Neural correlates of moral judgment in pedophilia

Pedophilia is a sexual preference that is often associated with child sex offending (CSO). Sexual urges towards prepubescent children and specifically acting upon those urges are universally regarded as immoral. However, up until now, it is completely unknown whether moral processing of sexual offenses is altered in pedophiles. A total of 31 pedophilic men and 19 healthy controls were assessed by using functional magnetic resonance imaging (fMRI) in combination with a moral judgment paradigm consisting of 36 scenarios describing different types of offenses. Scenarios depicting sexual offenses against children compared to those depicting adults were associated with higher pattern of activation in the left temporo-parietal-junction (TPJ) and left posterior insular cortex, the posterior cingulate gyrus as well as the precuneus in controls relative to pedophiles, and vice versa. Moreover, brain activation in these areas were positively associated with ratings of moral reprehensibility and negatively associated with decision durations, but only in controls. Brain activation, found in key areas related to the broad network of moral judgment, theory of mind and (socio-)moral disgust - point to different moral processing of sexual offenses in pedophilia in general. The lack of associations between brain activation and behavioral responses in pedophiles further suggest a biased response pattern or dissected implicit valuation processes

Deficiency in IκBα in the intestinal epithelium leads to spontaneous inflammation and mediates apoptosis in the gut

The IκB-Kinase (IKK)-NF-κB signalling pathway plays a multifaceted role in inflammatory bowel disease (IBD): on the one hand, it protects from apoptosis; on the other, it activates transcription of numerous inflammatory cytokines and chemokines. Although several murine models of IBD rely on disruption of IKK-NF-κB signalling, these involve either knockouts of a single family-member of NF-κB, or of upstream kinases that are known to have additional, NF-κB-independent, functions. This has made the distinct contribution of NF-κB to homeostasis in intestinal epithelium cells difficult to assess. To examine the role of constitutive NF-κB activation in intestinal epithelial cells, we generated a mouse model with a tissue-specific knockout of the direct inhibitor of NF-κB, Nfkbia/IκBα. We demonstrate that constitutive activation of NF-κB in intestinal epithelial cells induces several hallmarks of IBD including increased apoptosis, mucosal inflammation in both the small intestine and the colon, crypt hyperplasia, and depletion of Paneth cells, concomitant with aberrant Wnt signalling. To determine which NF-κB-driven phenotypes are cell-intrinsic, and which are extrinsic and thus require the immune compartment, we established a long-term organoid culture. Constitutive NF-κB promoted stem-cell proliferation, mis-localisation of Paneth cells, and sensitisation of intestinal epithelial cells to apoptosis in a cell-intrinsic manner. Increased number of stem cells was accompanied by a net increase in Wnt activity in organoids. Because aberrant Wnt signalling is associated with increased risk of cancer in IBD patients and because NFKBIA has recently emerged as a risk locus for IBD, our findings have critical implications for the clinic. In a context of constitutive NF-κB, our findings imply that general anti-inflammatory or immunosuppressive therapies should be supplemented with direct targeting of NF-κB within the epithelial compartment in order to attenuate apoptosis, inflammation, and hyperproliferation

Transcriptional repression of NFKBIA triggers constitutive IKK- and proteasome-independent p65/RelA activation in senescence

The IκB kinase (IKK)‐NF‐κB pathway is activated as part of the DNA damage response and controls both inflammation and resistance to apoptosis. How these distinct functions are achieved remained unknown. We demonstrate here that DNA double‐strand breaks elicit two subsequent phases of NF‐κB activation in vivo and in vitro, which are mechanistically and functionally distinct. RNA‐sequencing reveals that the first‐phase controls anti‐apoptotic gene expression, while the second drives expression of senescence‐associated secretory phenotype (SASP) genes. The rapidly activated first phase is driven by the ATM‐PARP1‐TRAF6‐IKK cascade, which triggers proteasomal destruction of inhibitory IκBα, and is terminated through IκBα re‐expression from the NFKBIA gene. The second phase, which is activated days later in senescent cells, is on the other hand independent of IKK and the proteasome. An altered phosphorylation status of NF‐κB family member p65/RelA, in part mediated by GSK3β, results in transcriptional silencing of NFKBIA and IKK‐independent, constitutive activation of NF‐κB in senescence. Collectively, our study reveals a novel physiological mechanism of NF‐κB activation with important implications for genotoxic cancer treatment

Identification of semicarbazones, thiosemicarbazones and triazine nitriles as inhibitors of Leishmania mexicana cysteine protease CPB

Cysteine proteases of the papain superfamily are present in nearly all eukaryotes. They play pivotal roles in the biology of parasites and inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas' disease and leishmaniasis. Homology modeling of the mature Leishmania mexicana cysteine protease CPB2.8 suggested that it differs significantly from bovine cathepsin B and thus could be a good drug target. High throughput screening of a compound library against this enzyme and bovine cathepsin B in a counter assay identified four novel inhibitors, containing the warhead-types semicarbazone, thiosemicarbazone and triazine nitrile, that can be used as leads for antiparasite drug design. Covalent docking experiments confirmed the SARs of these lead compounds in an effort to understand the structural elements required for specific inhibition of CPB2.8. This study has provided starting points for the design of selective and highly potent inhibitors of L. mexicana cysteine protease CPB that may also have useful efficacy against other important cysteine proteases

Expectation of sexual images of adults and children elicits differential dorsal anterior cingulate cortex activation in pedophilic sexual offenders and healthy controls

