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1.
J Neurosci Res ; 97(12): 1746-1747, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31612587
2.
Arthritis Rheumatol ; 71(6): 964-971, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30614663

RESUMO

OBJECTIVE: To generate a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology. METHODS: An international, multidisciplinary panel of experts was invited to participate in a 3-round Delphi exercise developed using a survey based on items identified by a scoping review. In round 1, participants were asked to identify omissions and clarify ambiguities regarding the items in the survey. In round 2, participants were asked to rate the validity and feasibility of the items using Likert-type scales ranging from 1 to 9 (where 1 = very invalid/unfeasible, 5 = uncertain, and 9 = very valid/feasible). In round 3, participants reviewed the results and comments from round 2 and were asked to provide final ratings. Items rated as highly valid and feasible (median scores ≥7 for each) in round 3 were selected as the provisional core set of items. A consensus meeting using a nominal group technique was conducted to further reduce the core set of items. RESULTS: Ninety-nine experts from 16 countries participated in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13, in the categories hypertension, renal insufficiency, proteinuria, and hemolysis. Eleven experts took part in the nominal group technique discussion, where consensus was achieved in 5 domains: blood pressure, acute kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and renal histopathology. CONCLUSION: A core set of items that characterize SRC was identified using consensus methodology. This core set will be used in future data-driven phases of this project to develop classification criteria for SRC.


Assuntos
Lesão Renal Aguda/classificação , Hipertensão Maligna/classificação , Rim/patologia , Escleroderma Sistêmico/complicações , Lesão Renal Aguda/etiologia , Anemia Hemolítica/classificação , Anemia Hemolítica/etiologia , Pressão Sanguínea , Técnica Delfos , Humanos , Hipertensão/classificação , Hipertensão/etiologia , Hipertensão Maligna/etiologia , Proteinúria/classificação , Proteinúria/etiologia , Índice de Gravidade de Doença
3.
Autoimmun Rev ; 16(4): 407-415, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28212921

RESUMO

OBJECTIVE: The absence of a gold standard for scleroderma renal crisis (SRC) has hindered our understanding of this problem. The objective of this scoping review was to identify the criteria used to define SRC in order to guide the development of a consensus definition for SRC. METHODS: We conducted a search in three databases: Medline, Embase and non-Ovid Pubmed. Papers were eligible for inclusion if they were full-length articles in English whose main topic was SRC or scleroderma renal disease. Two reviewers independently screened eligible papers for final study selection. Data was extracted using a customized form. A web-based survey of members of the Scleroderma Clinical Trials Consortium was used to identify unpublished definitions of SRC. RESULTS: We identified 415 papers that met inclusion criteria. Forty original definitions of SRC were identified from 36 studies, 9 reviews and 2 editorials. There was significant heterogeneity in definitions. As a rule, though, in addition to new-onset hypertension and acute kidney injury, other common items used to define SRC included hypertensive encephalopathy and seizures, microangiopathic hemolytic anemia and characteristic changes on kidney biopsy. The web-based survey identified unpublished definitions of SRC that were largely consistent with the results of the published literature. CONCLUSION: SRC was defined in a minority of studies and criteria were heterogeneous. A consensus definition of SRC is urgently needed to standardize data collection on SRC and further our understanding of this serious problem.


Assuntos
Insuficiência Renal Crônica/etiologia , Escleroderma Sistêmico/complicações , Doenças Autoimunes , Humanos
4.
Clin Exp Rheumatol ; 34 Suppl 100(5): 106-109, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27749244

RESUMO

The UK Scleroderma Study Group developed guidelines on the diagnosis and management of scleroderma renal crisis (SRC) based on best available evidence and clinical experience. SRC is characterised by the acute onset of severe hypertension and acute kidney injury. Current strategies to reduce the associated morbidity and mortality include identifying at risk patients to aid early diagnosis. ACE inhibitor therapy should be lifelong in all patients, regardless of whether they require renal replacement therapy. Patients with SRC may recover renal function up to 3 years after the crisis, most often within 12 to 18 months.


