Connectivity models in the neural face perception domain – interfaces to understand the human brain in health and disease?

The recognition and processing of faces is a core competence of our human brain, in which many neuronal areas are involved. Faces are not only a means to recognize and distinguish between individuals, but also a means to convey emotions, intentions, or trustworthiness of our counterpart. The processing of faces is an orchestrated interaction of a multitude of neuronal regions. This interplay can be quantified at the neuronal level using so-called e↵ective connectivity analysis. The most common e↵ective connectivity analysis, which is also used in the present work, is called Dynamic Causal Modeling. With its help, interregional interactions are modelled at the neuronal level, and at the measurable level – such as with functional magnetic resonance imaging – evidence is found for the probability of the presence of neuronal connections and also their quantitative expression. E↵ective connectivity analyses can thus reveal the couplings between brain areas during specific cognitive processes, such as face perception. The way we process faces also changes when, for example, mental illness is present. Thus, negative emotions such as fear may be perceived disproportionately more intense, or positive emotions such as joy less intense. The evaluation of neuronal parameters in face processing could be used in clinical practice, e.g. for the early detection of mental illnesses or the quantification of therapy success. A prerequisite for clinical application is the reliability of the modeling method. Thus, results of models should be generalizable and not depend on certain nuances of the modeling. Furthermore, the interpretability of many model parameters turns out to be dicult. However, this is necessary to be able to describe causal relationships. In the present dissertation, so-called Dynamic Causal Models are applied in the field of neural face processing. In a first study a clinical context is used. Here, neural models of emotion regulation in face processing were used to identify potential consequences of risk factors for the development of mental illness. In another study, the generalizability of neural network models was tested in a healthy population. Here, many limitations of the method as a whole were revealed. In a final study, both observed and simulated data were used to uncover more limitations in the interpretation of model parameters.Die Erkennung und Verarbeitung von Gesichtern ist eine Kernkompetenz unseres menschlichen Gehirns, an welcher viele neuronale Areale beteiligt sind. Gesichter dienen nicht nur zur Erkennung und Unterscheidung zwischen Individuen, sondern transportieren zum Beispiel auch Emotionen, Absichten, oder Vertrauenswürdigkeit unseres Gegenübers. Dabei ist die Verarbeitung von Gesichtern ein orchestriertes Zusammenspiel einer Vielzahl von neuronalen Regionen. Dieses Zusammenspiel kann mittels der sogenannten effektiven Konnektivitätsanalyse auf neuronaler Ebene quantifiziert werden. Die häufigste, und auch in der vorliegenden Arbeit verwendete Konnektivitätsanalyse trägt den Namen Dynamic Causal Modeling. Mit ihrer Hilfe modelliert man interregionale Interaktionen auf neuronaler Ebene, und findet auf messbarer Ebene – wie z.B. mit funktioneller Magnetresonanztomographie – Hinweise für die Wahrscheinlichkeit neuronaler Verbindungen und auch deren quantitative Ausprägung. Mit Hilfe von effektiven Konnektivitätsanalysen können somit die Kopplungen zwischen Hirnarealen bei bestimmten kognitiven Vorgängen, wie z.B. der Gesichterwahrnehmung, aufgedeckt werden. Die Art und Weise, wie wir Gesichter verarbeiten, ändert sich beispielsweise, wenn z.B. psychische Erkrankungen vorliegen. So können negative Emotionen wie Furcht unproportional stärker wahrgenommen werden, oder positive Emotionen wie Freude weniger stark. Die Auswertung neuronaler Kennwerte bei der Gesichterverarbeitung könnte perspektivisch im klinischen Alltag zum Einsatz kommen, z.B. zur Früherkennung von psychischen Erkrankungen, oder der Quantifizierung von Therpieerfolg. Voraussetzung für einen klinischen Einsatz ist jedoch eine Verlässlichkeit der Modellierungsmethode. So sollten Ergebnisse von Modellen generalisierbar sein, und nicht von bestimmten Nuancen der Modellierung abhängen. Weiterhin stellt sich die Interpretatierbarkeit vieler Modellparameter als schwierig heraus. Diese ist jedoch notwendig, um ursächliche Zusammenhänge beschreiben zu können. In der vorliegenden Dissertation werden sogenannte Dynamic Causal Models im Bereich der neuronalen Gesichterverarbeitung eingesetzt. In einer ersten Studie wird ein klinischer Kontext herangezogen. Hier wurden anhand neuronaler Modelle der Emotionsregulation in der Gesichterverarbeitung Auswirkungen von möglichen Risikofaktoren zur Entwicklung psychischer Erkrankungen auf die Hirnkonnektivität erkannt. In einer weiteren Studie wird die Generalisier- barkeit neuronaler Netzwerkmodelle an einer gesunden Population erprobt. Hier zeigten sich viele Limitationen der Methode als Ganzes auf. In einer letzten Studie werden sowohl mit echten, als auch mit simulierten Daten, weitere Limitationen in der Interpretation von Modellparametern aufgedeckt

