Sororin is an evolutionary conserved antagonist of WAPL.

Cohesin mediates sister chromatid cohesion to enable chromosome segregation and DNA damage repair. To perform these functions, cohesin needs to be protected from WAPL, which otherwise releases cohesin from DNA. It has been proposed that cohesin is protected from WAPL by SORORIN. However, in vivo evidence for this antagonism is missing and SORORIN is only known to exist in vertebrates and insects. It is therefore unknown how important and widespread SORORIN's functions are. Here we report the identification of SORORIN orthologs in Schizosaccharomyces pombe (Sor1) and Arabidopsis thaliana (AtSORORIN). sor1Δ mutants display cohesion defects, which are partially alleviated by wpl1Δ. Atsororin mutant plants display dwarfism, tissue specific cohesion defects and chromosome mis-segregation. Furthermore, Atsororin mutant plants are sterile and separate sister chromatids prematurely at anaphase I. The somatic, but not the meiotic deficiencies can be alleviated by loss of WAPL. These results provide in vivo evidence for SORORIN antagonizing WAPL, reveal that SORORIN is present in organisms beyond the animal kingdom and indicate that it has acquired tissue specific functions in plants.

Quantitative imaging of loop extruders rebuilding interphase genome architecture after mitosis.

How cells establish the interphase genome organization after mitosis is incompletely understood. Using quantitative and super-resolution microscopy, we show that the transition from a Condensin to a Cohesin-based genome organization occurs dynamically over two hours. While a significant fraction of Condensins remains chromatin-bound until early G1, Cohesin-STAG1 and its boundary factor CTCF are rapidly imported into daughter nuclei in telophase, immediately bind chromosomes as individual complexes and are sufficient to build the first interphase TAD structures. By contrast, the more abundant Cohesin-STAG2 accumulates on chromosomes only gradually later in G1, is responsible for compaction inside TAD structures and forms paired complexes upon completed nuclear import. Our quantitative time-resolved mapping of mitotic and interphase loop extruders in single cells reveals that the nested loop architecture formed by sequential action of two Condensins in mitosis is seamlessly replaced by a less compact, but conceptually similar hierarchically nested loop architecture driven by sequential action of two Cohesins.

Active afforestation of drained peatlands is not a viable option under the EU Nature Restoration Law.

The EU Nature Restoration Law (NRL) is critical for the restoration of degraded ecosystems and active afforestation of degraded peatlands has been suggested as a restoration measure under the NRL. Here, we discuss the current state of scientific evidence on the climate mitigation effects of peatlands under forestry. Afforestation of drained peatlands without restoring their hydrology does not fully restore ecosystem functions. Evidence on long-term climate benefits is lacking and it is unclear whether CO2 sequestration of forest on drained peatland can offset the carbon loss from the peat over the long-term. While afforestation may offer short-term gains in certain cases, it compromises the sustainability of peatland carbon storage. Thus, active afforestation of drained peatlands is not a viable option for climate mitigation under the EU Nature Restoration Law and might even impede future rewetting/restoration efforts. Instead, restoring hydrological conditions through rewetting is crucial for effective peatland restoration.

Decomposition of Reinforcement Learning Deficits in Disordered Gambling via Drift Diffusion Modeling and Functional Magnetic Resonance Imaging.

Gambling disorder is associated with deficits in reward-based learning, but the underlying computational mechanisms are still poorly understood. Here, we examined this issue using a stationary reinforcement learning task in combination with computational modeling and functional resonance imaging (fMRI) in individuals that regular participate in gambling (n = 23, seven fulfilled one to three DSM 5 criteria for gambling disorder, sixteen fulfilled four or more) and matched controls (n = 23). As predicted, the gambling group exhibited substantially reduced accuracy, whereas overall response times (RTs) were not reliably different between groups. We then used comprehensive modeling using reinforcement learning drift diffusion models (RLDDMs) in combination with hierarchical Bayesian parameter estimation to shed light on the computational underpinnings of this performance deficit. In both groups, an RLDDM in which both non-decision time and decision threshold (boundary separation) changed over the course of the experiment accounted for the data best. The model showed good parameter and model recovery, and posterior predictive checks revealed that, in both groups, the model accurately reproduced the evolution of accuracies and RTs over time. Modeling revealed that, compared to controls, the learning impairment in the gambling group was linked to a more rapid reduction in decision thresholds over time, and a reduced impact of value-differences on the drift rate. The gambling group also showed shorter non-decision times. FMRI analyses replicated effects of prediction error coding in the ventral striatum and value coding in the ventro-medial prefrontal cortex, but there was no credible evidence for group differences in these effects. Taken together, our findings show that reinforcement learning impairments in disordered gambling are linked to both maladaptive decision threshold adjustments and a reduced consideration of option values in the choice process.

