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Summary: Background: Phenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies. Methods: We studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models. Findings: 304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR = 1.39, 95% CI 1.08, 1.80, padj = 0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of +0.19 higher than relatives with a milder phenotype (padj = 0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype–phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (padj = 0.0010), the effect was not significant for SCN1B p.Cys121Trp. Interpretation: We provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with ‘monogenic’ epilepsies. In GEFS+ families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients. Funding: National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.

Compondo uma espécie de nova trilogia que revê a anterior das “cartas das Fontaínhas”, Juventude em Marcha (2006), Cavalo Dinheiro (2014) e Vitalina Varela (2019) de Pedro Costa ampliam seu foco no bairro marginal da periferia de Lisboa para as experiências da diáspora cabo-verdiana residente em Portugal e para a sua existência fraturada no tempo e no espaço, marcada pela emigração forçada, pela discriminação e pelo abandono. Mas, em vez de trabalhar essas vidas negadas apenas como material narrativo, os filmes de Costa também as incorporam na forma composicional. A natureza não consecutiva dos planos, a utilização do claro-escuro e dos limiares que fazem do invisível parte constitutiva do enquadramento e a rarefação da fala (quase sempre sob a forma de monólogos) são apenas alguns dos modos como o cinema de Costa ecoa a experiência de vida de suas personagens na própria estrutura do filme. Neste artigo, proponho que essa matriz composicional também alude (embora de forma não referencial) à dimensão histórica e geopolítica do Atlântico luso como origem do Plantationoceno colonial-moderno e do seu correlato contemporâneo, o “devir-Negro do mundo” (Mbembe, 2014).

Abstract The “dorsal pons”, or “dorsal pontine tegmentum” (dPnTg), is part of the brainstem. It is a complex, densely packed region whose nuclei are involved in regulating many vital functions. Notable among them are the parabrachial nucleus, the Kölliker Fuse, the Barrington nucleus, the locus coeruleus, and the dorsal, laterodorsal, and ventral tegmental nuclei. In this study, we applied single-nucleus RNA-seq (snRNA-seq) to resolve neuronal subtypes based on their unique transcriptional profiles and then used multiplexed error robust fluorescence in situ hybridization (MERFISH) to map them spatially. We sampled ~1 million cells across the dPnTg and defined the spatial distribution of over 120 neuronal subtypes. Our analysis identified an unpredicted high transcriptional diversity in this region and pinpointed the unique marker genes of many neuronal subtypes. We also demonstrated that many neuronal subtypes are transcriptionally similar between humans and mice, enhancing this study’s translational value. Finally, we developed a freely accessible, GPU and CPU-powered dashboard ( http://harvard.heavy.ai:6273/ ) that combines interactive visual analytics and hardware-accelerated SQL into a data science framework to allow the scientific community to query and gain insights into the data.

Der Begriff des Erzählens hat eine erstaunliche Karriere hingelegt. So kennen z.B. schon seit einiger Zeit auch Wirtschaft oder Politik das ,Storytelling‘. Ein derart erweitertes Verständnis von Narrativen wirft Fragen auf, wenn sich das Ganze zudem digital potenziert. Entsprechend versucht das vorliegende Heft, eine möglichst große Bandbreite für den Deutschunterricht aufzuzeigen. Das reicht vom schriftsprachlichen Erzählen (Otten / Ohlhus sowie Führer / Gerjets) über mediale Inszenierungen der Populärkultur (Meer / Bary sowie Wolbring) und aktuelle Kinder- und Jugendmedien (Krichel) bis hin zu wissenschaftsgeschichtlichen und methodischen Fragen: Welchen Narrativen folgte die Disziplin der Deutschdidaktik historisch (Dawidowski / Eickmeyer) und welchen folgt sie aktuell hinsichtlich möglicher Neuorientierungen wie z. B. bei den Digital Humanities (Herz)? Veränderte mediale Erscheinungsformen fordern schließlich immer wieder dazu heraus, deutschdidaktische Fragen zu (re-)perspektivieren.

