Structural basis of the Integrator complex assembly and association with transcription factors.

Integrator is a multi-subunit protein complex responsible for premature transcription termination of coding and non-coding RNAs. This is achieved via two enzymatic activities, RNA endonuclease and protein phosphatase, acting on the promoter-proximally paused RNA polymerase Ⅱ (RNAPⅡ). Yet, it remains unclear how Integrator assembly and recruitment are regulated and what the functions of many of its core subunits are. Here, we report the structures of two human Integrator sub-complexes: INTS10/13/14/15 and INTS5/8/10/15, and an integrative model of the fully assembled Integrator bound to the RNAPⅡ paused elongating complex (PEC). An in silico protein-protein interaction screen of over 1,500 human transcription factors (TFs) identified ZNF655 as a direct interacting partner of INTS13 within the fully assembled Integrator. We propose a model wherein INTS13 acts as a platform for the recruitment of TFs that could modulate the stability of the Integrator's association at specific loci and regulate transcription attenuation of the target genes.

Keeping up with ourselves: Multimodal processes underlying body ownership across the lifespan.

The sense of a bodily self is thought to depend on adaptive weighting and integration of bodily afferents and prior beliefs. While the physical body changes in shape, size, and functionality across the lifespan, the sense of body ownership remains relatively stable. Yet, little is known about how multimodal integration underlying such sense of ownership is altered in ontogenetic periods of substantial physical changes. We aimed to study this link for the motor and the tactile domain in a mixed-realty paradigm where participants ranging from 7 to 80 years old saw their own body with temporally mismatching multimodal signals. Participants were either stroked on their hand or moved it, while they saw it in multiple trials with different visual delays. For each trial, they judged the visuo-motor/tactile synchrony and rated the sense of ownership for the seen hand. Visual dependence and proprioceptive acuity were additionally assessed. The results show that across the lifespan body ownership decreases with increasing temporal multisensory mismatch, both in the tactile and the motor domain. We found an increased sense of ownership with increasing age independent of delay and modality. Delay sensitivity during multisensory conflicts was not consistently related to age. No effects of age were found on visual dependence or proprioceptive accuracy. The results are at least partly in line with an enhanced weighting of top-down and a reduced weighting of bottom-up signals for the momentary sense of bodily self with increasing age.

Non-coplanar helimagnetism in the layered van-der-Waals metal DyTe3.

Van-der-Waals magnetic materials can be exfoliated to realize ultrathin sheets or interfaces with highly controllable optical or spintronics responses. In majority, these are collinear ferro-, ferri-, or antiferromagnets, with a particular scarcity of lattice-incommensurate helimagnets of defined left- or right-handed rotation sense, or helicity. Here, we report polarized neutron scattering experiments on DyTe3, whose layered structure has highly metallic tellurium layers separated by double-slabs of dysprosium square nets. We reveal cycloidal (conical) magnetic textures, with coupled commensurate and incommensurate order parameters, and probe the evolution of this ground state in a magnetic field. The observations are well explained by a one-dimensional spin model, with an off-diagonal on-site term that is spatially modulated by DyTe3's unconventional charge density wave (CDW) order. The CDW-driven term couples to antiferromagnetism, or to the net magnetization in an applied magnetic field, and creates a complex magnetic phase diagram indicative of competing interactions in this easily cleavable van-der-Waals helimagnet.

Duration of face mask exposure matters: evidence from Swiss and Brazilian kindergartners' ability to recognise emotions.

Wearing facial masks became a common practice worldwide during the COVID-19 pandemic. This study investigated (1) whether facial masks that cover adult faces affect 4- to 6-year-old children's recognition of emotions in those faces and (2) whether the duration of children's exposure to masks is associated with emotion recognition. We tested children from Switzerland (N = 38) and Brazil (N = 41). Brazil represented longer mask exposure due to a stricter mandate during COVID-19. Children had to choose a face displaying a specific emotion (happy, angry, or sad) when the face wore either no cover, a facial mask, or sunglasses. The longer hours of mask exposure were associated with better emotion recognition. Controlling for the hours of exposure, children were less likely to recognise emotions in partially hideen faces. Moreover, Brazilian children were more accurate in recognising happy faces than Swiss children. Overall, facial masks may negatively impact children's emotion recognition. However, prolonged exposure appears to buffer the lack of facial cues from the nose and mouth. In conclusion, restricting facial cues due to masks may impair kindergarten children's emotion recognition in the short run. However, it may facilitate their broader reading of facial emotional cues in the long run.

