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1.
J Med Genet ; 60(6): 597-607, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36328423

RESUMO

BACKGROUND: Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder: childhood apraxia of speech (CAS), and yet few cases have been reported, limiting knowledge of the condition. METHODS: Here we phenotyped 28 individuals from 17 families with pathogenic FOXP2-only variants (12 loss-of-function, five missense variants; 14 males; aged 2 to 62 years). Health and development (cognitive, motor, social domains) were examined, including speech and language outcomes with the first cross-linguistic analysis of English and German. RESULTS: Speech disorders were prevalent (23/25, 92%) and CAS was most common (22/25, 88%), with similar speech presentations across English and German. Speech was still impaired in adulthood, and some speech sounds (eg, 'th', 'r', 'ch', 'j') were never acquired. Language impairments (21/25, 84%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/26, 38%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (10/24, 42%). Physical features were common (22/27, 81%) but with no consistent pattern. Cognition ranged from average to mildly impaired and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition. CONCLUSIONS: Although we identify an increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared with other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entry point for examining the neurobiological bases of speech disorder.


Assuntos
Apraxias , Transtornos da Linguagem , Masculino , Humanos , Criança , Distúrbios da Fala/genética , Transtornos da Linguagem/epidemiologia , Transtornos da Linguagem/genética , Fala , Apraxias/genética , Mutação de Sentido Incorreto/genética , Fatores de Transcrição Forkhead/genética
2.
Strahlenther Onkol ; 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37713170

RESUMO

PURPOSE: Patient misidentification in radiation oncology (RO) is a significant concern due to the potential harm to patient health and the burden on healthcare systems. Electronic patient identification systems (ePIS) are increasingly being used as an alternative or supplement to organizational systems (oPIS). The objective of this study was to assess the usability and usefulness of ePIS and oPIS in German-speaking countries. METHODS: A cross-sectional survey was designed by a group of experts from various professional backgrounds in RO. The survey consisted of 38 questions encompassing quantitative and qualitative data on usability, user experience, and usefulness of PIS. It was available between August and October 2022. RESULTS: Of 118 eligible participants, 37% had implemented some kind of ePIS. Overall, 22% of participants who use an oPIS vs. 10% of participants who use an ePIS reported adverse events in terms of patients' misidentification in the past 5 years. Frequent or very frequent drop-outs of electronic systems were reported by 31% of ePIS users. Users of ePIS significantly more often affirmed a positive cost-benefit ratio of ePIS as well as an improvement of workflow, whereas users of oPIS more frequently apprehended a decrease in staffs' attention through ePIS. The response rate was 8%. CONCLUSION: The implementation of ePIS can contribute to efficient PI and improved processes. Apprehensions by oPIS users and assessments of ePIS users differ significantly in aspects of the perceived usefulness of ePIS. However, technical problems need to be addressed to ensure the reliability of ePIS. Further research is needed to assess the impact of different PIS on patient safety in RO.

3.
Plant Cell ; 30(3): 717-736, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29514942

RESUMO

RecQ DNA helicases are genome surveillance proteins found in all kingdoms of life. They are characterized best in humans, as mutations in RecQ genes lead to developmental abnormalities and diseases. To better understand RecQ functions in plants we concentrated on Arabidopsis thaliana and Physcomitrella patens, the model species predominantly used for studies on DNA repair and gene targeting. Phylogenetic analysis of the six P. patens RecQ genes revealed their orthologs in humans and plants. Because Arabidopsis and P. patens differ in their RecQ4 and RecQ6 genes, reporter and deletion moss mutants were generated and gene functions studied in reciprocal cross-species and cross-kingdom approaches. Both proteins can be found in meristematic moss tissues, although at low levels and with distinct expression patterns. PpRecQ4 is involved in embryogenesis and in subsequent development as demonstrated by sterility of ΔPpRecQ4 mutants and by morphological aberrations. Additionally, ΔPpRecQ4 displays an increased sensitivity to DNA damages and an increased rate of gene targeting. Therefore, we conclude that PpRecQ4 acts as a repressor of recombination. In contrast, PpRecQ6 is not obviously important for moss development or DNA repair but does function as a potent enhancer of gene targeting.


