Independent Functions Research Articles

Changes in Serum IL-12 Levels following the Administration of H1-Antihistamines in Patients with Chronic Spontaneous Urticaria.

Research regarding the role of the IL-12 cytokine family in modulating immune and inflammatory responses is continuously evolving. In this study, the contribution of the p35 and p40 subunits as monomers (noted as IL-12p35 and IL-12p40) and heterodimers (noted as IL-12p70 or IL-12p35/p40) was analysed in the pathophysiology and progression of chronic spontaneous urticaria (CSU). We conducted a longitudinal, case-control study involving 42 CSU cases and 40 control cases comprising adults without associated conditions. Serial measurements were performed to assess the serum levels of IL-12p70, IL-12p35, and IL-12p40 at the onset of the disease (pre-therapy phase) and 6 weeks after the initiation of the treatment (post-therapy phase). During the pre-therapeutic phase of CSU, elevated serum levels of IL-12 cytokine subtypes were detected compared to the control group. The relationship between IL-12 profiles and the course of CSU highlighted the pro-inflammatory role of IL-12p70 and the anti-inflammatory role of IL-12p35. Significant correlations were observed between IL-12p70 levels and the duration of the disease, as well as between IL-12 and the effectiveness of H1-antihistamines. The molecular background for the pleiotropic activities mediated by IL-12-derived cytokines in patients with CSU lies in the strict regulation of the production, signalling pathways, and cytokine-specific influences on the same pathophysiological events. The results of the present study suggest that the superficial layers of the skin serve as a cellular source of IL-12, a cytokine produced through antigenic stimulation. In patients with CSU, we identified independent, additive, or divergent functions of IL-12p70, IL-12p35, and IL-12p40, all relevant to systemic inflammation. These findings prove that the prototype programming of IL-12 is abnormal in CSU.

Relationship between fear of COVID-19 and mental health of Chinese nurses: The mediating effects of psychological capital and burnout.

The aim of the study was to investigate the correlation between fear of COVID-19 and mental health of nurses and the effects of psychological capital and burnout in this relation. A cross-sectional study. The online surveys were conducted among mainland Chinese nurses. Participants (n = 445; average age 32.89 ± 6.76 years) completed an online-questionnaire based on the Fear of COVID-19 Scale, the Psychological Capital Scale, Maslach Burnout Inventory Human Services Survey for Medical Professionals Scale and the 12-Item Short Form Health Survey. Data analysis was conducted by Pearson's correlation analysis, Harman single-factor test and the bootstrap method for mediating effect testing. (1) The study demonstrated a significant direct effect of fear of COVID-19 on nurses' mental health, as well as on mediating factors such as burnout and psychological capital. (2) Regression analyses confirmed that while psychological capital bolstered mental health, burnout undermined it, with fear of COVID-19 further imposing a negative influence. (3) Fear of COVID-19 exerted an effect on the mental health of nurses by the independent and chain intermediary functions of psychological capital and burnout, resulting in a total mediating effect of -0.233.

FORECASTING INNOVATION ACTIVITY OF ENTERPRISES IN EXTREME CONDITIONS: APPLIED ASPECT

The article develops a strategy of innovation activity of an industrial enterprise on the basis of its innovation profile. For this purpose, the production and economic activity of PE "GALAVTOPROMMAST" was researched and analyzed, its innovation activity was analyzed, the trends in the development of production and economic activity of this enterprise over the past 3-5 years and trends in the development of innovation activity were studied, the results of the study of trends in the problem and a measure to improve the strategy of innovation activity of PE "GALAVTOPROMMAST" has been developed. The success of the innovation strategy of an industrial enterprise depends on the ability of this enterprise to successfully carry out various areas of innovation activity, rationally combining them with each other. If there is no good compatibility between the individual areas of innovation activity, then the enterprise has neither a clear innovation strategy nor a sustainable advantage. Management in this case is reduced only to exercising control over independent functions, and operational efficiency determines the relative performance of the enterprise. The article develops a model for forecasting strategies of innovation activity of PE «GALAVTOPROMMAST» on the basis of the innovation profile of enterprise.