Speaker Competence Affects Prefrontal Theta and Occipital Alpha Power during Selective Word Learning in Preschoolers.

In the present study, we investigated the cognitive processes underlying selective word learning in preschoolers. We measured rhythmic neural activity in the theta (4-8 Hz) and alpha frequency range (7-12 Hz) in 67 four-year-olds. EEG was recorded during anticipation and encoding of novel labeling events performed by a speaker who had previously shown either competence (correct) or incompetence (incorrect) in labeling familiar objects. In both groups, children selected the target object equally often upon recall. However, children observing the incompetent speaker revealed weaker representations of novel words indicated by an increased likelihood for selecting familiar but incorrect items upon recall. Modulations in theta and alpha power suggest differential processing of novel label-object pairs depending on the speakers' competence. In the incompetent, but not the competent, speaker condition, increases in prefrontal theta power during anticipation and encoding were related to increased recall success. Findings suggest that theta power in the present study reflects cognitive control. In both conditions, occipital alpha power-indicating attentional processes-reflected familiarity with novel items, but in opposite directions. In familiar item trials, alpha power was increased observing the incompetent and decreased observing the competent speaker. Thus, both cognitive control and attention processes during word learning are differentially affected by speaker characteristics.

Hand eczema symptoms, exposures and skin care in orthodontics : A national, cross-sectional questionnaire-based survey.

OBJECTIVES: Occupational hand eczema is a common inflammatory skin condition among healthcare professionals. Orthodontists are frequently exposed to a variety of irritating and allergenic substances, and therefore they belong to a predisposed group to develop hand eczema. However, current data on the prevalence and predisposing factors among orthodontists to provide adequate prophylaxis are lacking. METHODS: An anonymous online survey was conducted in Germany between January and February 2023 and distributed to 2402 orthodontists. The questionnaire addressed general information on current skin status, as well as occupational skin exposure and skin care. RESULTS: A total of 209 orthodontists responded to the survey. Seventy-four percent reported experiencing hand eczema-specific symptoms within the last 12 months, with 24% describing moderate and 10% describing severe symptoms. The average daily glove wearing time was stated to be 6 ± 2 h. The most frequently reported triggers at work were frequent hand washing (62.7%) and hand disinfection (59.1%). Among all the respondents, 22.6% stated not using either barrier cream or moisturizer. CONCLUSIONS: This study showed a high prevalence of hand eczema symptoms among orthodontists, which is probably due to frequent disinfection, hand washing, and contact with allergens such as acrylates. In this professional group especially, against a background of future increasing acrylate and epoxy resin exposures due to in-office three-dimensional printing processes, timely education and skin protection could decisively counteract the pathogenesis of hand eczema.

Obesity is linked to disease severity in moderate to severe atopic dermatitis-Data from the prospective observational TREATgermany registry.

BACKGROUND: There are conflicting data on a potential association between obesity and atopic dermatitis (AD). The purpose of this study was to investigate the relationship between obesity and AD disease severity. METHODS: Patients from the TREATgermany registry cohort were divided into three groups according to their body mass index (BMI). Due to low numbers, underweight patients (BMI <18.5 kg/m2) were excluded from the analysis. Physician- and patient-reported disease severity scores as well as additional phenotypic characteristics were evaluated for association with BMI. Generalized linear mixed models and multinomial logit models, respectively, were applied to investigate the association of BMI, age, sex and current systemic AD treatment with disease severity. RESULTS: This study encompassed 1416 patients, of which 234 (16.5%) were obese (BMI ≥30 kg/m2). Obesity was associated with lower educational background and smoking. Otherwise, obese and non-obese AD patients had similar baseline characteristics. Increased BMI was associated with higher oSCORAD (adjusted ß: 1.24, 95% CI: 1.05-1.46, p = 0.013) and Patient-oriented eczema measure (POEM) (adjusted ß: 1.09, 95% CI: 1.01-1.17, p = 0.038). However, the absolute difference in the overall oSCORAD was small between obese and non-obese AD patients (Δ oSCORAD = 2.5). Allergic comorbidity was comparable between all three groups, with the exception of asthma which was more pronounced in obese patients (p < 0.001). DISCUSSION: In this large and well-characterized AD patient cohort, obesity is significantly associated with physician- and patient-assessed measures of AD disease severity. However, the corresponding effect sizes were low and of questionable clinical relevance. The overall prevalence of obesity among the German AD patients was lower than in studies on other AD cohorts from different countries, which confirms previous research on the German population and suggests regional differences in the interdependence of AD and obesity prevalence.

