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Interpretation of surface fault scarps and palaeoseismic trenches is a key component of estimating fault slip rates, earthquake recurrence rates and maximum magnitudes for hazard assessments. Often these analyses rely on the assumption that successive earthquakes all breached the surface and that the ruptures are recorded topographically, or by the deposits exposed in a trench. The M w7.2 1992 Suusamyr earthquake, Kyrgyzstan, is an apparently problematic case for such analyses because its ruptures show significant displacement but are only mapped as having broken the surface along small, disparate portions of the fault. Here we present the results of surveys conducted along the Suusamyr Fault to establish whether that is the case. Two sets of ruptures were identified following the earthquake. They are unusually short for their displacement and are separated by a 25 km gap. Using satellite imagery, high-resolution digital elevation models and palaeoseismic trenching we first reassess the distribution of the 1992 ruptures and then reconstruct the Holocene earthquake record to establish the extent to which the 1992 earthquake is representative of the rupture behaviour of this fault. We find evidence for at least two prehistoric surface rupturing earthquakes in the Holocene: one ∼3 ka and one >8 ka that, along with the modern event, gives recurrence intervals of ∼3 and ∼5 kyr. Within spatial gaps between segments of the 1992 ruptures there are clear prehistoric surface ruptures and the ruptures in each prehistoric earthquake were discontinuous. We conclude that there is significant variability in the surface rupture pattern of successive earthquakes on the Suusamyr Fault, with implications for the completeness of palaeoseismic records obtained from thrust scarps. [ABSTRACT FROM AUTHOR]

The implementation of targeted molecular therapies and immunotherapy in melanoma vastly improved the therapeutic outcome in patients with limited efficacy of surgical intervention. Nevertheless, a large fraction of patients with melanoma still remain refractory or acquire resistance to these new forms of treatment, illustrating a need for improvement. Here, we report that the clinically relevant combination of mitogen-activated protein (MAP) kinase pathway inhibitors dabrafenib and trametinib synergize with RIG-I agonist-induced immunotherapy to kill BRAF-mutated human and mouse melanoma cells. Kinase inhibition did not compromise the agonist-induced innate immune response of the RIG-I pathway in host immune cells. In a melanoma transplantation mouse model, the triple therapy outperformed individual therapies. Our study suggests that agonist-induced activation of RIG-I with its synthetic ligand 3pRNA could vastly improve tumor control in a substantial fraction of patients with melanoma receiving MAP kinase inhibitors., Competing Interests: G.H. is an inventor on a patent covering synthetic RIG-I ligands. M.R. and G.H. were co-founders of Rigontec GmbH. J.L.S.-B. is a co-founder and shareholder of LAMPseq Diagnostics., (© 2024 The Authors.)

A counterpossible is a counterfactual whose antecedent is impossible. The vacuity thesis says all counterpossibles are true solely because their antecedents are impossible. Recently, some have rejected the vacuity thesis by citing purported non-vacuous counterpossibles in science. One limitation of this work, however, is that it is not grounded in experimental data. Do scientists actually reason non-vacuously about counterpossibles? If so, what is their basis for doing so? We presented biologists ( N = 86) with two counterfactual formulations of a well-known model in biology, the antecedents of which contain what many philosophers would characterize as a metaphysical impossibility. Participants consistently judged one counterfactual to be true, the other to be false, and they explained that they formed these judgments based on what they perceived to be the mathematical relationship between the antecedent and consequent. Moreover, we found no relationship between participants' judgments about the (im)possibility of the antecedent and whether they judged a counterfactual to be true or false. These are the first experimental results on counterpossibles in science with which we are familiar. We present a modal semantics that can capture these judgments, and we deal with a host of potential objections that a defender of the vacuity thesis might make., (© The Author(s), under exclusive licence to Springer Nature B.V. 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The SARS-CoV-2 pandemic has underscored the need for rapidly usable prophylactic and antiviral treatments against emerging viruses. The targeted stimulation of antiviral innate immune receptors can trigger a broad antiviral response that also acts against new, unknown viruses. Here, we used the K18-hACE2 mouse model of COVID-19 to examine whether activation of the antiviral RNA receptor RIG-I protects mice from lethal SARS-CoV-2 infection and reduces disease severity. We found that prophylactic, systemic treatment of mice with the specific RIG-I ligand 3pRNA, but not type I interferon, 1-7 days before viral challenge, improved survival of mice by up to 50%. Survival was also improved with therapeutic 3pRNA treatment starting 1 day after viral challenge. This improved outcome was associated with lower viral load in oropharyngeal swabs and in the lungs and brains of 3pRNA-treated mice. Moreover, 3pRNA-treated mice exhibited reduced lung inflammation and developed a SARS-CoV-2-specific neutralizing antibody response. These results demonstrate that systemic RIG-I activation by therapeutic RNA oligonucleotide agonists is a promising strategy to convey effective, short-term antiviral protection against SARS-CoV-2 infection, and it has great potential as a broad-spectrum approach to constrain the spread of newly emerging viruses until virus-specific therapies and vaccines become available., Competing Interests: M.S. and G.H. are inventors on a patent on RIG-I ligands., (© 2022 The Authors.)

