Investigation of serum amyloid a within animal species focusing on the 1-25 amino acid region.

AA amyloidosis, characterized by the misfolding of serum amyloid A (SAA) protein, is the most common amyloid protein disorder across multiple species. SAA is a positive-acute phase protein synthesized by the liver in response to inflammation or stress, and it normally associates with high-density lipoprotein at its N-terminus. In this study, we focused on the 1-25 amino acid (aa) region of the complete 104 aa SAA sequence to examine the aggregation propensity of AA amyloid. A library comprising eight peptides from different species was assembled for analysis. To access the aggregation propensity of each peptide region, a bioinformatic study was conducted using the algorithm TANGO. Congo red (CR) binding assays, Thioflavin T (ThT) assays, and transmission electron microscopy (TEM) were utilized to evaluate whether the synthesized peptides formed amyloid-like fibrils. All synthetic SAA 1-25 congeners resulted in amyloid-like fibrils formation (per CR and/or ThT staining and TEM detection) at the exception of the ferret SAA1-25 fragment, which generated plaque-like materials by TEM. Ten residues were preserved among SAA 1-25 congeners resulting in amyloid-like fibrils, i.e. F6, E9, A10, G13, D16, M17, A20, Y21, D23, and M24. Amino acid residues highlighted by this study may have a role in increasing the propensity for amyloid-like fibril formation. This study put an emphasis on region 1-25 in the mechanism of SAA1 misfolding.

Diabetes mellitus drug discovery: insights into targeting feline and human amylin with small molecules.

BACKGROUND: Type 2 diabetes (T2D) is a health concern for both humans and cats, with cases rising over the past decade. Around 70% of patients from either species exhibit pancreatic aggregates of islet amyloid polypeptide (IAPP), a protein that proves toxic upon misfolding. These misfolded protein aggregates congregate in the islets of Langerhans of the pancreas, diminishing the capability of ß-cells to produce insulin and further perpetuating disease. OBJECTIVE: Our team's drug discovery program is investigating newly synthesized compounds that could diminish aggregates of both human and feline IAPP, potentially disrupting the progression of T2D. MATERIAL AND METHODS: We prepared 24 compounds derived from diaryl urea, as ureas have previously demonstrated great potential at reducing accumulations of misfolded proteins. Biophysical methods were employed to analyze the anti-aggregation activity of these compounds at inhibiting and/or disrupting IAPP fibril formation in vitro. RESULTS: The results demonstrate that compounds 12 and 24 were most effective at reducing the fibrillization and aggregation of both human and feline IAPP. When compared with the control for each experiment, samples treated with either compound 12 or 24 exhibited fewer accumulations of amyloid-like fibrils. CONCLUSION: Urea-based compounds, such as compounds 12 and 24, may prove crucial in future pre-clinical studies in the search for therapeutics for T2D.

Hyperphosphorylated tau (p-tau) and drug discovery in the context of Alzheimer's disease and related tauopathies.

Alzheimer's disease (AD) is the most common form of dementia, characterized by intracellular neurofibrillary tangles (NFTs) and extracellular ß-amyloid (ßA) plaques. No disease-modifying therapy is currently available to prevent the progression of, or cure, the disease. Misfolded hyperphosphorylated tau (p-tau) is considered a pivotal point in the pathogenesis of AD and other tauopathies. Compelling evidence suggests that it is a key driver of the accumulation of NFTs and can be directly correlated with the extent of dementia in patients with AD. Therefore, inhibiting tau hyperphosphorylation-induced aggregation could be a viable strategy to discover and develop therapeutics for patients with AD.

Recent Advances in the Discovery of Therapeutics to Curtail Islet Amyloid Polypeptide Aggregation for Type 2 Diabetes Treatment.

