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Current theories of Autism Spectrum Disorder (ASD) suggest atypical use of context in ASD, but little is known about how these atypicalities influence speech perception. We examined the influence of contextual information (lexical, spectral, and temporal) on phoneme categorization of people with ASD and in typically developed (TD) people. Across three experiments, we found that people with ASD used all types of contextual information for disambiguating speech sounds to the same extent as TD; yet they exhibited a shallower identification curve when phoneme categorization required temporal processing. Overall, the results suggest that the observed atypicalities in speech perception in ASD, including the reduced sensitivity observed here, cannot be attributed merely to the limited ability to utilize context during speech perception.

Abstract Background The ability of skeletal muscle to respond adequately to changes in nutrient availability, known as metabolic flexibility, is essential for the maintenance of metabolic health and loss of flexibility contributes to the development of diabetes and obesity. The tumour suppressor protein, p53, has been linked to the control of energy metabolism. We assessed its role in the acute control of nutrient allocation in skeletal muscle in the context of limited nutrient availability. Methods A mouse model with inducible deletion of the p53‐encoding gene, Trp53, in skeletal muscle was generated using the Cre‐loxP‐system. A detailed analysis of nutrient metabolism in mice with control and knockout genotypes was performed under ad libitum fed and fasting conditions and in exercised mice. Results Acute deletion of p53 in myofibres of mice activated catabolic nutrient usage pathways even under ad libitum fed conditions, resulting in significantly increased overall energy expenditure (+10.6%; P = 0.0385) and a severe nutrient deficit in muscle characterized by depleted intramuscular glucose and glycogen levels (−62,0%; P

Abstract Intelectin-1 (ITLN1; also Omentin-1, OMNT1) is secreted by adipose tissue (AT) and plays an important role in glucose metabolism regulation, with links to obesity-associated diseases. ITLN1 activity so far has rarely been investigated using RNA-sequencing and in larger cohorts. We evaluated ITLN1 expression among three clinical cohorts of the Leipzig Obesity BioBank—a cross-sectional cohort comprising of 1480 people, a cohort of people with metabolically healthy or unhealthy obesity (31 insulin-sensitive, 42 insulin-resistant individuals with obesity), and a longitudinal two-step bariatric surgery cohort (n = 65). We hypothesized that AT ITLN1 expression is associated with serum omentin-1, clinical parameters associated with obesity, and with weight loss after bariatric surgery. We also investigated the correlation of AT ITLN1 expression with genes related to inflammatory response, lipid metabolism, obesity, and regulation of energy balance. Likewise, we inspected gene group expression and metabolic pathways associated with ITLN1 expression using gene set enrichment and gene correlation analysis. We show that ITLN1 expression differs in VAT and SAT, and should therefore be analyzed separately. Furthermore, ITLN1 expression increases with VAT tissue mass, but is negatively affected by AT tissue dysfunction among individuals with unhealthy obesity, corroborated by interplay with genes related to tissue inflammation. Gene set enrichment and gene correlation analysis of ITLN1 expression suggest that AT ITLN1 expression is related to local inflammatory processes in AT, but also in processes such as regulation of appetite, energy balance, and maintenance of body weight.

Abstract GAIN-2 trial evaluated the optimal intense dose-dense (idd) strategy for high-risk early breast cancer. This study reports the secondary endpoints pathological complete response (pCR) and overall survival (OS). Patients (n = 2887) were randomized 1:1 between idd epirubicin, nab-paclitaxel, and cyclophosphamide (iddEnPC) versus leukocyte nadir-based tailored regimen of dose-dense EC and docetaxel (dtEC-dtD) as adjuvant therapy, with neoadjuvant therapy allowed after amendment. At median follow-up of 6.5 years (overall cohort) and 5.7 years (neoadjuvant cohort, N = 593), both regimens showed comparable 5-year OS rates (iddEnPC 90.8%, dtEC-dtD 90.0%, p = 0.320). In the neoadjuvant setting, iddEnPC yielded a higher pCR rate than dtEC-dtD (51.2% vs. 42.6%, p = 0.045). Patients achieving pCR had significantly improved 5-year iDFS (88.7% vs. 70.1%, HR 0.33, p

Studies on the quality of nature of science (NOS) representations in school science textbooks report them being mostly of implicit manner and not fully adequate. However, the often underlying NOS framework of the consensus list in these studies is criticized as undifferentiated and inadequate. The family resemblance approach (FRA) to NOS shows potential to give differentiated insights into the appropriateness of NOS representations with avoidance of specifying certain philosophical directions. Based on a fine-grained differentiated FRA category system (11 main categories, e.g., "knowledge"; 52 subcategories, e.g., "hypotheses"), the quality of cognitive-epistemic NOS representations identified in seven biology school textbooks from Germany was analyzed. For this, a category system was developed. Cognitive-epistemic NOS representations in four chapters of each of the seven textbooks were evaluated regarding manner (implicit, explicit) and adequacy (adequate, (partly) not adequate). Results indicate, among others, that explicit representations of the cognitive-epistemic system of science were mainly placed in the introduction chapters, whereas subject-related chapters include mostly implicit representations. In this article, we present the evaluation of the quality of cognitive-epistemic NOS representations and discuss implications for science education.

