The activating signal co-integrator 1 complex subunit 3 (ASCC3) is a multifunctional protein. However, little is known about its role in replication stress. Here, we report that ASCC3 is recruited to stalled forks by its binding partner ASCC2, whose recruitment to stalled forks requires both its ubiquitin binding activity and polyubiquitylation of PCNA at K164 catalyzed by SHPRH, HLTF, and RFWD3. Upon replication stress, ASCC3 unwinds DNA, and this unwinding activity is required for SMARCAL1 recruitment, restrained fork progression, and fork degradation in BRCA1/BRCA2-deficient cells. ASCC3 unwinds DNA to remodel gap-containing fork substrates in vitro, suggesting that ASCC3 promotes fork reversal. In addition, ASCC3 stimulates RPA accumulation on ssDNA upon replication stress, promoting efficient ATR activation. Furthermore, ASCC3 antagonizes RAD51-mediated recombination and prevents the accumulation of chromosome breaks/gaps and mis-segregation upon replication stress. Our work underscores a critical role of ASCC3 in controlling multiple replication stress responses to maintain genomic stability.

Characterization of intracellular synapse heterogeneity aids in understanding the intricate computational logic of neuronal circuits. Despite recent advances in connectomics, the spatial patterns of synapses and their inter-individual variability remain largely unknown. Using directed split-GFP reconstitution, we achieved visualization of endogenous Bruchpilot (Brp), a presynaptic active zone (AZ) scaffold protein, in a cell-type-specific manner. By developing a high-throughput quantification pipeline, we profiled AZ structures in identified neurons of the mushroom body circuit, where intracellular synaptic patterns are crucial due to compartmentalized connectivity. Quantitative characterization of the pattern of Brp clusters across multiple individuals revealed cell-type-dependent synaptic heterogeneity and stereotypy. Furthermore, we discovered previously unidentified sub-compartmental synapse configuration and its transient structural plasticity triggered by associative learning. These profiles reveal multilayered spatial configurations of AZs, from stereotyped overall AZ distribution patterns to local arrangements of neighboring synapses.

The brain is thought to optimise behaviour by generating predictions based on learned statistical regularities. Predictive processing seemingly explains expectation suppression (ES), the attenuation of neural activity in response to expected stimuli. However, the mechanisms behind ES are unclear, with conflicting evidence for alternative models. Sharpening models propose that expectations suppress neurons away from the expected stimulus, increasing the signal-to-noise ratio and boosting decoding for expected stimuli. In contrast, dampening models posit that expectations suppress neurons that are tuned to the expected stimuli, reducing overall response magnitude and decoding accuracy. The opposing process theory (OPT) suggests that both processes occur at different time points, namely that initial sharpening is followed by later dampening of the neural representations of the expected stimulus. Here we test this theory and shed light on the dynamics of expectation effects, both at single-trial level and over time. Thirty-one participants completed a statistical learning task in which a ‘leading’ image from one category predicted a ‘trailing’ image from a different category. Multivariate EEG analyses decoded stimulus information related to the trailing category. Within-trial, expectation increased decoding accuracy at early latencies and decreased it at later latencies, in line with OPT. However, across trials, stimulus expectation decreased decoding accuracy in initial trials and increased it in later trials. We theorise that these dissociable dynamics of expectation effects within and across trials support hierarchical learning mechanisms. While within-trial results support the OPT, across-trial results suggest that sharpening and dampening effects emerge at distinct stages of associative learning.

