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Sihvonen A.J.,University of Turku | Sihvonen A.J.,University of HelsinkiHelsinki | Ripolles P.,Lhospitalet Of Llobregat | Ripolles P.,University of Barcelona | And 5 more authors.
Journal of Neuroscience | Year: 2016

Although acquired amusia is a relatively common disorder after stroke, its precise neuroanatomical basis is still unknown. To evaluate which brain regions form the neural substrate for acquired amusia and its recovery, we performed a voxel-based lesion-symptom mapping (VLSM) and morphometry (VBM) study with 77 human stroke subjects. Structural MRIs were acquired at acute and 6 month poststroke stages. Amusia and aphasia were behaviorally assessed at acute and 3 month poststroke stages using the Scale and Rhythm subtests of the Montreal Battery of Evaluation of Amusia (MBEA) and language tests. VLSM analyses indicated that amusia was associated with a lesion area comprising the superior temporal gyrus, Heschl’s gyrus, insula, and striatum in the right hemisphere, clearly different from the lesion pattern associated with aphasia. Parametric analyses of MBEA Pitch and Rhythm scores showed extensive lesion overlap in the right striatum, as well as in the right Heschl’s gyrus and superior temporal gyrus. Lesions associated with Rhythm scores extended more superiorly and posterolaterally. VBM analysis of volume changes from the acute to the 6 month stage showed a clear decrease in gray matter volume in the right superior and middle temporal gyri in nonrecovered amusic patients compared with nona-music patients. This increased atrophy was more evident in anterior temporal areas in rhythm amusia and in posterior temporal and temporoparietal areas in pitch amusia. Overall, the results implicate right temporal and subcortical regions as the crucial neural substrate for acquired amusia and highlight the importance of different temporal lobe regions for the recovery of amusia after stroke. © 2016 the authors.


Shahbazi M.-A.,University of HelsinkiHelsinki | Makila E.,University of Turku | Shrestha N.,University of HelsinkiHelsinki | Salonen J.,University of Turku | And 2 more authors.
Chemistry of Materials | Year: 2015

Interfacial polymerization of uniform template-free nanostructures is very challenging since many factors play determinant roles in the final structure of the resulting nanoassemblies. Here, we present a single oxidative coupling method for the synthesis of different nanoshapes by addition or substitution of a methyl group on aniline monomers to freely alter the mechanism of monomer-to-polymer conversion. Well-defined nanotubes, nanohollows, and solid nanospheres are obtained from aniline, N-methylaniline, and 2-methylaniline polymerizations, respectively. We found that the extent of hydrophobicity and protonation under mild acidic conditions determines the monomers' arrangement in micelle or droplet form, reactivity, and nucleation mechanism. These can subsequently affect the final morphology through a fusion process to form tubular structures, external flux of monomers to form nanohollows, and intradroplet oxidation to form solid nanospheres. Altered biological responses, such as cytocompatibility, redox response, hemocompatibility, and cell proliferation, are also found to be dependent on the position of the methyl group in the nanostructures. © 2015 American Chemical Society.


PubMed | Aalto UniversityHelsinki, University of Valencia, University of HelsinkiHelsinki and University of Helsinki
Type: | Journal: Frontiers in cellular neuroscience | Year: 2016

Neuronal plasticity peaks during critical periods of postnatal development and is reduced towards adulthood. Recent data suggests that windows of juvenile-like plasticity can be triggered in the adult brain by antidepressant drugs such as Fluoxetine. Although the exact mechanisms of how Fluoxetine promotes such plasticity remains unknown, several studies indicate that inhibitory circuits play an important role. The polysialylated form of the neural cell adhesion molecules (PSA-NCAM) has been suggested to mediate the effects of Fluoxetine and it is expressed in the adult brain by mature interneurons. Moreover, the enzymatic removal of PSA by neuroaminidase-N not only affects the structure of interneurons but also has been shown to play a role in the onset of critical periods during development. We have here used ocular dominance plasticity in the mouse visual cortex as a model to investigate whether removal of PSA might influence the Fluoxetine-induced plasticity. We demonstrate that PSA removal in the adult visual cortex alters neither the baseline ocular dominance, nor the fluoxetine-induced shift in the ocular dominance. We also show that both chronic Fluoxetine treatment and PSA removal independently increase the basal FosB expression in parvalbumin (PV) interneurons in the primary visual cortex. Therefore, our data suggest that although PSA-NCAM regulates inhibitory circuitry, it is not required for the reactivation of juvenile-like plasticity triggered by Fluoxetine.