In humans with type 2 diabetes, at least 70% of patients exhibit islet amyloid plaques formed by misfolding islet amyloid polypeptides (IAPP). The oligomeric conformation and accumulation of the IAPP plaques lead to a panoply of cytotoxic effects on the islet ß-cells. Currently, no marketed therapies for the prevention or elimination of these amyloid deposits exist, and therefore significant efforts are required to address this gap. To date, most of the experimental treatments are limited to only in vitro stages of testing. In general, the proposed therapeutics use various targeting strategies, such as binding to the N-terminal region of islet amyloid polypeptide on residues 1-19 or the hydrophobic region of IAPP. Other strategies include targeting the peptide self-assembly through π-stacking. These methods are realized by using several different families of compounds, four of which are highlighted in this review: naturally occurring products, small molecules, organometallic compounds, and nanoparticles. Each of these categories holds immense potential to optimize and develop inhibitor(s) of pancreatic amyloidosis in the near future.

Revisiting misfolding propensity of serum amyloid A1: Special focus on the signal peptide region.

AA amyloidosis is the result of overproduction and aberrant processing of acute-phase serum amyloid A1 (SAA1) by hepatocytes. Proteolytic cleavage of SAA1 is believed to play a central role in AA amyloid formation. The SAA1 protein undergoes a cleavage of 18 residues consisting of the signal peptide at the N-terminal region. To better understand the mechanism behind systemic amyloidosis in the SAA1 protein, we studied the misfolding propensity of the signal peptide region. We first examined the signal peptide amino acid SAA derived from different animal species. A library of 16 peptides was designed to evaluate the propensity of aggregation. The amyloidogenic potential of each SAA1 signal peptide homolog was assessed using in silico Tango program, thioflavin T (ThT) fluorescence, transmission electron microscopy (TEM), and seeding with misfolded human SAA1 signal peptide. After 7 days of incubation, most of the SAA1 signal peptide fragments had the propensity to form fibrils at a concentration of 100 µM in 50 mM Tris buffer at 37 °C by TEM. All peptides were able to generate fibrils at a higher concentration, i.e 500 µM in 25 mM Tris buffer with 50% HFIP, by ThT. All SAA1 signal synthetic peptides designed from the different animal species had the propensity to misfold and form fibrils, particularly in species with low occurrence of systemic amyloidosis. The human SAA1 signal peptide region was capable to seed the SAA1 1-25 and 32-47 peptide regions. Characterizing fibrillar conformations are relevant for seeding intact and/or fragmented SAA, which may contribute, to the mechanism of protein misfolding. This research signifies the importance of the signal peptide region and its possible contribution to the misfolding of aggregation-prone proteins.

The stochastic nature of larval connectivity among nearshore marine populations.

Many nearshore fish and invertebrate populations are overexploited even when apparently coherent management structures are in place. One potential cause of mismanagement may be a poor understanding and accounting of stochasticity, particularly for stock recruitment. Many of the fishes and invertebrates that comprise nearshore fisheries are relatively sedentary as adults but have an obligate larval pelagic stage that is dispersed by ocean currents. Here, we demonstrate that larval connectivity is inherently an intermittent and heterogeneous process on annual time scales. This stochasticity arises from the advection of pelagic larvae by chaotic coastal circulations. This result departs from typical assumptions where larvae simply diffuse from one site to another or where complex connectivity patterns are created by transport within spatially complicated environments. We derive a statistical model for the expected variability in larval settlement patterns and demonstrate how larval connectivity varies as a function of different biological and physical processes. The stochastic nature of larval connectivity creates an unavoidable uncertainty in the assessment of fish recruitment and the resulting forecasts of sustainable yields.

Striking a balance between biodiversity conservation and socioeconomic viability in the design of marine protected areas.

