Identifying the social context of single- and mixed-species group formation in large African herbivores.

Despite continued interest in mixed-species groups, we still lack a unified understanding of how ecological and social processes work across scales to influence group formation. Recent work has revealed ecological correlates of mixed-species group formation, but the mechanisms by which concomitant social dynamics produce these patterns, if at all, is unknown. Here, we use camera trap data for six mammalian grazer species in Serengeti National Park. Building on previous work, we found that ecological variables, and especially forage quality, influenced the chances of species overlap over small spatio-temporal scales (i.e. on the scales of several metres and hours). Migratory species (gazelle, wildebeest and zebra) were more likely to have heterospecific partners available in sites with higher forage quality, but the opposite was true for resident species (buffalo, hartebeest and topi). These findings illuminate the circumstances under which mixed-species group formation is even possible. Next, we found that greater heterospecific availability was associated with an increased probability of mixed-species group formation in gazelle, hartebeest, wildebeest and zebra, but ecological variables did not further shape these patterns. Overall, our results are consistent with a model whereby ecological and social drivers of group formation are species-specific and operate on different spatio-temporal scales. This article is part of the theme issue 'Mixed-species groups and aggregations: shaping ecological and behavioural patterns and processes'.

A 'dynamic' landscape of fear: prey responses to spatiotemporal variations in predation risk across the lunar cycle.

Ambiguous empirical support for 'landscapes of fear' in natural systems may stem from failure to consider dynamic temporal changes in predation risk. The lunar cycle dramatically alters night-time visibility, with low luminosity increasing hunting success of African lions. We used camera-trap data from Serengeti National Park to examine nocturnal anti-predator behaviours of four herbivore species. Interactions between predictable fluctuations in night-time luminosity and the underlying risk-resource landscape shaped herbivore distribution, herding propensity and the incidence of 'relaxed' behaviours. Buffalo responded least to temporal risk cues and minimised risk primarily through spatial redistribution. Gazelle and zebra made decisions based on current light levels and lunar phase, and wildebeest responded to lunar phase alone. These three species avoided areas where likelihood of encountering lions was high and changed their behaviours in risky areas to minimise predation threat. These patterns support the hypothesis that fear landscapes vary heterogeneously in both space and time.

Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online.

Familial Alzheimer's disease (AD) is an autosomal dominant disorder characterized by memory impairment and multiple cognitive deficits which occurs in mid to late life. Early onset AD has been associated with mutations in three genes, of which presenilin 1 (PS1) mutations are the most frequent. We sequenced the open reading frame from genomic DNA of a series of 21 early onset AD (AD3) UK families in which there were at least two affected individuals in two or more generations with a diagnosis of probable or definite AD. We found PS1 mutations in six of these families with no sequence variation in the remaining 15. The six families contained between them five different mutations of which two, I143F and P436S, have not been found elsewhere. I143F shows incomplete penetration within the affected family. P436S is the most carboxy-terminal presenilin 1 mutation reported to date.

Conformational properties of the prion octa-repeat and hydrophobic sequences.

We have used circular dichroism to study synthetic peptides from two important regions of the prion protein: the N-terminal octa-repeat domain and a highly conserved hydrophobic section. Our results show that the octa-repeat sequence in free solution can adopt a non-random, extended conformation with properties similar to the poly-L-proline type II left-handed helix. We also show that the conformation can be changed by temperature, organic solvents (e.g. acetonitrile) and on binding to phospholipid vesicles. We compared CD data from two peptides corresponding to the hydrophobic region between residues 106 and 136 which contained either methionine or valine at position 129. This variation represents a common polymorphism in humans which has been shown to influence predisposition towards iatrogenic and sporadic CJD. There was no detectable difference between the CD spectra of these peptides irrespective of the solvent conditions we used.

Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene.

Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative disorder characterized by the accumulation of aggregates of a cellular protein, PrP, in the brain. In both human and animals, genetic alterations to the gene encoding PrP (PRNP in human) modulate susceptibility to CJD. The recent epidemic of bovine spongi-form encephalopathy in the UK has raised the possibility of transmission from animal produce to humans. To provide a baseline against which to assess possible risk factors, we have determined the frequencies of predisposing mutations and allelic variants in PRNP and their relative contributions to disease. Systematic PRNP genotype analysis was performed on suspected CJD cases referred to the National Surveillance Unit in the UK over the period 1990-1993. Inspection of 120 candidate cases revealed 67 patients with definite and probable CJD, based on clinical and neuropathological criteria. No PRNP mutations were detected in any of the remaining 53 patients assessed as "non-CJD". A disease-associated mutation in the PRNP gene was identified in nine (13.4%) definite and probable cases of CJD, a reliable estimate of the incidence of PRNP-related inherited CJD based on a prospective epidemiological series. Within the group of sporadic CJD patients (lacking PRNP mutations), we confirmed that the genotype distribution with respect to the common methionine/valine (Met/Val) polymorphism at codon 129 within PRNP was significantly different from the normal Caucasian population. The incidence of Met homozygosity at this site was more than doubled and correlated with increased susceptibility to the development of sporadic CJD. Unlike other recent studies, Val homozygosity was also confirmed to be a significant risk factor in sporadic CJD, with the relative risks for the three genotypes Met/Met: Val/Val:Met/Val being 11:4:1.

