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Driscoll, Rosch et al. design transparent graphene-based surface probes to achieve simultaneous electrophysiological recording and calcium imaging of epileptic seizures in mice. This method could be used to investigate circuit dynamics during seizure onset and evolution with high temporal and spatial resolution.

Neuropteran larvae are fierce predators that use venom to attack and feed on arthropod prey. Neuropterans have adapted to diverse and sometimes extreme habitats, suggesting their venom may have evolved accordingly, but the ecology and evolution of venom deployment in different families is poorly understood. We applied spatial transcriptomics, proteomics, morphological analysis, and bioassays to investigate the venom systems in the antlion Euroleon nostras and the lacewing Chrysoperla carnea, which occupy distinct niches. Although the venom system morphology was similar in both species, we observed remarkable differences at the molecular level. E. nostras produces particularly complex venom secreted from three different glands, indicating functional compartmentalization. Furthermore, E. nostras venom and digestive tissues were devoid of bacteria, strongly suggesting that all venom proteins are of insect origin rather than the products of bacterial symbionts. We identified several toxins exclusive to E. nostras venom, including phospholipase A2 and several undescribed proteins with no homologs in the C. carnea genome. The compositional differences have significant ecological implications because only antlion venom conferred insecticidal activity, indicating its use for the immobilization of large prey. Our results indicate that molecular venom evolution plays a role in the adaptation of antlions to their unique ecological niche., (© 2024. The Author(s).)

Consciousness has been proposed to be supported by electrophysiological patterns poised at criticality, a dynamical regime which exhibits adaptive computational properties, maximally complex patterns and divergent sensitivity to perturbation. Here, we investigate dynamical properties of the resting-state electroencephalogram (EEG) of healthy subjects undergoing general anesthesia with propofol, xenon or ketamine. Importantly, all participants were unresponsive under anesthesia, while consciousness was retained only during ketamine anesthesia (in the form of vivid dreams), enabling an experimental dissociation between unresponsiveness and unconsciousness. For each condition, we measure (i) avalanche criticality, (ii) chaoticity, and (iii) criticality-related metrics, revealing that states of unconsciousness are characterized by a distancing from both avalanche criticality and the edge of chaos. We then ask whether these same dynamical properties are predictive of the perturbational complexity index (PCI), a TMS-based measure that has shown remarkably high sensitivity in detecting consciousness independently of behavior. We successfully predict individual subjects' PCI values with considerably high accuracy from resting-state EEG dynamical properties alone. Our results establish a firm link between perturbational complexity and criticality, and provide further evidence that criticality is a necessary condition for the emergence of consciousness., (© 2024. The Author(s).)

Oscillatory activity is commonly observed during the maintenance of information in short-term memory, but its role remains unclear. Non-oscillatory models of short-term memory storage are able to encode stimulus identity through their spatial patterns of activity, but are typically limited to either an all-or-none representation of stimulus amplitude or exhibit a biologically implausible exact-tuning condition. Here we demonstrate a simple mechanism by which oscillatory input enables a circuit to generate persistent or sequential activity that encodes information not only in the spatial pattern of activity, but also in the amplitude of activity. This is accomplished through a phase-locking phenomenon that permits many different amplitudes of persistent activity to be stored without requiring exact tuning of model parameters. Altogether, this work proposes a class of models for the storage of information in working memory, a potential role for brain oscillations, and a dynamical mechanism for maintaining multi-stable neural representations., (© 2023. Springer Nature Limited.)

The intrinsically disordered protein tau aggregates into β-sheet amyloid fibrils that spread in human brains afflicted with Alzheimer's disease and other neurodegenerative diseases. Tau interaction with lipid membranes might play a role in the formation and spreading of these pathological aggregates. Here we investigate the conformation and assembly of membrane-induced tau aggregates using solid-state NMR and transmission electron microscopy. A tau construct that encompasses the microtubule-binding repeats and a proline-rich domain is reconstituted into cholesterol-containing phospholipid membranes. 2D 13 C- 13 C correlation spectra indicate that tau converted from a random coil to a β-sheet conformation over weeks. Small unilamellar vesicles (SUVs) cause different equilibrium conformations from large unilamellar vesicles (LUVs) and multilamellar vesicles (MLVs). Importantly, SUV-bound tau developed long fibrils that exhibit the characteristic β-sheet chemical shifts of Tyr310 in heparin-fibrillized tau. In comparison, LUVs and MLVs do not induce fibrils but cause different β-sheet aggregates. Lipid-protein correlation spectra indicate that these tau aggregates reside at the membrane-water interface, without inserting into the middle of the lipid bilayer. Removal of cholesterol from the SUVs abolished the fibrils, indicating that both membrane curvature and cholesterol are required for tau fibril formation. These results have implications for how lipid membranes might nucleate tau aggregates., (© 2023. The Author(s).)

