Lung development is governed by tightly regulated signaling mechanisms, including endocytosis-mediated pathways critical for epithelial–mesenchymal communication and tissue remodeling. This study investigated the effects of Dab1 deficiency on the expression of endocytic and signaling-related proteins, Megalin, Cubilin, Caveolin-1, GIPC1, and Dab2IP, during embryonic lung development in yotari mice. Using immunofluorescence and quantitative image analysis, protein expressions were compared between yotari and wild-type embryos at gestational days E13.5 and E15.5. Results showed significantly reduced expression of Caveolin-1 in the yotari epithelium across both stages, along with diminished mesenchymal levels of Megalin and GIPC1 at E13.5. Cubilin and Dab2IP expression patterns showed no statistically significant differences, although developmental and compartmental shifts were observed. These findings suggest that Dab1 deficiency selectively disrupts endocytic and signaling scaffolds crucial for branching morphogenesis and alveolar maturation. The altered spatiotemporal expression of these proteins underscores the essential role of Dab1 in regulating lung epithelial–mesenchymal dynamics and maintaining developmental homeostasis during critical stages of organogenesis.

Abstract Despite striking successes in identifying novel biomarkers for improved patient stratification and predicting disease progression, numerous challenges remain in the effective integration and exploitation of multiomic data in biomedical applications beyond cancer, for which most bioinformatics strategies are developed and validated. That focus on cancer severely limits the effective development and advancement of algorithms in machine learning and artificial intelligence that do not suffer degraded out-of-domain performance. Generalizability and interpretability of models, however, are also required for robust insights that may translate into clinical practice. Work across different independent datasets is critical for establishing models robust towards unwanted variation in assays, protocols, and cohort populations. Disease-specific context like ethnicity, socioeconomic background, sex, lifestyle, disease phase, and tissue type also strongly affect molecular profiles. We here discuss atherosclerotic cardiovascular disease (ASCVD) as a high-impact non-cancer use case for the challenges remaining in the development and application of the latest bioinformatics approaches to multiomics data integration. ASCVD remains the leading cause of death globally. Disease aetiology, progression, and therapy outcome depend on a complex interplay of genetic, environmental, and lifestyle factors. Integrating these diverse data types effectively remains a challenge but holds transformative potential for personalized medicine. Discovery and access to data of sufficient diversity and extent form key bottlenecks. We here compile a first comprehensive overview of key data sets in ASCVD to complement the established cancer-focused resources as a foundation for future effective development and application of state-of-the-art bioinformatics tools for multiomic data integration.

A Boolean-algebraic framework for maximal-degree U-k-seminets is presented, unifying combinatorial and algebraic properties. This work extends Aczel’s quasigroup theory and Belousov’s k-net constructions by introducing a computational framework for U-k-seminets of maximal degree µ. Key results include: (1) explicit bounds for µ in terms of set cardinality t and t-order d (µ = t−d+2), (2) existence conditions for nonequipotent sets, and (3) inequalities governing µ and t ((t+2)/2 < µ ≤ t). Theorems are validated via tabulated solutions for m = t−d, demonstrating scalable applications in finite geometry and network design. The framework bridges partial quasigroups and block designs, offering algorithmic tools for seminets with maximal degree constraints.