Assuntos
Arabidopsis/metabolismo , Bryopsida/metabolismo , Reparo do DNA/genética , Proteínas de Plantas/metabolismo , RecQ Helicases/metabolismo , Arabidopsis/genética , Bryopsida/genética , Genoma de Planta/genética , Filogenia , Proteínas de Plantas/genética , RecQ Helicases/genética
4.
Neuroimage ; 116: 68-79, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25976924

RESUMO

Ventral striatal activity has been previously shown to correspond well to reward value mediated by music. Here, we investigate the dynamic brain response to music and manipulated counterparts using functional magnetic resonance imaging (fMRI). Counterparts of musical excerpts were produced by either manipulating the consonance/dissonance of the musical fragments or playing them backwards (or both). Results show a greater involvement of the ventral striatum/nucleus accumbens both when contrasting listening to music that is perceived as pleasant and listening to a manipulated version perceived as unpleasant (backward dissonant), as well as in a parametric analysis for increasing pleasantness. Notably, both analyses yielded a ventral striatal response that was strongest during an early phase of stimulus presentation. A hippocampal response to the musical stimuli was also observed, and was largely mediated by processing differences between listening to forward and backward music. This hippocampal involvement was again strongest during the early response to the music. Auditory cortex activity was more strongly evoked by the original (pleasant) music compared to its manipulated counterparts, but did not display a similar decline of activation over time as subcortical activity. These findings rather suggest that the ventral striatal/nucleus accumbens response during music listening is strongest in the first seconds and then declines.


Assuntos
Percepção Auditiva/fisiologia , Música/psicologia , Núcleo Accumbens/fisiologia , Estriado Ventral/fisiologia , Estimulação Acústica , Adulto , Córtex Auditivo/fisiologia , Mapeamento Encefálico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Recompensa , Adulto Jovem
5.
Proc Natl Acad Sci U S A ; 109(18): 7121-5, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22511719

RESUMO

Monkeys can easily form lasting central representations of visual and tactile stimuli, yet they seem unable to do the same with sounds. Humans, by contrast, are highly proficient in auditory long-term memory (LTM). These mnemonic differences within and between species raise the question of whether the human ability is supported in some way by speech and language, e.g., through subvocal reproduction of speech sounds and by covert verbal labeling of environmental stimuli. If so, the explanation could be that storing rapidly fluctuating acoustic signals requires assistance from the motor system, which is uniquely organized to chain-link rapid sequences. To test this hypothesis, we compared the ability of normal participants to recognize lists of stimuli that can be easily reproduced, labeled, or both (pseudowords, nonverbal sounds, and words, respectively) versus their ability to recognize a list of stimuli that can be reproduced or labeled only with great difficulty (reversed words, i.e., words played backward). Recognition scores after 5-min delays filled with articulatory-suppression tasks were relatively high (75-80% correct) for all sound types except reversed words; the latter yielded scores that were not far above chance (58% correct), even though these stimuli were discriminated nearly perfectly when presented as reversed-word pairs at short intrapair intervals. The combined results provide preliminary support for the hypothesis that participation of the oromotor system may be essential for laying down the memory of speech sounds and, indeed, that speech and auditory memory may be so critically dependent on each other that they had to coevolve.


Assuntos
Memória de Longo Prazo/fisiologia , Modelos Psicológicos , Estimulação Acústica , Adulto , Animais , Núcleo Arqueado do Hipotálamo/fisiologia , Percepção Auditiva/fisiologia , Discriminação Psicológica/fisiologia , Feminino , Humanos , Masculino , Córtex Motor/fisiologia , Fonética , Primatas/psicologia , Psicoacústica , Especificidade da Espécie , Adulto Jovem
6.
J Affect Disord ; 348: 398-408, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38123075

RESUMO

BACKGROUND: Despite the importance of positive emotions for affective psychopathology, prior research primarily focused on negative emotion regulation. To address this gap, this ecological momentary assessment study compared a broad set of emotion regulation strategies in the context of positive versus negative emotions regarding their effectiveness and associations with depressive symptoms. METHODS: We analyzed data from 1066 participants who were notified five times daily for seven consecutive days to complete a smartphone survey assessing their predominant emotions, strategies to regulate them, and subsequent emotional outcomes. RESULTS: Findings show that the effectiveness of most regulation strategies depended on whether the emotional context was positive or negative. While acceptance and savoring predicted improved emotional outcomes across emotional contexts, reappraisal and problem-solving were associated with deteriorated emotional outcomes and increased depressive symptoms when regulating positive but not negative emotions. LIMITATIONS: Future studies should replicate our findings in demographically and culturally diverse clinical samples to improve generalizability. CONCLUSION: These results emphasize that strategies effective for regulating negative emotions may be less helpful in the context of positive emotions. Thus, context-specific interventions may be a promising approach to improve the treatment of affective disorders.