A prion disease with a novel 96-base pair insertional mutation in the prion protein gene.

There are coding mutations in the prion protein gene in familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease, and other phenotypes that make up the inherited prion diseases. Insertional mutations consisting of two, five, six, seven, eight, and nine additional octapeptide repeat elements are seen in the inherited prion diseases and usually present as atypical dementias with considerable intrafamilial phenotypic variability. A four-octarepeat insertion was reported previously in an individual without neurodegenerative disease who died of hepatic cirrhosis. Here we report a novel four-octarepeat insertional mutation in a case with classical clinical, electroencephalographic and histopathologic features of CJD with the unusual finding of pronounced prion protein immunoreactivity of the molecular layer of the cerebellum.

Unaltered susceptibility to BSE in transgenic mice expressing human prion protein.

Prion diseases are transmissible neurodegenerative conditions of humans and animals. Prions consist principally of a post-translationally modified form of prion protein (PrP), PrP(Sc), which is partly protease resistant. Transmission of prion diseases between species is limited by a 'species barrier' determined in part by the degree of sequence homology between host PrP and inoculated PrP(Sc) (ref.3) and by prion strain type. The epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom and other countries has led to concerns that transmission to humans may occur by dietary exposure. BSE appears to be caused by a single strain, distinct from those of natural or experimental scrapie, which is also seen in the new prion diseases of cats and ruminants that have presumably arisen from dietary BSE exposure. Here we show that transgenic mice expressing human PrP in addition to mouse PrP can generate human PrP(Sc) and 'human' prions. These mice therefore provide a model to study experimentally the species barrier limiting BSE transmission to humans. Incubation periods to BSE in transgenic mice are not shortened by expression of human PrP, and only mouse PrP(Sc) is produced in response to such challenge.

Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein.

The prion protein (PrP) is central to the aetiology of the prion diseases, transmissible neurodegenerative conditions of humans and animals. PrP null mice show abnormalities of synaptic neurophysiology, in particular weakened GABAA receptor-mediated fast inhibition and impaired long-term potentiation in the hippocampus. Here we demonstrate that this PrP null phenotype is rescued in mice with a high copy number of a transgene encoding human PrP but not in low copy number mice, confirming the specificity of the phenotype for loss of function of PrP. The ability of human PrP to compensate for loss of murine PrP will allow direct study of the functional consequences of the 18 human PrP mutations, which cause the inherited prion diseases; this phenotype can now form the basis of the first functional assay for PrP.

Expression of functional muscarinic acetylcholine receptor subtypes in human corpus cavernosum and in cultured smooth muscle cells.

Relaxation of the trabecular smooth muscle, which is necessary for penile erection, is controlled locally by neurotransmitters and vasoactive agents. The goal of this study was to identify and characterize muscarinic acetylcholine receptor (mAChR) subtypes expressed in cultured human corpus cavernosum smooth muscle cells (HCC SMC). Binding analysis with L-[benzilic-4,4'-3H(N)]quinuclidinyl benzilate ([3H]QNB) demonstrated the expression of specific muscarinic receptor binding sites in HCC SMC. Analysis of total RNA isolated from whole corpus cavernosum tissue and smooth muscle cells, by RNase protection assays, demonstrated the expression of mRNA transcripts for m1, m2, m3, and m4 mAChR subtypes in whole tissue and m2 and m4 subtypes in cultured cells. In situ hybridization with specific m2 and m4 probes further confirmed the expression of m2 and m4 mRNA transcripts in cultured cells. Carbachol (CCh), a nonselective cholinergic agonist, inhibited cAMP synthesis at low concentrations (0.1-1 microM) and stimulated cAMP synthesis at high concentrations (100 microM), in cultured HCC SMC. CCh (100 microM) further augmented forskolin (FSK), isoproterenol (ISO), and prostaglandin E1 (PGE1)-induced cAMP synthesis. These observations suggest that, in vivo, in HCC, ACh may activate m3 mAChR subtypes on endothelial cells or m2 and m4 subtypes on the SMC. Although m2 and m4 are thought to inhibit adenylate cyclase (AC), the augmentation of cAMP synthesis by high concentrations of CCh in SMC suggests an alternative mechanism of coupling to G-proteins that stimulates AC activity. These studies show that HCC tissue expresses different subtypes of mAChR (m1, m2, m3, and m4), whereas cultured HCC SMC express m2 and m4 subtypes. It is suggested that m2 and m4 receptor subtypes may play an important role in maintaining trabecular smooth muscle tone in vivo. The augmentation of FSK-, ISO, and PGE1-induced cAMP synthesis by CCh suggests possible development of a multidrug therapeutic approach to treatment of erectile dysfunction.

