar wind plasma density and' dynamic pressure were less than 1 cm(-3) and 0.1 nPa respectively, while the interplanetary magnetic field was northward. The polar ionospheric data observed by the multi-instruments at Zhongshan Station in Antarctica on such special event day was compared with those of the control day (May 14). It was shown that geomagnetic activity was very quiet on May 11 at Zhongshan. The magnetic pulsation, which usually occurred at about magnetic noon, did not appear. The ionosphere was steady and stratified, and the F-2 layer spread very little. The critical frequency of dayside F-2 layer, f(0)F(2), was larger than that of control day, and the peak of f(0)F(2) appeared 2 hours earlier. The ionospheric drift velocity was less than usual. There were intensive auroral E-s appearing at magnetic noon. All this indicates that the polar ionosphere was extremely quiet and geomagnetic field was much more dipolar on May 11. There were some signatures of auroral substorm before midnight, such as the negative deviation of the geomagnetic H component, accompanied with auroral E-s and weak Pc3 pulsation.

Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation

We have identified truncating mutations in the human DLG3 ( neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation. DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane-associated guanylate kinase protein family. Neuronal SAP102 is expressed during early brain development and is localized to the postsynaptic density of excitatory synapses. It is composed of three amino-terminal PDZ domains, an src homology domain, and a carboxyl-terminal guanylate kinase domain. The PDZ domains interact directly with the NR2 subunits of the NMDA glutamate receptor and with other proteins responsible for NMDA receptor localization, immobilization, and signaling. The mutations identified in this study all introduce premature stop codons within or before the third PDZ domain, and it is likely that this impairs the ability of SAP102 to interact with the NMDA receptor and/or other proteins involved in downstream NMDA receptor signaling pathways. NMDA receptors have been implicated in the induction of certain forms of synaptic plasticity, such as long-term potentiation and long-term depression, and these changes in synaptic efficacy have been proposed as neural mechanisms underlying memory and learning. The disruption of NMDA receptor targeting or signaling, as a result of the loss of SAP102, may lead to altered synaptic plasticity and may explain the intellectual impairment observed in individuals with DLG3 mutations.

Electronic medical records may be inadequate for improving population health status through general practice: cervical smears as a case study

Objective: To determine whether routine electronic records are an accurate source of population health data in general practice through reviewing cervical smears rates in four South Australian practices. Methods: The cervical screening rate in a purposive sample of four general practices (three rural and one urban) was obtained using an audit of medical records and a telephone follow-up. Results: The cervical screening rate using only immediately available electronic medical records indicated an overall low rate for the participating practices (44.9%). However, telephone follow-up and adjustments to the denominator indicated the real rate to be 85.7%. The offer of appointments during the telephone follow-up further improved this rate for eligible women (93.8%). Conclusions and implications: Electronic medical records may be inadequate in preventive screening in general practice, without ensuring their accuracy. Updating records by telephone or personal follow-up produces a much more accurate denominator.

Anxiety-like symptoms induced by morphine withdrawal may be due to the sensitization of the dorsal periaqueductal grey

Withdrawal from morphine leads to the appearance of extreme anxiety accompanied of several physical disturbances, most of them linked to the activation of brainstem regions such as the locus coeruleus, ventral tegmental area, hypothalamic nuclei and periaqueductal grey (PAG). As anxiety remains one of the main components of morphine withdrawal the present study aimed to evaluating the influence of the dorsal aspects of the PAG on the production of this state, since this structure is well-known to be involved in defensive behaviour elicited by anxiety-evoking stimuli. Different groups of animals were submitted to 10 days of i.p. morphine injections, challenged 2 h after with an i.p. injection of naloxone (0.1 mg/kg), and submitted to the plus-maze, open-field and light-dark transition tests. The effects of morphine withdrawal on anxiety-induced Fos immunolabelling were evaluated in four animals that passed by the light-dark transition test randomly chosen for Fos-protein analysis. Besides the PAG, Fos neural expression was conducted in other brain regions involved in the expression of anxiety-related behaviours. Our results showed that morphine withdrawn rats presented enhanced anxiety accompanied of few somatic symptoms. Increased Fos immunolabelling was noted in brain regions well-known to modulate these states as the prelimbic cortex, nucleus accumbens, amygdala and paraventricular hypothalamus. Increased Fos labelling was also observed in the ventral and dorsal aspects of the PAG, a region involved in anxiety-related processes suggesting that this region could be a common neural substrate enlisted during anxiety evoked by dangerous stimuli as well as those elicited by opiate withdrawal. (c) 2008 Elsevier Inc. All rights reserved,