Assuntos
Depressão , Regulação Emocional , Humanos , Depressão/psicologia , Emoções/fisiologia , Inquéritos e Questionários , Transtornos do Humor , Avaliação Momentânea Ecológica
7.
Neuro Oncol ; 26(9): 1638-1650, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38813990

RESUMO

BACKGROUND: Surgical resection is the standard of care for patients with large or symptomatic brain metastases (BMs). Despite improved local control after adjuvant stereotactic radiotherapy, the risk of local failure (LF) persists. Therefore, we aimed to develop and externally validate a pre-therapeutic radiomics-based prediction tool to identify patients at high LF risk. METHODS: Data were collected from A Multicenter Analysis of Stereotactic Radiotherapy to the Resection Cavity of BMs (AURORA) retrospective study (training cohort: 253 patients from 2 centers; external test cohort: 99 patients from 5 centers). Radiomic features were extracted from the contrast-enhancing BM (T1-CE MRI sequence) and the surrounding edema (T2-FLAIR sequence). Different combinations of radiomic and clinical features were compared. The final models were trained on the entire training cohort with the best parameter set previously determined by internal 5-fold cross-validation and tested on the external test set. RESULTS: The best performance in the external test was achieved by an elastic net regression model trained with a combination of radiomic and clinical features with a concordance index (CI) of 0.77, outperforming any clinical model (best CI: 0.70). The model effectively stratified patients by LF risk in a Kaplan-Meier analysis (P < .001) and demonstrated an incremental net clinical benefit. At 24 months, we found LF in 9% and 74% of the low and high-risk groups, respectively. CONCLUSIONS: A combination of clinical and radiomic features predicted freedom from LF better than any clinical feature set alone. Patients at high risk for LF may benefit from stricter follow-up routines or intensified therapy.


Assuntos
Neoplasias Encefálicas , Imageamento por Ressonância Magnética , Radiocirurgia , Humanos , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Radiocirurgia/métodos , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética/métodos , Idoso , Prognóstico , Seguimentos , Adulto , Radiômica
8.
Hum Brain Mapp ; 34(7): 1579-90, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22359341

RESUMO

To date, the underlying cognitive and neural mechanisms of absolute pitch (AP) have remained elusive. In the present fMRI study, we investigated verbal and tonal perception and working memory in musicians with and without absolute pitch. Stimuli were sine wave tones and syllables (names of the scale tones) presented simultaneously. Participants listened to sequences of five stimuli, and then rehearsed internally either the syllables or the tones. Finally participants indicated whether a test stimulus had been presented during the sequence. For an auditory stroop task, half of the tonal sequences were congruent (frequencies of tones corresponded to syllables which were the names of the scale tones) and half were incongruent (frequencies of tones did not correspond to syllables). Results indicate that first, verbal and tonal perception overlap strongly in the left superior temporal gyrus/sulcus (STG/STS) in AP musicians only. Second, AP is associated with the categorical perception of tones. Third, the left STG/STS is activated in AP musicians only for the detection of verbal-tonal incongruencies in the auditory stroop task. Finally, verbal labelling of tones in AP musicians seems to be automatic. Overall, a unique feature of AP appears to be the similarity between verbal and tonal perception.


Assuntos
Mapeamento Encefálico , Encéfalo/irrigação sanguínea , Inibição Psicológica , Imageamento por Ressonância Magnética , Música , Discriminação da Altura Tonal/fisiologia , Estimulação Acústica , Adulto , Aprendizagem por Associação , Percepção Auditiva , Feminino , Lateralidade Funcional , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Memória de Curto Prazo , Oxigênio , Psicoacústica , Adulto Jovem
9.
Chemistry ; 19(41): 13714-9, 2013 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-24038571