Hepojoki S.,University of HelsinkiHelsinki | Rusanen J.,University of HelsinkiHelsinki | Hepojoki J.,University of HelsinkiHelsinki | Nurmi V.,University of HelsinkiHelsinki | And 7 more authors.
Journal of Clinical Microbiology | Year: 2015

In this study, we describe a competitive homogeneous immunoassay that makes use of Förster resonance energy transfer (FRET) in rapid detection of pathogen-specific antibodies. The assay principle is based on competition between a monoclonal antibody (MAb) and serum antibodies to a given antigen. In the assay, named competitive FRET immunoassay (CFRET-IA), the FRET signal is induced if MAb carrying a donor label binds to an acceptor-labeled antigen. Specific antibodies in serum compete for antigen binding, resulting in reduced FRET signal. The proof-of-principle for the assay was obtained using donor-labeled Puumala virus nucleocapsid protein (PUUV-N) and acceptor-labeled anti-PUUV-N MAb. The assay was evaluated by analyzing 329 clinical samples comprising 101 from individuals with acute PUUV infection, 42 from individuals with past infection, and 186 from individuals with PUUV-seronegative sera, and the results were compared to those of reference tests. The rapid serodiagnostic test we introduced herein performed with 100% sensitivity and 99% specificity for diagnosing acute hantavirus disease. Copyright © 2015, American Society for Microbiology. All Rights Reserved.


PubMed | University of HelsinkiHelsinki and University of Helsinki
Type: | Journal: Frontiers in human neuroscience | Year: 2016

We report a randomized controlled clinical trial of neurofeedback therapy intervention for ADHD/ADD in adults. We focus on internal mechanics of neurofeedback learning, to elucidate the primary role of cortical self-regulation in neurofeedback. We report initial results; more extensive analysis will follow.Trial has two phases: intervention and follow-up. The intervention consisted of neurofeedback treatment, including intake and outtake measurements, using a waiting-list control group. Treatment involved ~40 h-long sessions 2-5 times per week. Training involved either theta/beta or sensorimotor-rhythm regimes, adapted by adding a novel inverse-training condition to promote self-regulation. Follow-up (ongoing) will consist of self-report and executive function tests.Intake and outtake measurements were conducted at University of Helsinki. Treatment was administered at partner clinic Mental Capital Care, Helsinki.We randomly allocated half the sample then adaptively allocated the remainder to minimize baseline differences in prognostic variables.Waiting-list control design meant trial was not blinded.Fifty-four adult Finnish participants (mean age 36 years; 29 females) were recruited after screening by psychiatric review. Forty-four had ADHD diagnoses, 10 had ADD.Symptoms were assessed by computerized attention test (T.O.V.A.) and self-report scales, at intake and outtake. Performance during neurofeedback trials was recorded.PARTICIPANTS were recruited and completed intake measurements during summer 2012, before assignment to treatment and control, September 2012. Outtake measurements ran April-August 2013. After dropouts, 23 treatment and 21 waiting-list participants remained for analysis. Initial analysis showed that, compared to waiting-list control, neurofeedback promoted improvement of self-reported ADHD symptoms, but did not show transfer of learning to T.O.V.A. Comprehensive analysis will be reported elsewhere.Computer Enabled Neuroplasticity Treatment (CENT), ISRCTN13915109.


PubMed | Wageningen University, University of HelsinkiHelsinki and University of Helsinki
Type: | Journal: Frontiers in microbiology | Year: 2016

Akkermansia muciniphila is a common member of the human gut microbiota and belongs to the Planctomycetes-Verrucomicrobia-Chlamydiae superphylum. Decreased levels of A. muciniphila have been associated with many diseases, and thus it is considered to be a beneficial resident of the intestinal mucus layer. Surface-exposed molecules produced by this organism likely play important roles in colonization and communication with other microbes and the host, but the protein composition of the outer membrane (OM) has not been characterized thus far. Herein we set out to identify and characterize A. muciniphila proteins using an integrated approach of proteomics and computational analysis. Sarkosyl extraction and sucrose density-gradient centrifugation methods were used to enrich and fractionate the OM proteome of A. muciniphila. Proteins from these fractions were identified by LC-MS/MS and candidates for OM proteins derived from the experimental approach were subjected to computational screening to verify their location in the cell. In total we identified 79 putative OM and membrane-associated extracellular proteins, and 23 of those were found to differ in abundance between cells of A. muciniphila grown on the natural substrate, mucin, and those grown on the non-mucus sugar, glucose. The identified OM proteins included highly abundant proteins involved in secretion and transport, as well as proteins predicted to take part in formation of the pili-like structures observed in A. muciniphila. The most abundant OM protein was a 95-kD protein, termed PilQ, annotated as a type IV pili secretin and predicted to be involved in the production of pili in A. muciniphila. To verify its location we purified the His-Tag labeled N-terminal domain of PilQ and generated rabbit polyclonal antibodies. Immunoelectron microscopy of thin sections immunolabeled with these antibodies demonstrated the OM localization of PilQ, testifying for its predicted function as a type IV pili secretin in A. muciniphila. As pili structures are known to be involved in the modulation of host immune responses, this provides support for the involvement of OM proteins in the host interaction of A. muciniphila. In conclusion, the characterization of A. muciniphila OM proteome provides valuable information that can be used for further functional and immunological studies.