Background Pedophilic disorder is characterized by increased sexual interest towards children, with comparatively lesser interest towards adults. In real life, the behavior of subjects with pedophilic disorder is shaped by evaluative processes in response to sexually relevant cues. Therefore, brain activation during anticipation of sexually relevant cues is of potential interest. Whereas previous research demonstrated reduced activation when viewing adult (non-preferred) sexual stimuli in pedophilic sex offenders (PSOs), it is not known if anticipation of preferred versus unpreferred stimuli will elicit differential brain activation. Methods Two fMRI studies (1.5 and 7 Tesla) were conducted in separate samples, each with 26 subjects (13/13 PSOs/controls) to assess brain activity during expectancy of subsequent adult (non-preferred) sexual stimuli. In the second study (7 Tesla) additionally child (preferred) cues were presented. Results As predicted, expectancy of adult sexual stimuli generated smaller dorsal anterior cingulate cortex (dACC) activation in PSOs in both studies, driven by stronger activation during expectancy of adult erotic stimuli in non-pedophilic controls (HCs). In the second study, PSOs showed significantly increased activations in dACC during expectancy of child stimuli compared with expectancy of adult stimuli. This difference was significantly greater compared to the same contrast in HCs, thus demonstrating preference specificity of dACC activation. Conclusion Our findings support the notion of decreased brain activation to adult cues in PSOs and preference specificity in neural response during expectancy of erotic stimuli. The localization of these cue reactivity differences in the salience network supports the interpretation that PSOs show abnormally increased preparatory activation even before relevant sexual stimuli are actually presented

Evidence for superior neurobiological and behavioral inhibitory control abilities in non-offending as compared to offending pedophiles

Neurobehavioral models of pedophilia and child sexual offending suggest a pattern of temporal and in particular prefrontal disturbances leading to inappropriate behavioral control and subsequently an increased propensity to sexually offend against children. However, clear empirical evidence for such mechanisms is still missing. Using a go/nogo paradigm in combination with functional magnetic resonance imaging (fMRI) we compared behavioral performance and neural response patterns among three groups of men matched for age and IQ: pedophiles with (N = 40) and without (N = 37) a history of hands-on sexual offences against children as well as healthy non-offending controls (N = 40). As compared to offending pedophiles, non-offending pedophiles exhibited superior inhibitory control as reflected by significantly lower rate of commission errors. Group-by-condition interaction analysis also revealed inhibition-related activation in the left posterior cingulate and the left superior frontal cortex that distinguished between offending and non-offending pedophiles, while no significant differences were found between pedophiles and healthy controls. Both areas showing distinct activation pattern among pedophiles play a critical role in linking neural networks that relate to effective cognitive functioning. Data therefore suggest that heightened inhibition-related recruitment of these areas as well as decreased amount of commission errors is related to better inhibitory control in pedophiles who successfully avoid committing hands-on sexual offences against children

Autocrine LTA signaling drives NF-κB and JAK-STAT activity and myeloid gene expression in Hodgkin lymphoma

Persistent NF-κB activation is a hallmark of the malignant Hodgkin/Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL). Genomic lesions, Epstein-Barr virus infection, soluble factors and tumor-microenvironment interactions contribute to this activation. Here, in an unbiased approach to identify the cHL cell-secreted key factors for NF-κB activation, we have dissected the secretome of cultured cHL cells by chromatography and subsequent mass spectrometry. We identified lymphotoxin-α (LTA) as the causative factor for autocrine and paracrine activation of canonical and non-canonical NF-κB in cHL cell lines. Apart from inducing NF-κB, LTA promotes JAK2/STAT6 signaling. LTA and its receptor TNFRSF14 are transcriptionally activated by non-canonical NF-κB, creating a continuous feedback loop. Furthermore, LTA shapes the expression of cytokines, receptors, immune checkpoint ligands and adhesion molecules, including CSF2, CD40, PD-L1/-L2 and VCAM1. Comparison with single cell gene-activity profiles of human hematopoietic cells showed that LTA not only induces genes restricted to the lymphoid but also largely to the myeloid lineage. Thus, LTA sustains autocrine NF-κB activation, impacts activation of several signaling pathways and drives expression of genes essential for microenvironmental interactions and lineage ambiguity. These data provide a robust rationale for LTA-targeting as a treatment strategy for cHL patients

MEG reveals preference specific increases of sexual-image-evoked responses in paedophilic sexual offenders and healthy controls

OBJECTIVES: Paedophilic disorder is characterized by sexual attraction towards children. Classification of a counterpart as sexually attractive likely occurs rapidly, and involves both conscious and unconscious attentional and cognitive processes. Magnetoencephalography (MEG) is an imaging method especially well-suited to examine visual and attentional processes triggered by sexual images within the range of milliseconds. METHODS: We investigated brain responses to sexual images depicting adults (frequent) and children (infrequent stimulus) in seventeen paedophilic patients with a history of child sexual offending (P + CSO) and twenty healthy controls (HC) during a passive visual oddball paradigm. Event-related fields (ERF) were measured to extract the magnetic visual mismatch negativity (vMMNm), and how it relates to the processing of different classes of sexual stimuli. RESULTS: P + CSO exhibited significantly longer vMMNm latencies (100-180ms post-stimulus) than HC. Moreover, P + CSO showed widespread increased amplitudes in response to child images starting from P3a and P3b components and lasting up to 400ms post-stimulus presentation localized in frontal and temporal brain regions. CONCLUSIONS: This study uncovers the first MEG differences in automatic change detection between P + CSO and HC during the presentation of subliminal sexual images of adults and children, contributing towards a better understanding of the neurobiological processes of P + CSO