RESUMO

New spin labeling strategies have immense potential in studying protein structure and dynamics under physiological conditions with electron paramagnetic resonance (EPR) spectroscopy. Here, a new spin-labeled chemical recognition unit for switchable and concomitantly high affinity binding to His-tagged proteins was synthesized. In combination with an orthogonal site-directed spin label, this novel spin probe, Proxyl-trisNTA (P-trisNTA) allows the extraction of structural constraints within proteins and macromolecular complexes by EPR. By using the multisubunit maltose import system of E. coli: 1) the topology of the substrate-binding protein, 2) its substrate-dependent conformational change, and 3) the formation of the membrane multiprotein complex can be extracted. Notably, the same distance information was retrieved both in vitro and in situ allowing for site-specific spin labeling in cell lysates under in-cell conditions. This approach will open new avenues towards in-cell EPR.


Assuntos
Escherichia coli/química , Maltose/química , Proteínas/química , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Escherichia coli/metabolismo , Maltose/metabolismo , Ligação Proteica , Proteínas/metabolismo , Marcadores de Spin
10.
Memory ; 21(3): 377-95, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23116413

RESUMO

Aiming to further our understanding of fundamental mechanisms of auditory working memory (WM), the present study compared performance for three auditory materials (words, tones, timbres). In a forward recognition task (Experiment 1) participants indicated whether the order of the items in the second sequence was the same as in the first sequence. In a backward recognition task (Experiment 2) participants indicated whether the items of the second sequence were played in the correct backward order. In Experiment 3 participants performed an articulatory suppression task during the retention delay of the backward task. To investigate potential length effects the number of items per sequence was manipulated. Overall findings underline the benefit of a cross-material experimental approach and suggest that human auditory WM is not a unitary system. Whereas WM processes for timbres differed from those for tones and words, similarities and differences were observed for words and tones: Both types of stimuli appear to rely on rehearsal mechanisms, but might differ in the involved sensorimotor codes.


Assuntos
Idioma , Memória de Curto Prazo/fisiologia , Percepção da Altura Sonora/fisiologia , Estimulação Acústica , Adolescente , Adulto , Feminino , Humanos , Masculino , Música/psicologia , Fonética , Reconhecimento Psicológico
11.
Proc Natl Acad Sci U S A ; 107(14): 6146-51, 2010 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-20200313

RESUMO

Chemical biology aims for a perfect control of protein complexes in time and space by their site-specific labeling, manipulation, and structured organization. Here we developed a self-inactivated, lock-and-key recognition element whose binding to His-tagged proteins can be triggered by light from zero to nanomolar affinity. Activation is achieved by photocleavage of a tethered intramolecular ligand arming a multivalent chelator head for high-affinity protein interaction. We demonstrate site-specific, stable, and reversible binding in solution as well as at interfaces controlled by light with high temporal and spatial resolution. Multiplexed organization of protein complexes is realized by an iterative in situ writing and binding process via laser scanning microscopy. This light-triggered molecular recognition should allow for a spatiotemporal control of protein-protein interactions and cellular processes by light-triggered protein clustering.


Assuntos
Luz , Proteínas Periplásmicas de Ligação/química , Receptores de LDL/química , Receptores Virais/química , Quelantes/química , Cromatografia em Gel , Histidina/química , Proteínas Ligantes de Maltose , Estrutura Molecular , Ácido Nitrilotriacético/química , Oligopeptídeos/química , Proteínas Periplásmicas de Ligação/isolamento & purificação , Ligação Proteica , Conformação Proteica , Receptores de LDL/metabolismo , Receptores Virais/metabolismo , Rhinovirus/química , Rhinovirus/metabolismo , Rhinovirus/efeitos da radiação , Vírion/metabolismo , Vírion/efeitos da radiação
12.
Emotion ; 23(7): 1971-1984, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36689367