Corrigendum: Individuals under voluntary treatment with sexual interest in minors: what risk do they pose?

[This corrects the article DOI: 10.3389/fpsyt.2023.1277225.].

On the Benefit of Optimal Transport for Curriculum Reinforcement Learning.

Curriculum reinforcement learning (CRL) allows solving complex tasks by generating a tailored sequence of learning tasks, starting from easy ones and subsequently increasing their difficulty. Although the potential of curricula in RL has been clearly shown in various works, it is less clear how to generate them for a given learning environment, resulting in various methods aiming to automate this task. In this work, we focus on framing curricula as interpolations between task distributions, which has previously been shown to be a viable approach to CRL. Identifying key issues of existing methods, we frame the generation of a curriculum as a constrained optimal transport problem between task distributions. Benchmarks show that this way of curriculum generation can improve upon existing CRL methods, yielding high performance in various tasks with different characteristics.

Acceptance and Usability of a Soft Robotic, Haptic Feedback Seat for Autonomy Level Transitions in Highly Automated Vehicles.

Fully autonomous vehicles, capable of completing entire end-to-end journeys without the interference of a human driver, will be one of the biggest transforming technologies of the next decades. As the journey towards fully autonomous vehicles progresses, there will be an increase in the number of highly automated vehicles on the roads, requiring the human driver to take back control in situations, which cannot be handled by the vehicle autonomously. These human-robot take-over requests can lead to safety risks, in particular in scenarios when the driver fails to understand the take-over request and, hence, lacks situational awareness. This paper presents the acceptance and usability assessment of a haptic feedback driver seat capable of informing the driver of a take-over request through static mechano-tactile haptic feedback. The seat is equipped with an embedded array of soft pneumatic actuators, that have been fully modelled and characterised. The evaluation process of the haptic feedback seat engaged 21 participants who experienced both auditory and haptic feedback from the seat in a number of simulation experiments within a driving simulator. The vehicular technology was assessed through well-established methods to understand the acceptance (usefulness and satisfaction) and usability of the haptic feedback driver seat.

Identification, semi-quantification and risk assessment of contaminants of emerging concern in Flemish indoor dust through high-resolution mass spectrometry.

Indoor dust can contribute substantially to human exposure to known and contaminants of emerging concern (CECs). Novel compounds with high structural variability and different homologues are frequently discovered through screening of the indoor environment, implying that constant monitoring is required. The present study aimed at the identification and semi-quantification of CECs in 46 indoor dust samples collected in Belgium by liquid chromatography high-resolution mass spectrometry. Samples were analyzed applying a targeted and suspect screening approach; the latter based on a suspect list containing >4000 CECs. This allowed the detection of a total of 55 CECs, 34 and 21 of which were identified with confidence level (CL) 1/2 or CL 3, respectively. Besides numerous known contaminants such as di(2-ethylhexyl) phthalate (DEHP), di(2-ethylhexyl) adipate (DEHA) or tris(2-butoxyethyl) phosphate (TBOEP) which were reported with detection frequencies (DFs) > 90%, several novel CECs were annotated. These included phthalates with differing side chains, such as decyl nonyl and decyl undecyl phthalate detected with DFs >80% and identified through the observation of characteristic neutral losses. Additionally, two novel organophosphate flame retardants not previously described in indoor dust, i.e. didecyl butoxyethoxyethyl phosphate (DDeBEEP) and bis(butoxyethyl) butyl phosphate (BBEBP), were identified. The implementation of a dedicated workflow provided semi-quantitative concentrations for a set of suspects. Such data obtained for novel phthalates were in the same order of magnitude as the concentrations observed for legacy phthalates indicating their high relevance for human exposure. From the semi-quantitative data, estimated daily intakes and resulting hazard quotients (HQs) were calculated to estimate the exposure and potential health effects. Neither of the obtained HQ values exceeded the risk threshold, indicating no expected adverse health effects.

Variational Hierarchical Mixtures for Probabilistic Learning of Inverse Dynamics.

