RESUMO
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.
Assuntos
Aniridia/genética , Proteínas de Homeodomínio/genética , Malformações do Sistema Nervoso/genética , Transtornos do Olfato/genética , Telencéfalo/anormalidades , Adulto , Proteínas do Olho , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados , Proteínas RepressorasRESUMO
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.
Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Doença de Alzheimer/tratamento farmacológico , Descoberta de Drogas , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Proteínas tau/metabolismo , Tauopatias/tratamento farmacológicoRESUMO
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.
Assuntos
Doenças do Gato , Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Animais , Gatos , Humanos , Amiloide/análise , Amiloide/química , Amiloide/metabolismo , Doenças do Gato/tratamento farmacológico , Doenças do Gato/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/veterinária , Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/análise , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/química , Ilhotas Pancreáticas/metabolismo , Ureia/análogos & derivados , Ureia/análise , Ureia/farmacologia , Ureia/uso terapêuticoRESUMO
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.
Assuntos
Amiloidose , Proteína Amiloide A Sérica , Animais , Proteína Amiloide A Sérica/química , Proteína Amiloide A Sérica/metabolismo , Furões/metabolismo , Amiloidose/veterinária , Amiloidose/metabolismo , Peptídeos , Aminoácidos , AmiloideRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Compostos Organometálicos , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Amiloide/química , Ilhotas Pancreáticas/metabolismo , Compostos Organometálicos/metabolismoRESUMO
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.
RESUMO
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.
Assuntos
Peixes/crescimento & desenvolvimento , Invertebrados/crescimento & desenvolvimento , Animais , Larva/crescimento & desenvolvimento , Larva/fisiologia , Estágios do Ciclo de Vida , Modelos Biológicos , Oceanos e Mares , Processos Estocásticos , Fatores de TempoRESUMO
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.
Assuntos
Biodiversidade , Conservação dos Recursos Naturais/economia , Conservação dos Recursos Naturais/métodos , Pesqueiros/economia , Oceanos e Mares , Fatores SocioeconômicosRESUMO
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.
Assuntos
Genética Populacional , Dinâmica Populacional , Crescimento Demográfico , Grupos de População Animal/genética , Animais , Feminino , Masculino , Modelos Biológicos , Característica Quantitativa Herdável , Reprodução , Ovinos/genética , Ovinos/crescimento & desenvolvimentoRESUMO
OBJECTIVE: To determine whether proton magnetic resonance spectroscopy (MRS) demonstrates central nervous system abnormalities in asymptomatic HIV-1-infected individuals. DESIGN: Both prospective and retrospective cross-sectional analyses of MRS in asymptomatic HIV-infected individuals. SETTING: Two specialists HIV/AIDS outpatient facilities in London. PARTICIPANTS: Eighty-four HIV-1 seropositive asymptomatic men; 29 HIV-1 antibody-negative homosexual men at high-risk for HIV infection and 48 HIV-1 antibody-negative men at low-risk for HIV infection as controls. MAIN OUTCOME MEASURES: Single voxel, gradient-localized proton MRS performed at 1.5 T with 135 msec echo-time and 1,600 msec repeat-time in an 8 ml volume of interest positioned in the parieto-occipital white matter. Spectroscopic results were expressed as ratios between the areas under the N-acetyl (NA), creatine (Cr) and choline (Cho) resonance peaks. RESULTS: There were no differences between those controls at high and those at low-risk for HIV infection. Comparing the combined control groups with the asymptomatic seropositive patients there were statistically significant differences in NA/Cho, NA/Cr (both P < 0.05) and NA/(NA + Cho + Cr) (P < 0.01). CONCLUSION: Abnormalities in cerebral biochemistry may be demonstrated by proton MRS during asymptomatic HIV-1 infection.
Assuntos
Encéfalo/patologia , Soropositividade para HIV/patologia , HIV-1 , Contagem de Linfócito CD4 , Soronegatividade para HIV , Soropositividade para HIV/tratamento farmacológico , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Zidovudina/uso terapêuticoRESUMO
OBJECTIVE: To quantify the extent of hypothalamic damage after surgery for craniopharyngioma using magnetic resonance imaging (MRI) and to relate the findings to changes in body mass index (BMI). PATIENTS: Sixty-three survivors (36 males, 27 females) of childhood cramopharyngioma were treated surgically between 1973 and early 1994. METHODS: Cranial MRI was performed at a structured follow-up assessment 1.5-19.2 yr after the initial surgery. Hypothalamic damage was scored as 0 (no visible damage), 1 (intermediate), or 2 (severe). RESULTS: After surgery there was an increase in BMI standard deviation (SD) from diagnosis to study assessment in all but 7 patients. However, patients with MRI scores of 2 (n = 17) had a significantly greater increase in median BMI SD score at follow-up (+5.5 SD score), compared with +2.5 SD score and +1.1 SD score for patients with MRI scores of 1 or 0, respectively. Of the 17 cases with MRI scores of 2, 10 had a history of extreme weight loss or weight gain at presentation; preoperative neuroimaging demonstrated extensive hypothalamic infiltration by tumor in these cases. CONCLUSION: MRI gives sufficient anatomical definition to allow assessment of the extent of hypothalamic damage and, thereby, prediction of the patients most at risk for severe post-operative weight gain.
