Efficient cellular and humoral immune response and production of virus-neutralizing antibodies by the Hepatitis B Virus S/preS1 16-42 antigen

Despite the availability of improved antiviral therapies, infection with Hepatitis B virus (HBV) remains a3 significant health issue, as a curable treatment is yet to be discovered. Current HBV vaccines relaying on the efficient expression of the small (S) envelope protein in yeast and the implementation of mass vaccination programs have clearly contributed to containment of the disease. However, the lack of an efficient immune response in up to 10% of vaccinated adults, the controversies regarding the seroprotection persistence in vaccine responders and the emergence of vaccine escape virus mutations urge for the development of better HBV immunogens. Due to the critical role played by the preS1 domain of the large (L) envelope protein in HBV infection and its ability to trigger virus neutralizing antibodies, including this protein in novel vaccine formulations has been considered a promising strategy to overcome the limitations of S only-based vaccines. In this work we aimed to combine relevant L and S epitopes in chimeric antigens, by inserting preS1 sequences within the external antigenic loop of S, followed by production in mammalian cells and detailed analysis of their antigenic and immunogenic properties. Of the newly designed antigens, the S/preS116–42 protein assembled in subviral particles (SVP) showed the highest expression and secretion levels, therefore, it was selected for further studies in vivo. Analysis of the immune response induced in mice vaccinated with S/preS116–42- and S-SVPs, respectively, demonstrated enhanced immunogenicity of the former and its ability to activate both humoral and cellular immune responses. This combined activation resulted in production of neutralizing antibodies against both wild-type and vaccine-escape HBV variants. Our results validate the design of chimeric HBV antigens and promote the novel S/preS1 protein as a potential vaccine candidate for administration in poor-responders to current HBV vaccines.publishedVersio

Efficient cellular and humoral immune response and production of virus-neutralizing antibodies by the Hepatitis B Virus S/preS116-42 antigen

Despite the availability of improved antiviral therapies, infection with Hepatitis B virus (HBV) remains a3 significant health issue, as a curable treatment is yet to be discovered. Current HBV vaccines relaying on the efficient expression of the small (S) envelope protein in yeast and the implementation of mass vaccination programs have clearly contributed to containment of the disease. However, the lack of an efficient immune response in up to 10% of vaccinated adults, the controversies regarding the seroprotection persistence in vaccine responders and the emergence of vaccine escape virus mutations urge for the development of better HBV immunogens. Due to the critical role played by the preS1 domain of the large (L) envelope protein in HBV infection and its ability to trigger virus neutralizing antibodies, including this protein in novel vaccine formulations has been considered a promising strategy to overcome the limitations of S only-based vaccines. In this work we aimed to combine relevant L and S epitopes in chimeric antigens, by inserting preS1 sequences within the external antigenic loop of S, followed by production in mammalian cells and detailed analysis of their antigenic and immunogenic properties. Of the newly designed antigens, the S/preS116–42 protein assembled in subviral particles (SVP) showed the highest expression and secretion levels, therefore, it was selected for further studies in vivo. Analysis of the immune response induced in mice vaccinated with S/preS116–42- and S-SVPs, respectively, demonstrated enhanced immunogenicity of the former and its ability to activate both humoral and cellular immune responses. This combined activation resulted in production of neutralizing antibodies against both wild-type and vaccine-escape HBV variants. Our results validate the design of chimeric HBV antigens and promote the novel S/preS1 protein as a potential vaccine candidate for administration in poor-responders to current HBV vaccines

Exploring the reproducibility of functional connectivity alterations in Parkinson's disease.

Since anatomic MRI is presently not able to directly discern neuronal loss in Parkinson's Disease (PD), studying the associated functional connectivity (FC) changes seems a promising approach toward developing non-invasive and non-radioactive neuroimaging markers for this disease. While several groups have reported such FC changes in PD, there are also significant discrepancies between studies. Investigating the reproducibility of PD-related FC changes on independent datasets is therefore of crucial importance. We acquired resting-state fMRI scans for 43 subjects (27 patients and 16 normal controls, with 2 replicate scans per subject) and compared the observed FC changes with those obtained in two independent datasets, one made available by the PPMI consortium (91 patients, 18 controls) and a second one by the group of Tao Wu (20 patients, 20 controls). Unfortunately, PD-related functional connectivity changes turned out to be non-reproducible across datasets. This could be due to disease heterogeneity, but also to technical differences. To distinguish between the two, we devised a method to directly check for disease heterogeneity using random splits of a single dataset. Since we still observe non-reproducibility in a large fraction of random splits of the same dataset, we conclude that functional heterogeneity may be a dominating factor behind the lack of reproducibility of FC alterations in different rs-fMRI studies of PD. While global PD-related functional connectivity changes were non-reproducible across datasets, we identified a few individual brain region pairs with marginally consistent FC changes across all three datasets. However, training classifiers on each one of the three datasets to discriminate PD scans from controls produced only low accuracies on the remaining two test datasets. Moreover, classifiers trained and tested on random splits of the same dataset (which are technically homogeneous) also had low test accuracies, directly substantiating disease heterogeneity

Correction: Exploring the reproducibility of functional connectivity alterations in Parkinson's disease.