Small-cell lung cancer (SCLC) is a tobacco-associated neuroendocrine tumor comprising ~15% of lung cancers (~150,000 cases/year). For decades, outcomes stagnated: most patients present with extensive-stage disease, screening rarely detects early tumors, surgery is seldom feasible, and platinum-etoposide remained the first-line standard with median overall survival (OS) <12 months. Radiotherapy (including consolidative thoracic RT) and prophylactic cranial irradiation or MRI surveillance offered incremental gains. Two shifts have begun to change the field. First, four transcriptional subtypes (SCLC-A, -N, -P, and inflammatory SCLC-I) support a more personalized approach, with SCLC-I appearing more responsive to immune checkpoint inhibitors (ICI). Second, adding atezolizumab or durvalumab to chemotherapy in extensive-stage SCLC produced a modest median OS gain but, crucially, a tail of long-term survivors. Subsequent trials extended these advances: IMforte suggested benefit from lurbinectedin maintenance with atezolizumab in ES-SCLC, and ADRIATIC demonstrated a landmark OS improvement (~22 months) with durvalumab consolidation after concurrent chemoradiotherapy in limited-stage SCLC. Targeted strategies are now emerging. Delta-like ligand 3 (DLL3), overexpressed in >80% of SCLC, enables T-cell-redirecting therapy: the bispecific T-cell engager tarlatamab improved OS to 13.6 vs 8.3 months over standard second-line chemotherapy, with manageable cytokine release syndrome and occasional ICANS. B7 homolog 3 (B7-H3, CD276), uniformly expressed across SCLC subtypes and linked to poor prognosis, is another compelling target: the antibody-drug conjugate ifinatamab deruxtecan achieved a 54.8% response rate and meaningful survival in heavily pretreated patients, earning FDA Breakthrough designation. Together, DLL3- and B7-H3-directed therapies (with additional ADCs against Trop-2 and SEZ6 in development) are redefining second-line and later care. Key next steps include optimizing sequencing/combination strategies, managing BiTE-specific toxicities, and developing predictive biomarkers. After decades of futility, SCLC is transitioning from uniform chemotherapy to a precision-medicine paradigm with cautious optimism.

OBJECTIVE Previous studies have demonstrated that the speech reception threshold (SRT) can be estimated using scalp electroencephalography (EEG), referred to as SRTneuro. The present study assesses the feasibility of using ear-EEG, which allows for discreet measurement of neural activity from in and around the ear, to estimate the SRTneuro. Approach: Twenty young normal-hearing participants listened to audiobook excerpts at varying signal-to-noise ratios (SNRs) whilst wearing a 66-channel EEG cap and 12 ear-EEG electrodes. A linear decoder was trained on different electrode configurations to estimate the envelope of the audio excerpts from the EEG recordings. The reconstruction accuracy was determined by calculating the Pearson's correlation between the actual and the estimated envelope. A sigmoid function was then fitted to the reconstruction-accuracy-vs-SNR data points, with the midpoint of the sigmoid serving as the SRTneuro estimate for each participant. Main results: Using only in-ear electrodes , the estimated SRTneuro was within 3 dB of the behaviorally measured SRT (SRTbeh) for 6 out of 20 participants (30%). With electrodes placed both in and around the ear, the SRTneuro was within 3 dB of the SRTbeh for 19 out of 20 participants (95%) and thus on par with the reference estimate obtained from full-scalp EEG. Using only electrodes in and around the ear from the right side of the head, the SRTneuro remained within 3 dB of the SRTbeh for 19 out of 20 participants. .

Antimicrobial resistance is a considerable global health threat especially among low- and middle-income countries, exacerbated by considerable inappropriate dispensing of antibiotics. There have though been concerns with variable levels of dispensing of antibiotics without a prescription in South Africa. Consequently, a need to comprehensively estimate current levels of dispensing of antibiotics without a prescription, which was the aim of this study.Administer a previously piloted questionnaire to all currently operating community pharmacies in a rural province, where dispensing of antibiotics without a prescription is likely to be greatest. The questionnaire included data on the estimated prevalence of antibiotics dispensed, their class and indication, and whether dispensed without a prescription. Community pharmacies were categorized into three: Independent, Chain and Franchise.128/169 (75.7%) operational pharmacies participated, with independent pharmacies representing the majority (60.9%). There was a 78.3% response rate from 400 distributed questionnaires, including 106 pharmacists (33.9%) and 207 pharmacist assistants (66.1%) from 128 pharmacies. Antibiotics accounted for 47.9% (95% CI: 47.2%-48.6%) of all medicines dispensed. Penicillins were the most prevalent antibiotic dispensed (41.1%). Almost half (47.2%) of the antibiotics dispensed included macrolides, fluoroquinolones and cephalosporins, which are typically antibiotics from the Watch group. Sexually transmitted infections (33.5%) and upper respiratory tract infections (25.8%) were the most frequent indications for antibiotic dispensing. Overall, 69.3% of 128 participating pharmacies in this rural province in South Africa admitted to dispensing antibiotics without a prescription in the past 14 days, principally among independent pharmacies (98.7%). However, estimates suggest only 8.6% of the total volume of antibiotics being dispensed were dispensed without a prescription among the 88 community pharmacies admitting to this practice in the past 3 days. Encouragingly, 98.1% of community pharmacists and 97.6% of pharmacist assistants indicated they always or mostly offered symptomatic relief before dispensing antibiotics without a prescription to patients with self-limiting conditions.There were considerable concerns regarding the prescribing and dispensing of antibiotics in this rural province including Watch antibiotics. This included the number of community pharmacies, especially independent pharmacies, where patients could purchase antibiotics without a prescription. Multiple strategies involving all key stakeholder groups are need to improve future antibiotic use across South Africa and reduce AMR.