Assuntos
Craniofaringioma/cirurgia , Doenças Hipotalâmicas/diagnóstico , Imageamento por Ressonância Magnética , Obesidade/etiologia , Neoplasias Hipofisárias/cirurgia , Complicações Pós-Operatórias , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Doenças Hipotalâmicas/etiologia , Lactente , Masculino , Fatores de RiscoRESUMO
The clinical and angiographic correlations of small deep infarcts seen on computed tomography (CT) scan were studied in 297 consecutive patients. Some of these showed the features described by Fisher as part of the lacunar syndrome. In a large number, a source of emboli from either a cardiac or a carotid source was highly probable; in a smaller number, other vascular diseases were present. The finding of a small deep infarct on CT does not exclude the need for further investigation of a possible embolic source in selected patients.
Assuntos
Infarto Cerebral/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Idoso , Angiografia Cerebral , Infarto Cerebral/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Three patients presenting with visual failure had MRIs with hypersignal extending from the region of the optic chiasm along both optic tracts in 2 cases, and along 1 optic tract in the 3rd. In all patients intrinsic tumor of the chiasm was the most likely diagnosis based on MRI appearances, but all 3 had craniopharyngioma.
Assuntos
Craniofaringioma/patologia , Glioma/patologia , Imageamento por Ressonância Magnética , Neoplasias Hipofisárias/patologia , Vias Visuais/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quiasma Óptico/patologiaRESUMO
We performed brain MRIs on 21 patients with CNS sarcoidosis. Brain CTs were performed in 18 of these. Parenchymal lesions were seen in 17 of 21 with MRI, compared with 9 of 18 with CT. MRI detected a greater number of parenchymal lesions in cases where both CT and MRI were positive, and some lesions appeared more extensive with MRI than with CT. The most common MRI pattern was one of periventricular and multifocal white matter lesions (14 cases). Such a pattern is not specific, and other recognized causes for it were identified in four cases. It is likely, however, that sarcoid tissue causes this pattern in some cases, and confirmation was obtained from cerebral biopsy in one. In six patients, the white matter changes were indistinguishable from those seen in multiple sclerosis. Contrast-enhanced CT in two patients showed diffuse meningeal involvement not seen with MRI. MRI is the investigation of choice in detecting parenchymal changes in the brain of patients with CNS sarcoidosis and may prove useful in monitoring treatment in such cases.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico , Imageamento por Ressonância Magnética , Sarcoidose/diagnóstico , Adolescente , Adulto , Idoso , Encéfalo/patologia , Doenças do Sistema Nervoso Central/diagnóstico por imagem , Doenças do Sistema Nervoso Central/patologia , Feminino , Humanos , Hipertensão/diagnóstico , Masculino , Meninges/patologia , Pessoa de Meia-Idade , Nervo Óptico/patologia , Sarcoidose/diagnóstico por imagem , Sarcoidose/patologia , Medula Espinal/patologia , Tomografia Computadorizada por Raios XRESUMO
We performed MRI of brain and spinal cord on 80 patients with multiple sclerosis (MS). Using multi-array coils and fast spin echo, 139 intrinsic lesions were identified in 59 patients (74%). Lesions were more common in the cervical than in the thoracic cord. Cross-sectional areas of the cord, measured from axial images at four levels, showed atrophy in 40%. Clinical disability correlated with cord atrophy but not with cord lesion load. These results show that the use of multi-array coils and fast spin echo allows rapid and sensitive detection of spinal cord lesions in MS and that the cord is involved in the majority of patients. A lack of association between cord lesions and disability may relate to limitations in MR resolution but also suggests that the mechanisms of disability in MS are complex and multifactorial.
Assuntos
Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico , Medula Espinal/patologia , Adulto , Encéfalo/patologia , Humanos , Esclerose Múltipla/classificação , Pescoço , Recidiva , TóraxRESUMO
We describe a case of Behçet's disease with a slowly enlarging midbrain mass on magnetic resonance imaging, which resolved after 4 months of oral steroids.