The establishment of marine protected areas is often viewed as a conflict between conservation and fishing. We considered consumptive and nonconsumptive interests of multiple stakeholders (i.e., fishers, scuba divers, conservationists, managers, scientists) in the systematic design of a network of marine protected areas along California's central coast in the context of the Marine Life Protection Act Initiative. With advice from managers, administrators, and scientists, a representative group of stakeholders defined biodiversity conservation and socioeconomic goals that accommodated social needs and conserved marine ecosystems, consistent with legal requirements. To satisfy biodiversity goals, we targeted 11 marine habitats across 5 depth zones, areas of high species diversity, and areas containing species of special status. We minimized adverse socioeconomic impacts by minimizing negative effects on fishers. We included fine-scale fishing data from the recreational and commercial fishing sectors across 24 fisheries. Protected areas designed with consideration of commercial and recreational fisheries reduced potential impact to the fisheries approximately 21% more than protected areas designed without consideration of fishing effort and resulted in a small increase in the total area protected (approximately 3.4%). We incorporated confidential fishing data without revealing the identity of specific fisheries or individual fishing grounds. We sited a portion of the protected areas near land parks, marine laboratories, and scientific monitoring sites to address nonconsumptive socioeconomic goals. Our results show that a stakeholder-driven design process can use systematic conservation-planning methods to successfully produce options for network design that satisfy multiple conservation and socioeconomic objectives. Marine protected areas that incorporate multiple stakeholder interests without compromising biodiversity conservation goals are more likely to protect marine ecosystems.

Estimating individual contributions to population growth: evolutionary fitness in ecological time.

Ecological and evolutionary change is generated by variation in individual performance. Biologists have consequently long been interested in decomposing change measured at the population level into contributions from individuals, the traits they express and the alleles they carry. We present a novel method of estimating individual contributions to population growth and changes in distributions of quantitative traits and alleles. An individual's contribution to population growth is an individual's realized annual fitness. We demonstrate how the quantities we develop can be used to address a range of empirical questions, and provide an application to a detailed dataset of Soay sheep. The approach provides results that are consistent with those obtained using lifetime estimates of individual performance, yet is substantially more powerful as it allows lifetime performance to be decomposed into annual survival and fecundity contributions.

Retrograde amnesia and the volume of critical brain structures.

There are many controversies concerning the structural basis of retrograde amnesia (RA). One view is that memories are held briefly within a medial temporal store ("hippocampal complex") before being "consolidated" or reorganised within temporal neocortex and/or networks more widely distributed within the cerebral cortex. An alternative view is that the medial temporal lobes are always involved in the storage and retrieval (reactivation) of autobiographical memories (multiple trace theory). The present study used quantitative magnetic resonance imaging (MRI) in 40 patients with focal pathology/volume loss in different sites, to examine the correlates of impairment on three different measures of RA. The findings supported the view that widespread neural networks are involved in the storage and retrieval of autobiographical and other remote memories. Brain volume measures in critical structures could account for 60% of variance on autobiographical memory measures (for incidents and facts) in diencephalic patients and for 60-68% of variance in patients with frontal lesions. Significant correlations with medial temporal lobe volume were found only in the diencephalic group, in whom they were thought to reflect thalamic changes, but not in patients with herpes encephalitis or hypoxia in whom the temporal lobes were particularly implicated. The latter finding fails to support one of the main predictions of multiple trace theory, as presently expounded.

Single-species models for many-species food webs.

Most species live in species-rich food webs; yet, for a century, most mathematical models for population dynamics have included only one or two species. We ask whether such models are relevant to the real world. Two-species population models of an interacting consumer and resource collapse to one-species dynamics when recruitment to the resource population is unrelated to resource abundance, thereby weakening the coupling between consumer and resource. We predict that, in nature, generalist consumers that feed on many species should similarly show one-species dynamics. We test this prediction using cyclic populations, in which it is easier to infer underlying mechanisms, and which are widespread in nature. Here we show that one-species cycles can be distinguished from consumer resource cycles by their periods. We then analyse a large number of time series from cyclic populations in nature and show that almost all cycling, generalist consumers examined have periods that are consistent with one-species dynamics. Thus generalist consumers indeed behave as if they were one-species populations, and a one-species model is a valid representation for generalist population dynamics in many-species food webs.

Cerebellar volumes in newly diagnosed and chronic epilepsy.