Well-calibrated probabilistic regression models are a crucial learning component in robotics applications as datasets grow rapidly and tasks become more complex. Unfortunately, classical regression models are usually either probabilistic kernel machines with a flexible structure that does not scale gracefully with data or deterministic and vastly scalable automata, albeit with a restrictive parametric form and poor regularization. In this paper, we consider a probabilistic hierarchical modeling paradigm that combines the benefits of both worlds to deliver computationally efficient representations with inherent complexity regularization. The presented approaches are probabilistic interpretations of local regression techniques that approximate nonlinear functions through a set of local linear or polynomial units. Importantly, we rely on principles from Bayesian nonparametrics to formulate flexible models that adapt their complexity to the data and can potentially encompass an infinite number of components. We derive two efficient variational inference techniques to learn these representations and highlight the advantages of hierarchical infinite local regression models, such as dealing with non-smooth functions, mitigating catastrophic forgetting, and enabling parameter sharing and fast predictions. Finally, we validate this approach on large inverse dynamics datasets and test the learned models in real-world control scenarios.

Individuals under voluntary treatment with sexual interest in minors: what risk do they pose?

Child Sexual Abuse (CSA) and the production, use, and distribution of Child Sexual Abuse Material (CSAM) are key threats to children's mental health. From the perspective of indicated prevention, it can be assumed that some persons with a sexual interest in children commit such unreported crimes. Accordingly, the German Network kein Täter werden (meaning do not offend) has implemented a confidential treatment service for persons with a sexual interest in minors who voluntarily seek therapy, might or might not have offended but have not yet been detected or have fulfilled all legal requirements (here referred to as non-forensic individuals). However, this offer has been questioned for investing resources in a group which critics consider as low risk. The following study addresses the question of recidivism risks for CSA or viewing CSAM among non-forensic individuals. We found significantly higher rates of CSA/CSAM in our participants' history compared to a German study on a representative sample of males. Regarding CSAM, the recidivism rate of 39% was found to be 11 times higher than the expected recidivism rate based on previous publications. Regarding CSA, the recidivism rate of 14% was not significantly different from the expected rate reported for subjects with a conviction for a sexual contact offense. Among various risk instruments, only the CPORT with CASIC rating was able to predict CSA (AUC = 0.69, 95% CI = 0.55, 0.82) and CSAM (AUC = 0.63, 95% CI = 0.53, 0.73) among individuals with a history of CSAM, but with poor discrimination. We conclude that a large proportion of our sample poses a substantial risk and therefore treatment resources are well invested. However, further studies are needed to improve risk assessment among non-forensic clients.

The landscape of open science in behavioral addiction research: Current practices and future directions.

Open science refers to a set of practices that aim to make scientific research more transparent, accessible, and reproducible, including pre-registration of study protocols, sharing of data and materials, the use of transparent research methods, and open access publishing. In this commentary, we describe and evaluate the current state of open science practices in behavioral addiction research. We highlight the specific value of open science practices for the field; discuss recent field-specific meta-scientific reviews that show the adoption of such practices remains in its infancy; address the challenges to engaging with open science; and make recommendations for how researchers, journals, and scientific institutions can work to overcome these challenges and promote high-quality, transparently reported behavioral addiction research. By collaboratively promoting open science practices, the field can create a more sustainable and productive research environment that benefits both the scientific community and society as a whole.

Cohesin and CTCF do not assemble TADs in Xenopus sperm and male pronuclei.

Paternal genomes are compacted during spermiogenesis and decompacted following fertilization. These processes are fundamental for inheritance but incompletely understood. We analyzed these processes in the frog Xenopus laevis, whose sperm can be assembled into functional pronuclei in egg extracts in vitro. In such extracts, cohesin extrudes DNA into loops, but in vivo cohesin only assembles topologically associating domains (TADs) at the mid-blastula transition (MBT). Why cohesin assembles TADs only at this stage is unknown. We first analyzed genome architecture in frog sperm and compared it to human and mouse. Our results indicate that sperm genome organization is conserved between frogs and humans and occurs without formation of TADs. TADs can be detected in mouse sperm samples, as reported, but these structures might originate from somatic chromatin contaminations. We therefore discuss the possibility that the absence of TADs might be a general feature of vertebrate sperm. To analyze sperm genome remodeling upon fertilization, we reconstituted male pronuclei in Xenopus egg extracts. In pronuclei, chromatin compartmentalization increases, but cohesin does not accumulate at CTCF sites and assemble TADs. However, if pronuclei are formed in the presence of exogenous CTCF, CTCF binds to its consensus sites, and cohesin accumulates at these and forms short-range chromatin loops, which are preferentially anchored at CTCF's N terminus. These results indicate that TADs are only assembled at MBT because before this stage CTCF sites are not occupied and cohesin only forms short-range chromatin loops.