Towards minimizing efforts for Morphing Attacks -- Deep embeddings for morphing pair selection and improved Morphing Attack Detection

Face Morphing Attacks pose a threat to the security of identity documents, especially with respect to a subsequent access control process, because it enables both individuals involved to exploit the same document. In this study, face embeddings serve two purposes: pre-selecting images for large-scale Morphing Attack generation and detecting potential Morphing Attacks. We build upon previous embedding studies in both use cases using the MagFace model. For the first objective, we employ an pre-selection algorithm that pairs individuals based on face embedding similarity. We quantify the attack potential of differently morphed face images to compare the usability of pre-selection in automatically generating numerous successful Morphing Attacks. Regarding the second objective, we compare embeddings from two state-of-the-art face recognition systems in terms of their ability to detect Morphing Attacks. Our findings demonstrate that ArcFace and MagFace provide valuable face embeddings for image pre-selection. Both open-source and COTS face recognition systems are susceptible to generated attacks, particularly when pre-selection is based on embeddings rather than random pairing which was only constrained by soft biometrics. More accurate face recognition systems exhibit greater vulnerability to attacks, with COTS systems being the most susceptible. Additionally, MagFace embeddings serve as a robust alternative for detecting morphed face images compared to the previously used ArcFace embeddings. The results endorse the advantages of face embeddings in more effective image pre-selection for face morphing and accurate detection of morphed face images. This is supported by extensive analysis of various designed attacks. The MagFace model proves to be a powerful alternative to the commonly used ArcFace model for both objectives, pre-selection and attack detection

Expression of citrulline and homocitrulline residues in the lungs of non-smokers and smokers : implications for autoimmunity in rheumatoid arthritis

Introduction: Smoking is a well-established risk factor for rheumatoid arthritis (RA), and it has been proposed that smoking-induced citrullination renders autoantigens immunogenic. To investigate this mechanism, we examined human lung tissue from 40 subjects with defined smoking status, with or without chronic obstructive pulmonary disease (COPD), and control tissues from other organs for citrullinated proteins and the deiminating enzymes peptidylarginine deiminase type-2 (PAD2) and -4 (PAD4). Methods: Lung tissue samples, dissected from lobectomy specimens from 10 never smokers, 10 smokers without airflow limitation, 13 COPD smokers and eight COPD ex-smokers, and control tissue samples (spleen, skeletal muscle, liver, ovary, lymph node, kidney and heart), were analysed for citrullinated proteins, PAD2 and PAD4 by immunoblotting. Citrulline and homocitrulline residues in enolase and vimentin were analysed by partial purification by gel electrophoresis followed by mass spectrometry in 12 of the lung samples and one from each control tissues. Band intensities were scored semi-quantitatively and analysed by two-tailed Mann-Whitney T-test. Results: Within the lung tissue samples, citrullinated proteins, PAD2 and PAD4 were found in all samples, with an increase in citrullination in COPD (P = 0.039), but minimal difference between smokers and non-smokers (P = 0.77). Citrullination was also detected at lower levels in the tissues from other organs, principally in lymph node, kidney and skeletal muscle. Mass spectrometry of the lung samples showed that vimentin was citrullinated at positions 71, 304, 346, 410 and 450 in non-smokers and smokers both with and without COPD. A homocitrulline at position 104 was found in four out of six COPD samples and one out of six non-COPD. Citrulline-450 was also found in three of the control tissues. There were no citrulline or homocitrulline residues demonstrated in a-enolase. Conclusions: We have shown evidence of citrullination of vimentin, a major autoantigen in RA, in both non-smokers and smokers. The increase in citrullinated proteins in COPD suggests that citrullination in the lungs of smokers is mainly due to inflammation. The ubiquity of citrullination of vimentin in the lungs and other tissues suggests that the relationship between smoking and autoimmunity in RA may be more complex than previously thought

PfHPRT: a new biomarker candidate of acute Plasmodium falciparum infection.