The proximate regulation of prosocial behaviour: towards a conceptual framework for comparative research.

Humans and many other animal species act in ways that benefit others. Such prosocial behaviour has been studied extensively across a range of disciplines over the last decades, but findings to date have led to conflicting conclusions about prosociality across and even within species. Here, we present a conceptual framework to study the proximate regulation of prosocial behaviour in humans, non-human primates and potentially other animals. We build on psychological definitions of prosociality and spell out three key features that need to be in place for behaviour to count as prosocial: benefitting others, intentionality, and voluntariness. We then apply this framework to review observational and experimental studies on sharing behaviour and targeted helping in human children and non-human primates. We show that behaviours that are usually subsumed under the same terminology (e.g. helping) can differ substantially across and within species and that some of them do not fulfil our criteria for prosociality. Our framework allows for precise mapping of prosocial behaviours when retrospectively evaluating studies and offers guidelines for future comparative work.

How Do Spinopelvic Characteristics Change Post-Total Hip Arthroplasty? A Longitudinal Assessment Raising Awareness of the Postoperative Period.

BACKGROUND: Spinopelvic characteristics, including sacral slope (SS), are commonly evaluated in different positions pre-total hip arthroplasty (THA). This study aimed to: 1) investigate the change in spinopelvic parameters at 7 days (early) and 1-year post-THA; and 2) identify patient characteristics associated with a change in SS of more than 7° post-THA. METHODS: We prospectively studied 250 patients who underwent unilateral THA [132 women, age 66 years (range, 32 to 88)] and underwent biplanar images preoperatively and at 7 days and 1-year post-THA. Parameters measured included pelvic incidence, standing lumbar lordosis, SS, and proximal femoral angle (PFA). A SS change ≥ 7° was considered the threshold as it would result in more than a 5° change in cup orientation. RESULTS: Early post-THA SSstanding remained within ± 6º from preoperative measurements in 75% of patients, reduced by ≥ 7° in 9%, and increased by ≥ 7° in 16%. Those that showed a reduction in SS had the lowest PFA and the highest SS pre-THA (P = .028, .107, and < 0.001, respectively). From 7 days until the 1-year mark, pelvic tilt increased, SS reduced (mean: -4º, range: -29 to 17º, P < .001), and patients stood with greater hip extension ΔPFAstanding (mean 7°, range: -34 to 37°, P < .001). At 1 year, SSseated had remained within ± 6º, relative to the pre-THA value, in 49% of patients. CONCLUSIONS: Standing spinopelvic characteristics, especially SSstanding, remain within ±6° in three-quarters of patients both early- and at 1-year post-THA. In the remaining cases, pelvic tilt changes significantly. In 9% of cases, SS reduces ≥ 7° early THA, probably due to the alleviation of fixed-flexion contractures. The SSseated changes by ≥ ± 7° in almost 50% of cases in this study, and its clinical value as a preoperative planning tool should be questioned. LEVEL OF EVIDENCE: Level II, diagnostic study.

A redox switch allows binding of Fe(II) and Fe(III) ions in the cyanobacterial iron-binding protein FutA from Prochlorococcus.