Assuntos
Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/terapia , Hipertensão/diagnóstico , Hipertensão/terapia , Nefrologia/normas , Terapia de Substituição Renal/normas , Reumatologia/normas , Escleroderma Sistêmico/complicações , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/mortalidade , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Antiarrítmicos/administração & dosagem , Anticonvulsivantes/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Consenso , Procedimentos Clínicos/normas , Esquema de Medicação , Medicina Baseada em Evidências/normas , Humanos , Hipertensão/etiologia , Hipertensão/mortalidade , Valor Preditivo dos Testes , Fatores de Risco , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/mortalidade , Escleroderma Sistêmico/terapia , Resultado do Tratamento , Reino Unido
5.
Alzheimers Dement (Amst) ; 2: 39-48, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27239535

RESUMO

The mechanisms underlying Alzheimer's disease (AD) onset and progression are not yet elucidated. The extent to which alterations in the activity of individual neurons of an AD model are significant, and the phase at which they can be captured, point to the intensity of the pathology and imply the stage at which it can be detected. Using a machine-learning algorithm, we present a successful cell-by-cell classification of intracellularly recorded neurons from the B6C3 APPswe/PS1dE9 AD model, versus wildtypes controls, at both a late stage and at an early stage, when the plaque pathology and behavioral deficits are absent or rare. These results suggest that the deficits present in neuronal networks of both old and young transgenic animals are large enough to be apparent at the level of individual neurons, and that the pathology could be detected in nearly any given sample, even before pathologic signs.

6.
Sci Rep ; 6: 24560, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-27079783

RESUMO

Alzheimer's disease (AD) is the most common form of dementia. One of the neuropathological hallmarks of AD is the accumulation of amyloid-ß plaques. Overexpression of human amyloid precursor protein in transgenic mice induces hippocampal and neocortical amyloid-ß accumulation and plaque deposition that increases with age. The impact of these effects on neuronal population responses and network activity in sensory cortex is not well understood. We used Voltage Sensitive Dye Imaging, to investigate at high spatial and temporal resolution, the sensory evoked population responses in the barrel cortex of aged transgenic (Tg) mice and of age-matched non-transgenic littermate controls (Ctrl) mice. We found that a whisker deflection evoked abnormal sensory responses in the barrel cortex of Tg mice. The response amplitude and the spatial spread of the cortical responses were significantly larger in Tg than in Ctrl mice. At the network level, spontaneous activity was less synchronized over cortical space than in Ctrl mice, however synchronization during evoked responses induced by whisker deflection did not differ between the two groups. Thus, the presence of elevated Aß and plaques may alter population responses and disrupts neural synchronization in large-scale networks, leading to abnormalities in sensory processing.


Assuntos
Doença de Alzheimer/fisiopatologia , Modelos Animais de Doenças , Córtex Somatossensorial/fisiopatologia , Animais , Camundongos , Camundongos Transgênicos
7.
Brain Struct Funct ; 221(2): 1173-88, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25523106

RESUMO

UNLABELLED: The effect of Alzheimer's disease pathology on activity of individual neocortical neurons in the intact neural network remains obscure. Ongoing spontaneous activity, which constitutes most of neocortical activity, is the background template on which further evoked-activity is superimposed. We compared in vivo intracellular recordings and local field potentials (LFP) of ongoing activity in the barrel cortex of APP/PS1 transgenic mice and age-matched littermate CONTROLS, following significant amyloid-ß (Aß) accumulation and aggregation. We found that membrane potential dynamics of neurons in Aß-burdened cortex significantly differed from those of nontransgenic CONTROLS: durations of the depolarized state were considerably shorter, and transitions to that state frequently failed. The spiking properties of APP/PS1 neurons showed alterations from those of CONTROLS: both firing patterns and spike shape were changed in the APP/PS1 group. At the population level, LFP recordings indicated reduced coherence within neuronal assemblies of APP/PS1 mice. In addition to the physiological effects, we show that morphology of neurites within the barrel cortex of the APP/PS1 model is altered compared to CONTROLS. These results are consistent with a process where the effect of Aß on spontaneous activity of individual neurons amplifies into a network effect, reducing network integrity and leading to a wide cortical dysfunction.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Córtex Cerebral/patologia , Modelos Animais de Doenças , Masculino , Potenciais da Membrana , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Lobo Parietal/metabolismo , Lobo Parietal/patologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Córtex Somatossensorial
8.
Rheum Dis Clin North Am ; 41(3): 367-82, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26210124

