Search Results (122)

An adaptive neural network output-feedback control strategy is proposed in this paper for the distributed optimization problem (DOP) of high-order nonlinear stochastic multi-agent systems (MASs) driven by Lévy noise. On the basis of the penalty-function method, the consensus constraint is removed and the global objective function (GOF) is reconstructed. The stability of the system is analyzed by combining the generalized Itô’s formula with the Lyapunov function method. Moreover, the command filtering mechanism is introduced to solve the “complexity explosion” problem in the process of designing virtual controller, and the filter errors are compensated by introducing compensating signals. The proposed algorithm has been proved that the outputs of all agents converge to the optimal solution of the DOP with bounded errors. The simulation results demonstrate the effectiveness of the proposed approach. Full article

Slow-release fertilizer was developed by encapsulating NPK compound pellets with graphene oxide (GO) sheets employing a waterless synthesis technique. As-prepared GO sheets were characterized by XRD, Raman, XPS, FTIR, SEM, and EDS. The XRD patterns of the GO sheets indicate that the peak for the GO is observed at 2θ = 9.3°, and the peak (002) for graphite vanished. Moreover, a higher intensity ratio of the Raman ID/IG of the GO sheets than that of pristine graphite confirms the oxidation of the graphite. The FTIR and XPS analyses provided information on electronic structure, chemical structure, and oxygen-bonding neighbors. The SEM images indicated the GO sheet, whereby its morphology resembles a thin curtain or corrugated shape. The EDS spectrum of coated GO-F pellets revealed the distribution of C, O, N, P, and K elements in the synthesized materials. Afterwards, GO shell formation on fertilizer pellets greatly improved the slow-release characteristics of fertilizer, thus providing plants with their requisite nutrients and reducing environmental pollution. Full article

Background: Developmental and epileptic encephalopathies (DEE) are a group of disorders often linked to de novo mutations, including those in the ATP6V1A gene. These mutations, particularly dominant gain-of-function (GOF) variants, have been associated with a spectrum of phenotypes, ranging from severe DEE and infantile spasms to milder conditions like autism spectrum disorder and language delays. Methods: We aim to expand ATP6V1A-related disease spectrum by describing a six-year-old boy who presented with a febrile seizure, mild intellectual disability (ID), language delay, acquired microcephaly, and dysmorphic features. Results: Genetic analysis revealed a novel de novo heterozygous pathogenic variant (c.82G>A, p.Val28Met) in the ATP6V1A gene. He did not develop epilepsy, and neuroimaging remained normal over five years of follow-up. Although ATP6V1A mutations have traditionally been linked to severe neurodevelopmental disorders, often with early-onset epilepsy, they may exhibit milder, non-progressive phenotypes, challenging previous assumptions about the severity of ATP6V1A-related conditions. Conclusions: This case expands the known clinical spectrum, illustrating that not all patients with ATP6V1A mutations exhibit severe neurological impairment or epilepsy and underscoring the importance of including this gene in differential diagnoses for developmental delays, especially when febrile seizures or dysmorphic features are present. Broader genotype–phenotype correlations are essential for improving predictive accuracy and guiding clinical management, especially as more cases with mild presentations are identified. Full article

Flow processes onboard ships are common in order to transport fluids like oil, gas, and water. These processes are controlled by PID controllers, acting on the regulation valves as actuators. In case of a malfunction or refitting, a PID controller needs to be re-adjusted for the optimal control of the process. To avoid experimenting on operational real systems, models are convenient alternatives. When real-time information is needed, digital twin (DT) concepts become highly valuable. The aim of this paper is to analyze and determine the optimal NARX model architecture in order to achieve a higher-accuracy model of a ship’s flow process. An artificial neural network (ANN) was used to model the process in MATLAB. The experiments were performed using a multi-start approach to prevent overtraining. To prove the thesis, statistical analysis of the experimental results was performed. Models were evaluated for generalization using mean squared error (MSE), best fit, and goodness of fit (GoF) measures on two independent datasets. The results indicate the correlation between the number of input delays and the performance of the model. A permuted k-fold cross-validation analysis was used to determine the optimal number of voltage and flow delays, thus defining the number of model inputs. Permutations of training, test, and validation datasets were applied to examine bias due to the data arrangement during training. Full article