RESUMO

The strategy-situation fit hypothesis suggests that emotion regulation strategies are only beneficial to mental health if they meet contextual demands. Previous studies support this assumption but focused on properties of the emotional stimulus and reported cross-sectional associations with mental health, thus neglecting the social context and long-term mental health outcomes. To address these limitations, we examined (1) whether reappraisal, social sharing, and suppression varied depending on the social context (i.e., being alone, among close others, or nonclose others) and (2) whether specific strategy-context associations were linked to current, and (3) long-term mental health. The study consisted of two ecological momentary assessment (EMA) periods, separated by one year, and the second period occurred during COVID-19-related governmentally imposed social restrictions. This design allowed us to examine emotion regulation following social context changes. Our results indicate that emotion regulation varied by the social context. Reappraisal was used more frequently when being alone, suppression occurred more among nonclose others, and social sharing increased with close others. Regarding current mental health, more suppression was linked to higher depressive symptoms only when used in the presence of close others. In contrast, using suppression when being alone was linked to lower depressive symptoms. Finally, analyses with long-term outcomes revealed improved mental health when participants increased their use of reappraisal when being alone, and decreased reappraisal after a higher presence of close others. These findings could reflect the unique regulatory costs and benefits of different social situations and highlight the role of context-specific reappraisal for longer-term adaptiveness. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Assuntos
COVID-19 , Regulação Emocional , Humanos , Regulação Emocional/fisiologia , Estudos Transversais , Emoções/fisiologia , Meio Social
13.
Radiother Oncol ; 178: 109425, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36442609

RESUMO

BACKGROUND: Stereotactic radiotherapy is a standard treatment option for patients with brain metastases. The planning target volume is based on gross tumor volume (GTV) segmentation. The aim of this work is to develop and validate a neural network for automatic GTV segmentation to accelerate clinical daily routine practice and minimize interobserver variability. METHODS: We analyzed MRIs (T1-weighted sequence ± contrast-enhancement, T2-weighted sequence, and FLAIR sequence) from 348 patients with at least one brain metastasis from different cancer primaries treated in six centers. To generate reference segmentations, all GTVs and the FLAIR hyperintense edematous regions were segmented manually. A 3D-U-Net was trained on a cohort of 260 patients from two centers to segment the GTV and the surrounding FLAIR hyperintense region. During training varying degrees of data augmentation were applied. Model validation was performed using an independent international multicenter test cohort (n = 88) including four centers. RESULTS: Our proposed U-Net reached a mean overall Dice similarity coefficient (DSC) of 0.92 ± 0.08 and a mean individual metastasis-wise DSC of 0.89 ± 0.11 in the external test cohort for GTV segmentation. Data augmentation improved the segmentation performance significantly. Detection of brain metastases was effective with a mean F1-Score of 0.93 ± 0.16. The model performance was stable independent of the center (p = 0.3). There was no correlation between metastasis volume and DSC (Pearson correlation coefficient 0.07). CONCLUSION: Reliable automated segmentation of brain metastases with neural networks is possible and may support radiotherapy planning by providing more objective GTV definitions.


Assuntos
Neoplasias Encefálicas , Radiocirurgia , Humanos , Redes Neurais de Computação , Imageamento por Ressonância Magnética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Planejamento da Radioterapia Assistida por Computador , Processamento de Imagem Assistida por Computador
14.
Radiother Oncol ; 188: 109901, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37678623

RESUMO

BACKGROUND: Many automatic approaches to brain tumor segmentation employ multiple magnetic resonance imaging (MRI) sequences. The goal of this project was to compare different combinations of input sequences to determine which MRI sequences are needed for effective automated brain metastasis (BM) segmentation. METHODS: We analyzed preoperative imaging (T1-weighted sequence ± contrast-enhancement (T1/T1-CE), T2-weighted sequence (T2), and T2 fluid-attenuated inversion recovery (T2-FLAIR) sequence) from 339 patients with BMs from seven centers. A baseline 3D U-Net with all four sequences and six U-Nets with plausible sequence combinations (T1-CE, T1, T2-FLAIR, T1-CE + T2-FLAIR, T1-CE + T1 + T2-FLAIR, T1-CE + T1) were trained on 239 patients from two centers and subsequently tested on an external cohort of 100 patients from five centers. RESULTS: The model based on T1-CE alone achieved the best segmentation performance for BM segmentation with a median Dice similarity coefficient (DSC) of 0.96. Models trained without T1-CE performed worse (T1-only: DSC = 0.70 and T2-FLAIR-only: DSC = 0.73). For edema segmentation, models that included both T1-CE and T2-FLAIR performed best (DSC = 0.93), while the remaining four models without simultaneous inclusion of these both sequences reached a median DSC of 0.81-0.89. CONCLUSIONS: A T1-CE-only protocol suffices for the segmentation of BMs. The combination of T1-CE and T2-FLAIR is important for edema segmentation. Missing either T1-CE or T2-FLAIR decreases performance. These findings may improve imaging routines by omitting unnecessary sequences, thus allowing for faster procedures in daily clinical practice while enabling optimal neural network-based target definitions.