RESUMO

Systemic sclerosis is a multisystem disorder with a high associated mortality. The hallmark abnormalities of the disease are in the immune system, vasculature, and connective tissue. Systemic sclerosis occurs in susceptible individuals and is stimulated by initiating events that are poorly understood at present. In order for the disease phenotype to appear there is dysfunction in the homoeostatic mechanisms of immune tolerance, endothelial physiology, and extracellular matrix turnover. The progression of disease is not sequential but requires simultaneous dysfunction in these normal regulatory mechanisms. Better understanding of the interplay of these factors is likely to contribute to improved treatment options.


Assuntos
Escleroderma Sistêmico/etiologia , Autoanticorpos/imunologia , Quimiocinas/fisiologia , Fator de Crescimento do Tecido Conjuntivo/fisiologia , Citocinas/fisiologia , Progressão da Doença , Sistema Endócrino/fisiologia , Feminino , Fibroblastos/fisiologia , Estudo de Associação Genômica Ampla , Antígenos HLA/imunologia , Humanos , Imunidade Celular/fisiologia , Interleucinas/fisiologia , Neoplasias/complicações , Doença de Raynaud/complicações , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Vasoconstritores/farmacologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-26124707

RESUMO

Realizations of low firing rates in neural networks usually require globally balanced distributions among excitatory and inhibitory links, while feasibility of temporal coding is limited by neuronal millisecond precision. We show that cooperation, governing global network features, emerges through nodal properties, as opposed to link distributions. Using in vitro and in vivo experiments we demonstrate microsecond precision of neuronal response timings under low stimulation frequencies, whereas moderate frequencies result in a chaotic neuronal phase characterized by degraded precision. Above a critical stimulation frequency, which varies among neurons, response failures were found to emerge stochastically such that the neuron functions as a low pass filter, saturating the average inter-spike-interval. This intrinsic neuronal response impedance mechanism leads to cooperation on a network level, such that firing rates are suppressed toward the lowest neuronal critical frequency simultaneously with neuronal microsecond precision. Our findings open up opportunities of controlling global features of network dynamics through few nodes with extreme properties.


Assuntos
Potenciais de Ação/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Neurotransmissores/farmacologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Córtex Cerebral/citologia , Simulação por Computador , Estimulação Elétrica , Modelos Neurológicos , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos
10.
Neuron ; 85(5): 959-66, 2015 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-25704951

RESUMO

Pathological tau leads to dementia and neurodegeneration in tauopathies, including Alzheimer's disease. It has been shown to disrupt cellular and synaptic functions, yet its effects on the function of the intact neocortical network remain unknown. Using in vivo intracellular and extracellular recordings, we measured ongoing activity of neocortical pyramidal cells during various arousal states in the rTg4510 mouse model of tauopathy, prior to significant cell death, when only a fraction of the neurons show pathological tau. In transgenic mice, membrane potential oscillations are slower during slow-wave sleep and under anesthesia. Intracellular recordings revealed that these changes are due to longer Down states and state transitions of membrane potentials. Firing rates of transgenic neurons are reduced, and firing patterns within Up states are altered, with longer latencies and inter-spike intervals. By changing the activity patterns of a subpopulation of affected neurons, pathological tau reduces the activity of the neocortical network.


Assuntos
Potenciais de Ação , Neocórtex/fisiopatologia , Rede Nervosa/fisiopatologia , Tauopatias/fisiopatologia , Proteínas tau/biossíntese , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neocórtex/metabolismo , Rede Nervosa/metabolismo , Tauopatias/metabolismo , Proteínas tau/genética
11.
Kidney Int ; 87(2): 452-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25075771