The North Atlantic climate has been suggested to exert a major control on the hydroclimate of Inner Asia, but the direction and persistence of the temperature–moisture relationship remain unclear. Here, we present new varve-chronology-constrained geochemical and mineralogical records from Lake Shira in northern Inner Asia, revealing a cyclical succession of centennial-scale wet-dry climate intervals over the past ∼2500 years. Wet periods with high lake levels are interrupted by three arid intervals (350–479 CE, 1459–1534 CE, 1898–1928 CE), marked by low lake levels, high salinity and holomixis. The wet intervals coincide with the Roman Warm Period, the Medieval Warm Period and the middle–late Little Ice Age (LIA), and the dry phases with cold spells associated with the Dark Ages Cold Period and the beginning and end of the LIA. A phase of less intense aridity 349–296 BCE overlaps with the end of the Iron Age Cold Period. A thorough review of published climate data and our own findings shows that this pattern is primarily driven by thermal conditions in the North Atlantic region, where higher sea surface temperatures (reflected in elevated Atlantic Multidecadal Oscillation indices) promote more positive North Atlantic Oscillation states and intensify mid-latitude westerly moisture transport. Comparison of varve thickness measurements with observed/reconstructed climate records for the past 150 years indicates that sedimentation rate is mainly controlled by fluvial discharge to the lake. Although varve thickness tends to be negatively correlated with precipitation and temperature, several notable exceptions limit its use as independent climate proxy.

Pain and welfare monitoring is essential for ethical animal testing, but current cage-side assessments are qualitative and subjective. Here we present the GrimACE, a fully standardized and automated cage-side monitoring tool for mice, the most widely used animals in research. The GrimACE uses computer vision to provide automated mouse grimace scale (MGS) assessment together with pose estimation in a safe, dark environment. We validated the system by analyzing pain after brain surgeries (craniotomies) with head implants under two analgesia regimes. Human-expert and automated MGS scores showed very high correlation (Pearson’s r = 0.87). Both expert and automated scores revealed that a moderate increase in pain can be detected for up to 48 h after surgeries, but that both a single dose of meloxicam (5 mg/kg subcutaneuously) or three doses of buprenorphine (0.1 mg/kg) + meloxicam (5 mg/kg subcutaneuously) provide adequate and comparable pain management. Simultaneous pose estimation demonstrated that mice receiving buprenorphine + meloxicam showed increased movement 4 h after surgery, indicative of hyperactivity, a well-known side effect of opioid treatment. Significant weight loss was also detected in the buprenorphine + meloxicam treatment group compared with the meloxicam-only group. In addition, detailed BehaviorFlow analysis and automated MGS scoring of control animals suggests that habituation to GrimACE is unnecessary, and that measurements can be repeated multiple times, ensuring standardized postoperative recovery monitoring.

Television is a widely used medium for climate information worldwide, yet its role in public engagement remains underexplored. Here we examine both the representation of climate change on television and the audience engagement with it. We analysed 23,478 hours of programming across 20 German television channels over 61 days in 2022 and further assessed audience engagement with climate content through a representative survey (n = 1,445). In the beginning of the polycrisis context of autumn 2022—including war, inflation and energy insecurity—2.2% of broadcast hours addressed climate topics. Climate coverage was concentrated in news formats, reaching mostly to the climate-engaged majority, but remained largely invisible for climate-distant groups who prefer entertainment programmes. In addition, the results reveal unequal gender representation in television programmes and a perceived over-representation of politicians. Taken together, these findings suggest that strengthening inclusive storytelling, diversifying representation and innovating formats may enhance the reach and inclusivity of televised climate communication.

Background: Problematic social media use has been linked to reduced well-being and impulse control difficulties. While digital self-control apps show potential for reducing general app usage, they often lack customization, leading to limited effectiveness and increased user resistance. Their impact on problematic social media use remains uncertain.

Objective: This study evaluates the effectiveness of the Wellspent app, a customizable mobile intervention app designed to promote self-regulated social media use by targeting user-defined problematic app use and offering tailored behavioral nudges.

Methods: In a 3-week randomized controlled trial, 70 iPhone users (mean age 26.2, SD 5.6 years; 47/70, 67% female), regularly using at least 1 social media app, were randomly assigned to an intervention (n=35) or control group (n=35). The intervention group received personalized full-screen reminders with the option to quit or continue social media app use whenever an app session exceeded a self-defined time limit. Participants completed weekly online surveys measuring problematic social media use, problematic smartphone use, self-efficacy, and daily screen time on their most problematic app. Linear mixed models tested intervention effects.