IntroductionMusical roundness perception relies on consonance/dissonance within a rule-based harmonic context, but also on individual characteristics of the listener. The present work tackles these aspects in a combined psychoacoustic and neurophysiological study, taking into account participant’s musical aptitude.MethodsOur paradigm employed cadence-like four-chord progressions, based on Western music theory. Chord progressions comprised naturalistic and artificial sounds; moreover, their single chords varied regarding consonance/dissonance and harmonic function. Thirty participants listened to the chord progressions while their cortical activity was measured with magnetoencephalography; afterwards, they rated the individual chord progressions with respect to their perceived roundness.ResultsRoundness ratings differed according to the degree of dissonance in the dominant chord at the progression’s third position; this effect was pronounced in listeners with high musical aptitude. Interestingly, a corresponding pattern occurred in the neuromagnetic N1m response to the fourth chord (i.e., at the progression’s resolution), again with somewhat stronger differentiation among musical listeners. The N1m magnitude seemed to increase during chord progressions that were considered particularly round, with the maximum difference after the final chord; here, however, the musical aptitude effect just missed significance.DiscussionThe roundness of chord progressions is reflected in participant’s psychoacoustic ratings and in their transient cortical activity, with stronger differentiation among listeners with high musical aptitude. The concept of roundness might help to reframe consonance/dissonance to a more holistic, gestalt-like understanding that covers chord relations in Western music.

Abstract Birds are among the best-studied animal groups, but their prehistoric diversity is poorly known due to low fossilization potential. Hence, while many human-driven bird extinctions (i.e., extinctions caused directly by human activities such as hunting, as well as indirectly through human-associated impacts such as land use change, fire, and the introduction of invasive species) have been recorded, the true number is likely much larger. Here, by combining recorded extinctions with model estimates based on the completeness of the fossil record, we suggest that at least ~1300–1500 bird species (~12% of the total) have gone extinct since the Late Pleistocene, with 55% of these extinctions undiscovered (not yet discovered or left no trace). We estimate that the Pacific accounts for 61% of total bird extinctions. Bird extinction rate varied through time with an intense episode ~1300 CE, which likely represents the largest human-driven vertebrate extinction wave ever, and a rate 80 (60–95) times the background extinction rate. Thus, humans have already driven more than one in nine bird species to extinction, with likely severe, and potentially irreversible, ecological and evolutionary consequences.

The prior issue of Krisis (42:1) published Critical Naturalism: A Manifesto, with the aim to instigate a debate of the issues raised in this manifesto – the necessary re-thinking of the role (and the concept) of nature in critical theory in relation to questions of ecology, health, and inequality. Since Krisis considers itself a place for philosophical debates that take contemporary struggles as starting point, it issued an open call and solicited responses to the manifesto. This is one of the sixteen selected responses, which augment, specify, or question the assumptions and arguments of the manifesto.

Migraine headache is hypothesized to involve the activation and sensitization of trigeminal sensory afferents that innervate the cranial meninges. To better understand migraine pathophysiology and improve clinical translation, we used two-photon calcium imaging via a closed cranial window in awake mice to investigate changes in the responses of meningeal afferent fibers using a preclinical model of migraine involving cortical spreading depolarization (CSD). A single CSD episode caused a seconds-long wave of calcium activation that propagated across afferents and along the length of individual afferents. Surprisingly, unlike previous studies in anesthetized animals with exposed meninges, only a very small afferent population was persistently activated in our awake mouse preparation, questioning the relevance of this neuronal response to the onset of migraine pain. In contrast, we identified a larger subset of meningeal afferents that developed augmented responses to acute three-dimensional meningeal deformations that occur in response to locomotion bouts. We observed increased responsiveness in a subset of afferents that were already somewhat sensitive to meningeal deformation before CSD. Furthermore, another subset of previously insensitive afferents also became sensitive to meningeal deformation following CSD. Our data provides new insights into the mechanisms underlying migraine, including the emergence of enhanced meningeal afferent responses to movement-related meningeal deformations as a potential neural substrate underlying the worsening of migraine headache during physical activity.

Abstract Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake Ttr mNeonGreen mice via multi-day intracerebroventricular fiber photometry. Diurnal changes in ChP and CSF TTR levels correlated with CSF thyroid hormone levels. These datasets highlight an integrated platform for investigating diurnal control of brain states by the ChP and CSF.