Reduced Sensitivity to Non-Fear-Related Stimulus Changes in Panic Disorder

Panic disorder (PD) is associated with increased body vigilance and reduced cognitive resources directed at non-fear-related stimuli, particularly in the absence of stimulus-rich environments. To date, only few studies have investigated whether this deficit in PD is reflected in reduced mismatch negativity (MMN), an event-related potential indexing preattentive sensitivity to unexpected stimulus changes. We tested 35 patients affected by PD and 42 matched healthy controls in an oddball paradigm, using frequency and duration deviant stimuli to measure auditory MMN. PD patients displayed reduced duration MMN amplitudes in comparison to healthy controls. No group differences were detected for duration MMN latency, as well as frequency MMN indices. Results support the notion of reduced larly with regard to the preattentive processing of sound duration deviants. Additionally, our findings are in line with clinical studies reporting divergent deficits in preattentive processing of frequency and duration deviants

P50, N100, and P200 Sensory Gating in Panic Disorder

Panic disorder (PD) has been linked to abnormalities in information processing. However, only little evidence has been published for sensory gating in PD. Sensory gating describes the brain’s ability to exclude stimuli of low relevance from higher level information processing, thereby sustaining efficient cognitive processing. Deficits in sensory gating have been associated with various psychiatric conditions, most prominently schizophrenia. In this case-control event-related potential study, we tested 32 patients with PD and 39 healthy controls in a double click paradigm. Both groups were compared with regard to pre-attentive (P50), early-attentive (N100), and late-attentive (P200) sensory gating indices. Contrary to a hypothesized deficit, PD patients and healthy controls showed no differences in P50, N100 and P200 values. These results suggest that sensory gating seems to be functional across the pre-attentive, early-attentive, and late-attentive time span in this clinical population. Given this consistency across auditory sensory gating indices, further research aiming to clarify information processing deficits in PD should focus on other neurophysiological markers to investigate information processing deficits in PD (eg, P300, error-related negativity or mismatch negativity).Peer Reviewe

Quantitative and time-resolved miRNA pattern of early human T cell activation

T cells are central to the immune response against various pathogens and cancer cells. Complex networks of transcriptional and post-transcriptional regulators, including microRNAs (miRNAs), coordinate the T cell activation process. Available miRNA datasets, however, do not sufficiently dissolve the dynamic changes of miRNA controlled networks upon T cell activation. Here, we established a quantitative and time-resolved expression pattern for the entire miRNome over a period of 24 h upon human Tcell activation. Based on our time-resolved datasets, we identified central miRNAs and specified common miRNA expression profiles. We found the most prominent quantitative expression changes for miR155-5p with a range from initially 40 molecules/cell to 1600 molecules/cell upon T-cell activation. We established a comprehensive dynamic regulatory network of both the up- and downstream regulation of miR155. Upstream, we highlight IRF4 and its complexes with SPI1 and BATF as central for the transcriptional regulation of miR-155. Downstream of miR-155-5p, we verified 17 of its target genes by the time-resolved data recorded after T cell activation. Our data provide comprehensive insights into the range of stimulus induced miRNA abundance changes and lay the ground to identify efficient points of intervention for modifying the T cell response

Chemoradiotherapy-induced increase in Th17 cell frequency in cervical cancer patients is associated with therapy resistance and early relapse

Cervical cancer therapy is still a major clinical challenge, as patients substantially differ in their response to standard treatments, including chemoradiotherapy (CRT). During cervical carcinogenesis, T-helper (Th)-17 cells accumulate in the peripheral blood and tumor tissues of cancer patients and are associated with poor prognosis. In this prospective study, we find increased Th17 frequencies in the blood of patients after chemoradiotherapy and a post-therapeutic ratio of Th17/CD4+ T cells > 8% was associated with early recurrence. Furthermore, Th17 cells promote resistance of cervical cancer cells toward CRT, which was dependent on the AKT signaling pathway. Consistently, patients with high Th17 frequencies in pretherapeutic biopsies exhibit lower response to primary CRT. This work reveals a key role of Th17 cells in CRT resistance and elevated Th17 frequencies in the blood after CRT correspond with early recurrence. Our results may help to explain individual treatment responses of cervical cancer patients and suggest evaluation of Th17 cells as a novel predictive biomarker for chemoradiotherapy responses and as a potential target for immunotherapy in cervical cancer