Cerebellar atrophy is assumed to be a common finding in patients suffering from epilepsy. Anticonvulsants as well as seizure activity itself have been considered to be responsible for it but many studies have addressed these questions in specialised centres for epilepsy thus having a referral bias towards patients with severe epileptic syndromes. The purpose of this study was: 1. To develop a quantitative method on 3D-MRI data to achieve volume or planimetric measurements (of cerebrum, cerebellum and cerebellar substructures). 2. To investigate the prevalence of cerebellar atrophy (and substructure atrophy) in a prospectively investigated population-based cohort of patients with newly diagnosed and chronic epilepsy. 3. To quantify cerebellar atrophy in clinic-based patients, who had had atrophy previously diagnosed on routine visual MRI assessment. 4. To correlate the measures of atrophy with clinical features in both patient groups. A total of 57 patients with either newly diagnosed or chronic active epilepsy and 36 control subjects were investigated with a newly developed semiautomated method for cerebral as well as cerebellar volume measurements and substructure planimetry, corrected for intracranial volume. We did not find any significant atrophy in the population-based cohort of patients with newly diagnosed epilepsy or with chronic epilepsy. Visually diagnosed cerebellar atrophy was mostly confirmed and quantified by volumetric analysis. The clinical data suggested a correlation between cerebellar atrophy and the duration of the seizure disorder and also the total number of lifetime seizures experienced and the frequency of generalised tonic-clonic seizures per year. Volumetry on 3D-MRI yields reliable quantitative data which shows that cerebellar atrophy might be common in severe and/or longstanding epilepsy but not necessarily in unselected patient groups. The results do not support the proposition that cerebellar atrophy is a predisposing factor for epilepsy but rather are consistent with the view that cerebellar atrophy is the aftermath of epileptic seizures or anticonvulsant medication.

Habitat structure and population persistence in an experimental community.

Understanding spatial population dynamics is fundamental for many questions in ecology and conservation. Many theoretical mechanisms have been proposed whereby spatial structure can promote population persistence, in particular for exploiter-victim systems (host-parasite/pathogen, predator-prey) whose interactions are inherently oscillatory and therefore prone to extinction of local populations. Experiments have confirmed that spatial structure can extend persistence, but it has rarely been possible to identify the specific mechanisms involved. Here we use a model-based approach to identify the effects of spatial population processes in experimental systems of bean plants (Phaseolus lunatus), herbivorous mites (Tetranychus urticae) and predatory mites (Phytoseiulus persimilis). On isolated plants, and in a spatially undivided experimental system of 90 plants, prey and predator populations collapsed; however, introducing habitat structure allowed long-term persistence. Using mechanistic models, we determine that spatial population structure did not contribute to persistence, and spatially explicit models are not needed. Rather, habitat structure reduced the success of predators at locating prey outbreaks, allowing between-plant asynchrony of local population cycles due to random colonization events.

PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans.

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies.

Generalised cerebral atrophy following temporal lobectomy for intractable epilepsy associated with mesial temporal sclerosis.

Studies of post-operative imaging data have mainly concentrated on brain atrophy following radiotherapy and/or chemotherapy. We have investigated the effect of conventional surgery on the unresected brain tissue based on the comparison of magnetic resonance images acquired pre- and post-operatively in 13 subjects with a history of mesio-temporal epilepsy. The pre- and post-operative scans were co-registered prior to volumetric analysis. The total brain volume (TBV) was calculated by semi-automated segmentation, and the total volume loss was the difference between the post-operative and pre-operative TBV. The total volume of resection was determined by manual delineation in the post-operative scan. The atrophy volume in the post-operative scan was calculated as the difference between the total volume loss and the resection volume. In 6 cases, there was generalised cerebral atrophy of the order 4-5% of the total brain volume. In addition to the automated volumetric technique, the images were assessed by two expert neuroradiologists. There was complete correspondence between their assessment and the automated technique. The causes and significance of this phenomenon are unknown but it requires further investigation as it may be related to seizure control and neuropsychological changes following epilepsy surgery.

Supratentorial cavernous haemangiomas and epilepsy: a review of the literature and case series.

