What Happens in Between? Human Oscillatory Brain Activity Related to Crossmodal Spatial Cueing

Previous studies investigated the effects of crossmodal spatial attention by comparing the responses to validly versus invalidly cued target stimuli. Dynamics of cortical rhythms in the time interval between cue and target might contribute to cue effects on performance. Here, we studied the influence of spatial attention on ongoing oscillatory brain activity in the interval between cue and target onset. In a first experiment, subjects underwent periods of tactile stimulation (cue) followed by visual stimulation (target) in a spatial cueing task as well as tactile stimulation as a control. In a second experiment, cue validity was modified to be 50%, 75%, or else 25%, to separate effects of exogenous shifts of attention caused by tactile stimuli from that of endogenous shifts. Tactile stimuli produced: 1) a stronger lateralization of the sensorimotor beta-rhythm rebound (15–22 Hz) after tactile stimuli serving as cues versus not serving as cues; 2) a suppression of the occipital alpha-rhythm (7–13 Hz) appearing only in the cueing task (this suppression was stronger contralateral to the endogenously attended side and was predictive of behavioral success); 3) an increase of prefrontal gamma-activity (25–35 Hz) specifically in the cueing task. We measured cue-related modulations of cortical rhythms which may accompany crossmodal spatial attention, expectation or decision, and therefore contribute to cue validity effects. The clearly lateralized alpha suppression after tactile cues in our data indicates its dependence on endogenous rather than exogenous shifts of visuo-spatial attention following a cue independent of its modality

Molecular mechanisms and cellular functions of cGAS-STING signalling

The cGAS–STING signalling axis, comprising the synthase for the second messenger cyclic GMP–AMP (cGAS) and the cyclic GMP–AMP receptor stimulator of interferon genes (STING), detects pathogenic DNA to trigger an innate immune reaction involving a strong type I interferon response against microbial infections. Notably however, besides sensing microbial DNA, the DNA sensor cGAS can also be activated by endogenous DNA, including extranuclear chromatin resulting from genotoxic stress and DNA released from mitochondria, placing cGAS–STING as an important axis in autoimmunity, sterile inflammatory responses and cellular senescence. Initial models assumed that co-localization of cGAS and DNA in the cytosol defines the specificity of the pathway for non-self, but recent work revealed that cGAS is also present in the nucleus and at the plasma membrane, and such subcellular compartmentalization was linked to signalling specificity of cGAS. Further confounding the simple view of cGAS–STING signalling as a response mechanism to infectious agents, both cGAS and STING were shown to have additional functions, independent of interferon response. These involve non-catalytic roles of cGAS in regulating DNA repair and signalling via STING to NF-κB and MAPK as well as STING-mediated induction of autophagy and lysosome- dependent cell death. We have also learnt that cGAS dimers can multimerize and undergo liquid–liquid phase separation to form biomolecular condensates that could importantly regulate cGAS activation. Here, we review the molecular mechanisms and cellular functions underlying cGAS–STING activation and signalling, particularly highlighting the newly emerging diversity of this signalling pathway and discussing how the specificity towards normal, damage-induced and infection-associated DNA could be achieved

Harnessing DNA Double-Strand Break Repair for Cancer Treatment

DNA double-strand breaks (DSBs) are highly deleterious, with a single unrepaired DSB being sufficient to trigger cell death. Compared to healthy cells, cancer cells have a higher DSB burden due to oncogene-induced replication stress and acquired defects in DNA damage response (DDR) mechanisms. Consequently, hyperproliferating cancer cells rely on efficient DSB repair for their survival. Moreover, augmented DSB repair capacity is a major cause of radio- and chemoresistance and, ultimately, cancer recurrence. Although inherited DDR defects can predispose individuals to develop certain cancers, the very same vulnerability may be therapeutically exploited to preferentially kill tumor cells. A paradigm for DNA repair targeted therapy has emerged in cancers that exhibit mutations in BRCA1 or BRCA2 tumor suppressor genes, conferring a strong defect in homologous recombination, a major and error-free DSB repair pathway. Clinical validation of such approaches, commonly described as synthetic lethality (SL), has been provided by the regulatory approval of poly(ADP-ribose) polymerase 1 inhibitors (PARPi) as monotherapy for BRCA1/2-mutated breast and ovarian tumors. In this review, we will describe the different DSB repair mechanisms and discuss how their specific features could be exploited for cancer therapy. A major emphasis is put on advances in combinatorial treatment modalities and SL approaches arising from DSB repair pathway interdependencies

Die Trauma-Maschine

Trauma bleibt aufgrund der etymologischen Herkunft des Begriffs mit Verwundungen verbunden. In diesem Zusammenhang wird diskutiert, inwiefern körperliche Wunden Affekte symbolisieren, die mit Brüchen in Wahrnehmung, Sinnstiftung und letztlich auch der Identitätsfindung assoziiert sind. Die Studie geht der Frage nach, wodurch körperliche Verwundungen zum Ausdruck psychischer Ausnahmezustände erhoben werden. Diese Diskrepanz wird an psychoanalytische Diskurse und kulturwissenschaftliche Debatten herangeführt, die Trauma als Ausgangspunkt von Subjektivierung, Wahrnehmung und Identitätsbildung betrachten. Dabei werden zudem die Zusammenhänge zwischen Trauma, Unfällen und maschinellen Ausfällen beleuchtet, durch die Trauma als Anlass somatischer und psychischer Irritationen in den Fokus tritt. Im Anschluss rücken fünf ausgewählte Positionen der zeitgenössischen Kunst exemplarisch in den Fokus, um die eingehenden Diskussionen kontextuell zu vertiefen