Plasmodium falciparum is a protozoan parasite that causes human malaria. This parasitic infection accounts for approximately 655,000 deaths each year worldwide. Most deaths could be prevented by diagnosing and treating malaria promptly. To date, few parasite proteins have been developed into rapid diagnostic tools. We have combined a shotgun and a targeted proteomic strategy to characterize the plasma proteome of Gambian children with severe malaria (SM), mild malaria, and convalescent controls in search of new candidate biomarkers. Here we report four P. falciparum proteins with a high level of confidence in SM patients, namely, PF10_0121 (hypoxanthine phosphoribosyltransferase, pHPRT), PF11_0208 (phosphoglycerate mutase, pPGM), PF13_0141 (lactate dehydrogenase, pLDH), and PF14_0425 (fructose bisphosphate aldolase, pFBPA). We have optimized selected reaction monitoring (SRM) assays to quantify these proteins in individual patients. All P. falciparum proteins were higher in SM compared with mild cases or control subjects. SRM-based measurements correlated markedly with clinical anemia (low blood hemoglobin concentration), and pLDH and pFBPA were significantly correlated with higher P. falciparum parasitemia. These findings suggest that pHPRT is a promising biomarker to diagnose P. falciparum malaria infection. The diagnostic performance of this marker should be validated prospectively

Observing repetitive finger movements modulates response times of auditorily cued finger movements

Our motor and perceptual representations of actions seem to be intimately linked and the human mirror neuron system (MNS) has been proposed as the mediator. In two experiments, we presented biological or non-biological movement stimuli that were either congruent or incongruent to a required response prompted by a tone. When the tone occurred with the onset of the last movement in a series, i.e., it was perceived during the movement presentation, congruent biological stimuli resulted in faster reaction times than congruent non-biological stimuli. The opposite was observed for incongruent stimuli. When the tone was presented after visual movement stimulation, however, no such interaction was present. This implies that biological movement stimuli only affect motor behaviour during visual processing but not thereafter. These data suggest that the MNS is an “online” system; longstanding repetitive visual stimulation (Experiment 1) has no benefit in comparison to only one or two repetitions (Experiment 2)

DDsk2 regulates H2Bub1 and RNA polymerase II pausing at dHP1c complex target genes

© 2015 Macmillan Publishers Limited. All rights reserved. dDsk2 is a conserved extraproteasomal ubiquitin receptor that targets ubiquitylated proteins for degradation. Here we report that dDsk2 plays a nonproteolytic function in transcription regulation. dDsk2 interacts with the dHP1c complex, localizes at promoters of developmental genes and is required for transcription. Through the ubiquitin-binding domain, dDsk2 interacts with H2Bub1, a modification that occurs at dHP1c complex-binding sites. H2Bub1 is not required for binding of the complex; however, dDsk2 depletion strongly reduces H2Bub1. Co-depletion of the H2Bub1 deubiquitylase dUbp8/Nonstop suppresses this reduction and rescues expression of target genes. RNA polymerase II is strongly paused at promoters of dHP1c complex target genes and dDsk2 depletion disrupts pausing. Altogether, these results suggest that dDsk2 prevents dUbp8/Nonstop-dependent H2Bub1 deubiquitylation at promoters of dHP1c complex target genes and regulates RNA polymerase II pausing. These results expand the catalogue of nonproteolytic functions of ubiquitin receptors to the epigenetic regulation of chromatin modifications.This work was supported by grants from MICINN (CSD2006-49, BFU2009-07111 and BFU2012-30724) and the Generalitat de Catalunya (SGR2009-1023 and SGR2014-204). This work was carried out within the framework of the ‘Centre de Referència en Biotecnologia’ of the ‘Generalitat de Catalunya’. R.K. acknowledges receipt of a ‘La Caixa’ PhD fellowshipPeer Reviewe

BLM and BRCA1-BARD1 coordinate complementary mechanisms of joint DNA molecule resolution

The Bloom syndrome helicase BLM interacts with topoisomerase IIIα (TOP3A), RMI1, and RMI2 to form the BTR complex, which dissolves double Holliday junctions and DNA replication intermediates to promote sister chromatid disjunction before cell division. In its absence, structure-specific nucleases like the SMX complex (comprising SLX1-SLX4, MUS81-EME1, and XPF-ERCC1) can cleave joint DNA molecules instead, but cells deficient in both BTR and SMX are not viable. Here, we identify a negative genetic interaction between BLM loss and deficiency in the BRCA1-BARD1 tumor suppressor complex. We show that this is due to a previously overlooked role for BARD1 in recruiting SLX4 to resolve DNA intermediates left unprocessed by BLM in the preceding interphase. Consequently, cells with defective BLM and BRCA1-BARD1 accumulate catastrophic levels of chromosome breakage and micronucleation, leading to cell death. Thus, we reveal mechanistic insights into SLX4 recruitment to DNA lesions, with potential clinical implications for treating BRCA1-deficient tumors