Wastewaters from the textile industry have a high content of organic matter, high coloration, various minerals and metals, and often toxic and carcinogenic substances. Azo dyes are the most common used dyes in the textile industry. Due to their complex structure, the removal of azo dyes from wastewater is challenging. In this study, electrooxidation and the electro-Fenton process, as one of the most effective Electrochemical Advanced Oxidation Processes (EAOPs) for the removal of organic pollutants in wastewater, were used for the treatment of synthetic wastewater containing “Bemacid Red” dye as a pollutant. Several process parameters affecting the efficiency of OH. formation and dye degradation were examined. Stainless steel (SS) was used as the cathode material, and the anodes used were mixed metal oxides (MMO) - Ru mixed oxide (titanium substrate coated with 6g Ru/m2) and Ru-Ir mixed oxide (titanium substrate coated with 6g Ru- Ir/m2). The results showed that the Ru:SS electrode pair is more efficient comapred to the Ru-Ir:SS pair, and that the electro-Fenton process is more efficient compared to electrooxidation.

We study deterministic, discrete linear time-invariant systems with infinite-horizon discounted quadratic cost. It is well-known that standard stabilizability and detectability properties are not enough in general to conclude stability properties for the system in closed-loop with the optimal controller when the discount factor is small. In this context, we first review some of the stability conditions based on the optimal value function found in the learning and control literature and highlight their conservatism. We then propose novel (necessary and) sufficient conditions, still based on the optimal value function, under which stability of the origin for the optimal closed-loop system is guaranteed. Afterwards, we focus on the scenario where the optimal feedback law is not stabilizing because of the discount factor and the goal is to design an alternative stabilizing near-optimal static state-feedback law. We present both linear matrix inequality-based conditions and a variant of policy iteration to construct such stabilizing near-optimal controllers. The methods are illustrated via numerical examples.

Background/Objectives: The Reelin–Dab1 signaling pathway, known for its crucial role in neurodevelopment, particularly in neuronal migration and the formation of cortical layers, has been a subject of extensive research. However, its involvement in gastrointestinal organogenesis is a relatively unexplored area. Our study investigates the expression patterns of Dab1, Reelin, PGP9.5, and Sox2 during stomach development in yotari (Dab1−/−) mice and aims to shed light on how Dab1 inactivation affects epithelial–mesenchymal signaling dynamics, thereby contributing to a deeper understanding of this pathway’s non-neural functions. Methods: Embryonic stomach tissues from yotari and wild-type mice, collected at developmental stages E13.5 and E15.5, were examined by immunofluorescenceto evaluate the difference in expression of Dab1, Reelin, PGP9.5, and Sox2. Semi-quantitative scoring and quantitative image analysis were used to assess protein localization and intensity within epithelial and mesenchymal compartments. Results: Dab1 expression was significantly increased in both the epithelium and mesenchyme of yotari mice at E13.5 and E15.5. Reelin expression in the epithelium showed a visible but statistically non-significant decrease in yotari at E15.5, while mesenchymal expression remained low and significantly lower than controls. PGP9.5 expression was significantly reduced in yotari epithelium at E13.5, then strongly upregulated at E15.5. Mesenchymal PGP9.5 remained consistently high. Sox2 showed no statistically significant changes but increased semi-quantitatively in yotari epithelium and mesenchyme at E15.5. These findings highlight compartment-specific disruptions and potential compensatory mechanisms following Dab1 inactivation. Conclusions: Our findings indicate that Dab1 deficiency leads to distinct molecular changes in epithelial and mesenchymal compartments of the developing stomach. The Reelin–Dab1 axis appears critical for epithelial–mesenchymal coordination, while PGP9.5 and Sox2 upregulation in yotari mice may represent potential compensatory responses that could support epithelial integrity, although this remains speculative without functional validation.