The hippocampus is involved in processing a variety of mnemonic computations specifically the spatiotemporal components and emotional dimensions of contextual memory. Recent studies have demonstrated cellular heterogeneity along the hippocampal axis. The ventral hippocampus has been shown to be important in the processing of emotion and valence. Here, we combine transgenic and all-virus based activity-dependent tagging strategies to visualize multiple valence-specific engrams in the vHPC and demonstrate two partially segregated cell populations and projections that respond to appetitive and aversive experiences. Next, using RNA sequencing and DNA methylation sequencing approaches, we find that vHPC appetitive and aversive engram cells display different transcriptional programs and DNA methylation landscapes compared to a neutral engram population. Additionally, optogenetic manipulation of tagged cell bodies in vHPC is not sufficient to drive appetitive or aversive behavior in real-time place preference, stimulation of tagged vHPC terminals projecting to the amygdala and nucleus accumbens (NAc), but not the prefrontal cortex (PFC), showed the capacity drive preference and avoidance. These terminals also were able to change their capacity to drive behavior. We conclude that the vHPC contains genetically, cellularly, and behaviorally segregated populations of cells processing appetitive and aversive memory engrams., (© 2022. The Author(s).)

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in wildtype and transformed murine astrocytes, as well as patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned during early development by gonadal sex. These data provide a rationale for the further study of sex differences in radiation response and how senescence might be enhanced for radiation sensitization. The determination that p21 and gonadal sex are required for sex differences in radiation response will serve as a foundation for these future mechanistic studies., (© 2022. The Author(s).)

Significant advances have been made by identifying the levels of synchrony of the underlying dynamics of a given brain state. This research has demonstrated that non-conscious dynamics tend to be more synchronous than in conscious states, which are more asynchronous. Here we go beyond this dichotomy to demonstrate that different brain states are underpinned by dissociable spatiotemporal dynamics. We investigated human neuroimaging data from different brain states (resting state, meditation, deep sleep and disorders of consciousness after coma). The model-free approach was based on Kuramoto's turbulence framework using coupled oscillators. This was extended by a measure of the information cascade across spatial scales. Complementarily, the model-based approach used exhaustive in silico perturbations of whole-brain models fitted to these measures. This allowed studying of the information encoding capabilities in given brain states. Overall, this framework demonstrates that elements from turbulence theory provide excellent tools for describing and differentiating between brain states., (© 2022. The Author(s).)

The non-classical class Ib molecule human leukocyte antigen E (HLA-E) has limited polymorphism and can bind HLA class Ia leader peptides (VL9). HLA-E-VL9 complexes interact with the natural killer (NK) cell receptors NKG2A-C/CD94 and regulate NK cell-mediated cytotoxicity. Here we report the isolation of 3H4, a murine HLA-E-VL9-specific IgM antibody that enhances killing of HLA-E-VL9-expressing cells by an NKG2A + NK cell line. Structural analysis reveal that 3H4 acts by preventing CD94/NKG2A docking on HLA-E-VL9. Upon in vitro maturation, an affinity-optimized IgG form of 3H4 showes enhanced NK killing of HLA-E-VL9-expressing cells. HLA-E-VL9-specific IgM antibodies similar in function to 3H4 are also isolated from naïve B cells of cytomegalovirus (CMV)-negative, healthy humans. Thus, HLA-E-VL9-targeting mouse and human antibodies isolated from the naïve B cell antibody pool have the capacity to enhance NK cell cytotoxicity., (© 2022. The Author(s).)

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance., (© 2022. The Author(s).)

Low-level states of consciousness are characterized by disruptions of brain activity that sustain arousal and awareness. Yet, how structural, dynamical, local and network brain properties interplay in the different levels of consciousness is unknown. Here, we study fMRI brain dynamics from patients that suffered brain injuries leading to a disorder of consciousness and from healthy subjects undergoing propofol-induced sedation. We show that pathological and pharmacological low-level states of consciousness display less recurrent, less connected and more segregated synchronization patterns than conscious state. We use whole-brain models built upon healthy and injured structural connectivity to interpret these dynamical effects. We found that low-level states of consciousness were associated with reduced network interactions, together with more homogeneous and more structurally constrained local dynamics. Notably, these changes lead the structural hub regions to lose their stability during low-level states of consciousness, thus attenuating the differences between hubs and non-hubs brain dynamics., (© 2021. The Author(s).)

Death-associated protein kinase 2 (DAPK2) is a CaM-regulated Ser/Thr protein kinase, involved in apoptosis, autophagy, granulocyte differentiation and motility regulation, whose activity is controlled by autoinhibition, autophosphorylation, dimerization and interaction with scaffolding proteins 14-3-3. However, the structural basis of 14-3-3-mediated DAPK2 regulation remains unclear. Here, we structurally and biochemically characterize the full-length human DAPK2:14-3-3 complex by combining several biophysical techniques. The results from our X-ray crystallographic analysis revealed that Thr369 phosphorylation at the DAPK2 C terminus creates a high-affinity canonical mode III 14-3-3-binding motif, further enhanced by the diterpene glycoside Fusicoccin A. Moreover, concentration-dependent DAPK2 dimerization is disrupted by Ca 2+ /CaM binding and stabilized by 14-3-3 binding in solution, thereby protecting the DAPK2 inhibitory autophosphorylation site Ser318 against dephosphorylation and preventing Ca 2+ /CaM binding. Overall, our findings provide mechanistic insights into 14-3-3-mediated DAPK2 inhibition and highlight the potential of the DAPK2:14-3-3 complex as a target for anti-inflammatory therapies., (© 2021. The Author(s).)