15.
Psychiatry Res ; 314: 114547, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35779483

RESUMO

Post-traumatic stress disorder (PTSD) and borderline personality disorder (BPD) have been associated with an increased generation of false memories. We aimed to disentangle disorder-specific false memory in individuals with PTSD and BPD using the Deese-Roediger-McDermott (DRM) paradigm. It measures the tendency to mistakenly remember stimuli that are associated with actually presented material, but have not been presented. Participants with BPD without comorbid PTSD (n = 32), participants with PTSD without comorbid BPD (n = 28), and mentally healthy controls (HC, n = 30) were given a word recognition test after hearing neutral, emotionally negative, BPD-related and PTSD-related word lists. Compared to HC, participants with PTSD showed fewer false memories for neutral word material and no other differences. Participants with BPD showed no differences in false memory formation compared to HC, only more false memories for a BPD-related and a PTSD-related word list compared to PTSD. Our results indicate, that in the absence of BPD, increased false memory in PTSD cannot be observed. In addition, our findings do not suggest that individuals with BPD and HC differ in their false memory formation. More trauma-individualized material should be used in future studies on false memory in PTSD.


Assuntos
Transtorno da Personalidade Borderline , Transtornos de Estresse Pós-Traumáticos , Transtorno da Personalidade Borderline/complicações , Transtorno da Personalidade Borderline/psicologia , Comorbidade , Humanos , Memória , Rememoração Mental , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/psicologia
16.
J Am Chem Soc ; 133(21): 8090-3, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21545135

RESUMO

Single-molecule applications, saturated pattern excitation microscopy, and stimulated emission depletion (STED) microscopy demand bright as well as highly stable fluorescent dyes. Here we describe the synthesis of quantum-yield-optimized fluorophores for reversible, site-specific labeling of proteins or macromolecular complexes. We used polyproline-II (PPII) helices as sufficiently rigid spacers with various lengths to improve the fluorescence signals of a set of different trisNTA-fluorophores. The improved quantum yields were demonstrated by steady-state and fluorescence lifetime analyses. As a proof of principle, we characterized the trisNTA-PPII-fluorophores with respect to in vivo protein labeling and super-resolution imaging at synapses of living neurons. The distribution of His-tagged AMPA receptors (GluA1) in spatially restricted synaptic clefts was imaged by confocal and STED microscopy. The comparison of fluorescence intensity profiles revealed the superior resolution of STED microscopy. These results highlight the advantages of biocompatible and, in particular, small and photostable trisNTA-PPII-fluorophores in super-resolution microscopy.


Assuntos
Corantes Fluorescentes/síntese química , Microscopia de Fluorescência/métodos , Receptores de AMPA/química , Animais , Hipocampo/química , Microscopia Confocal/métodos , Neurônios/química , Ratos
17.
J Am Chem Soc ; 133(42): 16868-74, 2011 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-21910424

RESUMO

G-protein-coupled receptors (GPCRs) are ubiquitous mediators of signal transduction across cell membranes and constitute a very important class of therapeutic targets. In order to study the complex biochemical signaling network coupling to the intracellular side of GPCRs, it is necessary to engineer and control the downstream signaling components, which is difficult to realize in living cells. We have developed a bioanalytical platform enabling the study of GPCRs in their native membrane transferred inside-out from live cells to lectin-coated beads, with both membrane sides of the receptor being accessible for molecular interactions. Using heterologously expressed adenosine A(2A) receptor carrying a yellow fluorescent protein, we showed that the tethered membranes comprised fully functional receptors in terms of ligand and G protein binding. The interactions between the different signaling partners during the formation and subsequent dissociation of the ternary signaling complex on single beads could be observed in real time using multicolor fluorescence microscopy. This approach of tethering inside-out native membranes accessible from both sides is straightforward and readily applied to other transmembrane proteins. It represents a generic platform suitable for ensemble as well as single-molecule measurements to investigate signaling processes at plasma membranes.