RESUMO

Recently, intradialytic hypertension was reported to be associated with increased mortality for hemodialysis patients. To determine whether volume status plays a role in dialysis-associated hypertension, we prospectively audited 531 patients that had volume assessments measured by multiple-frequency bioelectrical impedance during their midweek dialysis session. Mean pre- and postdialysis weights were 73.2 vs 71.7 kg, and systolic blood pressures (SBPs) 140.5 vs. 130.3 mm Hg, respectively. Patients were divided into groups based on a fall in SBP of 20 mm Hg or more (32%), an increased SBP of 10 mm Hg or more (18%), and a stable group (50%). There were no differences in patient demographics, dialysis prescriptions, predialysis weight, total body (TBW), and extracellular (ECW) and intracellular water (ICW). However, the change in weight was significantly less in the increased blood pressure group (1.01 kg vs. stable 1.65, and 1.7 hypotensive). The ratio of ECW to TBW was significantly higher in the increased blood pressure group, particularly post dialysis (39.1 vs. stable 38.7% and fall in blood pressure group 38.7%). ECW overhydration was significantly greater in the increased blood pressure group post dialysis (0.7 (0.17 to 1.1) vs. stable 0.39 (-0.2 to 0.95) and fall in blood pressure group 0.38 (-0.19 to 0.86) liter). We found that patients who had increased blood pressure post dialysis had greater hydration status, particularly ECW. Thus, patients who increase their blood pressure post dialysis should have review of target weight, consideration of lowering the post-dialysis weight, and may benefit from increasing dialysis session time or frequency.


Assuntos
Pressão Sanguínea/fisiologia , Água Corporal/fisiologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Diálise Renal/efeitos adversos , Adulto , Idoso , Impedância Elétrica , Espaço Extracelular/fisiologia , Feminino , Humanos , Hipotensão/etiologia , Hipotensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
12.
Brain Struct Funct ; 220(6): 3721-31, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25230822

RESUMO

Periodic synchronization of activity among neuronal pools has been related to substantial neural processes and information throughput in the neocortical network. However, the mechanisms of generating such periodic synchronization among distributed pools of neurons remain unclear. We hypothesize that to a large extent there is interplay between the topology of the neocortical networks and their reverberating modes of activity. The firing synchronization is governed by a nonlocal mechanism, the network delay loops, such that distant neuronal pools without common drives can be synchronized. This theoretical interplay between network topology and the synchronized mode is verified using an iterative procedure of a single intracellularly recorded neuron in vivo, imitating the dynamics of the entire network. The input is injected to the neuron via the recording electrode as current and computed from the filtered, evoked spikes of its pre-synaptic sources, previously emulated by the same neuron. In this manner we approximate subthreshold synaptic inputs from afferent neuronal pools to the neuron. Embedding the activity of these recurrent motifs in the intact brain allows us to measure the effects of connection probability, synaptic strength, and ongoing activity on the neuronal synchrony. Our in vivo experiments indicate that an initial stimulus given to a single pool is dynamically evolving into the formations of zero-lag and cluster synchronization. By applying results from theoretical models and in vitro experiments to in vivo activity in the intact brain, we support the notion that this mechanism may account for the binding activity across distributed brain areas.


Assuntos
Sincronização Cortical , Modelos Neurológicos , Neocórtex/fisiologia , Neurônios/fisiologia , Potenciais de Ação , Animais , Ratos , Ratos Wistar
13.
BMC Nephrol ; 15: 133, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25128003

RESUMO

BACKGROUND: A translational study in renal transplantation suggested YKL-40, a chitinase 3-like-1 gene product, plays an important role in acute kidney injury (AKI) and repair, but data are lacking about this protein in urine from native human kidneys. METHODS: This is an ancillary study to a single-center, prospective observational cohort of patients with clinically-defined AKI according to AKI Network serum creatinine criteria. We determined the association of YKL -40 ≥ 5 ng/ml, alone or combined with neutrophil gelatinase-associated lipocalin (NGAL), in urine collected on the first day of AKI with a clinically important composite outcome (progression to higher AKI stage and/or in-hospital death). RESULTS: YKL-40 was detectable in all 249 patients, but urinary concentrations were considerably lower than in previously measured deceased-donor kidney transplant recipients. Seventy-two patients (29%) progressed or died in-hospital, and YKL-40 ≥ 5 ng/ml had an adjusted odds ratio (95% confidence interval) for the outcome of 3.4 (1.5-7.7). The addition of YKL-40 to a clinical model for predicting the outcome resulted in a continuous net reclassification improvement of 29% (P = 0.04). In patients at high risk for the outcome based on NGAL concentrations in the upper quartile, YKL-40 further partitioned the cohort into moderate-risk and very high-risk groups. CONCLUSIONS: Urine YKL-40 is associated with AKI progression and/or death in hospitalized patients and improves clinically determined risk reclassification. Combining YKL-40 with other AKI biomarkers like NGAL may further delineate progression risk, though additional studies are needed to determine whether YKL-40 has general applicability and to define its association with longer-term outcomes in AKI.