Neural precursor cell expressed developmentally down-regulated 4 ligase (Nedd4-2) is an E3 ubiquitin ligase that targets proteins for ubiquitination and endocytosis, thereby regulating numerous ion channels, membrane receptors and tumor suppressors. Nedd4-2 activity is regulated by autoinhibition, calcium binding, oxidative stress, substrate binding, phosphorylation and 14-3-3 protein binding. However, the structural basis of 14-3-3-mediated Nedd4-2 regulation remains poorly understood. Here, we combined several techniques of integrative structural biology to characterize Nedd4-2 and its complex with 14-3-3. We demonstrate that phosphorylated Ser 342 and Ser 448 are the key residues that facilitate 14-3-3 protein binding to Nedd4-2 and that 14-3-3 protein binding induces a structural rearrangement of Nedd4-2 by inhibiting interactions between its structured domains. Overall, our findings provide the structural glimpse into the 14-3-3-mediated Nedd4-2 regulation and highlight the potential of the Nedd4-2:14-3-3 complex as a pharmacological target for Nedd4-2-associated diseases such as hypertension, epilepsy, kidney disease and cancer., (© 2021. The Author(s).)

Casein kinase 2 (CK2) is a pleiotropic kinase phosphorylating substrates in different cellular compartments in eukaryotes. In the malaria parasite Plasmodium falciparum, PfCK2 is vital for asexual proliferation of blood-stage parasites. Here, we applied CRISPR/Cas9-based gene editing to investigate the function of the PfCK2α catalytic subunit in gametocytes, the sexual forms of the parasite that are essential for malaria transmission. We show that PfCK2α localizes to the nucleus and cytoplasm in asexual and sexual parasites alike. Conditional knockdown of PfCK2α expression prevented the transition of stage IV into transmission-competent stage V gametocytes, whereas the conditional knockout of pfck2a completely blocked gametocyte maturation already at an earlier stage of sexual differentiation. In summary, our results demonstrate that PfCK2α is not only essential for asexual but also sexual development of P. falciparum blood-stage parasites and encourage studies exploring PfCK2α as a potential target for dual-active antimalarial drugs.

Recent work has considered the relationship between value and confidence in both behavioural and neural representation. Here we evaluated whether the brain organises value and confidence signals in a systematic fashion that reflects the overall desirability of options. If so, regions that respond to either increases or decreases in both value and confidence should be widespread. We strongly confirmed these predictions through a model-based fMRI analysis of a mixed gambles task that assessed subjective value (SV) and inverse decision entropy (iDE), which is related to confidence. Purported value areas more strongly signalled iDE than SV, underscoring how intertwined value and confidence are. A gradient tied to the desirability of actions transitioned from positive SV and iDE in ventromedial prefrontal cortex to negative SV and iDE in dorsal medial prefrontal cortex. This alignment of SV and iDE signals could support retrospective evaluation to guide learning and subsequent decisions.

Uncovering cellular responses from heterogeneous genomic data is crucial for molecular medicine in particular for drug safety. This can be realized by integrating the molecular activities in networks of interacting proteins. As proof-of-concept we challenge network modeling with time-resolved proteome, transcriptome and methylome measurements in iPSC-derived human 3D cardiac microtissues to elucidate adverse mechanisms of anthracycline cardiotoxicity measured with four different drugs (doxorubicin, epirubicin, idarubicin and daunorubicin). Dynamic molecular analysis at in vivo drug exposure levels reveal a network of 175 disease-associated proteins and identify common modules of anthracycline cardiotoxicity in vitro, related to mitochondrial and sarcomere function as well as remodeling of extracellular matrix. These in vitro-identified modules are transferable and are evaluated with biopsies of cardiomyopathy patients. This to our knowledge most comprehensive study on anthracycline cardiotoxicity demonstrates a reproducible workflow for molecular medicine and serves as a template for detecting adverse drug responses from complex omics data.

In contrast to the vast majority of reptiles, the skulls of adult crown birds are characterized by a high degree of integration due to bone fusion, e.g., an ontogenetic event generating a net reduction in the number of bones. To understand this process in an evolutionary context, we investigate postnatal ontogenetic changes in the skulls of crown bird and non-avian theropods using anatomical network analysis (AnNA). Due to the greater number of bones and bone contacts, early juvenile crown birds have less integrated skulls, resembling their non-avian theropod ancestors, including Archaeopteryx lithographica and Ichthyornis dispars. Phylogenetic comparisons indicate that skull bone fusion and the resulting modular integration represent a peramorphosis (developmental exaggeration of the ancestral adult trait) that evolved late during avialan evolution, at the origin of crown-birds. Succeeding the general paedomorphic shape trend, the occurrence of an additional peramorphosis reflects the mosaic complexity of the avian skull evolution.