Assuntos
Membrana Celular/química , Receptores Acoplados a Proteínas G/química , Ligação Competitiva , Membrana Celular/metabolismo , Células HEK293 , Humanos , Proteínas Imobilizadas/química , Proteínas Imobilizadas/metabolismo , Ligantes , Porosidade , Receptores Acoplados a Proteínas G/metabolismo , Propriedades de Superfície
18.
Hum Brain Mapp ; 32(5): 771-83, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-20533560

RESUMO

Working memory (WM) for auditory information has been thought of as a unitary system, but whether WM for verbal and tonal information relies on the same or different functional neuroarchitectures has remained unknown. This fMRI study examines verbal and tonal WM in both nonmusicians (who are trained in speech, but not in music) and highly trained musicians (who are trained in both domains). The data show that core structures of WM are involved in both tonal and verbal WM (Broca's area, premotor cortex, pre-SMA/SMA, left insular cortex, inferior parietal lobe), although with significantly different structural weightings, in both nonmusicians and musicians. Additionally, musicians activated specific subcomponents only during verbal (right insular cortex) or only during tonal WM (right globus pallidus, right caudate nucleus, and left cerebellum). These results reveal the existence of two WM systems in musicians: A phonological loop supporting rehearsal of phonological information, and a tonal loop supporting rehearsal of tonal information. Differences between groups for tonal WM, and between verbal and tonal WM within musicians, were mainly related to structures involved in controlling, programming and planning of actions, thus presumably reflecting differences in action-related sensorimotor coding of verbal and tonal information.


Assuntos
Percepção Auditiva/fisiologia , Mapeamento Encefálico , Encéfalo/fisiologia , Memória de Curto Prazo/fisiologia , Música , Estimulação Acústica , Adulto , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Adulto Jovem
19.
Biophys J ; 99(4): 1303-10, 2010 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-20713016

RESUMO

Versatile superresolution imaging methods, able to give dynamic information of endogenous molecules at high density, are still lacking in biological science. Here, superresolved images and diffusion maps of membrane proteins are obtained on living cells. The method consists of recording thousands of single-molecule trajectories that appear sequentially on a cell surface upon continuously labeling molecules of interest. It allows studying any molecules that can be labeled with fluorescent ligands including endogenous membrane proteins on living cells. This approach, named universal PAINT (uPAINT), generalizes the previously developed point-accumulation-for-imaging-in-nanoscale-topography (PAINT) method for dynamic imaging of arbitrary membrane biomolecules. We show here that the unprecedented large statistics obtained by uPAINT on single cells reveal local diffusion properties of specific proteins, either in distinct membrane compartments of adherent cells or in neuronal synapses.


Assuntos
Fibroblastos/citologia , Fibroblastos/metabolismo , Imagem Molecular/métodos , Proteínas/metabolismo , Animais , Células COS , Sobrevivência Celular , Chlorocebus aethiops , Proteínas de Fluorescência Verde/metabolismo , Ligantes , Camundongos , Neurônios/citologia , Neurônios/metabolismo , Transporte Proteico , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo
20.
J Cataract Refract Surg ; 46(1): 8-13, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32050226

RESUMO

PURPOSE: To determine the long-term safety and effectiveness of a light-adjustable intraocular lens (LAL) over a period that is longer than reported in the literature at the time of the study. SETTING: University Eye Hospital, Bochum, Germany. DESIGN: Noninterventional observation. METHODS: In 445 patients, cataract surgery with LAL implantation was performed between April 2008 and December 2012. It was possible to contact 171 of these patients or their relatives through letter or telephone; 61 patients (103 eyes) agreed to participate in the long-term study and were examined. RESULTS: The mean time between the lock-in (final light treatment) and long-term visit was 7.2 years; 61 patients were included and examined. Corrected and uncorrected distance visual acuity was and remained good (n = 93). The refractive outcome was stable with minimal deviation. There were no significant changes in corneal thickness. In 2 patients, there were slight opacities of the IOL material without impact on visual acuity. Other eye diseases were within the normal range of the patients' age. CONCLUSION: Seven years after implantation and refractive adjustment, eyes with an LAL had stable refraction, good visual acuity, and no IOL-associated pathologies. The findings suggest that LAL technology is a safe and efficient method to achieve good visual results without long-term complications.


Assuntos
Implante de Lente Intraocular , Lentes Intraoculares , Facoemulsificação , Desenho de Prótese , Pseudofacia/fisiopatologia , Acuidade Visual/fisiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Luz , Masculino , Pessoa de Meia-Idade , Refração Ocular/fisiologia
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