Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids.

Disruptions in the tightly regulated process of human brain development have been linked to increased risk for brain and mental illnesses. While the genetic contribution to these diseases is well established, important environmental factors have been less studied at molecular and cellular levels. Here, we used single-cell and cell type-specific techniques to investigate the effect of glucocorticoid (GC) exposure, a mediator of antenatal environmental risk, on gene regulation and lineage specification in unguided human neural organoids. We characterized the transcriptional response to chronic GC exposure during neural differentiation and studied the underlying gene regulatory networks by integrating single-cell transcriptomics with chromatin accessibility data. We found lasting cell type-specific changes that included autism risk genes and several transcription factors associated with neurodevelopment. Chronic GC exposure influenced lineage specification primarily by priming the inhibitory neuron lineage through transcription factors like PBX3. We provide evidence for convergence of genetic and environmental risk factors through a common mechanism of altering lineage specification

A decision-theoretic model of perceptual multistability: perceptual switches as internal actions

Perceptual multistability has been studied for centuries using a diverse collection of approaches. Insights derived from this phenomenon range from core principles of information processing, such as perceptual inference, to high-level concerns, such as visual awareness. The dominant computational explanations of perceptual multistability are based on the Helmholtzian view of perception as inverse inference. However, these approaches struggle to account for the crucial role played by value, e.g., with percepts paired with reward dominating for longer periods than unpaired ones. In this study, we formulate perceptual multistability in terms of dynamic, value-based, choice, employing the formalism of a partially observable Markov decision process (POMDP). We use binocular rivalry as an example, considering different explicit and implicit sources of reward (and punishment) for each percept. The resulting values are time-dependent and influenced by novelty as a form of exploration. The solution of the POMDP is the optimal perceptual policy, and we show that this can replicate and explain several characteristics of binocular rivalry, ranging from classic hallmarks such as apparently spontaneous random switches with approximately gamma-distributed dominance periods to more subtle aspects such as the rich temporal dynamics of perceptual switching rates. Overall, our decision-theoretic perspective on perceptual multistability not only accounts for a wealth of unexplained data, but also opens up modern conceptions of internal reinforcement learning in service of understanding perceptual phenomena, and sensory processing more generally

SUMO2/3 conjugation of TDP-43 protects against aggregation.

Cytosolic aggregation of the RNA binding protein TDP-43 (transactive response DNA-binding protein 43) is a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. Here, we report that during oxidative stress, TDP-43 becomes SUMO2/3-ylated by the SUMO E3 ligase protein PIAS4 (protein inhibitor of activated STAT 4) and enriches in cytoplasmic stress granules (SGs). Upon pharmacological inhibition of TDP-43 SUMO2/3-ylation or PIAS4 depletion, TDP-43 enrichment in SGs is accompanied by irreversible aggregation. In cells that are unable to assemble SGs, SUMO2/3-ylation of TDP-43 is strongly impaired, supporting the notion that SGs are compartments that promote TDP-43 SUMO2/3-ylation during oxidative stress. Binding of TDP-43 to UG-rich RNA antagonizes PIAS4-mediated SUMO2/3-ylation, while RNA dissociation promotes TDP-43 SUMO2/3-ylation. We conclude that SUMO2/3 protein conjugation is a cellular mechanism to stabilize cytosolic RNA-free TDP-43 against aggregation

MolecularWebXR: Multiuser discussions in chemistry and biology through immersive and inclusive augmented and virtual reality

MolecularWebXR is a new web-based platform for education, science communication and scientific peer discussion in chemistry and biology, based on modern web-based Virtual Reality (VR) and Augmented Reality (AR). With no installs as it is all web-served, MolecularWebXR enables multiple users to simultaneously explore, communicate and discuss concepts about chemistry and biology in immersive 3D environments, by manipulating and passing around objects with their bare hands and pointing at different elements with natural hand gestures. Users may either be present in the same physical space or distributed around the world, in the latter case talking naturally with each other thanks to built-in audio. While MolecularWebXR offers the most immersive experience on high-end AR/VR headsets, its WebXR core also supports participation on consumer devices such as smartphones (with optional cardboard goggles for enhanced immersion), computers, and tablets. MolecularWebXR includes preset VR rooms covering topics in general, inorganic, and organic chemistry, as well as biophysics, structural biology, and general biology. Users can also add new content via the PDB2AR tool. We demonstrate MolecularWebXR's versatility and ease of use across a wide age range (12-80) in fully virtual and mixed real-virtual sessions at science outreach events, undergraduate and graduate courses, scientific collaborations, and conference presentations. MolecularWebXR is available for free use without registration at https://molecularwebxr.org. A blog post version of this preprint with embedded videos is available at https://go.epfl.ch/molecularwebxr-blog-post

