Polychlorinated trityl radicals for dynamic nuclear polarization: the role of chlorine nuclei

Polychlorinated trityl radicals bearing carboxylate substituents are water soluble persistent radicals that can be used for dynamic nuclear polarization. In contrast to other trityl radicals, the polarization mechanism differs from the classical solid effect. DFT calculations performed to rationalize this behaviour support the hypothesis that polarization is transferred from the unpaired electron to chlorine nuclei and from these to carbon by spin diffusion. The marked differences observed between neutral and anionic forms of the radical will be discussed.

Long-lived States in an intrinsically disordered protein domain

Long-lived states (LLS) are relaxation-favoured eigenstates of J-coupled magnetic nuclei. LLS were measured, along with classical 1H and 15 N relaxation rate constants, in aminoacids of the N-terminal Unique domain of the c-Src kinase (USrc), which is disordered in vitro under physiological conditions. The relaxation rates of LLS are a probe for motions and interactions in biomolecules. LLS of the aliphatic protons of glycines, with lifetimes ca. four times longer than their spin-lattice relaxation times, are reported for the first time in an intrinsically disordered protein domain (IDP). LLS relaxation experiments were integrated with 2D spectroscopy methods, further adapting them for studies on proteins.

Neutralizing antibodies in Multiple Sclerosis a model-based analysis of Interferon beta signaling pathway in macrophages

Multiple Sclerosis is the most common non-traumatic cause of neurologicaldisability in young people. There is no cure yet, and until recently, few long-termtherapies existed. Interferon beta (IFNβ) was the first treatment, and remains the mostcommonly prescribed. One of the most significant problems of IFNβ therapy is theproduction of drug specific antibodies. Up to 45% of patients develop neutralizingantibodies (NAbs) to IFNβ products. The neutralizing antibody binds to the biologicalagent preventing its interaction with its receptor, inhibiting the biological action of theprotein, which abrogates the clinical efficacy of IFNβ treatment. Interferon-betamediates its response by binding to its high affinity cell surface receptor and initiatingthe JAK/STAT signalling cascade. In this project we have analyzed the IFNβ signalingpathway in macrophages when neutralizing antibodies are present. The response tothis pathway after IFNβ stimulation shows a transient oscillatory rhythm of STAT1phosphorylation, which varies as NAbs concentration increases. To improve ourunderstanding of that behavior, we extended an existing mathematical model based onnonlinear ordinary differential equations of JAK/STAT pathway by including IFN-NAbassociation and IFN-activation receptor. Combining our theoretical model withexperimental data we could study the role of neutralizing antibodies on the molecularresponse and determine its lifetime after cytokine stimulation.

Meta-structure correlation in protein space unveils different selection rules for folded and intrinsically disordered proteins

The number of existing protein sequences spans a very small fraction of sequence space. Natural proteins have overcome a strong negative selective pressure to avoid the formation of insoluble aggregates. Stably folded globular proteins and intrinsically disordered proteins (IDP) use alternative solutions to the aggregation problem. While in globular proteins folding minimizes the access to aggregation prone regions IDPs on average display large exposed contact areas. Here, we introduce the concept of average meta-structure correlation map to analyze sequence space. Using this novel conceptual view we show that representative ensembles of folded and ID proteins show distinct characteristics and responds differently to sequence randomization. By studying the way evolutionary constraints act on IDPs to disable a negative function (aggregation) we might gain insight into the mechanisms by which function - enabling information is encoded in IDPs.

The psychosocial difficulties in brain disorders that explain short term changes in health outcomes.

BACKGROUND: This study identifies a set of psychosocial difficulties that are associated with short term changes in health outcomes across a heterogeneous set of brain disorders, neurological and psychiatric. METHODS: Longitudinal observational study over approximately 12 weeks with three time points of assessment and 741 patients with depression, bipolar disorders, multiple sclerosis, parkinson's disease, migraine, traumatic brain injury and stroke. The data on disability was collected with the checklist of the International Classification of Functioning, Disability and Health. The selected health outcomes were the Short Form 36 and the World Health Organization Disability Assessment Schedule. Multilevel models for change were applied controlling for age, gender and disease severity. RESULTS: The psychosocial difficulties that explain the variability and change over time of the selected health outcomes were energy and drive, sleep, and emotional functions, and a broad range of activities and participation domains, such as solving problems, conversation, areas of mobility and self-care, relationships, community life and recreation and leisure. CONCLUSIONS: Our findings are of interest to researchers and clinicians for interventions and health systems planning as they show that in addition to difficulties that are diagnostic criteria of these disorders, there are other difficulties that explain small changes in health outcomes over short periods of time.