The marine cyanobacterium Prochlorococcus is a main contributor to global photosynthesis, whilst being limited by iron availability. Cyanobacterial genomes generally encode two different types of FutA iron-binding proteins: periplasmic FutA2 ABC transporter subunits bind Fe(III), while cytosolic FutA1 binds Fe(II). Owing to their small size and their economized genome Prochlorococcus ecotypes typically possess a single futA gene. How the encoded FutA protein might bind different Fe oxidation states was previously unknown. Here, we use structural biology techniques at room temperature to probe the dynamic behavior of FutA. Neutron diffraction confirmed four negatively charged tyrosinates, that together with a neutral water molecule coordinate iron in trigonal bipyramidal geometry. Positioning of the positively charged Arg103 side chain in the second coordination shell yields an overall charge-neutral Fe(III) binding state in structures determined by neutron diffraction and serial femtosecond crystallography. Conventional rotation X-ray crystallography using a home source revealed X-ray-induced photoreduction of the iron center with observation of the Fe(II) binding state; here, an additional positioning of the Arg203 side chain in the second coordination shell maintained an overall charge neutral Fe(II) binding site. Dose series using serial synchrotron crystallography and an XFEL X-ray pump-probe approach capture the transition between Fe(III) and Fe(II) states, revealing how Arg203 operates as a switch to accommodate the different iron oxidation states. This switching ability of the Prochlorococcus FutA protein may reflect ecological adaptation by genome streamlining and loss of specialized FutA proteins.

Symptom severity reflected by NYHA grade is independently associated with pruritus in chronic heart failure patients.

BACKGROUND: Pruritus is a symptom profoundly impairing patients' quality of life (QoL). It is a common symptom in chronic heart failure (CHF) patients of yet unknown nature. The aim of this study was to evaluate the risk factors of pruritus in CHF patients. METHODS: For this monocentric, prospective cohort study, CHF patients were recruited and CHF symptoms, comorbidities and drug intake were assessed using a structured report. Additionally, a questionnaire evaluated pruritus symptoms. Detailed medical histories including laboratory test results were retrieved from patient files for all participants. RESULTS: We evaluated data from 550 CHF patients. Of those, 25.3% reported pruritus to occur frequently (3-5 times per week), often (1-2 times per week) or daily. Patients of higher NYHA classes (NYHA III + IV) experienced significantly more pruritus (31.2%) than lower NYHA classes (NYHA I + II) (21.1%, p = 0.024). Patients with pruritus reported disproportionately often concomitant stasis dermatitis (p = 0.026) and chronic lung disease (p = 0.014). Other parameters reflecting cardiac, liver, kidney and thyroid function, as well as medical therapies showed no significant differences between patients with and without pruritus. In the multivariate logistic regression analysis, only NYHA class (p = 0.016, OR 1.55, 95% confidence interval (CI): [1.09; 2.20]) and elevated leukocyte count (p = 0.007, OR 1.11, CI [1.03; 1.21]) remained significantly associated with pruritus in CHF patients. CONCLUSIONS: NYHA class is an independent predictor for pruritus in CHF patients. Besides NYHA class, leukocyte count was also associated with increased pruritus. Pruritus may impair QoL in CHF patients and should thus be included in the assessment of those patients. We suggest that providing best care for CHF patients can be achieved through an interdisciplinary approach of cardiologists and dermatologists and should include a pruritus assessment.

What's the point? Infants' and adults' perception of different pointing gestures.

Adults and infants as young as 4 months old orient to pointing gestures. Although adults are shown to orient faster to index-finger pointing than other hand shapes, it is unknown whether hand shapes influence infants' perception of pointing. In this study, we used a spatial cueing paradigm on an eye tracker to investigate whether and to what extent adults and 12-month-old infants orient their attention in the direction of pointing gestures with different hand shapes: index finger, whole hand, and pinky finger. Furthermore, we assessed infants' and their parents' pointing production. Results revealed that adults showed a reliable cueing effect: shorter saccadic reaction times (SRTs) to congruent than incongruent targets, for all hand shapes. However, they did not show a larger cueing effect triggered by the index or any other finger. This contradicts previous findings and is discussed with respect to the differences in methodology. Infants showed a cueing effect only for the whole hand but not for the index or pinky fingers. The current results suggest that infants' orienting to pointing may be more robust for the whole hand shape in the first year, and tuning in to the social-communicative relevance of the canonical index finger shape may develop later or require additional social-communicative cues.

Mini-review: Wild laughs: Ontogenesis and phylogenesis of humour.

This mini-review discusses the existing evidence on various forms of humour and humour-like behaviour in non-human animals, combining ontogenetic and phylogenetic perspectives. The first section describes humour-like behaviours, from the simplest to the most complex form (from laughing, tickling, joking, and chasing to ToM humour). In the second section, we propose the SPeCies (Social, Physiological, and Cognitive) Perspective, which frames the various types of humour based on Social motivation, Physiological state, and Cognitive skills. Finally, in the third section, we discuss future directions for further development.