A mouse model to distinguish NLRP6-mediated inflammasome-dependent and -independent functions

The NOD-like receptor (NLR) family pyrin domain containing 6 (NLRP6) serves as a sensor for microbial dsRNA or lipoteichoic acid (LTA) in intestinal epithelial cells (IECs), and initiating multiple pathways including inflammasome pathway and type I interferon (IFN) pathway, or regulating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. NLRP6 can exert its function in both inflammasome-dependent and inflammasome-independent manners. However, there is no tool to distinguish the contribution of individual NLRP6-mediated pathway to the physiology and pathology in vivo. Here, we validated that Arg39 and Trp50 residues in the pyrin domain (PYD) of murine NLRP6 are required for ASC recruitment and inflammasome activation, but are not important for the RNA binding and PYD-independent NLRP6 oligomerization. We further generated the Nlrp6R39E&W50E mutant mice, which showed reduced inflammasome activation in either steady state intestine or during viral infection. However, the type I IFN production in cells or intestine tissue from Nlrp6R39E&W50E mutant mice remain normal. Interestingly, NLRP6-mediated inflammasome activation or the IFN-I production seems to play distinct roles in the defense responses against different types of RNA viruses. Our work generated a useful tool to study the inflammasome-dependent role of NLRP6 in vivo, which might help to understand the complexity of multiple pathways mediated by NLRP6 in response to the complicated and dynamic environmental cues in the intestine.

A novel aminopeptidase N/CD13 inhibitor selectively targets an endothelial form of CD13 after coupling to proteins

Aminopeptidase N/CD13, a membrane-bound enzyme upregulated in tumor vasculature and involved in angiogenesis, can be used as a receptor for the targeted delivery of drugs to tumors through ligand-directed targeting approaches. We describe a novel peptide ligand (VGCARRYCS, called “G4”) that recognizes CD13 with high affinity and selectivity. Enzymological and computational studies showed that G4 is a competitive inhibitor that binds to the catalytic pocket of CD13 through its N-terminal region. Fusing the peptide C-terminus to tumor necrosis factor-alpha (TNF) or coupling it to a biotin/avidin complex causes loss of binding and inhibitory activity against different forms of CD13, including natural or recombinant ectoenzyme and a membrane form expressed by HL60 promyelocytic leukemia cells (likely due to steric hindrance), but not binding to a membrane form of CD13 expressed by endothelial cells (ECs). Furthermore, G4-TNF systemically administered to tumor-bearing mice exerted anticancer effects through a CD13-targeting mechanism, indicating the presence of a CD13 form in tumor vessels with an accessible binding site. Biochemical studies showed that most CD13 molecules expressed on the surface of ECs are catalytically inactive. Other functional assays showed that these molecules can promote endothelial cell adhesion to plates coated with G4-avidin complexes, suggesting that the endothelial form of CD13 can exert catalytically independent biological functions. In conclusion, ECs express a catalytically inactive form of CD13 characterized by an accessible conformation that can be selectively targeted by G4-protein conjugates. This form of CD13 may represent a specific target receptor for ligand-directed targeted delivery of therapeutics to tumors.

Deeply integrating latent consistent representations in high-noise multi-omics data for cancer subtyping.

Cancer is a complex and high-mortality disease regulated by multiple factors. Accurate cancer subtyping is crucial for formulating personalized treatment plans and improving patient survival rates. The underlying mechanisms that drive cancer progression can be comprehensively understood by analyzing multi-omics data. However, the high noise levels in omics data often pose challenges in capturing consistent representations and adequately integrating their information. This paper proposed a novel variational autoencoder-based deep learning model, named Deeply Integrating Latent Consistent Representations (DILCR). Firstly, multiple independent variational autoencoders and contrastive loss functions were designed to separate noise from omics data and capture latent consistent representations. Subsequently, an Attention Deep Integration Network was proposed to integrate consistent representations across different omics levels effectively. Additionally, we introduced the Improved Deep Embedded Clustering algorithm to make integrated variable clustering friendly. The effectiveness of DILCR was evaluated using 10 typical cancer datasets from The Cancer Genome Atlas and compared with 14 state-of-the-art integration methods. The results demonstrated that DILCR effectively captures the consistent representations in omics data and outperforms other integration methods in cancer subtyping. In the Kidney Renal Clear Cell Carcinoma case study, cancer subtypes were identified by DILCR with significant biological significance and interpretability.