Prion protein is necessary for normal synaptic function.

The prion diseases are neurodegenerative conditions, transmissible by inoculation, and in some cases inherited as an autosomal dominant disorder. They include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. The prion consists principally of a post-translationally modified form of a host-encoded glycoprotein (PrPC), designated PrPSc (ref. 1); the normal cellular function of PrPC is, however, unknown. Although PrP is highly conserved among mammals and widely expressed in early embryogenesis, mice homozygous for disrupted PrP genes appear developmentally and behaviourally normal. PrP is a protein anchored to the neuronal surface by glycosylphosphatidylinositol, suggesting a role in cell signalling or adhesion. Here we report that hippocampal slices from PrP null mice have weakened GABAA (gamma-aminobutyric acid type A) receptor-mediated fast inhibition and impaired long-term potentiation. This impaired synaptic inhibition may be involved in the epileptiform activity seen in Creutzfeldt-Jakob disease and we argue that loss of function of PrPC may contribute to the early synaptic loss and neuronal degeneration seen in these diseases.

Molecular genetics of human prion diseases.

Human prion diseases occur in inherited, sporadic and acquired forms. The inherited forms are associated with coding mutations in the prion protein gene and the identification of one of these pathogenic mutations allows definitive diagnosis and has resulted in a widening of the previously recognized phenotypic spectrum of these diseases. Study of acquired prion disease provides evidence for genetic susceptibility to development of disease following treatment with contaminated pituitary hormones. Sporadic prion disease occurs predominantly in individuals homozygous with respect to a common PrP polymorphism at residue 129. The identification of pathogenic PrP alleles and the role of the codon 129 PrP gene polymorphism in determining susceptibility to prion disease provides strong support for the idea that an abnormal isoform of PrP, PrPSc, is the principal constituent of the prion and that its propagation involves direct PrP-PrP interactions which occur most readily between identical PrP molecules.

The human SRY transcript.

SRY encodes the Y-linked testis-determining factor in humans. A predominant 900 bp transcript originates from a single exon and encompasses the putative SRY coding sequence. We show that in human adult testis SRY transcription involves multiple start sites. In addition to a previously defined major initiation site, transcripts originating at least 410 bp upstream of this site were detected. Using a cDNA specific RT-PCR assay, embryonic and adult human tissues were screened for SRY expression. In humans, SRY transcription is not restricted to the presumptive and the mature gonadal tissues in the embryo and the adult respectively but can be detected in a range of other locations. Two human cell lines, NTERA-2 cl.D1 (NT2/D1) and Hep G2, have been identified which express SRY at similar levels to adult testis. The NT2/D1 SRY transcripts appear to have the same structure as those in adult testis. HMBA-induced differentiation of NT2/D1 cells results in a diminution of SRY mRNA, while transcription of SRY in retinoic acid differentiated NT2/D1 is unaffected.

Prion diseases in humans and their relevance to other neurodegenerative diseases.

Molecular genetics has led to considerable advances in our understanding of the transmissible spongiform encephalopathies. The identification of pathogenic mutations in the prion protein gene has enabled a molecular reclassification of the familial forms of these diseases, which may now be referred to as inherited prion diseases. Prion diseases of both humans and animals are associated with deposition of an abnormal isoform of a host-encoded protein, the prion protein (PrP). Human prion diseases have inherited, sporadic and acquired forms. A considerable body of evidence now supports the idea that the transmissible agent in these diseases may be an abnormal isoform of the prion protein. The identification of pathogenic mutations in the PrP gene has enabled the identification of cases of inherited prion disease that would not have been recognised using existing clinical and pathological diagnostic criteria. Since marked clinical and neuropathological overlap between the different neurodegenerative disorders is well recognised, PrP gene analysis is of increasing importance in differential diagnosis. Frontal lobe dementia of non-Alzheimer type and Pick's disease share a number of important clinical and pathological features with prion diseases, and could be considered as candidate prion diseases. However, we have not been able to demonstrate either PrP mutations or the presence of the disease-associated isoform of prion protein in several well-characterised families with these disorders.

Deletions in the prion protein gene are not associated with CJD.

The human prion diseases (spongiform encephalopathies) Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler syndrome (GSS), are neurodegenerative disorders characterised by the accumulation of an abnormal isoform of the prion protein. The normal prion protein is a phosphatidyl inositol anchored, membrane bound sialoglycoprotein of widespread tissue distribution but expressed predominantly in the brain. 15% of prion diseases are autosomal dominant genetic disorders associated with mutations in the gene encoding the prion protein. To date six pathogenic amino acid substitutions have been identified in affected family members, in addition to five distinct insertional events which occur within a region of the protein comprising four tandem octapeptide repeats. We have investigated deletions within this region and have identified three specific deletions. We report here that these deletions are not associated with CJD and represent a new class of polymorphism within the prion protein gene.