Results: While no significant reduction in problematic social media use or increase in self-efficacy was observed, the intervention group showed a significant reduction in daily screen time on their most problematic app by approximately 29 minutes (estimate=−29.35, SE 6.84, 95% CI −42.79 to –15.99; P<.001), and a significant decrease in perceived problematic smartphone use (estimate=−0.46, SE 0.18, 95% CI −0.80 to –0.11; P=.01).

Conclusions: The Wellspent app demonstrated short-term efficacy in reducing problematic smartphone use. By allowing users to tailor interventions to their personal goals, the app shows promise as a self-directed tool to support healthier digital habits. Further research should explore long-term effects and feature-specific impacts.

Mental disorders affect not only mothers themselves but also their children and partners. Borderline personality disorder (BPD) in particular is thought to impact the mother–child relationship, but comparisons with mothers with other mental disorders are scarce. Many studies use questionnaires without examining if self-report corresponds to observable behaviour. We assessed the perceived mother–child relationship using the Parenting Relationship Questionnaire and the Child Relationship Behaviour Inventory in three groups: (1) mothers with BPD, (2) mothers with anxiety and/or depression and (3) mothers without mental disorders with preschool children. Additionally, mother–child interactions during free-play and structured tasks were video-recorded and coded using the Coding Interactive Behaviour system. Compared with mothers without mental disorders, both clinical groups perceived their relationship with the child, their own parenting skills and their children's behaviour as less positive. Mothers with BPD felt less confident and more frustrated than those with anxiety and/or depression. No significant group differences emerged in observed behaviour (e.g., sensitivity, intrusiveness), and correlations between self-report and observation were low. Overall, mothers with BPD face similar challenges as mothers with anxiety or depressive disorders, but they experience particular distress when it comes to relating to and controlling their child's affect. While mothers in both clinical groups are able to foster positive relationships with their children in a controlled laboratory setting, they find it difficult to maintain these skills permanently (e.g., during negative child affect).

The ancient city of Pompeii, destroyed by the eruption of Mt. Vesuvius in AD 79, shows technological improvements to its water supply after becoming a Roman colony. Its inhabitants relied on wells for their water supply prior to the installation of a Roman aqueduct. Carbonate incrustations deposited in various components of the city’s hydraulic infrastructure, including the aqueduct, its water towers, the well shafts, and pools of the public baths. The stable isotope and trace element composition of these carbonates differ markedly between structures supplied by wells and those fed by the aqueduct, reflecting the contrasting origins of their source waters. While the aqueduct was fed by karst springs, the wells tapped into highly mineralized groundwater from volcanic deposits. These geochemical distinctions allow for a detailed reconstruction of Pompeii’s water management system, particularly the transition from well- to aqueduct-based water supply. The periodicity of δ13C variations in carbonate crusts sampled from well, pools, and drainage channels of the Republican Baths offers insights into the operation and maintenance of the facility. δ13C values show a sharp drop from wells to bathing pools, suggesting contamination by human waste and implying that the bath water was not regularly replenished in the Republican Baths.

Asthma is the most common chronic disease among children, with more than 300 million cases worldwide. Over the past several decades, asthma incidence has grown, and epidemiological studies identify the modernized lifestyle as playing a strong contributing role in this phenomenon. In particular, lifestyle factors that modify the maternal gut microbiome during pregnancy, or the infant microbiome in early life, can act as developmental programming events which determine health or disease susceptibility later in life. Microbial colonization of the gut begins at birth, and factors such as delivery mode, breastfeeding, diet, antibiotic use, and exposure to environmental bacteria influence the development of the infant microbiome. Colonization of the gut microbiome is crucial for proper immune system development and disruptions to this process can predispose a child to asthma development. Here, we describe the importance of early-life events for shaping immune responses along the gut-lung axis and why they may provide a window of opportunity for asthma prevention.