The liver is a central metabolic organ that regulates numerous physiological processes, including glucose and lipid metabolism, detoxification, and the synthesis of essential proteins and bile. Bile acids (BAs), synthesized from cholesterol in hepatocytes, not only facilitate the emulsification and absorption of dietary fats but also act as potent signaling molecules through receptors such as the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease globally, closely linked with obesity, insulin resistance, and other components of metabolic syndrome. In MASLD, the metabolism of BAs is markedly disrupted, resulting in alterations in their synthesis, composition, and signaling activity. These changes contribute to hepatic steatosis, inflammation, and fibrosis, thereby exacerbating metabolic dysfunction and liver damage. The altered profiles and signaling activity of BAs in MASLD patients suggest that BAs act not only as biomarkers of disease severity, but also as active mediators of its pathogenesis. Modulators of BA signaling pathways, especially FXR agonists, are the focus of intense research for their potential to beneficially influence liver steatosis and inflammation in MASLD. Recent research has yielded promising results, indicating potential therapeutic application and the introduction of novel agents aimed at modulating BA homeostasis and function. This minireview outlines the physiological roles of BAs, seeks to advance the elucidation of the mechanisms by which their dysregulation contributes to MASLD progression, and highlights current and emerging therapeutic approaches. A deeper understanding of these complex interactions is essential for improving the diagnosis, prognosis and treatment of MASLD.

Introduction Ibrutinib has made significant contributions to the treatment of chronic lymphocytic leukemia (CLL) with recognized cardiovascular toxicities in some patients. This study aimed to assess the incidence of cardiotoxicity in CLL patients treated with ibrutinib and identify associated risk factors. Methods This retrospective cohort study analyzed 79 CLL patients treated with ibrutinib at the University Clinical Center of Serbia. Patient characteristics, treatment outcomes, and cardiovascular events were analyzed to determine the incidence of cardiotoxicity and its potential predictors. Results The median age at diagnosis was 58 years, with 63.3% male patients. Pre-existing cardiovascular conditions were present in 55.7% of patients. Cardiotoxicity occurred in 29.1% of patients, with atrial fibrilation developing in 10.1% patients (37.5% grade 3), leading to therapy discontinuation in 62.5% of those affected. Also, we diagnosed hypertension in 15.2%, heart failure in 7.6%, and myocardial infarction in 2.5% of patients. Furthermore, one case (1.3%) of sudden cardiac death was recorded. The administration of ibrutinib was ceased in 9 patients due to cardiotoxic effects. Patients with prior cardiovascular disease had a threefold increased risk of developing cardiotoxicity (HR=2.850; p=0.031). A history of hypertension was significantly associated withthe worsening of hypertension during ibrutinib therapy (HR=7.935; p=0.009). No significant associations were found between cardiotoxicity and other factors such as age, sex, number of prior treatment lines, clinical stage, or cytogenetic abnormalities. Discussion This study underscores the importance of cardiovascular monitoring in CLL patients undergoing ibrutinib therapy, particularly those with pre-existing cardiovascular conditions. These findings highlight the need for individualized treatment planning and close follow-up to mitigate the risk of cardiotoxicity and optimize patient outcomes.

We introduce TROOP, a tree-based Riccati optimistic online planner, that is designed to generate near-optimal control laws for discrete-time switched linear systems with switched quadratic costs. The key challenge that we address is balancing computational resources against control performance, which is important as constructing near-optimal inputs often requires substantial amount of computations. TROOP addresses this trade-off by adopting an online best-first search strategy inspired by A*, allowing for efficient estimates of the optimal value function. The control laws obtained guarantee both near-optimality and stability properties for the closed-loop system. These properties depend on the planning depth, which determines how far into the future the algorithm explores and is closely related to the amount of computations. TROOP thus strikes a balance between computational efficiency and control performance, which is illustrated by numerical simulations on an example.