The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations in the TP53 gene, which not only abrogate the tumor-suppressive functions but also confer p53 mutant proteins with oncogenic potential. The latter is achieved through so-called gain-of-function (GOF) mutations that promote cancer progression, metastasis, and therapy resistance by deregulating transcriptional networks, signaling pathways, metabolism, immune surveillance, and cellular compositions of the microenvironment. Despite recent progress in understanding the complexity of mutp53 in neoplastic development, the exact mechanisms of how mutp53 contributes to cancer development and how they escape proteasomal and lysosomal degradation remain only partially understood. In this review, we address recent findings in the field of oncogenic functions of mutp53 specifically regarding, but not limited to, its implications in metabolic pathways, the secretome of cancer cells, the cancer microenvironment, and the regulating scenarios of the aberrant proteasomal degradation. By analyzing proteasomal and lysosomal protein degradation, as well as its connection with autophagy, we propose new therapeutical approaches that aim to destabilize mutp53 proteins and deactivate its oncogenic functions, thereby providing a fundamental basis for further investigation and rational treatment approaches for TP53-mutated cancers. Full article

Background: The predictive and prognostic role of BRAF alterations has been evaluated in colorectal cancer (CRC); however, BRAF alterations have not been fully characterized in non-CRC gastrointestinal (GI) malignancies. In the present study, we report the frequency and spectrum of BRAF alterations among patients with non-CRC GI malignancies. Methods: Patients with CRC and non-CRC GI malignancies who underwent somatic tumor profiling via a tissue-based or liquid-based assay were included in this study. Gain-of-function BRAF alterations were defined as pathogenic/likely pathogenic somatic short variants (SVs), copy number amplifications ≥8, or fusions (RNA or DNA). Results: Among 51,560 patients with somatic profiling, 40% had CRC and 60% had non-CRC GI malignancies. BRAF GOF alterations were seen more frequently in CRC (8.9%) compared to non-CRC GI malignancies (2.2%) (p < 0.001). Non-CRC GI malignancies with the highest prevalence of BRAF GOF alterations were bile duct cancers (4.1%) and small intestine cancers (4.0%). Among BRAF GOF alterations, class II (28% vs. 6.8%, p < 0.001) and class III (23% vs. 14%, p < 0.001) were more common in non-CRC GI malignancies. Among class II alterations, rates of BRAF amplifications (3.1% vs. 0.3%, p < 0.001) and BRAF fusions (12% vs. 2.2%, p < 0.001) were higher in non-CRC GI malignancies compared to CRC. Conclusions: Non-CRC GI malignancies demonstrate a distinct BRAF alteration profile compared to CRC, with a higher frequency of class II and III mutations, and more specifically, a higher incidence of BRAF fusions. Future studies should evaluate clinical implications for the management of non-CRC GI patients with BRAF alterations, especially BRAF fusions. Full article

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called “triple-negative” GISTs. Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify “triple-negative” patients. Results: Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5–191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a BRAF V600E mutation and two with NF1 loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with TP53 LOF mutations, one with NTRK3 fusion (ETV6-NTRK3), one with PTEN deletion, one with FGFR1 gain-of-function (GOF) mutation (K654E), one with CHEK2 LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one with FANCA deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Conclusions: Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy. Full article

The remote sensing of turbidity and suspended particulate matter (SPM) relies on atmospheric corrections and bio-optical algorithms, but there is no one method that has better accuracy than the others for all satellites, bands, study areas, and purposes. Here, we evaluated different combinations of satellites (Landsat-8, Sentinel-2, and Sentinel-3), atmospheric corrections (ACOLITE and POLYMER), algorithms (single- and multiband; empirical and semi-analytical), and bands (665 and 865 nm) to estimate turbidity and SPM in Patos Lagoon (Brazil). The region is suitable for a case study of the regionality of remote-sensing algorithms, which we addressed by regionally recalibrating the coefficients of the algorithms using a method for geophysical observation models (GeoCalVal). Additionally, we examined the results associated with the use of different statistical parameters for classifying algorithms and introduced a new metric (GoF) that reflects performance. The best performance was achieved via POLYMER atmospheric correction and the use of single-band algorithms. Regarding SPM, the recalibrated coefficients yielded a better performance, but, for turbidity, a tradeoff between two statistical parameters occurred. Therefore, the uncertainties in the atmospheric corrections and algorithms used were analyzed based on previous studies. In the future, we suggest the use of in situ radiometric data to better evaluate atmospheric corrections, radiative transfer modeling to bridge data gaps, and multisensor data merging for compiling climate records. Full article