Scope: A long-term vegan diet carries the risk of insufficient protein and micronutrient intake for older adults. However, even a short-term (48 h) vegan diet exerts positive metabolic effects in younger adults. In this study, we investigate the feasibility and effects of a short-term vegan challenge on metabolic and inflammatory markers in older adults. Method and results: In this randomized controlled crossover-study, 30 healthy older adults (>= 65 years) are assigned to either a 48 h ad libitum vegan or omnivorous diet. During the vegan diet, participants exhibit lower protein (p = 0.001) and fat intake as well as higher carbohydrate and dietary fiber intake, resulting in a lower caloric intake (all p < 0.001). Insulin concentrations (p = 0.042) and insulin resistance (p = 0.036) decline only after the vegan diet. The study observes reductions in serum glucose (p < 0.001), triglyceride (p = 0.005), and hsCRP (p = 0.044) concentrations and weight (p < 0.001), independent of the diet. Participants with low-grade inflammation exhibit notable metabolic improvements after the vegan diet. Conclusion: Improvements in insulin homeostasis are observed after the vegan diet, but meeting protein requirements are not feasible during the short-term vegan challenge despite dietary counseling, which warrants concern.

We classify gapped phases and characteristic nodal points of non-Hermitian band structures on two-dimensional nonorientable parameter spaces. Such spaces arise in a wide range of physical systems in the presence of nonsymmorphic parameter space symmetries. For gapped phases, we find that nonorientable spaces provide a natural setting for exploring fundamental structural problems in braid group theory, such as torsion and conjugacy. Gapless systems, which host exceptional points (EPs), explicitly violate fermion doubling, even in two-band models. We demonstrate that EPs traversing the nonorientable parameter space exhibit non-Abelian charge inversion. These braided phases and their transitions leave distinct signatures in the form of bulk Fermi arc degeneracies, offering a concrete route toward experimental realization and verification.

Excessive exposure to ultraviolet (UV) light leads to acute and chronic UV damage and is the main risk factor for the development of skin cancer. In most countries with western lifestyle, the topical application of sunscreens on UV-exposed skin areas is by far the most frequently used preventive measure against sunburn. Further than preventing sunburns, increasing numbers of consumers are appreciating sunscreens with a medium- to high-level sun protective factor (SPF) as basis for sustainable-skin ageing or skin cancer prevention programs. However, recent investigations indicate that clinically significant DNA damages as well as a lasting impairment of cutaneous immunosurveillance already occur far below the standard of one minimal erythema dose (MED) sunburn level, which contributes to the current discussion of the clinical value of high-protective SPF values. Ex vivo investigations on human skin showed that the application of SPF30 reduces DNA damage for a day long sun exposure (24 MED) drastically by about 53% but is significantly surpassed by SPF100 reducing DNA damage by approx. 73%. Further analysis on different SPF protection levels in UV-exposed cell culture assays focusing on IL-18, cell vitality and cis/trans-urocanic acid support these findings. Whereas SPF30 and SPF50+ sunscreens already offer a solid UVB cover for most indications, our results indicate that SPF100 provides significant additional protection against mutagenic (non-apoptotic-) DNA damage and functional impairment of the cutaneous immunosurveillance and therefore qualifies as an optimized sunscreen for specifically vulnerable patient groups such as immunosuppressed patients, or skin cancer patients.