Catalytic isoforms of AMP-activated protein kinase differentially regulate IMPDH activity and photoreceptor neuron function.

AMP-activated protein kinase (AMPK) plays a crucial role in maintaining ATP homeostasis in photoreceptor neurons. AMPK is a heterotrimeric protein consisting of α, β, and γ subunits. The independent functions of the 2 isoforms of the catalytic α subunit, PRKAA1 and PRKAA2, are uncharacterized in specialized neurons, such as photoreceptors. Here, we demonstrate in mice that rod photoreceptors lacking PRKAA2, but not PRKAA1, showed altered levels of cGMP, GTP, and ATP, suggesting isoform-specific regulation of photoreceptor metabolism. Furthermore, PRKAA2-deficient mice displayed visual functional deficits on electroretinography and photoreceptor outer segment structural abnormalities on transmission electron microscopy consistent with neuronal dysfunction, but not neurodegeneration. Phosphoproteomics identified inosine monophosphate dehydrogenase (IMPDH) as a molecular driver of PRKAA2-specific photoreceptor dysfunction, and inhibition of IMPDH improved visual function in Prkaa2 rod photoreceptor-knockout mice. These findings highlight a therapeutically targetable PRKAA2 isoform-specific function of AMPK in regulating photoreceptor metabolism and function through a potentially previously uncharacterized mechanism affecting IMPDH activity.

Classification aggregation without unanimity

A classification is a surjective mapping from a set of objects to a set of categories. A classification aggregation function aggregates every vector of classifications into a single one. We show that every citizen sovereign and independent classification aggregation function is essentially a dictatorship. This impossibility implies an earlier result of Maniquet and Mongin (2016), who show that every unanimous and independent classification aggregation function is a dictatorship. The relationship between the two impossibilities is reminiscent to the relationship between Wilson’s (1972) and Arrow’s (1951) impossibilities in preference aggregation. Moreover, while the Maniquet-Mongin impossibility rests on the existence of at least three categories, we propose an alternative proof technique that covers the case of two categories, except when the number of objects is also two. We also identify all independent and unanimous classification aggregation functions for the case of two categories and two objects.

CircPTEN-MT from PTEN regulates mitochondrial energy metabolism

Phosphatase and tensin homolog (PTEN) is a multifunctional gene involved in a variety of physiological and pathological processes. Circular RNAs (circRNAs) are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins. However, PTEN-related circRNAs are largely unknown. Here, we report that circPTEN- mitochondria (MT) (hsa_circ_0002934) is a circular RNA encoded by exons 3, 4, and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism. CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), which regulates posttranscriptional gene expression in mitochondria. Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator (SRA) stem-loop interacting RNA binding protein (SLIRP) and inhibits the polyadenylation of mitochondrial mRNA, which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production. Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism. This study expands our understanding of the role of PTEN, which produces both linear and circular RNAs with different and independent functions.

Sequences of independent functions and structure of rearrangement invariant spaces

The main aim of the survey is to present results of the last decade on the description of subspaces spanned by independent functions in $L_p$-spaces and Orlicz spaces on the one hand, and in general rearrangement invariant spaces on the other. A new approach is proposed, which is based on a combination of results in the theory of rearrangement invariant spaces, methods of the interpolation theory of operators, and some probabilistic ideas. The problem of the uniqueness of the distribution of a function such that a sequence of its independent copies spans a given subspace is considered. A general principle is established for the comparison of the complementability of subspaces spanned by a sequence of independent functions in a rearrangement invariant space on $[0,1]$ and by pairwise disjoint copies of these functions in a certain space on the half-line $(0,\infty)$. As a consequence of this principle we obtain, in particular, the classical Dor-Starbird theorem on the complementability of subspaces spanned by independent functions in the $L_p$-spaces. Bibliography: 103 titles.