TP53 mutations are prevalent in various cancers, yet the complexity of apoptotic pathway deregulation suggests the involvement of additional factors. HOPS/TMUB1 is known to extend the half-life of p53 under normal and stress conditions, implying a regulatory function. This study investigates, for the first time, the potential modulatory role of the ubiquitin-like-protein HOPS/TMUB1 in p53-mutants. A comprehensive analysis of apoptosis in the most frequent p53-mutants, R175, R248, and R273, in SKBR3, MIA PaCa2, and H1975 cells indicates that the overexpression of HOPS induces apoptosis at least equivalent to that caused by DNA damage. Immunoprecipitation assays confirm HOPS binding to p53-mutant forms. The interaction of HOPS/TMUB1 with p53-mutants strengthens its effect on the apoptotic cascade, showing a context-dependent gain or loss of function. Gene expression analysis of the MYC and TP63 genes shows that H1975 exhibit a gain-of-function profile, while SKBR3 promote apoptosis in a TP63-dependent manner. The TCGA data further corroborate HOPS/TMUB1’s positive correlation with apoptotic genes BAX, BBC3, and NOXA1, underscoring its relevance in patient samples. Notably, singular TP53 mutations inadequately explain pathway dysregulation, emphasizing the need to explore additional contributing factors. These findings illuminate the intricate interplay among TP53 mutations, HOPS/TMUB1, and apoptotic pathways, providing valuable insights for targeted cancer interventions. Full article

Empagliflozin is a sodium–glucose cotransporter 2 (SGLT2) inhibitor that is commonly used for the treatment of type 2 diabetes mellitus (T2DM). CKD-370 was newly developed as a cocrystal formulation of empagliflozin with co-former L-proline, which has been confirmed to be bioequivalent in South Korea. This study aimed to quantify the differences in the absorption phase and pharmacokinetic (PK) parameters of two empagliflozin formulations in healthy subjects by using population PK analysis. The plasma concentration data of empagliflozin were obtained from two randomized, open-label, crossover, phase 1 clinical studies in healthy Korean subjects after a single-dose administration. A population PK model was constructed by using a nonlinear mixed-effects (NLME) approach (Monolix Suite 2021R1). Interindividual variability (IIV) and interoccasion variability (IOV) were investigated. The final model was evaluated by goodness-of-fit (GOF) diagnostic plots, visual predictive checks (VPCs), prediction errors, and bootstrapping. The PK of empagliflozin was adequately described with a two-compartment combined transit compartment model with first-order absorption and elimination. Log-transformed body weight significantly influenced systemic clearance (CL) and the volume of distribution in the peripheral compartment (V2) of empagliflozin. GOF plots, VPCs, prediction errors, and the bootstrapping of the final model suggested that the proposed model was adequate and robust, with good precision at different dose strengths. The cocrystal form did not affect the absorption phase of the drug, and the PK parameters were not affected by the different treatments. Full article

Design patterns provide solutions to recurring problems in software design and development, promoting scalability, readability, and maintainability. While past research focused on the utilization of the design patterns and performance, there is limited insight into their impact on program evolution. Dependency signifies relationships between program elements, reflecting a program’s structure and interaction. High dependencies indicate complexity and potential flaws, hampering system quality and maintenance. This paper presents how design patterns influence software evolution by analyzing dependencies using the Abstract Syntax Tree (AST) to examine dependency patterns during evolution. We employed three widely adopted design patterns from the Gang of Four (GoF) as experimental examples. The results show that design patterns effectively reduce dependencies, lowering system complexity and enhancing quality. Full article