Background: The study of blood trauma, such as hemolysis in blood-carrying devices, is crucial due to the high incidence of adverse events like alteration of blood function, bleeding, and multi-organ failure. The extent of flow-induced hemolysis, predominantly influenced by stress duration and intensity, is described by established model parameters based on the power law approach. In recent years, various parameters were determined using different Couette shearing devices and donor species. However, they have not been validated due to limited experimental data. Methods: This study provides hemolysis measurements in a Couette shearing device and evaluates the suitability of different power law parameters. The revised Couette shearing device generates well-defined dynamic stress loads that are repeatedly applied to blood samples at a defined temperature. Human blood samples with an adjusted hematocrit of 30%, were tested with varying repetitions (20 to 80 times). The half-sinusoidal stress loads had amplitudes of 73 to 140 Pa and exposure times of 24 msec per repetition. The parameters of five common power law hemolysis approaches were then compared with the experimental data. Results: The prediction with the power law model parameters C = 3.458 x 10-6, alpha = 0.2777 and beta = 2.0639 showed a good agreement with the experimental results. Conclusion: The effect of multiple short-time stresses on hemolysis was investigated to validate the power law hemolysis model with the Couette shearing device of this study.

Functional coatings based on amphiphilic polymer co-networks (ACNs) offer a versatile alternative to hydrogel coatings with enhanced mechanical stability and tunable properties. This study explores ACN thin films composed of star-shaped poly(ε-caprolactone) (PCL) and poly(ethylene glycol) (PEG) with varying PEG content to optimize amphiphilic balance for cell adhesion. Low-PEG films (9 and 15 wt.%) promote protein adsorption and cell attachment, whereas PEG-rich films (38 and 47 wt.%) exhibit negligible protein adsorption and effectively inhibit cell adhesion. Crucially, an ultrathin decellularized and digested extracellular matrix (dECM) coating, physically anchored via hydrophobic interactions, provides cell-recognition cues and restores cell adhesiveness on PEG-rich ACN films. Film stiffness and roughness modulate cellular metabolic activity but do not affect initial cell adhesion, reaching attachment levels comparable to or exceeding those on tissue culture polystyrene. Drug-proxy uptake depends strongly on network composition and swelling, with the highest uptake of Lucifer Yellow in PCL10_PEG10 films (∼180 ng cm−2) and markedly higher uptake of Nile Red (∼10 µg cm−2). These results demonstrate that ACNs provide versatile biointerfaces with controlled molecular affinity, uptake capacity, and cell-material interactions, while ultrathin dECM coatings offer a universal strategy to enhance bioactivity of PEG-rich films.

Objectives: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Roughly a quarter of paediatric patients with NAFLD develop nonalcoholic steatohepatitis and fibrosis. Here, we evaluated the diagnostic accuracy of previously published noninvasive fibrosis scores to predict liver fibrosis in a large European cohort of paediatric patients with NAFLD. Methods: The 457 patients with biopsy-proven NAFLD from 10 specialized centers were included. We assessed diagnostic accuracy for the prediction of any (F >= 1), moderate (F >= 2) or advanced (F >= 3) fibrosis for the AST/platelet ratio (APRI), Fibrosis 4 score (FIB-4), paediatric NAFLD fibrosis score (PNFS) and paediatric NAFLD fibrosis index (PNFI). Results: Patients covered the full spectrum of fibrosis (F0: n = 103; F1: n = 230; F2: n = 78; F3: n = 44; F4: n = 2). None of the scores were able to accurately distinguish the presence of any fibrosis from no fibrosis. For the detection of moderate fibrosis, area under the receiver operating characteristic curve (AUROC) were: APRI: 0.697, FIB-4: 0.663, PNFI: 0.515, PNFS: 0.665, while for detection of advanced fibrosis AUROCs were: APRI: 0.759, FIB-4: 0.611, PNFI: 0.521, PNFS: 0.712. Fibrosis scores showed no diagnostic benefit over using ALT <= 50/ > 50 IU/L as a cut-off. Conclusions: Established fibrosis scores lack diagnostic accuracy to replace liver biopsy for staging of fibrosis, giving similar results as compared to using ALT alone. New diagnostic tools are needed for Noninvasive risk-stratification in paediatric NAFLD.