How do molecular motors fold the genome?

A potential mechanism of DNA loop extrusion by molecular motors is discussed.

A human-centered safe robot reinforcement learning framework with interactive behaviors.

Deployment of Reinforcement Learning (RL) algorithms for robotics applications in the real world requires ensuring the safety of the robot and its environment. Safe Robot RL (SRRL) is a crucial step toward achieving human-robot coexistence. In this paper, we envision a human-centered SRRL framework consisting of three stages: safe exploration, safety value alignment, and safe collaboration. We examine the research gaps in these areas and propose to leverage interactive behaviors for SRRL. Interactive behaviors enable bi-directional information transfer between humans and robots, such as conversational robot ChatGPT. We argue that interactive behaviors need further attention from the SRRL community. We discuss four open challenges related to the robustness, efficiency, transparency, and adaptability of SRRL with interactive behaviors.

Dopamine regulates decision thresholds in human reinforcement learning in males.

Dopamine fundamentally contributes to reinforcement learning, but recent accounts also suggest a contribution to specific action selection mechanisms and the regulation of response vigour. Here, we examine dopaminergic mechanisms underlying human reinforcement learning and action selection via a combined pharmacological neuroimaging approach in male human volunteers (n = 31, within-subjects; Placebo, 150 mg of the dopamine precursor L-dopa, 2 mg of the D2 receptor antagonist Haloperidol). We found little credible evidence for previously reported beneficial effects of L-dopa vs. Haloperidol on learning from gains and altered neural prediction error signals, which may be partly due to differences experimental design and/or drug dosages. Reinforcement learning drift diffusion models account for learning-related changes in accuracy and response times, and reveal consistent decision threshold reductions under both drugs, in line with the idea that lower dosages of D2 receptor antagonists increase striatal DA release via an autoreceptor-mediated feedback mechanism. These results are in line with the idea that dopamine regulates decision thresholds during reinforcement learning, and may help to bridge action selection and response vigor accounts of dopamine.

Chronic Deep Brain Stimulation of the Human Nucleus Accumbens Region Disrupts the Stability of Intertemporal Preferences.

When choosing between rewards that differ in temporal proximity (intertemporal choice), human preferences are typically stable, constituting a clinically relevant transdiagnostic trait. Here we show, in female and male human patients undergoing deep brain stimulation (DBS) of the anterior limb of the internal capsule/NAcc region for treatment-resistant obsessive-compulsive disorder, that long-term chronic (but not phasic) DBS disrupts intertemporal preferences. Hierarchical Bayesian modeling accounting for temporal discounting behavior across multiple time points allowed us to assess both short-term and long-term reliability of intertemporal choice. In controls, temporal discounting was highly reliable, both long-term (6 months) and short-term (1 week). In contrast, in patients undergoing DBS, short-term reliability was high, but long-term reliability (6 months) was severely disrupted. Control analyses confirmed that this effect was not because of range restriction, the presence of obsessive-compulsive disorder symptoms or group differences in choice stochasticity. Model-agnostic between- and within-subject analyses confirmed this effect. These findings provide initial evidence for long-term modulation of cognitive function via DBS and highlight a potential contribution of the human NAcc region to intertemporal preference stability over time.SIGNIFICANCE STATEMENT Choosing between rewards that differ in temporal proximity is in part a stable trait with relevance for many mental disorders, and depends on prefrontal regions and regions of the dopamine system. Here we show that chronic deep brain stimulation of the human anterior limb of the internal capsule/NAcc region for treatment-resistant obsessive-compulsive disorder disrupts the stability of intertemporal preferences. These findings show that chronic stimulation of one of the brain's central motivational hubs can disrupt preferences thought to depend on this circuit.

PAC-Bayes Bounds for Bandit Problems: A Survey and Experimental Comparison.