The Dinarides fold-thrust belt on the Balkan Peninsula resulted from convergence between the Adriatic and Eurasian plates since Mid-Jurassic times. Under the Dinarides, S-wave receiver functions, P-wave tomographic models, and shear-wave splitting data show anomalously thin lithosphere overlying a short down-flexed slab geometry. This geometry suggests a delamination of Adriatic lithosphere. Here, we link the evolution of this continental convergence system to hitherto unreported sets of extensively uplifted Oligocene-Miocene (28-17 Ma) marine terraces preserved at elevations of up to 600 m along the Dinaric coastal range. River incision on either side of the Mediterranean-Black Sea drainage divide is comparable to the amounts of terrace uplift. The preservation of the uplifted terraces implies that the most External Dinarides did not experience substantial deformation other than surface uplift in the Neogene. These observations and the contemporaneous emplacement of igneous rocks (33-22 Ma) in the internal Dinarides suggest that the Oligo-Miocene orogen-wide uplift was driven by post-break-off delamination of the Adriatic lithospheric mantle, this was followed by isostatic readjustment of the remaining crust. Our study details how lithospheric delamination exerts an important control on crustal deformation and that its crustal signature and geomorphic imprint can be preserved for millions of years.

Schizophrenia is characterized by dysfunctions in neural circuits that can be investigated with electrophysiological methods, such as EEG and MEG. In the present human study, we examined event-related fields (ERFs), in a sample of medication-naive, first-episode schizophrenia (FE-ScZ) patients (n = 14) and healthy control participants (n = 17) during perception of Mooney faces to investigate the integrity of neuromagnetic responses and their experience-dependent modification. ERF responses were analyzed for M100, M170, and M250 components at the sensor and source levels. In addition, we analyzed peak latency and adaptation effects due to stimulus repetition. FE-ScZ patients were characterized by significantly impaired sensory processing, as indicated by a reduced discrimination index (A'). At the sensor level, M100 and M170 responses in FE-ScZ were within the normal range, whereas the M250 response was impaired. However, source localization revealed widespread elevated activity for M100 and M170 in FE-ScZ and delayed peak latencies for the M100 and M250 responses. In addition, M170 source activity in FE-ScZ was not modulated by stimulus repetitions. The present findings suggest that neural circuits in FE-ScZ may be characterized by a disturbed balance between excitation and inhibition that could lead to a failure to gate information flow and abnormal spreading of activity, which is compatible with dysfunctional glutamatergic neurotransmission.

Autism spectrum disorder (ASD) is a common developmental disorder characterized by communication difficulties and impaired social interaction. Recent results suggest altered brain dynamics as a potential cause of symptoms in ASD. Here, we aim to describe potential information-processing consequences of these alterations by measuring active information storage (AIS)-a key quantity in the theory of distributed computation in biological networks. AIS is defined as the mutual information between the past state of a process and its next measurement. It measures the amount of stored information that is used for computation of the next time step of a process. AIS is high for rich but predictable dynamics. We recorded magnetoencephalography (MEG) signals in 10 ASD patients and 14 matched control subjects in a visual task. After a beamformer source analysis, 12 task-relevant sources were obtained. For these sources, stationary baseline activity was analyzed using AIS. Our results showed a decrease of AIS values in the hippocampus of ASD patients in comparison with controls, meaning that brain signals in ASD were either less predictable, reduced in their dynamic richness or both. Our study suggests the usefulness of AIS to detect an abnormal type of dynamics in ASD. The observed changes in AIS are compatible with Bayesian theories of reduced use or precision of priors in ASD.