OBJECTIVES: To characterise the clinical features and response to treatment of supratentorial cavernomas associated with epilepsy. METHODS: A systematic review of the literature was carried out and a retrospective case series of patients with cavernoma diagnosed by MRI and/or histology was compiled. Patient selection biases in the literature review were reduced as far as possible by selection of unbiased publications. RESULTS: In the literature, cavernomas were relatively less common in the frontal lobes. There were multiple cavernomas in 23% of cases. The main clinical manifestations were seizures (79%) and haemorrhage (16%). The annual haemorrhage rate was 0.7%. The outcome after excision was good with improvement in seizures in 92% of patients. In the case series the surgical outcome was less favourable, reflecting inclusion of a higher proportion of patients with intractable epilepsy. In both the literature review and the case series, outcome was poorer in cases with a longer duration of seizures at the time of surgery. CONCLUSIONS: The good surgical results, particularly in cases treated earlier, and the significant cumulative haemorrhage rate, suggest that excision is the optimum treatment. However, these factors have not been examined prospectively and, despite the availability of several retrospective studies, the optimum treatment, particularly for non-intractable cases, will only be determined by a prospective study.

Cognitive deficits associated with frontal-lobe infarction in children with sickle cell disease.

This study examined the cognitive manifestations of frontal-lobe infarction in a population of children with sickle cell disease (SCD). Forty-one patients with SCD underwent MRI. Five patients with stroke symptoms had large infarcts encroaching on the tissue of the frontal lobes. Four patients without symptoms had smaller frontal-lobe infarcts. The patients with stroke were significantly impaired on measures of intelligence, memory, and frontal-lobe function (Wisconsin Card Sorting Test, WCST) compared with both the patients with normal MRI scans (N=30) and a group of sibling controls (N=15), who did not differ from each other. Patients with covert infarction obtained scores on the intelligence tests and the WCST that fell in between those of the stroke patients and the other two groups. This trend toward impairment suggests that patients with covert infarction are at similar risk for cognitive deficits to those with stroke.

Evidence of CNS impairment in HIV infection: clinical, neuropsychological, EEG, and MRI/MRS study.

OBJECTIVES: To identify by clinical examination, EEG, MRI, and proton spectroscopy, and neuropsychological assessment the prevalence of signs of CNS involvement in patients infected with HIV, and to relate such findings to the evidence of immunosuppression. METHODS: The design was a cross sectional analysis of a cohort of male patients with infected HIV with an AIDS defining diagnosis or low CD4 count (<350), and seropositive asymptomatic subjects, both groups being followed up in a longitudinal study. Control groups consisted of seronegative subjects from the same genitourinary medicine clinics. RESULTS: This report sets out the cross sectional findings at the seventh visit in the longitudinal study. Patients with AIDS had more signs of neurological dysfunction, poorer performance on a neuropsychological test battery, were more likely to have an abnormal EEG, and to have abnormalities on MRI. They more often had cerebral atrophy, abnormal appearing white matter, and abnormal relaxometry and spectroscopy. There was little evidence of abnormality in seropositive people who had a CD4 count >350 compared with seronegative people from a similar background. CONCLUSIONS: Detailed testing failed to disclose significant CNS impairment without immunosuppression in men infected with HIV. Findings from MRI and magnetic resonance spectroscopy (MRS) correlated with those of the neurological examination and neuropsychological assessment. A combination of such assessments offers a simple surrogate for studies of CNS involvement in HIV disease.

Spatial structure, environmental heterogeneity, and population dynamics: analysis of the coupled logistic map.