Background and objective: Among many treatment approaches for chronic low back pain (CLBP), self-management techniques are becoming increasingly important. The aim of this paper was to (a) provide an overview of existing digital self-help interventions for CLBP and (b) examine the effect of these interventions in reducing pain intensity, pain catastrophizing and pain disability. Databases and data treatment: Following the PRISMA guideline, a systematic literature search was conducted in the MEDLINE, EMBASE, PsychInfo, CINAHL and Cochrane databases. We included randomized controlled trials from the last 10 years that examined the impact of digital self-management interventions on at least one of the three outcomes in adult patients with CLBP (duration >= 3 months). The meta-analysis was based on random-effects models. Standardized tools were used to assess the risk of bias (RoB) for each study and the quality of evidence for each outcome. Results: We included 12 studies (n = 1545). A small but robust and statistically significant pooled effect was found on pain intensity (g = 0.24; 95% CI [0.09, 0.40], k = 12) and pain disability (g = 0.43; 95% CI [0.27, 0.59], k = 11). The effect on pain catastrophizing was not significant (g = 0.38; 95% CI [-0.31, 1.06], k = 4). The overall effect size including all three outcomes was g = 0.33 (95% CI [0.21, 0.44], k = 27). The RoB of the included studies was mixed. The quality of evidence was moderate or high. Conclusion: In summary, we were able to substantiate recent evidence that digital self-management interventions are effective in the treatment of CLBP. Given the heterogeneity of interventions, further research should aim to investigate which patients benefit most from which approach. Significance: This meta-analysis examines the effect of digital self-management techniques in patients with CLBP. The results add to the evidence that digital interventions can help patients reduce their pain intensity and disability. A minority of studies point towards the possibility that digital interventions can reduce pain catastrophizing. Future research should further explore which patients benefit most from these kinds of interventions.

Aim: The aim of the study was to evaluate the duration of mother's own milk (MOM) provision to preterm very low-birth weight (VLBW, <1500 g) infants during the COVID-19 pandemic. We hypothesised that COVID-19 restrictions would reduce the duration of MOM provision. Methods: This retrospective study compared VLBW infants born at the Berlin university hospital during the pandemic (15 March 2020 to 14 March 2021, n = 108) with infants born in the pre-pandemic year (01 January 2019 to 31 January 2019, n = 121). We calculated the duration of MOM provision and analysed factors associated with its early cessation. Results: During the pandemic, the rate of primiparous mothers increased from 29% to 44% while the distribution of all other parental and infants' characteristics remained similar. There were no differences in the median duration of MOM provision (47 vs. 51 days), feeding type (MOM 67% vs. 65%) and breastfeeding rates at discharge (exclusive, 8% vs. 13%; partial 69% vs. 60%). Cox proportional hazard analysis revealed smoking during pregnancy and parental school education consistently as independent risk factors for early cessation of MOM provision. Conclusion: Supply of MOM for VLBW infants can be upheld also during pandemic restrictions.

We study the distribution of envy in random matching markets under the Deferred Acceptance (DA) algorithm. Using tools from applied probability, we compute the expected number of proposing agents whom nobody envies and those who envy nobody. We obtain an exact finite-market expression for the former, based on a connection with the coupon collector problem, and asymptotic bounds for the latter. To put these quantities into perspective, we compare them to their counterparts under Random Serial Dictatorship (RSD): while RSD assigns a constant fraction of agents to their top choice, both DA and RSD leave exactly Hn proposing agents unenvied in expectation. Our results show that these clearly unimprovable proposing agents constitute a vanishing fraction of the market.

This paper studies how minimum wages affect the wage distribution if firms face financial constraints. Using German employer-employee data and firm balance sheets, we document that the within-firm wage dispersion decreases more with higher minimum wages when firms are financially constrained. We introduce financial frictions into a search and matching labor market model with stochastic job matching, imperfect information, and endogenous effort. In line with the empirical literature, the model predicts that a higher minimum wage reduces hirings and separations. Firms become more selective such that their employment and wage dispersion fall. If effort increases strongly, firms may increase employment at the expense of higher wage dispersion. Financially constrained firms are more selective and reward effort less. As a result, within-firm wage dispersion and employment in these firms fall more with the minimum wage.