Assuntos
Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/urina , Adipocinas/urina , Progressão da Doença , Hospitalização , Lectinas/urina , Lesão Renal Aguda/mortalidade , Idoso , Biomarcadores/urina , Proteína 1 Semelhante à Quitinase-3 , Estudos de Coortes , Feminino , Hospitalização/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Estudos Prospectivos
14.
Neurobiol Aging ; 35(9): 1982-91, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24792906

RESUMO

The effects of amyloid-ß on the activity and excitability of individual neurons in the early and advanced stages of the pathological progression of Alzheimer's disease remain unknown. We used in vivo intracellular recordings to measure the ongoing and evoked activity of pyramidal neurons in the frontal cortex of APPswe/PS1dE9 transgenic mice and age-matched nontransgenic littermate controls. Evoked excitability was altered in both transgenic groups: neurons in young transgenic mice displayed hypoexcitability, whereas those in older transgenic mice displayed hyperexcitability, suggesting changes in intrinsic electrical properties of the neurons. However, the ongoing activity of neurons in both young and old transgenic groups showed signs of hyperexcitability in the depolarized state of the membrane potential. The membrane potential of neurons in old transgenic mice had an increased tendency to fail to transition to the depolarized state, and the depolarized states had shorter durations on average than did controls. This suggests a combination of both intrinsic electrical and synaptic dysfunctions as mechanisms for activity changes at later stages of the neuropathological progression.


Assuntos
Envelhecimento/fisiologia , Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/fisiologia , Lobo Frontal/citologia , Células Piramidais/fisiologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Progressão da Doença , Potenciais Evocados , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Potenciais da Membrana , Camundongos Transgênicos
15.
J Nanobiotechnology ; 11: 32, 2013 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-24059692

RESUMO

BACKGROUND: Tau dysfunction is believed to be the primary cause of neurodegenerative disorders referred to as tauopathies, including Alzheimer's disease, Pick's disease, frontotemporal dementia and Parkinsonism. The role of microglial cells in the pathogenesis of tauopathies is still unclear. The activation of microglial cells has been correlated with neuroprotective effects through the release of neurotrophic factors and through clearance of cell debris and phagocytosis of cells with intracellular inclusions. In contrast, microglial activation has also been linked with chronic neuroinflammation contributing to the development of neurodegenerative diseases such as tauopathies. Microglial activation has been recently reported to precede tangle formation and the attenuation of tau pathology occurs after immunosuppression of transgenic mice. METHODS: Here we report the specific inhibition of microglial cells in rTg4510 tau-mutant mice by using fibrin γ377-395 peptide conjugated to iron oxide (γ-Fe2O3) nanoparticles of 21 ± 3.5 nm diameter. RESULTS: Stabilization of the peptide by its covalent conjugation to the γ-Fe2O3 nanoparticles significantly decreased the number of the microglial cells compared to the same concentration of the free peptide. The specific microglial inhibition induces different effects on tau pathology in an age dependent manner. The reduction of activation of microglial cells at an early age increases the number of neurons with hyperphosphorylated tau in transgenic mice. In contrast, reduction of activation of microglial cells reduced the severity of the tau pathology in older mice. The number of neurons with hyperphosphorylated tau and the number of neurons with tangles are reduced than those in animals not receiving the fibrin γ377-395 peptide-nanoparticle conjugate. CONCLUSIONS: These results demonstrate a differential effect of microglial activity on tau pathology using the fibrin γ377-395 peptide-nanoparticle conjugate, depending on age and/or stage of the neuropathological accumulation and aggregation.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Compostos Férricos/química , Microglia/efeitos dos fármacos , Nanopartículas/química , Peptídeos/farmacologia , Fatores Etários , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Contagem de Células , Fibrina/química , Humanos , Proteínas Imobilizadas , Injeções Intraventriculares , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Microglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Tamanho da Partícula , Peptídeos/síntese química , Fosforilação/efeitos dos fármacos , Índice de Gravidade de Doença , Fatores de Tempo , Proteínas tau/genética , Proteínas tau/metabolismo
16.
Acta Crystallogr D Biol Crystallogr ; 69(Pt 8): 1463-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23897469