Cardiac motion estimation by joint alignment of tagged MRI sequences

Image registration has been proposed as an automatic method for recovering cardiac displacement fields from Tagged Magnetic Resonance Imaging (tMRI) sequences. Initially performed as a set of pairwise registrations, these techniques have evolved to the use of 3D+t deformation models, requiring metrics of joint image alignment (JA). However, only linear combinations of cost functions defined with respect to the first frame have been used. In this paper, we have applied k-Nearest Neighbors Graphs (kNNG) estimators of the -entropy (H ) to measure the joint similarity between frames, and to combine the information provided by different cardiac views in an unified metric. Experiments performed on six subjects showed a significantly higher accuracy (p < 0.05) with respect to a standard pairwise alignment (PA) approach in terms of mean positional error and variance with respect to manually placed landmarks. The developed method was used to study strains in patients with myocardial infarction, showing a consistency between strain, infarction location, and coronary occlusion. This paper also presentsan interesting clinical application of graph-based metric estimators, showing their value for solving practical problems found in medical imaging.

Natalizumab versus Interferon B-1b to prevent CDMS in patients with CIS and poor prognostic factors: research protocol

About 85% of multiple sclerosis (MS) cases start as clinically isolated syndrome (CIS).When patients present with a CIS, clinicians face with many questions, most of themrelated with prognosis and treatment. Thereby, patients with CIS have been focus ofresearch. Several studies have demonstrated a relationship between positive IgM lipidspecific oligoclonal band pattern in CSF and higher lesion load on MRI brain scan, higher number of relapses and greater disability, even at the first stages of the disease. On the other hand, no studies have used this previous evidence to treat with more aggressive disease modifying therapy in initial stages of disease course to prevent the earlier axonal damage. The aim of this study is to assess the most effective approved treatment for MS and current therapy for CIS patients presenting high risk to develop CDMS and with biomarkers of poor prognosis. Among this group of patients any disease activity will eventually lead to disability. Therefore, the earlier the treatment is initiated, the more effective to prevent disability will be. It is considered that “time lost is brain lost” and since once damage is established, there is no therapy to be regained later on. In this phase III clinical trial, 172 patients will be randomized 1:1 to receive Interferon β-1b or natalizumab over 96 weeks. Time to develop clinical definitive multiple sclerosis (CDMS) will be included as primary endpoint. Other secondary endpoints will include clinical data, magnetic resonance imaging (MRI) measurements and quality of life tests

Natalizumab versus Interferon B-1b to prevent CDMS in patients with CIS and poor prognostic factors: research protocol

About 85% of multiple sclerosis (MS) cases start as clinically isolated syndrome (CIS).When patients present with a CIS, clinicians face with many questions, most of themrelated with prognosis and treatment. Thereby, patients with CIS have been focus ofresearch. Several studies have demonstrated a relationship between positive IgM lipidspecific oligoclonal band pattern in CSF and higher lesion load on MRI brain scan, higher number of relapses and greater disability, even at the first stages of the disease. On the other hand, no studies have used this previous evidence to treat with more aggressive disease modifying therapy in initial stages of disease course to prevent the earlier axonal damage. The aim of this study is to assess the most effective approved treatment for MS and current therapy for CIS patients presenting high risk to develop CDMS and with biomarkers of poor prognosis. Among this group of patients any disease activity will eventually lead to disability. Therefore, the earlier the treatment is initiated, the more effective to prevent disability will be. It is considered that “time lost is brain lost” and since once damage is established, there is no therapy to be regained later on. In this phase III clinical trial, 172 patients will be randomized 1:1 to receive Interferon β-1b or natalizumab over 96 weeks. Time to develop clinical definitive multiple sclerosis (CDMS) will be included as primary endpoint. Other secondary endpoints will include clinical data, magnetic resonance imaging (MRI) measurements and quality of life tests

Brain functional abnormality in schizo-affective disorder: an fMRI study.