Open die forging is one of the oldest manufacturing methods known to remove defects in the ingot resulting from the casting process. The improved properties of the final component are highly dependent on the strain distribution. Although sinusoidal equations and empirical formulations have been already used to estimate the strain, they have been applied only to the core of the workpiece. In this work, a novel approach is presented to model the equivalent strain distribution in 2D cross-sections, in the direction of the press, of open die forged components using neural networks. The proposed method efficiently combines a parametric sinusoidal function with a neural network to learn the complex relationships between the process parameters and the resulting local strain. The neural network is trained on a dataset of finite element (FE) simulations of rectangular geometries that cover a wide range of aspect ratios, bite ratios, and height reductions. The presented methodology with near real-time prediction capabilities shows good agreement with FE results. Moreover, the parametric function captures the characteristic pattern of the strain distribution and reveals certain physical relationships affecting the deformation of the material. These patterns are later examined by analyzing the parameters identified in the parametric sinusoidal function.

Human peptidylarginine deiminase isoform VI (PAD6), which is predominantly limited to cytoplasmic lattices in the mammalian oocytes in ovarian tissue, is essential for female fertility. It belongs to the peptidylarginine deiminase (PAD) enzyme family that catalyzes the conversion of arginine residues to citrulline in proteins. In contrast to other members of the family, recombinant PAD6 was previously found to be catalytically inactive. We sought to provide structural insight into the human homologue to shed light on this observation. We report here the first crystal structure of PAD6, determined at 1.7 Å resolution. PAD6 follows the same domain organization as other structurally known PAD isoenzymes. Further structural analysis and size-exclusion chromatography show that PAD6 behaves as a homodimer similar to PAD4. Differential scanning fluorimetry suggests that PAD6 does not coordinate Ca2+ which agrees with acidic residues found to coordinate Ca2+ in other PAD homologs not being conserved in PAD6. The crystal structure of PAD6 shows similarities with the inactive state of apo PAD2, in which the active site conformation is unsuitable for catalytic citrullination. The putative active site of PAD6 adopts a non-productive conformation that would not allow protein–substrate binding due to steric hindrance with rigid secondary structure elements. This observation is further supported by the lack of activity on the histone H3 and cytokeratin 5 substrates. These findings suggest a different mechanism for enzymatic activation compared with other PADs; alternatively, PAD6 may exert a non-enzymatic function in the cytoplasmic lattice of oocytes and early embryos.

Abstract Background While indirect comparison of infliximab (IFX) and vedolizumab (VDZ) in adults with Crohn’s disease (CD) or ulcerative colitis (UC) shows that IFX has better effectiveness during induction, and comparable efficacy during maintenance treatment, comparative data specific to subcutaneous (SC) IFX (i.e., CT-P13 SC) versus VDZ are limited. Aim Pooled analysis of randomised studies to compare efficacy and safety with IFX SC and VDZ in moderate-to-severe inflammatory bowel disease. Methods Parallel-group, randomised studies evaluating IFX SC and VDZ in patients with moderate-to-severe CD or UC were identified. Eligible studies reported ≥ 1 prespecified outcome of interest at Week 6 (reflecting treatment during the induction phase) and/or at 1 year (Weeks 50-54; reflecting treatment during the maintenance phase). Prespecified efficacy and safety outcomes considered in this pooled analysis included the proportions of patients achieving disease-specific clinical responses, clinical remission, or discontinuing due to lack of efficacy, and the proportions of patients experiencing adverse events (AEs), serious AEs, infections, serious infections, or discontinuing due to AEs. Data from multiple studies or study arms were extracted and pooled using a random-effect model; comparative analyses were performed separately for patients with CD and UC. Results We identified three eligible CD trials and four eligible UC trials that assigned over 1200 participants per disease cohort to either IFX SC or VDZ. In patients with CD, intravenous induction therapy with IFX demonstrated better efficacy (non-overlapping 95% confidence intervals [CIs]) compared with VDZ; during the maintenance phase, IFX SC showed numerically better efficacy (overlapping 95% CIs) than VDZ. A lower proportion of IFX SC-treated patients discontinued therapy due to lack of efficacy over 1 year. In patients with UC, efficacy profiles were similar with IFX SC and VDZ during the induction and maintenance phases, and a lower proportion of IFX SC-treated patients discontinued therapy due to lack of efficacy over 1 year. In both cohorts, safety profiles for IFX SC and VDZ were generally comparable during 1 year. Conclusion IFX SC demonstrated better efficacy than VDZ in patients with CD, and similar efficacy to VDZ in patients with UC; 1-year safety was comparable with IFX SC and VDZ.