RESUMO

Reported here are measurements of the penetration depth and spatial distribution of photoelectron (PE) damage excited by 18.6 keV X-ray photons in a lysozyme crystal with a vertical submicrometre line-focus beam of 0.7 µm full-width half-maximum (FWHM). The experimental results determined that the penetration depth of PEs is 5 ± 0.5 µm with a monotonically decreasing spatial distribution shape, resulting in mitigation of diffraction signal damage. This does not agree with previous theoretical predication that the mitigation of damage requires a peak of damage outside the focus. A new improved calculation provides some qualitative agreement with the experimental results, but significant errors still remain. The mitigation of radiation damage by line focusing was measured experimentally by comparing the damage in the X-ray-irradiated regions of the submicrometre focus with the large-beam case under conditions of equal exposure and equal volumes of the protein crystal, and a mitigation factor of 4.4 ± 0.4 was determined. The mitigation of radiation damage is caused by spatial separation of the dominant PE radiation-damage component from the crystal region of the line-focus beam that contributes the diffraction signal. The diffraction signal is generated by coherent scattering of incident X-rays (which introduces no damage), while the overwhelming proportion of damage is caused by PE emission as X-ray photons are absorbed.


Assuntos
Cristalografia por Raios X/instrumentação , Cristalografia por Raios X/métodos , Modelos Moleculares , Muramidase/química , Fótons , Conformação Proteica , Raios X
17.
J Neurosci ; 33(2): 473-84, 2013 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-23303928

RESUMO

Information processing in behaving animals has been the target of many studies in the striatum; however, its dynamics and complexity remain to a large extent unknown. Here, we chronically recorded neuronal populations in dorsal striatum as mice were exposed to a novel environment, a paradigm which enables the dissociation of locomotion and environmental recognition. The findings indicate that non-overlapping populations of striatal projection neurons-the medium spiny neurons-reliably encode locomotion and environmental identity, whereas two subpopulations of short-spike interneurons encode distinct information: the fast spiking interneurons preferentially encode locomotion whereas the second type of interneurons preferentially encodes environmental identity. The three neuronal subgroups used cell-type specific coding schemes. This study provides evidence for the existence of parallel processing circuits within the sensorimotor region of the striatum.


Assuntos
Meio Ambiente , Locomoção/fisiologia , Neostriado/fisiologia , /fisiologia , Algoritmos , Animais , Comportamento Animal/fisiologia , Interpretação Estatística de Dados , Eletrodos Implantados , Fenômenos Eletrofisiológicos , Feminino , Interneurônios/fisiologia , Análise dos Mínimos Quadrados , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Neostriado/citologia , Neurônios/classificação , Neurônios/fisiologia , Neurônios/ultraestrutura , Distribuição de Poisson , Máquina de Vetores de Suporte
18.
J Neurosci ; 32(33): 11241-9, 2012 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-22895708