A short BRCA2-derived cell-penetrating peptide targets RAD51 function and confers hypersensitivity towards PARP inhibition

Under conditions of genotoxic stress, cancer cells strongly rely on efficient DNA repair to survive and proliferate. The human BRCA2 tumor suppressor protein is indispensable for the repair of DNA double-strand breaks by homologous recombination (HR) by virtue of its ability to promote RAD51 loading onto single-stranded DNA. Therefore, blocking the interaction between BRCA2 and RAD51 could significantly improve the efficacy of conventional anti-cancer therapies. However, targeting protein-protein interaction (PPI) interfaces has proven challenging because flat and large PPI surfaces generally do not support binding of small molecule inhibitors. In contrast, peptides are more potent for targeting PPIs but are otherwise difficult to deliver into cells. Here, we report that a synthetic 16-mer peptide derived from the BRC4 repeat motif of BRCA2 is capable of blocking RAD51 binding to BRCA2. Efficient non-cytotoxic cellular uptake of a nona-arginine (R9)-conjugated version of the BRC4 peptide interferes with DNA damage-induced RAD51 foci formation and HR. Moreover, transduction of the BRC4 peptide impairs replication fork protective function of BRCA2 and triggers MRE11-dependent degradation of nascent DNA in response to DNA replication stress. Finally, the BRC4 cell-penetrating peptide (CPP) confers selective hypersensitivity to PARP inhibition in cancer cells but spares non-cancerous cells. Taken together, our data highlight an innovative approach to develop novel peptide-based DNA repair inhibitors and establish BRCA2-derived CPPs as promising anti-cancer agents

Automatic Sequential NOESY Assignment and NMR Structure Improvement by X-Ray

We are developing AUREMOL1 (www.auremol.de), which goal is the reliable and automatic structure determination of biological macro molecules such as proteins from NMR data. For a fully automatic sequential NOESY assignment the tool ASSIGN2 has been developed. The required input consists of a homologous structure for a NOESY spectrum simulation and the experimental NOESY spectrum. ASSIGN fits the simulated NOE signals to the experimental spectrum. The fit quality given by a probability depends on the line shapes and volumes of the signals. The assignment is varied by moving or swapping spin system assignments using a Monte Carlo approach. A threshold accepting algorithm (TA3) is employed to find the maximum of accordance

Proprioceptive head posture-related processing in human polysensory cortical areas

Besides visual input and vestibular afferents, proprioceptive input from muscle spindle receptors of the neck region contributes to the perception of egocentric space. Using fMRI we performed a neck muscle vibration paradigm in humans in order to detect brain areas involved in processing changes of the head position in relation to the rest of the body. We identified a network of primary and secondary cortical areas: (I) regions that presumably receive direct proprioceptive thalamic input such as areas 3a, 2, S2 and the parieto-insular vestibular cortex (PIVC), (II) foci in the intraparietal sulcus, motor and premotor areas, and the frontal eye field (FEF). Activation of the former reflect early stages of proprioceptive processing, nevertheless these areas contain polysensory subdivisions such as area 3aNv, which also receives vestibular afferents. Together with area PIVC and the vestibular field in area 2 (2v), area 3aNv constitutes the inner vestibular circuit, an interconnected cortical triangle of polysensory areas that project to the posterior parietal cortex (PPC), which is known to be involved in polysensory integration. With respect to possible analogies in the monkey, we speculate that the activation we observed in the PPC is closely related to the LIP and VIP regions of the macaque

Human cortical areas involved in sustaining perceptual stability during smooth pursuit eye movements

Because both, eye movements and object movements induce an image motion on the retina, eye movements must be compensated to allow a coherent and stable perception of our surroundings. The inferential theory of perception postulates that retinal image motion is compared with an internal reference signal related to eye movements. This mechanism allows to distinguish between the potential sources producing retinal image motion. Referring to this theory, we investigated referential calculation during smooth pursuit eye movements (SPEM) in humans using event-related functional magnetic resonance imaging (fMRI). The blood oxygenation level dependent (BOLD) response related to SPEM in front of a stable background was measured for different parametric steps of preceding motion stimuli and therefore assumed for different states of the referential system. To achieve optimally accurate anatomy and more detectable fMRI signal changes in group analysis, we applied cortex-based statistics both to all brain volumes and to defined regions of interest. Our analysis revealed that the activity in a temporal region as well as the posterior parietal cortex (PPC) depended on the velocity of the preceding stimuli. Previous single-cell recordings in monkeys demonstrated that the visual posterior sylvian area (VPS) is relevant for perceptual stability. The activation apparent in our study thus may represent a human analogue of this area. The PPC is known as being strongly related to goal-directed eye movements. In conclusion, temporal and parietal cortical areas may be involved in referential calculation and thereby in sustaining visual perceptual stability during eye movements