Assuntos
Síndrome de Behçet/diagnóstico , Encéfalo/patologia , Imageamento por Ressonância Magnética , Síndrome de Behçet/complicações , Síndrome de Behçet/tratamento farmacológico , Criança , Feminino , Humanos , Doenças do Sistema Nervoso/etiologia , Esteroides/uso terapêutico , Uveíte/complicações , Uveíte/tratamento farmacológicoRESUMO
It is time-consuming to detect intrinsic spinal cord lesions in multiple sclerosis (MS) by MRI using conventional surface coils and T2-weighted spin-echo pulse sequences. Multi-array coils and fast spin-echo pulse sequences permit the generation of high-resolution T2-weighted sagittal images of the whole spinal cord in about 5 minutes. Using these advances, we found an area of high signal within the cord in only 1/45 (2%) healthy subjects aged 18 to 72 years, whereas 26% of those who underwent brain imaging had cerebral white matter abnormalities. Degenerative vertebral column changes, especially in the cervical region, were present in 64% and were associated with cord compression in 11%. Cord cross-sectional areas in mm2, measured from axial gradient-echo images, were usually highly reproducible and showed a significant correlation with the subject's height. We conclude that (1) MRI signal abnormalities within the spinal cord may be more specific for MS than cerebral white matter lesions, especially in subjects over 50 years old; (2) asymptomatic degenerative changes in the vertebral column are common, even in younger adults; (3) measurement of cord cross-sectional area should allow accurate quantitation of the degree of atrophy in MS and other spinal cord diseases; and (4) multi-array coils and fast spin echo represent an important advance in MRI of the spinal cord.
Assuntos
Imageamento por Ressonância Magnética/métodos , Medula Espinal/anatomia & histologia , Adolescente , Adulto , Idoso , Encéfalo/anatomia & histologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Valores de ReferênciaRESUMO
We performed 15 dynamic gadolinium-DTPA (Gd-DTPA)-enhanced MRI studies in 8 patients with relapsing and remitting multiple sclerosis; 7 were follow-up studies. We measured the time course of enhancement in 102 enhancing lesions for up to 384 minutes, with rest breaks. Immediate postcontrast MRIs demonstrated many different patterns of enhancement. We observed both uniformly enhancing and ring enhancing lesions. The enhancing regions were often less extensive than the corresponding high signal on T2-weighted images. Three lesions were seen with Gd-DTPA but not on unenhanced scans; 1 was seen on unenhanced scans 10 days later, suggesting that blood-brain barrier disturbance may precede other MRI signs of MS lesions. Three months later, some high-signal areas on T2-weighted scans had decreased in size to resemble the areas previously outlined by Gd-DTPA. This technique provides useful information about the pathogenesis and behavior of MS lesions.
Assuntos
Barreira Hematoencefálica , Meios de Contraste , Gadolínio , Imageamento por Ressonância Magnética , Esclerose Múltipla/patologia , Compostos Organometálicos , Ácido Pentético , Adolescente , Adulto , Meios de Contraste/farmacocinética , Feminino , Gadolínio/farmacocinética , Gadolínio DTPA , Humanos , Aumento da Imagem , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/metabolismo , Compostos Organometálicos/farmacocinética , Ácido Pentético/farmacocinéticaRESUMO
Magnetic resonance imaging (MRI) of the optic nerves using the STIR (short inversion time inversion recovery) sequence was performed in 37 adult patients with a recent or past attack of optic neuritis. MRI revealed high-signal regions in 84% of symptomatic and 20% of asymptomatic nerves. The mean longitudinal extent of lesions was 1 cm. Slow or poor visual recovery was associated with more extensive lesions, or lesions within the optic canal. Disk swelling was usually associated with anterior lesions but also occurred with lesions in the canal. Visual evoked potentials were even more sensitive than MRI in detecting lesions and are still the investigation of choice in suspected demyelinating disease involving the optic nerve.
Assuntos
Imageamento por Ressonância Magnética , Nervo Óptico/patologia , Neurite Óptica/diagnóstico , Adulto , Feminino , Humanos , MasculinoRESUMO
Gadolinium (Gd)-DTPA enhanced magnetic resonance imaging (MRI) was performed in 15 systemic lupus erythematosus patients with past (12) or present (3) features suggesting central nervous system (CNS) involvement. Symptomatic Gd-DTPA enhancing lesions were seen in 2 patients, and immunosuppressive treatment was associated with a rapid reversal of enhancement. The pattern of enhancement was different from that usually seen in multiple sclerosis. Gd-DTPA enhanced MRI may sometimes be useful in demonstrating the activity of CNS lupus.