Introduction: High-frequency oscillations are important for sensory processing and dysfunctions in the amplitude and synchrony of beta- and gamma-band oscillations have been demonstrated in schizophrenia (ScZ). However, the presence of aberrant high-frequency oscillations in first-episode (FE), medication-naive patients during sensory processing is unclear., Methods: Magnetoencephalographic (MEG) data were recorded from 15 never-medicated, FE-ScZ patients and 20 matched healthy controls during the perception of Mooney faces. MEG data were analysed for spectral power and single-sensor phase-locking in the beta (13-25Hz) and gamma- (25-140Hz) frequency range., Results: FE-ScZ patients were characterized by significantly impaired sensory processing as indicated by a reduced discrimination index (A'). Impaired behavioural performance in ScZ-patients was accompanied by decreased spectral power in the high- (60-120Hz) gamma-band range. In contrast, oscillations in the lower (25-60Hz) gamma-band were largely intact and beta-band oscillations were increased. Analysis of cross-frequency coupling showed a reduced correlation between 60 and 120Hz amplitude values and beta-band power in FE-ScZ-patients relative to controls., Discussion: Our findings show that impaired sensory processing in medication-naive, FE-schizophrenia is related to a dysregulation of neural oscillations which involves both an impairment in the generation of high gamma-band activity as well as a failure to downregulate task-irrelevant beta-band activity. Because of the interrelationship of these dysfunctions and the role of inhibitory networks in the shaping of high-frequency activity, aberrant neural oscillations in FE-schizophrenia may be linked to dysfunctions in the excitation-inhibition (E/I)-balance., (© 2013.)

Current theories of the pathophysiology of schizophrenia have focused on abnormal temporal coordination of neural activity. Oscillations in the gamma-band range (>25 Hz) are of particular interest as they establish synchronization with great precision in local cortical networks. However, the contribution of high gamma (>60 Hz) oscillations toward the pathophysiology is less established. To address this issue, we recorded magnetoencephalographic (MEG) data from 16 medicated patients with chronic schizophrenia and 16 controls during the perception of Mooney faces. MEG data were analysed in the 25-150 Hz frequency range. Patients showed elevated reaction times and reduced detection rates during the perception of upright Mooney faces while responses to inverted stimuli were intact. Impaired processing of Mooney faces in schizophrenia patients was accompanied by a pronounced reduction in spectral power between 60-120 Hz (effect size: d = 1.26) which was correlated with disorganized symptoms (r = -0.72). Our findings demonstrate that deficits in high gamma-band oscillations as measured by MEG are a sensitive marker for aberrant cortical functioning in schizophrenia, suggesting an important aspect of the pathophysiology of the disorder.

Current theories of the pathophysiology of autism spectrum disorders (ASD) have focused on abnormal temporal coordination of neural activity in cortical circuits as a core impairment of the disorder. In the current study, we examined the possibility that gamma-band activity may be crucially involved in aberrant brain functioning in ASD. Magneto-encephalographic (MEG) data were recorded from 13 adult human participants with ASD and 16 controls during the presentation of Mooney faces. MEG data were analyzed in the 25-150 Hz frequency range and a beamforming approach was used to identify the sources of spectral power. Participants with ASD showed elevated reaction times and reduced detection rates during the perception of upright Mooney faces, while responses to inverted stimuli were in the normal range. Impaired perceptual organization in the ASD group was accompanied by a reduction in both the amplitude and phase locking of gamma-band activity. A beamforming approach identified distinct networks during perceptual organization in controls and participants with ASD. In controls, perceptual organization of Mooney faces involved increased 60-120 Hz activity in a frontoparietal network, while in the ASD group stronger activation was found in visual regions. These findings highlight the contribution of impaired gamma-band activity toward complex visual processing in ASD, suggesting atypical modulation of high-frequency power in frontoposterior networks.

Perceptual closure refers to the coherent perception of an object under circumstances when the visual information is incomplete. Although the perceptual closure index observed in electroencephalography reflects that an object has been recognized, the full spatiotemporal dynamics of cortical source activity underlying perceptual closure processing remain unknown so far. To address this question, we recorded magnetoencephalographic activity in 15 subjects (11 females) during a visual closure task and performed beamforming over a sequence of successive short time windows to localize high-frequency gamma-band activity (60-100 Hz). Two-tone images of human faces (Mooney faces) were used to examine perceptual closure. Event-related fields exhibited a magnetic closure index between 250 and 325 ms. Time-frequency analyses revealed sustained high-frequency gamma-band activity associated with the processing of Mooney stimuli; closure-related gamma-band activity was observed between 200 and 300 ms over occipitotemporal channels. Time-resolved source reconstruction revealed an early (0-200 ms) coactivation of caudal inferior temporal gyrus (cITG) and regions in posterior parietal cortex (PPC). At the time of perceptual closure (200-400 ms), the activation in cITG extended to the fusiform gyrus, if a face was perceived. Our data provide the first electrophysiological evidence that perceptual closure for Mooney faces starts with an interaction between areas related to processing of three-dimensional structure from shading cues (cITG) and areas associated with the activation of long-term memory templates (PPC). Later, at the moment of perceptual closure, inferior temporal cortex areas specialized for the perceived object are activated, i.e., the fusiform gyrus related to face processing for Mooney stimuli.