RESUMO

Amyloid-ß plaques are one of the major neuropathological features in Alzheimer's disease (AD). Plaques are found in the extracellular space of telencephalic structures, and have been shown to disrupt neuronal connectivity. Since the disruption of connectivity may underlie a number of the symptoms of AD, understanding the distribution of plaques in the neuropil in relation to the connectivity pattern of the neuronal network is crucial. We measured the distribution and clustering patterns of plaques in the vibrissae-receptive primary sensory cortex (barrel cortex), in which the cortical columnar structure is anatomically demarcated by boundaries in Layer IV. We found that the plaques are not distributed randomly with respect to the barrel structures in Layer IV; rather, they are more concentrated in the septal areas than in the barrels. This difference was not preserved in the supragranular extensions of the functional columns. When comparing the degree of clustering of plaques between primary sensory cortices, we found that the degree of plaques clustering is significantly higher in somatosensory cortex than in visual cortex, and these differences are preserved in Layers II/III. The degree of areal discontinuity is therefore correlated with the patterns of neuropathological deposits. The discontinuous anatomical structure of this area allows us to make predictions about the functional effects of plaques on specific patterns of computational disruption in the AD brain.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Mapeamento Encefálico , Vias Neurais/patologia , Placa Amiloide/metabolismo , Córtex Somatossensorial/metabolismo , Córtex Somatossensorial/patologia , Fatores Etários , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Benzotiazóis , Modelos Animais de Doenças , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Modelos Neurológicos , Mutação/genética , Presenilina-1/genética , Tiazóis
19.
Front Syst Neurosci ; 5: 47, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21720524

RESUMO

Studies of animal models of Huntington's disease (HD) have revealed that neocortical and neostriatal neurons of these animals in vitro exhibit a number of morphological and physiological changes, including increased input resistance and changes in neocortical synaptic inputs. We measured the functional effects of polyglutamate accumulation in neocortical neurons in R6/2 mice (8-14 weeks of age) and their age-matched non-transgenic littermates using in vivo intracellular recordings. All neurons showed spontaneous membrane potential fluctuations. The current/voltage and the firing properties of the HD neocortical neurons were significantly altered, especially in the physiologically relevant current range around and below threshold. As a result, membrane potential transitions from the Down state to Up state were evoked with smaller currents in HD neocortical neurons than in controls. The excitation-to-frequency curves of the HD mice were significantly steeper than those of controls, indicating a smaller input-output dynamic range for these neurons. Increased likelihood of Down to Up state transitions could cause pathological recruitment of corticostriatal assemblies by increasing correlated neuronal activity. We measured coherence of the in vivo intracellular recordings with simultaneously recorded electrocorticograms. We found that the peak of the coherence at <5 Hz was significantly smaller in the HD animals, indicating that the amount of coherence in the state transitions of single neurons is less correlated with global activity than non-transgenic controls. We propose that decreased correlation of neocortical inputs may be a major physiological cause underlying the errors in sensorimotor pattern generation in HD.

20.
Acta Crystallogr D Biol Crystallogr ; 66(Pt 12): 1287-94, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21123868

RESUMO

Recently, strategies to reduce primary radiation damage have been proposed which depend on focusing X-rays to dimensions smaller than the penetration depth of excited photoelectrons. For a line focus as used here the penetration depth is the maximum distance from the irradiated region along the X-ray polarization direction that the photoelectrons penetrate. Reported here are measurements of the penetration depth and distribution of photoelectron damage excited by 18.6 keV photons in a lysozyme crystal. The experimental results showed that the penetration depth of ~17.35 keV photoelectrons is 1.5 ± 0.2 µm, which is well below previous theoretical estimates of 2.8 µm. Such a small penetration depth raises challenging technical issues in mitigating damage by line-focus mini-beams. The optimum requirements to reduce damage in large crystals by a factor of 2.0-2.5 are Gaussian line-focus mini-beams with a root-mean-square width of 0.2 µm and a distance between lines of 2.0 µm. The use of higher energy X-rays (> 26 keV) would help to alleviate some of these requirements by more than doubling the penetration depth. It was found that the X-ray dose has a significant contribution from the crystal's solvent, which initially contained 9.0%(w/v) NaCl. The 15.8 keV photoelectrons of the Cl atoms and their accompanying 2.8 keV local dose from the decay of the resulting excited atoms more than doubles the dose deposited in the X-ray-irradiated region because of the much greater cross-section and higher energy of the excited atom, degrading the mitigation of radiation damage from 2.5 to 2.0. Eliminating heavier atoms from the solvent and data collection far from heavy-atom absorption edges will significantly improve the mitigation of damage by line-focus mini-beams.


Assuntos
Cristalografia por Raios X/métodos , Fótons , Doses de Radiação
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