Parametric Body Reconstruction Based on a Single Front Scan Point Cloud.

Full-body 3D scanning simplifies the acquisition of digital body models. However, current systems are bulky, intricate, and costly, with strict clothing constraints. We propose a pipeline that combines inner body shape inference and parametric model registration for reconstructing the corresponding body model from a single front scan of a clothed body. Three networks modules (Scan2Front-Net, Front2Back-Net, and Inner2Corr-Net) with relatively independent functions are proposed for predicting front inner, back inner, and parametric model reference point clouds, respectively. We consider the back inner point cloud as an axial offset of the front inner point cloud and divide the body into 14 parts. This offset relationship is then learned within the same body parts to reduce the ambiguity of the inference. The predicted front and back inner point clouds are concatenated as inner body point cloud, and then reconstruction is achieved by registering the parametric body model through a point-to-point correspondence between the reference point cloud and the inner body point cloud. Qualitative and quantitative analysis show that the proposed method has significant advantages in terms of body shape completion and reconstruction body model accuracy.

The role of primary cilia in congenital heart defect-associated neurological impairments.

Congenital heart disease (CHD) has, despite significant improvements in patient survival, increasingly become associated with neurological deficits during infancy that persist into adulthood. These impairments afflict a wide range of behavioral domains including executive function, motor learning and coordination, social interaction, and language acquisition, reflecting alterations in multiple brain areas. In the past few decades, it has become clear that CHD is highly genetically heterogeneous, with large chromosomal aneuploidies and copy number variants (CNVs) as well as single nucleotide polymorphisms (SNPs) being implicated in CHD pathogenesis. Intriguingly, many of the identified loss-of-function genetic variants occur in genes important for primary cilia integrity and function, hinting at a key role for primary cilia in CHD. Here we review the current evidence for CHD primary cilia associated genetic variants, their independent functions during cardiac and brain development and their influence on behavior. We also highlight the role of environmental exposures in CHD, including stressors such as surgical factors and anesthesia, and how they might interact with ciliary genetic predispositions to determine the final neurodevelopmental outcome. The multifactorial nature of CHD and neurological impairments linked with it will, on one hand, likely necessitate therapeutic targeting of molecular pathways and neurobehavioral deficits shared by disparate forms of CHD. On the other hand, strategies for better CHD patient stratification based on genomic data, gestational and surgical history, and CHD complexity would allow for more precise therapeutic targeting of comorbid neurological deficits.

Involving Distinguished Temporal Graph Convolutional Networks for Skeleton-Based Temporal Action Segmentation

For RGB-based temporal action segmentation (TAS), excellent methods that capture frame-level features have achieved remarkable performance. However, for motion-centered TAS, it is still challenging for existing methods that ignore the extraction of spatial features of joints. In addition, inaccurate action boundaries caused by the frames of similar motion destroy the integrity of the action segments. To alleviate the issues, an end-to-end Involving Distinguished Temporal Graph Convolutional Networks called IDT-GCN is proposed. First, we construct an enhanced spatial graph structure that adaptively captures the similar and differential dependencies between joints in a single topology through learning two independent correlation modeling functions. Then, the proposed Involving Distinguished Graph Convolutional (ID-GC) models the spatial correlations of different actions in a video by using multiple enhanced topologies on the corresponding channels. Furthermore, we design a generic modeling temporal action regression network, termed Temporal Segment Regression (TSR), to extract segmented encoding features and action boundary representations by modeling action sequences. Combining them with label smoothing modules, we develop powerful spatial-temporal graph convolutional networks (IDT-GCN) for fine-grained TAS, which notably outperforms state-of-the-art methods on the MCFS-22 and MCFS-130 datasets. Adding TSR to TCN-based baseline methods achieves competitive performance compared with the state-of-the-art transformer-based methods on RGB-based datasets, i.e., Breakfast and 50Salads. Further experimental results on the action recognition task verify the superiority of the enhanced spatial graph structure over the previous graph convolutional networks.