PubMed | University of HelsinkiHelsinki, University of Helsinki and Aalto University
Type: | Journal: Frontiers in cellular neuroscience | Year: 2016

Kainate type of glutamate receptors (KARs) are highly expressed during early brain development and may influence refinement of the circuitry, via modulating synaptic transmission and plasticity. KARs are also localized to axons, however, their exact roles in regulating presynaptic processes remain controversial. Here, we have used a microfluidic chamber system allowing specific manipulation of KARs in presynaptic neurons to study their functions in synaptic development and function in vitro. Silencing expression of endogenous KARs resulted in lower density of synaptophysin immunopositive puncta in microfluidically isolated axons. Various recombinant KAR subunits and pharmacological compounds were used to dissect the mechanisms behind this effect. The calcium permeable (Q) variants of the low-affinity (GluK1-3) subunits robustly increased synaptophysin puncta in axons in a manner that was dependent on receptor activity and PKA and PKC dependent signaling. Further, an associated increase in the mean active zone length was observed in electron micrographs. Selective presynaptic expression of these subunits resulted in higher success rate of evoked EPSCs consistent with higher probability of glutamate release. In contrast, the calcium-impermeable (R) variant of GluK1 or the high-affinity subunits (GluK4,5) had no effect on synaptic density or transmission efficacy. These data suggest that calcium permeable axonal KARs promote efferent connectivity by increasing the density of functional presynaptic release sites.


Shcherbakova D.M.,Yeshiva University | Baloban M.,Yeshiva University | Pletnev S.,Leidos Inc. | Malashkevich V.N.,Yeshiva University | And 4 more authors.
Chemistry and Biology | Year: 2015

Summary Near-infrared fluorescent proteins (NIR FPs) engineered from bacterial phytochromes (BphPs) are the probes of choice for deep-tissue imaging. Detection of several processes requires spectrally distinct NIR FPs. We developed an NIR FP, BphP1-FP, which has the most blue-shifted spectra and the highest fluorescence quantum yield among BphP-derived FPs. We found that these properties result from the binding of the biliverdin chromophore to a cysteine residue in the GAF domain, unlike natural BphPs and other BphP-based FPs. To elucidate the molecular basis of the spectral shift, we applied biochemical, structural and mass spectrometry analyses and revealed the formation of unique chromophore species. Mutagenesis of NIR FPs of different origins indicated that the mechanism of the spectral shift is general and can be used to design multicolor NIR FPs from other BphPs. We applied pairs of spectrally distinct point cysteine mutants to multicolor cell labeling and demonstrated that they perform well in model deep-tissue imaging. © 2015 Elsevier Ltd.


Szwajda A.,University of HelsinkiHelsinki | Gautam P.,University of HelsinkiHelsinki | Karhinen L.,University of HelsinkiHelsinki | Jha S.K.,University of HelsinkiHelsinki | And 7 more authors.
Chemistry and Biology | Year: 2015

Summary Chemical perturbation screens offer the possibility to identify actionable sets of cancer-specific vulnerabilities. However, most inhibitors of kinases or other cancer targets result in polypharmacological effects, which complicate the identification of target dependencies directly from the drug-response phenotypes. In this study, we developed a chemical systems biology approach that integrates comprehensive drug sensitivity and selectivity profiling to provide functional insights into both single and multi-target oncogenic signal addictions. When applied to 21 breast cancer cell lines, perturbed with 40 kinase inhibitors, the subtype-specific addiction patterns clustered in agreement with patient-derived subtypes, while showing considerable variability between the heterogeneous breast cancers. Experimental validation of the top predictions revealed a number of co-dependencies between kinase targets that led to unexpected synergistic combinations between their inhibitors, such as dasatinib and axitinib in the triple-negative basal-like HCC1937 cell line. © 2015 Elsevier Ltd.


Annila A.,University of HelsinkiHelsinki | Baverstock K.,University of Eastern Finland
Communicative and Integrative Biology | Year: 2016

The second law of thermodynamics is on one hand understood to account for irrevocable flow of energy from the top down, on the other hand it is seen to imply irreversible increase of disorder. This tension between the 2 stances is resolved in favor of the free energy consumption when entropy is derived from the statistical mechanics of open systems. The change in entropy is shown to map directly to the decrease in free energy without any connotation attached to disorder. Increase of disorder, just as order, is found to be merely a consequence of free energy consumption. The erroneous association of disorder with entropy stems from an unwarranted assumption that a system could undergo changes of state without concomitant dissipation, i.e., a change in energy. © 2016 The Author(s). Published with license by Taylor & Francis. © Arto Annila and Keith Baverstock.

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