Background.Schizo-affective disorder has not been studied to any significant extent using functional imaging. The aim of this study was to examine patterns of brain activation and deactivation in patients meeting strict diagnostic criteria for the disorder. METHOD: Thirty-two patients meeting research diagnostic criteria (RDC) for schizo-affective disorder (16 schizomanic and 16 schizodepressive) and 32 matched healthy controls underwent functional magnetic resonance imaging (fMRI) during performance of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups. RESULTS: Controls showed activation in a network of frontal and other areas and also deactivation in the medial frontal cortex, the precuneus and the parietal cortex. Schizo-affective patients activated significantly less in prefrontal, parietal and temporal regions than the controls, and also showed failure of deactivation in the medial frontal cortex. When task performance was controlled for, the reduced activation in the dorsolateral prefrontal cortex (DLPFC) and the failure of deactivation of the medial frontal cortex remained significant. CONCLUSIONS: Schizo-affective disorder shows a similar pattern of reduced frontal activation to schizophrenia. The disorder is also characterized by failure of deactivation suggestive of default mode network dysfunction.

Brain functional abnormality in schizo-affective disorder: an fMRI study.

Background.Schizo-affective disorder has not been studied to any significant extent using functional imaging. The aim of this study was to examine patterns of brain activation and deactivation in patients meeting strict diagnostic criteria for the disorder. METHOD: Thirty-two patients meeting research diagnostic criteria (RDC) for schizo-affective disorder (16 schizomanic and 16 schizodepressive) and 32 matched healthy controls underwent functional magnetic resonance imaging (fMRI) during performance of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups. RESULTS: Controls showed activation in a network of frontal and other areas and also deactivation in the medial frontal cortex, the precuneus and the parietal cortex. Schizo-affective patients activated significantly less in prefrontal, parietal and temporal regions than the controls, and also showed failure of deactivation in the medial frontal cortex. When task performance was controlled for, the reduced activation in the dorsolateral prefrontal cortex (DLPFC) and the failure of deactivation of the medial frontal cortex remained significant. CONCLUSIONS: Schizo-affective disorder shows a similar pattern of reduced frontal activation to schizophrenia. The disorder is also characterized by failure of deactivation suggestive of default mode network dysfunction.

Brain functional abnormality in schizo-affective disorder: an fMRI study.

Background.Schizo-affective disorder has not been studied to any significant extent using functional imaging. The aim of this study was to examine patterns of brain activation and deactivation in patients meeting strict diagnostic criteria for the disorder. METHOD: Thirty-two patients meeting research diagnostic criteria (RDC) for schizo-affective disorder (16 schizomanic and 16 schizodepressive) and 32 matched healthy controls underwent functional magnetic resonance imaging (fMRI) during performance of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups. RESULTS: Controls showed activation in a network of frontal and other areas and also deactivation in the medial frontal cortex, the precuneus and the parietal cortex. Schizo-affective patients activated significantly less in prefrontal, parietal and temporal regions than the controls, and also showed failure of deactivation in the medial frontal cortex. When task performance was controlled for, the reduced activation in the dorsolateral prefrontal cortex (DLPFC) and the failure of deactivation of the medial frontal cortex remained significant. CONCLUSIONS: Schizo-affective disorder shows a similar pattern of reduced frontal activation to schizophrenia. The disorder is also characterized by failure of deactivation suggestive of default mode network dysfunction.

Functional connectivity of reward processing in the brain

Controversial results have been reported concerning the neural mechanisms involved in the processing of rewards and punishments. On the one hand, there is evidence suggesting that monetary gains and losses activate a similar fronto-subcortical network. On the other hand, results of recent studies imply that reward and punishment may engage distinct neural mechanisms. Using functional magnetic resonance imaging (fMRI) we investigated both regional and interregional functional connectivity patterns while participants performed a gambling task featuring unexpectedly high monetary gains and losses. Classical univariate statistical analysis showed that monetary gains and losses activated a similar fronto-striatallimbic network, in which main activation peaks were observed bilaterally in the ventral striatum. Functional connectivity analysis showed similar responses for gain and loss conditions in the insular cortex, the amygdala, and the hippocampus that correlated with the activity observed in the seed region ventral striatum, with the connectivity to the amygdala appearing more pronounced after losses. Larger functional connectivity was found to the medial orbitofrontal cortex for negative outcomes. The fact that different functional patterns were obtained with both analyses suggests that the brain activations observed in the classical univariate approach identifi es the involvement of different functional networks in the current task. These results stress the importance of studying functional connectivity in addition to standard fMRI analysis in reward-related studies.