[This corrects the article DOI: 10.1371/journal.pone.0188196.]

MODIFICĂRI ÎN CONECTIVITATEA FUNCȚIONALĂ A STĂRII DE REPAUS ÎNTR-UN STUDIU FOLOSIND STIMULAREA NATURALISTICĂ

Naturalistic stimulation has had increasing influence on cognitive neuroscience in the last decade. Several studies have used naturalistic stimulation to investigate the connectivity dynamics under pathological condition or in healthy children for studying the developing brain. However, little is known about the connectivity changes during watching a movie in healthy, adult population. Our aim is to delineate the potential dynamic connectivity pattern of the healthy, mature brain during naturalistic movie watching compared to complete rest. In an observational case series, eleven healthy adult volunteers with no history of psychiatric or neurological illness underwent two magnetic resonance echo-planar imaging acquisitions. During the first acquisition they were asked to rest with their eyes closed and during the subsequent acquisition they watched a movie clip with slow human body movements. The Independent Component Analysis provided neural components which were further submitted to intra- and inter-network analyses. We found significantly increased intra-network connectivity during movie watching for the extrastriate visual and for the posterior visual networks. The inter-network analysis showed that for the extravisual and primary visual pair, the connectivity was lower during movie watching compared to rest condition. We also found significant uncoupling between the anterior Default Mode Network and the secondary somatosensory network during movie watching. These findings suggest greater visual network segregation during movie watching in order to support processing of complex stimuli. The decoupling of the secondary somatosensory network from the anterior Default Mode Network during movie watching suggest a somatosensory function segregation and its important role in processing information from observing the naturalistic movements of others. Brain imaging measures of major brain networks can contribute to early identification of risk for common psychiatric disorders hence facilitating preventive therapy.     Keywords: naturalistic stimulation , rest, conectivityStimularea naturalistică a avut o influență crescândă asupra neuroștiințelor cognitive în ultimul deceniu. Mai multe studii au folosit stimularea naturalistică pentru a investiga dinamica conectivității în condiții patologice sau la copiii sănătoși pentru studierea creierului în curs de dezvoltare. Cu toate acestea, se știe puțin despre schimbările de conectivitate în timpul vizionării unui film într-o populație adultă sănătoasă. Scopul nostru este de a delimita tiparul potențial de conectivitate dinamică a creierului sănătos și matur în timpul vizionării de filme ȋn mod natural, comparativ cu starea de repaus completă. Într-un studiu observaţional de gen serie de cazuri, unsprezece voluntari adulți sănătoși, fără antecedente de boli psihiatrice sau neurologice, au fost expuşi la două achiziții de imagistică eco-planară prin rezonanță magnetică. În timpul primei achiziții li s-a cerut să stea relaxaţi cu ochii închiși, iar în timpul achiziției ulterioare au urmărit un clip cu mișcări lente ale corpului uman. Analiza componentelor independente a furnizat componente neuronale care au fost ulterior supuse analizelor intra și inter-rețea. Am constatat o creștere semnificativă a conectivității intra-rețea în timpul vizionării filmelor pentru rețelele vizuale extrastriate și pentru rețelele vizuale posterioare. Analiza inter-rețea a arătat că, pentru perechea vizuală extrastriată și primară, conectivitatea a fost mai mică în timpul vizionării filmului comparativ cu starea de repaus. De asemenea, am constatat o decuplare semnificativă între nodul anterior al rețelei Default mode și rețeaua somatosenzorială secundară în timpul vizionării filmului. Aceste descoperiri sugerează o segregare vizuală mai mare a rețelei în timpul vizionării de filme, pentru a sprijini procesarea stimulilor complecşi. Decuplarea rețelei somatosenzoriale secundare de rețeaua Default mode anterioară în timpul vizionării filmului sugerează o segregare a funcției somatosenzoriale și rolul său important în procesarea informațiilor prin observarea mișcărilor naturale ale altor persoane. Investigarea imagistică a rețelelor majore ale creierului poate contribui la identificarea timpurie a riscului dezvoltării de tulburări psihiatrice, facilitând astfel prevenţia.   Cuvinte cheie: stimulare naturalistică, repaus, conectivitat

Diffusion abnormality maps in demyelinating disease: correlations with clinical scores