Spatial extent can have two important consequences for population dynamics: It can generate spatial structure, in which individuals interact more intensely with neighbors than with more distant conspecifics, and it allows for environmental heterogeneity, in which habitat quality varies spatially. Studies of these features are difficult to interpret because the models are complex and sometimes idiosyncratic. Here we analyze one of the simplest possible spatial population models, to understand the mathematical basis for the observed patterns: two patches coupled by dispersal, with dynamics in each patch governed by the logistic map. With suitable choices of parameters, this model can represent spatial structure, environmental heterogeneity, or both in combination. We synthesize previous work and new analyses on this model, with two goals: to provide a comprehensive baseline to aid our understanding of more complex spatial models, and to generate predictions about the effects of spatial structure and environmental heterogeneity on population dynamics. Spatial structure alone can generate positive, negative, or zero spatial correlations between patches when dispersal rates are high, medium, or low relative to the complexity of the local dynamics. It can also lead to quasiperiodicity and hyperchaos, which are not present in the nonspatial model. With density-independent dispersal, spatial structure cannot destabilize equilibria or periodic orbits that would be stable in the absence of space. When densities in the two patches are uncorrelated, the probability that the population in a patch reaches extreme low densities is reduced relative to the same patch in isolation; this "rescue effect" would reduce the probability of metapopulation extinction beyond the simple effect of spreading of risk. Pure environmental heterogeneity always produces positive spatial correlations. The dynamics of the entire population is approximated by a nonspatial model with mean patch characteristics. This approximation worsens as the difference between the patches increases and the dispersal rate decreases: Under extreme conditions, destabilization of equilibria and periodic orbits occurs at mean parameter values lower than those predicted by the mean parameters. Apparent within-patch dynamics are distorted: The local population appears to have the wrong growth parameter and a constant number of immigrants (or emigrants) per generation. Adding environmental heterogeneity to spatial structure increases the occurrence of spatially correlated population dynamics, but the resulting temporal dynamics are more complex than would be predicted by the mean parameter values. The three classes of spatial pattern (positive, negative, and zero correlation), while still mathematically distinct, become increasingly similar phenomenologically.

Central motor conduction time in progressive multiple sclerosis. Correlations with MRI and disease activity.

The purpose of this study was to relate abnormalities of motor conduction time to the presence of spinal cord MRI lesions in progressive multiple sclerosis and to investigate the relationship between changes in motor conduction over time and clinical and MRI changes. Central motor conduction time (CMCT), serial MRI of the brain and spinal cord, and clinical evaluations were carried out in 20 patients with primary and secondary progressive multiple sclerosis. CMCT was carried out at the beginning and end of the study whilst the clinical and MRI examinations occurred at monthly intervals for 12 months. Median CMCT to abductor pollicis brevis was 14.8 ms (range 8.8-27.4 ms). The response latency to tibialis anterior correlated with disability measured on the Expanded Disability Status Scale. Latencies to upper limb muscles correlated with cervical MRI lesion load and the presence of atrophy of the cervical cord. Over the 12-month study period, 15 of 19 patients deteriorated clinically. However, an increase in motor response latencies occurred only in the four patients who had developed new cord lesions. The results suggest that prolonged CMCT is related to spinal cord lesion load and that, over time, changes in the CMCT occur only when spinal cord lesion load increases. Clinical change in progressive multiple sclerosis may therefore occur without either the development of new lesions on MRI scans or an increase in motor conduction time. This suggests that clinical deterioration in these patients may occur by a mechanism other than increasing demyelination. This may be progressive axonal degeneration.

The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A 10-year follow-up.

A definitive diagnosis of multiple sclerosis cannot be made at presentation on patients with a clinically isolated syndrome of the optic nerve, spinal cord or brainstem suggestive of demyelination, as dissemination in time is not established. To determine the long-term risk of abnormalities on brain MRI for the development of multiple sclerosis and disability we performed a 10-year follow-up on 81 such patients who had T2-weighted brain MRI at presentation. Initial brain MRI was abnormal in 54 (67%). Follow up of those patients with an abnormal MRI revealed progression to clinically definite multiple sclerosis in 45 out of 54 (83%), of whom 11 (20%) had relapsing/remitting disease (EDSS > 3), 13 (24%) secondary progressive and 21 (39%) benign (relapsing/remitting with EDSS < or = 3) disease. For those with a normal MRI progression to clinically definite multiple sclerosis occurred in only three out of 27 (11%), all benign. There was a significant relationship between the number of lesions at presentation and both EDSS (r = 0.45, P < 0.001) and the type of disease at follow-up (P < 0.0001). Brain MRI at presentation with a clinically isolated syndrome is predictive of the long-term risk of subsequent development of multiple sclerosis, the type of disease and extent of disability.