Long-Term Neuroanatomical Consequences of Childhood Maltreatment: Reduced Amygdala Inhibition by Medial Prefrontal Cortex

Similar to patients with Major depressive disorder (MDD), healthy subjects at risk for depression show hyperactivation of the amygdala as a response to negative emotional expressions. The medial prefrontal cortex is responsible for amygdala control. Analyzing a large cohort of healthy subjects, we aimed to delineate malfunction in amygdala regulation by the medial prefrontal cortex in subjects at increased risk for depression, i.e., with a family history of affective disorders or a personal history of childhood maltreatment. We included a total of 342 healthy subjects from the FOR2107 cohort (www.for2107.de). An emotional face-matching task was used to identify the medial prefrontal cortex and right amygdala. Dynamic Causal Modeling (DCM) was conducted and neural coupling parameters were obtained for healthy controls with and without particular risk factors for depression. We assigned a genetic risk if subjects had a first-degree relative with an affective disorder and an environmental risk if subjects experienced childhood maltreatment. We then compared amygdala inhibition during emotion processing between groups. Amygdala inhibition by the medial prefrontal cortex was present in subjects without those two risk factors, as indicated by negative model parameter estimates. Having a genetic risk (i.e., a family history) did not result in changes in amygdala inhibition compared to no risk subjects. In contrast, childhood maltreatment as environmental risk has led to a significant reduction of amygdala inhibition by the medial prefrontal cortex. We propose a mechanistic explanation for the amygdala hyperactivity in subjects with particular risk for depression, in particular childhood maltreatment, caused by a malfunctioned amygdala downregulation via the medial prefrontal cortex. As childhood maltreatment is a major environmental risk factor for depression, we emphasize the importance of this potential early biomarker

Identification of potentially zoonotic parasites in captive orangutans and semi-captive mandrills: phylogeny and morphological comparison

Cysts and trophozoites of vestibuliferid ciliates and larvae of Strongyloides were found in fecal samples from captive orangutans Pongo pygmaeus and P. abelii from Czech and Slovak zoological gardens. As comparative material, ciliates from semi-captive mandrills Mandrillus sphinx from Gabon were included in the study. Phylogenetic analysis of the detected vestibuliferid ciliates using ITS1-5.8s-rRNA-ITS2 and partial 18S rDNA revealed that the ciliates from orangutans are conspecific with Balantioides coli lineage A, while the ciliates from mandrills clustered with Buxtonella-like ciliates from other primates. Morphological examination of the cysts and trophozoites using light microscopy did not reveal differences robust enough to identify the genera of the ciliates. Phylogenetic analysis of detected L1 larvae of Strongyloides using partial cox1 revealed Strongyloides stercoralis clustering within the cox1 lineage A infecting dogs, humas and other primates. The sequences of 18S rDNA support these results. As both B. coli and S. stercoralis are zoonotic parasites and the conditions in captive and semi-captive settings may facilitate transmission to humans, prophylactic measures should reflect the findings

SARS-CoV-2 mutations affect antigen processing by the proteasome to alter CD8+ T cell responses

Mutations within viral epitopes can result in escape from T cells, but the contribution of mutations in flanking regions of epitopes in SARS-CoV-2 has not been investigated. Focusing on two SARS-CoV-2 nucleoprotein CD8+ epitopes, we investigated the contribution of these flanking mutations to proteasomal processing and T cell activation. We found decreased NP9-17-B*27:05 CD8+ T cell responses to the NP-Q7K mutation, likely due to a lack of efficient epitope production by the proteasome, suggesting immune escape caused by this mutation. In contrast, NP-P6L and NP-D103 N/Y mutations flanking the NP9-17-B*27:05 and NP105-113-B*07:02 epitopes, respectively, increased CD8+ T cell responses associated with enhanced epitope production by the proteasome. Our results provide evidence that SARS-CoV-2 mutations outside the epitope could have a significant impact on proteasomal processing, either contributing to T cell escape or enhancement that may be exploited for future vaccine design