PAC-Bayes has recently re-emerged as an effective theory with which one can derive principled learning algorithms with tight performance guarantees. However, applications of PAC-Bayes to bandit problems are relatively rare, which is a great misfortune. Many decision-making problems in healthcare, finance and natural sciences can be modelled as bandit problems. In many of these applications, principled algorithms with strong performance guarantees would be very much appreciated. This survey provides an overview of PAC-Bayes bounds for bandit problems and an experimental comparison of these bounds. On the one hand, we found that PAC-Bayes bounds are a useful tool for designing offline bandit algorithms with performance guarantees. In our experiments, a PAC-Bayesian offline contextual bandit algorithm was able to learn randomised neural network polices with competitive expected reward and non-vacuous performance guarantees. On the other hand, the PAC-Bayesian online bandit algorithms that we tested had loose cumulative regret bounds. We conclude by discussing some topics for future work on PAC-Bayesian bandit algorithms.

Cohesin mediates DNA loop extrusion and sister chromatid cohesion by distinct mechanisms.

Cohesin connects CTCF-binding sites and other genomic loci in cis to form chromatin loops and replicated DNA molecules in trans to mediate sister chromatid cohesion. Whether cohesin uses distinct or related mechanisms to perform these functions is unknown. Here, we describe a cohesin hinge mutant that can extrude DNA into loops but is unable to mediate cohesion in human cells. Our results suggest that the latter defect arises during cohesion establishment. The observation that cohesin's cohesion and loop extrusion activities can be partially separated indicates that cohesin uses distinct mechanisms to perform these two functions. Unexpectedly, the same hinge mutant can also not be stopped by CTCF boundaries as well as wild-type cohesin. This suggests that cohesion establishment and cohesin's interaction with CTCF boundaries depend on related mechanisms and raises the possibility that both require transient hinge opening to entrap DNA inside the cohesin ring.

Die Neustrukturierung der Notaufnahme gemäß dem G-BA-Beschluss zu einem gestuften System von Notfallstrukturen.

BACKGROUND: There is no assessment of the effects regarding the decision of the Federal Joint Committee from April 19th, 2018 which demands a central and interdisciplinary emergency room system under the control of a professionally and organizationally independent administration. The aim of this study was to solicit the current opinion of leading orthopedic surgeons regarding the above-mentioned decision. MATERIAL AND METHODS: An online questionnaire was sent to all 731 members of the Verband Leitender Orthopäden und Unfallchirurgen (www.vlou.de) to compare the opinion of these leading physicians on their current and future emergency room system. RESULTS: The majority of the 179 responding surgeons consider emergency room systems with primary treatment of orthopedic patients by orthopedic surgeons in certain aspects to be more appropriate suitable than systems without such primary treatment. It is also not yet clear how work-related accidents should be treated according to the specifications of the German statutory accident insurance (DGUV®). The provision of training content could become more difficult if the ER rotation of orthopedic surgeons is not any longer part of these new ER concepts. CONCLUSION: The consequences of the decision of the Federal Joint Committee from April 19th, 2018 need to be reevaluated continuously and, if necessary, optimised accordingly, taking into account competing requirements, such as training regulations and the SGB VII.

Erotic cue exposure increases physiological arousal, biases choices toward immediate rewards, and attenuates model-based reinforcement learning.

Computational psychiatry focuses on identifying core cognitive processes that appear altered across distinct psychiatric disorders. Temporal discounting of future rewards and model-based control during reinforcement learning have proven as two promising candidates. Despite its trait-like stability, temporal discounting may be at least partly under contextual control. Highly arousing cues were shown to increase discounting, although evidence to date remains somewhat mixed. Whether model-based reinforcement learning is similarly affected by arousing cues remains unclear. Here, we tested cue-reactivity effects (erotic pictures) on subsequent temporal discounting and model-based reinforcement learning in a within-subjects design in n = 39 healthy heterosexual male participants. Self-reported and physiological arousal (cardiac activity and pupil dilation) were assessed before and during cue exposure. Arousal was increased during exposure of erotic versus neutral cues both on the subjective and autonomic level. Erotic cue exposure increased discounting as reflected by more impatient choices. Hierarchical drift diffusion modeling (DDM) linked increased discounting to a shift in the starting point bias of evidence accumulation toward immediate options. Model-based control during reinforcement learning was reduced following erotic cues according to model-agnostic analysis. Notably, DDM linked this effect to attenuated forgetting rates of unchosen options, leaving the model-based control parameter unchanged. Our findings replicate previous work on cue-reactivity effects in temporal discounting and for the first time show similar effects in model-based reinforcement learning in a heterosexual male sample. This highlights how environmental cues can impact core human decision processes and reveal that comprehensive modeling approaches can yield novel insights in reward-based decision processes.