Background and purpose - Magnetic resonance imaging (MRI) has been explored as a noninvasive tool to assess pathology in multiple sclerosis (MS) patients. However, the correlation between classical MRI measures and physical disability is modest in MS. The diffusion tensor imaging (DTI) MRI technique holds particular promise in this regard. The present study shows brain regions where FA and individual diffusivities abnormalities are present and check their correlations with physical disability clinical scores. Methods - Eight patients and 12 matched healthy controls were recruited. The Multiple Sclerosis Functional Composite was administered. For MR-DTI acquisitions, a Genesis Signa 1.5T MR system, an EP/SE scanning sequence, 25 gradient directions were used. Results - Tract Based Spatial Statistics (TBSS) group comparisons showed reduced FA and increased individual diffusivities in several brain regions in patients. Significant correlations were found between FA and: EDSS, 9-HPT(NON)DOM and 25FW score; between \u3bb2 and: P100 (r&l), 9-HPT(NON)DOM and 25FW; between \u3bb3 and: 9-HPT(NON)DOM and 25FW score. Conclusions - Fractional anisotropy and individual radial diffusivities proved to be important markers of motor disabilities in MS patients when the disease duration mean and the disability scores values range are relatively high.Peer reviewed: YesNRC publication: Ye

Exploring the reproducibility of functional connectivity alterations in Parkinson’s disease

<div><p>Since anatomic MRI is presently not able to directly discern neuronal loss in Parkinson’s Disease (PD), studying the associated functional connectivity (FC) changes seems a promising approach toward developing <i>non-invasive</i> and <i>non-radioactive</i> neuroimaging markers for this disease. While several groups have reported such FC changes in PD, there are also significant discrepancies between studies. Investigating the reproducibility of PD-related FC changes on independent datasets is therefore of crucial importance. We acquired resting-state fMRI scans for 43 subjects (27 patients and 16 normal controls, with 2 replicate scans per subject) and compared the observed FC changes with those obtained in two independent datasets, one made available by the PPMI consortium (91 patients, 18 controls) and a second one by the group of Tao Wu (20 patients, 20 controls). Unfortunately, PD-related functional connectivity changes turned out to be non-reproducible across datasets. This could be due to disease heterogeneity, but also to technical differences. To distinguish between the two, we devised a method to directly check for disease heterogeneity using random splits of a single dataset. Since we still observe <i>non-reproducibility</i> in a large fraction of random splits of the same dataset, we conclude that functional heterogeneity may be a dominating factor behind the lack of reproducibility of FC alterations in different rs-fMRI studies of PD. While <i>global</i> PD-related functional connectivity changes were non-reproducible across datasets, we identified a few <i>individual brain region pairs</i> with marginally consistent FC changes across all three datasets. However, training classifiers on each one of the three datasets to discriminate PD scans from controls produced only low accuracies on the remaining two test datasets. Moreover, classifiers trained and tested on random splits <i>of the same dataset</i> (which are technically homogeneous) also had low test accuracies, directly substantiating disease heterogeneity.</p></div

Average accuracies for classifiers trained on dataset 1 and tested on dataset 2 for all dataset pairs using standard preprocessing (‘standard’), global signal regression (GS) and respectively bandpass filtering (0.01–0.1Hz).

<p>Here, SVM (linear Support Vector Machine) and GNB (Gaussian Naïve Bayes) classifiers used <i>N</i> = 5000 features—see Fig B in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0188196#pone.0188196.s001" target="_blank">S1 File</a> for classifier accuracies for varying <i>N</i>. As an example, NEUROCON-PPMI denotes classifiers trained on NEUROCON and tested on PPMI data.</p

<i>Aggregated</i> average accuracies for classifiers trained on each of the 3 datasets using standard preprocessing (‘standard’), global signal regression (GS) and respectively bandpass filtering (0.01–0.1Hz).

<p>Classifiers were trained with <i>N</i> = 10,50,100,500,5000 features. As an example, NEUROCON(10) refers to the aggregated accuracy (Aacc(NEUROCON-PPMI) + Aacc(NEUROCON-TaoWu))/2 for classifiers trained on NEUROCON and tested on PPMI and respectively TaoWu data using <i>N</i> = 10 features. SVM—linear SVM classifier, GNB—Gaussian Naïve Bayes classifier.</p

Reproducibility measure <i>R</i> and associated <i>p</i>-value <i>p</i> for various pairwise comparisons between datasets with standard highpass preprocessing (‘standard’), global signal regression (GS) and respectively bandpass filter (BP) (‘0’–‘low in scanner motion’, ‘center32’–scans performed at a single PPMI center).

<p>Reproducibility measure <i>R</i> and associated <i>p</i>-value <i>p</i> for various pairwise comparisons between datasets with standard highpass preprocessing (‘standard’), global signal regression (GS) and respectively bandpass filter (BP) (‘0’–‘low in scanner motion’, ‘center32’–scans performed at a single PPMI center).</p