Automatic imitation in school-aged children.

Children imitate others for different reasons: To learn from others and to reach social goals such as affiliation or prosociality. So far, imitative acts have been measured using diverging methods in children and adults. Here, we investigated whether school-aged children's imitation can be measured via their automatic imitation with a classical imitation-inhibition task (Brass et al., 2000) as has been used in adults. To this end, we measured automatic imitation in N=94 7-8-year-olds and N=10 adults. The results were similar in children and adults: Observing actions that are incongruent with participants' actions interferes with their responses resulting in increased reaction times and error rates. This shows that assessing automatic imitation via the imitation-inhibition task is feasible in children, and creates the basis for future studies to compare the behaviour of different age groups with the same imitation task.

Reply to Alt et al. Comment on "Lunz et al. Impact and Modification of the New PJI-TNM Classification for Periprosthetic Joint Infections. J. Clin. Med. 2023, 12, 1262".

We greatly appreciate the comments made by Alt et al. [...].

PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection.

Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-γ (IFN-γ)-inducible antimicrobial factors, such as the guanylate binding proteins (GBPs), promote cell-intrinsic defense by attacking intracellular pathogens and by inducing programmed cell death. Working in human macrophages, we discovered that GBP1 expression in the absence of IFN-γ killed the cells and induced Golgi fragmentation. IFN-γ exposure improved macrophage survival through the activity of the kinase PIM1. PIM1 phosphorylated GBP1, leading to its sequestration by 14-3-3σ, which thereby prevented GBP1 membrane association. During Toxoplasma gondii infection, the virulence protein TgIST interfered with IFN-γ signaling and depleted PIM1, thereby increasing GBP1 activity. Although infected cells can restrain pathogens in a GBP1-dependent manner, this mechanism can protect uninfected bystander cells. Thus, PIM1 can provide a bait for pathogen virulence factors, guarding the integrity of IFN-γ signaling.

Humoral and cellular immune responses in fully vaccinated individuals with or without SARS-CoV-2 breakthrough infection: Results from the CoV-ADAPT cohort.

Despite recent advances in prophylactic vaccination, SARS-CoV-2 infections continue to cause significant morbidity. A better understanding of immune response differences between vaccinated individuals with and without later SARS-CoV-2 breakthrough infection is urgently needed. CoV-ADAPT is a prospective long-term study comparing humoral (anti-spike-RBD-IgG, neutralization capacity, avidity) and cellular (spike-induced T-cell interferon-γ [IFN-γ] release) immune responses in individuals vaccinated against SARS-CoV-2 at four different time points (three before and one after third vaccination). In this cohort study, 62 fully vaccinated individuals presented with SARS-CoV-2 breakthrough infections vs 151 without infection 3-7 months following third vaccination. Breakthrough infections significantly increased anti-spike-RBD-IgG (p < 0.01), but not spike-directed T-cell IFN-γ release (TC) or antibody avidity. Despite comparable surrogate neutralization indices, the functional neutralization capacity against SARS-CoV-2-assessed via a tissue culture-based assay-was significantly higher following breakthrough vs no breakthrough infection. Anti-spike-RBD-IgG and antibody avidity decreased with age (p < 0.01) and females showed higher anti-spike-RBD-IgG (p < 0.01), and a tendency towards higher antibody avidity (p = 0.051). The association between humoral and cellular immune responses previously reported at various time points was lost in subjects after breakthrough infections (p = 0.807). Finally, a machine-learning approach based on our large immunological dataset (a total of 49 variables) from different time points was unable to predict breakthrough infections (area under the curve: 0.55). In conclusion, distinct differences in humoral vs cellular immune responses in fully vaccinated individuals with or without breakthrough infection could be demonstrated. Breakthrough infections predominantly drive the humoral response without boosting the cellular component. Breakthrough infections could not be predicted based on immunological data, which indicates a superior role of environmental factors (e.g., virus exposure) in individualized risk assessment.

Childhood poisonings: Effects of ambiguous product characteristics on preschool children's categorization of household chemicals.