Abstract In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, the impact of fasting regimens on the regulation of AT immune infiltration is still elusive. Here we show that intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, this increase in LAM abundance is strongly p53 dependent and partly mediated by p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation during IF, increases the catabolic state of adipocytes, and enhances systemic metabolic flexibility and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to efficacy of a fasting-mimicking diet and that the expression of p53 and TREM2 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signalling in adipocytes dictates LAM accumulation in AT under IF and modulates fasting effectiveness in mice and humans.

In science education, learners' conceptions of scientists and their work are often assessed by the Draw-A-Scientist Test (DAST). Due to validity concerns, methodical literature demands the development of alternative instruments to measure learners' conceptions validly and efficiently. This study presents an instrument with 29 rating scale items to assess pre-service teachers' (PSTs) Views of Scientists, their Activities, and Locations (VoSAL). The items were developed based on theoretical considerations, previous findings, and repeated discussions by biology education experts. After several steps of test development, PSTs filled out the questionnaire (N = 1,098). Exploratory factor analyses and reliability measurements mostly confirm the proposed structure. Groups comparisons were performed regarding the results from pre-service biology teachers of three different study stages (n[subscript "freshmen"] = 114; n[subscript "second"] and third years = 124; n[subscript "graduates" = 107). Analyses of variance and corresponding post-hoc tests showed that undergraduates (freshmen, second and third years) differ significantly from graduates regarding the scales "stereotypical appearance," "inquiry location," and "scientific activity," with undergraduates having more stereotypical conceptions than graduates. In sum, the VoSAL can be utilized to gain valid data of PSTs' conceptions about scientists and their work. Also, the VoSAL can be considered efficient since the test time is between 5 and 10 min. Thus, the questionnaire is valuable in studies that aim to introduce and expose PSTs to realistic science images.

Background: To overcome variability in spoken language, listeners utilize various types of context information for disambiguating speech sounds. Context effects have been shown to be affected by cognitive load. However, previous results are mixed regarding the influence of cognitive load on the use of context information in speech perception. Purpose: We tested a population characterized by an attention-deficit/hyperactivity disorder (ADHD) to better understand the relationship between attention (or internal cognitive load) and context effects. Method: The use of acoustic versus lexical properties of the surrounding signal to disambiguate speech sounds was examined in listeners with ADHD and neurotypical listeners.Results: Compared to neurotypicals, individuals with ADHD relied more strongly on lexical context for speech perception; however, reliance on acoustic context information from speech rate did not differ. Conclusion: These findings confirm that cognitive load impacts the use of high-level but not low-level context information in speech and imply that speech recognition deficits in ADHD likely arise due to impaired higher order cognitive processes.

Astrophysical tests of the stability—or not—of fundamental couplings (e.g., can the numerical value ∼1/137 of the fine-structure constant α = e2/ℏc vary with astronomical time?) are a very active area of observational research. Using a specific α-free non-relativistic and nonlinear isotropic quantum model compatible with its quantum electrodynamics (QED) counterpart yields the 99% accurate solution α = 7.364 × 10−3 vs its experimental value 7.297 × 10−3. The ∼1% error is due to the deliberate use of mean-field Hartree approximation involving lowest-order QED in the calculations. The present theory has been checked by changing the geometry of the model. Moreover, it fits the mathematical solution of the original nonlinear integro-differential Hartree system by use of a rapidly convergent series of nonlinear eigenstates [G. Reinisch, Phys. Lett. A 498, 129347 (2024)]. These results strongly suggest the mathematical transcendental nature—e.g., like for π or e—of α’s numerical value of ∼1/137 and, hence, its astrophysical as well as its cosmological stability.

Previous research about the presence of nature of science (NOS) within science textbooks has been found to be lacking in sufficient coverage. However, given the shift in how scholars conceive of NOS, the shortcomings may not be present in the textbooks but rather in the NOS frameworks used to analyze textbooks. Whereas traditional NOS has taken a more generalized approach to describing scientific practices, the family resemblance approach (FRA) to NOS recognizes variability in the scientific disciplines as reported by practicing scientists as well as philosophers and historians of science. Instead of suggesting that NOS can be applied equally in educational settings to all scientific disciplines, the FRA accounts for cognitive-epistemic and social-instructional conceptual elements which more authentically represent science. This study sought to evaluate textbooks using this more recent NOS conceptualization to explore the potential range of NOS aspects. Using the proposed FRA categories, seven German biology textbooks were analyzed with qualitative content analysis. The combination of cognitive-epistemic and social-institutional systems of science revealed that the FRA was a suitable mechanism for analyzing textbooks' coverage of NOS. Notably, FRA's distinct attention to modeling (absent from the discipline-general NOS approach) revealed its presence in textbooks that would have gone unnoticed. Another finding was that the textbooks tended to emphasize the cognitive-epistemic systems over the social-institutional. Finally, this study found that even with a broader set of categories and subcategories to the FRA, the application to analyze was reliable.