Primary immune regulatory disorders (PIRDs) constitute a spectrum of inborn errors of immunity (IEIs) that are primarily characterized by autoimmunity, lymphoproliferation, atopy, and malignancy. In PIRDs, infections are infrequent compared to other IEIs. While susceptibility to infection primarily stems from antibody deficiency, it is sometimes associated with additional innate immune and T or NK cell defects. The use of immunotherapy and chemotherapy further complicates the immune landscape, increasing the risk of diverse infections. Recurrent sinopulmonary infections, particularly bacterial infections such as those associated with staphylococcal and streptococcal organisms, are the most reported infectious manifestations. Predisposition to viral infections, especially Epstein–Barr virus (EBV)-inducing lymphoproliferation and malignancy, is also seen. Notably, mycobacterial and invasive fungal infections are rarely documented in these disorders. Knowledge about the spectrum of infections in these disorders would prevent diagnostic delays and prevent organ damage. This review delves into the infection profile specific to autoimmune lymphoproliferative syndrome (ALPS), Tregopathies, and syndromes with autoimmunity within the broader context of PIRD. Despite the critical importance of understanding the infectious aspects of these disorders, there remains a scarcity of comprehensive reports on this subject. Full article

The Janus kinase (JAK) family is a small group of protein tyrosine kinases that represent a central component of intracellular signaling downstream from a myriad of cytokine receptors. The JAK3 family member performs a particularly important role in facilitating signal transduction for a key set of cytokine receptors that are essential for immune cell development and function. Mutations that impact JAK3 activity have been identified in a number of human diseases, including somatic gain-of-function (GOF) mutations associated with immune cell malignancies and germline loss-of-function (LOF) mutations associated with immunodeficiency. The structure, function and impacts of both GOF and LOF mutations of JAK3 are highly conserved, making animal models highly informative. This review details the biology of JAK3 and the impact of its perturbation in immune cell-related diseases, including relevant animal studies. Full article

The problem of examining how well the data fit a supposed distribution is very important, and it must be confirmed prior to any data analysis, because many data analysis methods assume a specific distribution of data. For this purpose, histograms or Q-Q plots are employed for the assessment of data distribution. Additionally, a GoF TstS utilizes distance measurements between the empirical distribution function and the theoretical cumulative distribution function (cdf) to evaluate data distribution. In life-testing or reliability studies, the observed failure time of test units may not be recorded in some situations. The GoF TstSs for completely observed data can no longer be used in progressive type II censored data (PrCsD). In this paper, we suggest a GoF TstSs and new plot method for the GoF test of symmetric and asymmetric location-scale distribution (LoScD) based on PrCsD. The power of the suggested TstSs is estimated through Monte Carlo (MC) simulations, and it is compared with that of the TstSs using the order statistics (OrSt). Furthermore, we analyzed real data examples (symmetric and asymmetric data). Full article

The disruptive effect of radio frequency interference (RFI) on global navigation satellite system (GNSS) signals is well known, and in the last four decades, many have been investigated as countermeasures. Recently, low-Earth orbit (LEO) satellites have been looked at as a good opportunity for GNSS RFI monitoring, and the last five years have seen the proliferation of many commercial and academic initiatives. In this context, this paper proposes a new spaceborne system to detect, classify, and localize terrestrial GNSS RFI signals, particularly jamming and spoofing, for civil use. This paper presents the implementation of the RFI detection software module to be hosted on a nanosatellite. The whole development work is described, including the selection of both the target platform and the algorithms, the implementation, the detection performance evaluation, and the computational load analysis. Two are the implemented RFI detectors: the chi-square goodness-of-fit (GoF) algorithm for non-GNSS-like interference, e.g., chirp jamming, and the snapshot acquisition for GNSS-like interference, e.g., spoofing. Preliminary testing results in the presence of jamming and spoofing signals reveal promising detection capability in terms of sensitivity and highlight room to optimize the computational load, particularly for the snapshot-acquisition-based RFI detector. Full article