Untersuchung der Mismatch-Negativität (MMN) bei Patienten mit Panikstörung

Bei Patienten mit Panikstörung findet man Hinweise auf Störungen der kognitiven Verarbeitung von Reizen. Betroffene weisen eine erhöhte Aufmerksamkeit hinsichtlich eigener körperlicher Veränderungen sowie reduzierte kognitive Ressourcen auf. Diese zeigt sich insbesondere in Form eines Fokus auf primär nicht-angstinduzierende Stimuli in einem stimulusreichen Umfeld, da die Patienten auf vermeintlich angstbezogene Reize fokussieren. Vor diesem Hintergrund existieren gegenwärtig nur wenige Studien, die sich mit der Frage beschäftigten, ob die defizitäre kognitive Verarbeitung bei Patienten mit Panikstörung mit einer reduzierten Mismatch-Negativität (MMN) korreliert. Bei der MMN handelt es sich um eine Komponente der ereigniskorrelierten Potentiale (EKP), die durch Stimulusabweichung bei repetitiver auditorischer Stimulation ausgelöst wird. Studien weisen darauf hin, dass die MMN ein Korrelat von präattentiven Vorgängen ist. Im Rahmen der dieser Dissertation zugrundeliegenden Studie wurden 77 Studienteilnehmer (35 Patienten mit Panikstörung, 42 gesunde Probanden) hinsichtlich der MMN untersucht. Die MMN wurde mit Hilfe eines Odball-Paradigmas untersucht, in dem abweichende Stimuli für Tonhöhe und Tonlänge verwendet wurden. Patienten mit Panikstörung wiesen im Vergleich zu der gesunden Probandengruppe eine reduzierte MMN auf. Die in der Dauer devianten Stimuli unterschieden sich hinsichtlich der Amplitude signifikant zwischen den Gruppen. Darüber hinaus zeigte sich weder ein signifikanter Gruppen-unterschied für die MMN-Latenz noch für die MMN-Frequenz. Die Hypothese, dass bei Patienten mit Panikstörung Defizite der sensorischen Informationsverarbeitung vorliegen, konnte durch die elektrophysiologischen Daten gestützt werden. Die Ergebnisse zeigen, dass Patienten weniger Aufmerksamkeit auf neutrale Umgebungsreize richten, da möglicherweise die Konzentration auf Körpersymptome erhöht ist. Der signifikante Gruppenunterschied in der MMN-Amplitude der Devianzen (Dauer) ist ein Er-klärungsansatz für die Annahme einer verminderten Empfindlichkeit gegenüber nicht angstbe-dingten Reizänderungen bei Patienten mit Panikstörung. Die Ergebnisse sprechen für eine reduzierte Informationsverarbeitung der neutralen Umgebungsreize. Der fehlende Gruppenunterschied für die MMN-Frequenz und die gleichzeitige Schalldauerab-weichung liefern Hinweise darauf, dass die kognitiven Defizite eine komplexe Störung repräsentieren, die mehrere Hirnareale umfasst. Im Gegensatz dazu scheint es bei der Beteiligung bei möglichen Frequenzabweichungen um primär auditorische Netzwerke zu handeln. Auch die Annahme, dass die Verarbeitung von Schalldauerabweichungen stärker beeinflusst wird und diese sensitiver auf Gruppendifferenzen reagieren als Schallfrequenzabweichungen sollte in Betracht gezogen werden. Die Ergebnisse der vorliegenden Studie deuten auf eine gestörte Signal-Rausch-Diskriminierung bei der Panikstörung hin. Dies ist ein Hinweis darauf, dass Patienten teilweise nicht korrekt zwischen relevanten und irrelevanten Reizen unterscheiden können, was letztendlich die Entstehung und Aufrechterhaltung der Panikstörung begünstigen könnte. Die Ergebnisse zeigen ferner, dass Diskriminationslernen in der Therapie der Panikstörung eine Therapieoption sein könnte.In panic disorder, there is evidence of disturbances in the cognitive processing of stimuli. Affected persons often show increased attention to their own physical changes combined with reduced cognitive function. This is particularly evident when focusing on primarily non-anxiety-induced stimuli in a stimulusrich environment, as these patients concentrate on supposedly anxiety-related stimuli. There are only a few studies addressing the question of whether the deficit in cognitive processing in patients with panic disorder correlates with reduced mismatch negativity (MMN). Mismatch negativity is a component of event-related potentials (EKP) which are triggered by stimulus deviation during repetitive auditory stimulation. Studies indicate that the MMN correlates to preattentive processes in particular. In the present trial, 77 participants (35 patients with panic disorder, 42 healthy subjects) were examined with regard to the MMN. The MMN was tested using an odball paradigm in which different stimuli were used for pitch and tone length. Patients with panic disorder showed a re-duced MMN compared to the healthy group of subjects. The stimuli deviating in tone length differed significantly in amplitude between the groups. Furthermore, there was no significant difference in MMN latency or MMN frequency between the groups. The view that patients with panic disorder have deficits when processing sensory information could be supported by the electrophysiological data. The results show that patients pay less attention to neutral environmental stimuli, as the concentration on body symptoms may be increased. The significant group difference in the MMN amplitude of the deviants (duration) is an explanatory approach for the assumption of a reduced sensitivity to non-anxiety-related stimulus changes in patients with panic disorder. The results suggest a reduced information processing of neutral stimuli. The missing group difference for MMN frequency and the simultaneous sound duration devia-tion provide evidence that the cognitive deficits are a complex disorder involving several brain areas. In contrast, the involvement in possible frequency deviations appears to be primarily audi-tory networks. Also, the assumption that the processing of sound duration deviations is more strongly influ-enced and that they react more sensitively to group differences than sound frequency deviations should be considered. The present study supports the assumption that patients are unable to distinguish correctly between relevant and irrelevant stimuli. This indicates a disturbed signal-to-noise discrimination, which ultimately supports the development and maintenance of panic disorder as a clinical condition. The results show that learning to discriminate could be a therapeutic option in panic disorder

Kinetic and Structural Characterization of the Self-Labeling Protein Tags HaloTag7, SNAP-tag, and CLIP-tag

The self-labeling protein tags (SLPs) HaloTag7, SNAP-tag, and CLIP-tag allow the covalent labeling of fusion proteins with synthetic molecules for applications in bioimaging and biotechnology. To guide the selection of an SLP-substrate pair and provide guidelines for the design of substrates, we report a systematic and comparative study of the labeling kinetics and substrate specificities of HaloTag7, SNAP-tag, and CLIP-tag. HaloTag7 reaches almost diffusion-limited labeling rate constants with certain rhodamine substrates, which are more than 2 orders of magnitude higher than those of SNAP-tag for the corresponding substrates. SNAP-tag labeling rate constants, however, are less affected by the structure of the label than those of HaloTag7, which vary over 6 orders of magnitude for commonly employed substrates. Determining the crystal structures of HaloTag7 and SNAP-tag labeled with fluorescent substrates allowed us to rationalize their substrate preferences. We also demonstrate how these insights can be exploited to design substrates with improved labeling kinetics.ISSN:0006-2960ISSN:1520-499