Structural changes induced by daily music listening in the recovering brain after middle cerebral artery stroke: a voxel-based morphometry study

Music is a highly complex and versatile stimulus for the brain that engages many temporal, frontal, parietal, cerebellar, and subcortical areas involved in auditory, cognitive, emotional, and motor processing. Regular musical activities have been shown to effectively enhance the structure and function of many brain areas, making music a potential tool also in neurological rehabilitation. In our previous randomized controlled study, we found that listening to music on a daily basis can improve cognitive recovery and improve mood after an acute middle cerebral artery stroke. Extending this study, a voxel-based morphometry (VBM) analysis utilizing cost function masking was performed on the acute and 6-month post-stroke stage structural magnetic resonance imaging data of the patients (n = 49) who either listened to their favorite music [music group (MG), n = 16] or verbal material [audio book group (ABG), n = 18] or did not receive any listening material [control group (CG), n = 15] during the 6-month recovery period. Although all groups showed significant gray matter volume (GMV) increases from the acute to the 6-month stage, there was a specific network of frontal areas [left and right superior frontal gyrus (SFG), right medial SFG] and limbic areas [left ventral/subgenual anterior cingulate cortex (SACC) and right ventral striatum (VS)] in patients with left hemisphere damage in which the GMV increases were larger in the MG than in the ABG and in the CG. Moreover, the GM reorganization in the frontal areas correlated with enhanced recovery of verbal memory, focused attention, and language skills, whereas the GM reorganization in the SACC correlated with reduced negative mood. This study adds on previous results, showing that music listening after stroke not only enhances behavioral recovery, but also induces fine-grained neuroanatomical changes in the recovering brain.

Caracterização morfoanatômica do melão gália no ponto de colheita

O objetivo deste trabalho foi caracterizar morfoanatomicamente o melão 'Gália', com ênfase no exocarpo e mesocarpo, no ponto de colheita. Os frutos foram obtidos em propriedade comercial localizada no município de Mossoró-RN, aos 65 dias de cultivo após a semeadura. Em laboratório, realizou-se a caracterização morfológica através da determinação da massa, espessura da polpa, comprimento longitudinal e transversal, relação de formato e índice de rendilhamento. Análises em tomografia de ressonância magnética nuclear foram realizadas para a determinação da integridade dos tecidos. As análises anatômicas foram realizadas utilizando-se de microscopia de luz e eletrônica de varredura. O melão Gália, híbrido 'Solar King', foi caracterizado como fruto do tipo baga, de formato esférico, com massa média de 1.021 g. As imagens sugerem que, na região do mesocarpo, o metabolismo acentuado e o amadurecimento mais avançado nos tecidos do centro do fruto podem ser responsáveis pelo descolamento da placenta e o amaciamento mais rápido dos tecidos em volta da cavidade interna. As áreas rendilhadas, juntamente com as ceras epicuticulares e a estrutura adensada das primeiras camadas subepidérmicas podem contribuir para o controle da perda de umidade do fruto e a resistência às injúrias mecânicas.

Injúrias mecânicas e seus efeitos na qualidade de mamões golden

O objetivo do trabalho foi identificar as injúrias mecânicas que ocorrem em mamões 'Golden' e avaliar seus efeitos na qualidade dos frutos armazenados a 22ºC e 85% UR durante 10 dias. As injúrias identificadas como abrasão, corte e amassado foram reproduzidas nos frutos. As abrasões foram provocadas com lixa grão 200, numa área de 6cm². Os cortes foram realizados com incisões de 30 mm de comprimento e 5 mm de profundidade. O amassado foi provocado pelo impacto dos frutos, que foram deixados cair de uma altura de 2 m. Cada fruto recebeu 2 injúrias em lados opostos, na região de maior diâmetro. Mamões intactos foram utilizados como controle. A região danificada pela abrasão não desenvolveu cor amarelo-alaranjada; ocorreu escurecimento da casca, comprovado pelos menores valores de luminosidade e cromaticidade. Abrasão e impacto levaram a maior redução da firmeza da polpa e perda de massa. Imagens de ressonância magnética revelaram que frutos danificados pelas injúrias perderam sua integridade, o que foi identificado por áreas claras devido à presença de água livre. A qualidade de mamões 'Golden' é prejudicada por injúrias mecânicas, principalmente pelo impacto pela abrasão.