Working memory capacity predicts sensitivity to prosodic structure

Listeners vary in the perception and interpretation of speech prosody (the variations in intonation, loudness, and rhythm of spoken language). The source of this variability is unknown. We investigated whether the ability to recognise and classify prosodic structure is related to working memory (WM) capacity. This hypothesis stems from the tight connection between prosodic and syntactic (grammatical) structure, while processing syntax is known to relate to WN capacity. Healthy adult speakers of Dutch judged prosodic structures in a gating paradigm. The phrases contained early and late intonational cues that signalled whether the phrases contained an internal grouping or not. Listeners also took part in WM (digit span) and processing speed (letter comparison) tasks. There was an interaction between performance in the prosody judgement and WM tasks: high-WM listeners were better at classifying prosodic structure and required less prosodic information to detect the correct structure. There was no interaction between prosody processing and processing speed, suggesting that the interaction between prosodic judgement and WM capacity was not due to motivational or attentional differences. The results demonstrate a close relationship between prosody processing and WM abilities, implying that WM is an important component of prosody processing

Unionsrechtliche Regressionsverbote: Transparenzgebote oder Pflicht zur überschießenden Umsetzung? Auslegungsoptionen und Implikationen für die CSDDD-Umsetzung im Wege einer LkSG-Reform

Regressionsverbote in mindestharmonisierenden europäischen Richtlinien legen fest, unter welchen Voraussetzungen die Mitgliedstaaten ein über die Mindestvorgaben hinausgehendes nationales Schutzniveau zurückschneiden dürfen. Der Beitrag untersucht anlässlich des Regressionsverbots in Art. EU_RL_2024_1760 Artikel 1 EU_RL_2024_1760 Artikel 1 Absatz II CSDDD den bisherigen Umgang mit derartigen Klauseln in der Rechtsprechung des EuGH und argumentiert für eine primärrechtskonforme Auslegung als bloßes Transparenzgebot. Er kommt zu dem Ergebnis, dass Art. EU_RL_2024_1760 Artikel 1 EU_RL_2024_1760 Artikel 1 Absatz II CSDDD einem Rückschnitt des LkSG-Anwendungsbereichs auf die Mindestvorgaben der Richtlinie nicht grundsätzlich entgegensteht.Non-regression clauses in EU directives determine the conditions under which Member States may reduce the level of protection that exceeds the minimum requirements of a directive. This article examines how such clauses have been dealt with in the case law of the ECJ to date and argues in favour of an interpretation in conformity with primary law as mere transparency requirements. With a view to the transposition of the CSDDD into German law, it concludes that the non-regression clause in Art. EU_RL_2024_1760 Artikel 1 EU_RL_2024_1760 Artikel 1 Absatz (2) CSDDD does not categorically prevent a reduction of the LkSG’s scope of application according to the directive’s minimum requirements

Pearls on a String: Dark and Bright Galaxies on a Strikingly Straight and Narrow Filament

We identify a chain of galaxies along an almost straight line in the nearby Universe with a projected length of similar to 5 Mpc. The galaxies are distributed within projected distances of only 7-105 kpc from the axis of the identified filament. They have redshifts in a very small range of z = 0.0361-0.0370 so that their radial velocities are consistent with galaxy proper motions. The filament galaxies are mainly star forming and have stellar masses in a range of 10(9.1)-10(10.7)M(circle dot). We search for systems with similar geometrical properties in the full-sky mock galaxy catalog of the MillenniumTNG simulations and find that, although such straight filaments are unusual and rare, they are predicted by Lambda CDM simulations (4% incidence). We study the cold H I gas in a 1.3 Mpc section of the filament through H I 21 cm emission line observations and detect 11 H I sources, many more than expected from the H I mass function in a similar volume. They have H I masses 10(8.5)-10(9.5)M(circle dot) and are mostly within similar to 120 kpc projected distance from the filament axis. None of these H i sources has a confirmed optical counterpart. Their darkness together with their large H I 21 cm line widths indicates that they contain gas that might not yet be virialized. These clouds must be marking the peaks of the dark matter and H I distributions over large scales within the filament. The presence of such gas clouds around the filament spines is predicted by simulations, but this is the first time that the existence of such clouds in a filament is observationally confirmed

Breaking Barriers in PROTAC Design: Improving Solubility of USP7-Targeting Degraders

The development of von Hippel–Lindau (VHL) hijacking proteolysis-targeting chimeras (PROTACs) has been hindered by suboptimal physicochemical properties, including high total polar surface area (TPSA), high hydrogen bond donor (HBD) counts, and poor solubility. This study explores a novel approach to enhance the physicochemical characteristics of VHL-recruiting USP7 degraders while maintaining their efficacy. By systematically optimizing the lipophilicity, hydrogen bond donor count, and the TPSA of USP-targeting moieties, we designed a series of VHL-based degraders with improved solubility and target degradation potential. The introduction of a constrained six-membered ring in the VHL-binding scaffold or the incorporation of solubilizing groups in the VHL ligand moiety notably improved aqueous solubility without compromising degradation activity. Among the compounds resulting from the latter approach, the bis-basic piperazine-modified PROTAC 40 showed a remarkable 170-fold increase in solubility compared to its precursor while retaining high target selectivity and degradation efficiency. This study demonstrates that tailored modifications to the VHL-binding scaffold can yield solubility-enhanced PROTACs with broad applicability. The methodology may be extended to other E3 ligases to expand the arsenal of degraders for in vivo studies