This study investigated preschool children's categorization and risk perception of products with ambiguous product characteristics (e.g., food-like packaging). These characteristics make it difficult for preschool children to categorize household chemicals correctly. This, therefore, increases the risk of unintentional poisoning. We hypothesized that ambiguity arises from different product characteristics, such as the type of packaging, the products' scent, or the packaging's color and transparency. In four behavioral tasks, N = 108 preschool children (M = 43 months, SD = 3) categorized different products and household chemicals with various types of packaging, colors, and scents. Individually wrapped dishwasher tablets were more likely to be categorized as edible than unwrapped ones. Furthermore, children who had interacted with any type of dishwasher tablet in the last 6 months performed better in identifying dishwasher tablets, regardless of packaging type. Household chemicals with a fruity scent were more likely to be categorized as drinkable than those with a chlorine scent. Finally, the children considered black bottles more dangerous and preferred them less than bottles of a different color. In contrast, bottle transparency generally did not seem to affect risk perception and preference. These findings confirm that ambiguous product characteristics influence children's categorization of unknown products and, thus, their risk perception and decision-making. Manufacturers and caregivers are advised to reduce the ambiguity of household chemicals by designing more neutral product packaging and choosing products with more neutral elements, respectively.

DISCOVER-EEG: an open, fully automated EEG pipeline for biomarker discovery in clinical neuroscience.

Biomarker discovery in neurological and psychiatric disorders critically depends on reproducible and transparent methods applied to large-scale datasets. Electroencephalography (EEG) is a promising tool for identifying biomarkers. However, recording, preprocessing, and analysis of EEG data is time-consuming and researcher-dependent. Therefore, we developed DISCOVER-EEG, an open and fully automated pipeline that enables easy and fast preprocessing, analysis, and visualization of resting state EEG data. Data in the Brain Imaging Data Structure (BIDS) standard are automatically preprocessed, and physiologically meaningful features of brain function (including oscillatory power, connectivity, and network characteristics) are extracted and visualized using two open-source and widely used Matlab toolboxes (EEGLAB and FieldTrip). We tested the pipeline in two large, openly available datasets containing EEG recordings of healthy participants and patients with a psychiatric condition. Additionally, we performed an exploratory analysis that could inspire the development of biomarkers for healthy aging. Thus, the DISCOVER-EEG pipeline facilitates the aggregation, reuse, and analysis of large EEG datasets, promoting open and reproducible research on brain function.

What Is the Correlation between Clinical and Radiographic Findings in Patients with Advanced Osteoarthritis of the Knee?

Knee range of motion and patient-reported outcome measures (PROMs) are often used as screening tools to assess the severity of knee osteoarthritis and guide the decision to refer patients to an arthroplasty clinic. However, there is little understanding regarding the correlation between these factors. Thus, the purpose of this study was to determine the correlation between patient-reported clinical function measured with the Oxford Knee Score (OKS), pain assessed using the visual analog scale (VAS), knee range of motion (ROM), and characteristic radiographic features in patients with advanced osteoarthritis of the knee. A prospective analysis of a consecutive series of 138 patients with advanced unilateral osteoarthritis (OA) of the knee was performed. The severity of radiographic OA was classified according to the most commonly used Kellgren and Lawrence classification (K&L). Spearman's rank correlation analysis and multiple linear regression analysis were performed. The OKS was used as a dependent variable and was adjusted for pain, ROM, and nine standardized radiographic parameters on multiple views of the tibiofemoral and patellofemoral joint. OKS and pain correlated weakly with the K&L grade (r = -0.289; p = 0.001; r = 0.258; p = 0.002). K&L grade and the degree of patellofemoral joint space narrowing were identified as independent factors being associated with a poorer OKS (coefficient -4.528, p = 0.021; coefficient -2.211, p = 0.038). Slightly worse results were identified for OKS and pain in patients with K&L grade 4 osteoarthritis compared to patients with K&L grade 3 osteoarthritis (∆OKS 5.5 points, p < 0.001; ∆VAS 1.7 points, p = 0.003). There was no significant difference for passive range of motion between patients with K&L grade 3 or 4. When counseling patients with advanced knee osteoarthritis who may be eligible for knee arthroplasty, it is essential to give primary consideration to pain levels and self-reported limitations experienced during daily activities. Relying solely on knee ROM and PROMs is not an effective screening method for guiding the decision to refer patients to an arthroplasty clinic.