Training future veterinarians for the english professional communication by means of situa-tional tasks

The article examines the possibilities and effectiveness of using the method of solving professional situations in the process of preparing future doctors of veterinary medicine for professional English-language communication. The expediency of the formation of professional communication for future veterinarians is substantiated. The essence of foreign language professional communication, which is an integral component of the professional competence of a modern specialist, is clarified. It is emphasized that a powerful potential for the development of professional English communication has the application of professional situations (situational tasks or problems that a veterinarian may face in his/her practice). Situational tasks are aimed at the implementation of such functions as the organization of cognitive and independent activities, effective and corrective functions. The requirements for the situational tasks are characterized by: a real professional situation, emerging professional conflict (controversial issue), tension of the situation (perhaps the urgency of the solution), complexity and ambiguity of the problem, clarity of description of the subjects of the problem or situation, multivariate solutions, limiting conditions. Examples of professional situations that can be used in the preparation for professional English communication of future veterinarians in English language classes are offered. It was found that the use of situational tasks develops professional English-speaking communication skills and the ability to perceive verbal information from a professional point of view, to independently interpret, make decisions and determine optimal ways of its implementation.

Cluster analysis as a tool for quantifying structure-transport properties in simulations of superconcentrated electrolyte.

Using molecular dynamics simulations and graph-theory-based cluster analysis, we investigate the structure-transport properties of typical water-in-salt electrolytes. We demonstrate that ions exhibit distinct dynamics across different ionic clusters-namely, solvent-separated ion pairs (SSIPs), contact ion pairs (CIPs), and aggregates (AGGs). We assess the average proportions of various ionic species and their lifetimes. Our method reveals a dynamic decoupling of ion kinetics, with each species independently contributing to the overall molecular motion. This is evidenced by the fact that the total velocity autocorrelation function (VACF) and power spectrum can be expressed as a weighted sum of independent functions for each species. The experimental data on the ionic conductivity of the studied LiTFSI electrolytes align well with our theoretical predictions at various concentrations, based on the proportions and diffusion coefficients of free ions derived from our analysis. The insights gained into the solvation structures and dynamics of different ionic species enable us to elucidate the physical mechanisms driving ion transport in such superconcentrated electrolytes, providing a comprehensive framework for the future design and optimization of electrolytes.

Replication stress response in fission yeast differentially depends on maintaining proper levels of Srs2 helicase and Rrp1, Rrp2 DNA translocases.

Homologous recombination is a key process that governs the stability of eukaryotic genomes during DNA replication and repair. Multiple auxiliary factors regulate the choice of homologous recombination pathway in response to different types of replication stress. Using Schizosaccharomyces pombe we have previously suggested the role of DNA translocases Rrp1 and Rrp2, together with Srs2 helicase, in the common synthesis-dependent strand annealing sub-pathway of homologous recombination. Here we show that all three proteins are important for completion of replication after hydroxyurea exposure and provide data comparing the effect of overproduction of Srs2 with Rrp1 and Rrp2. We demonstrate that Srs2 localises to rDNA region and is required for proper replication of rDNA arrays. Upregulation of Srs2 protein levels leads to enhanced replication stress, chromosome instability and viability loss, as previously reported for Rrp1 and Rrp2. Interestingly, our data suggests that dysregulation of Srs2, Rrp1 and Rrp2 protein levels differentially affects checkpoint response: overproduction of Srs2 activates simultaneously DNA damage and replication stress response checkpoints, while cells overproducing Rrp1 mainly launch DNA damage checkpoint. On the other hand, upregulation of Rrp2 primarily leads to replication stress response checkpoint activation. Overall, we propose that Srs2, Rrp1 and Rrp2 have important and at least partially independent functions in the maintenance of distinct difficult to replicate regions of the genome.

A Fanca knockout mouse model reveals novel Fancd2 function

Fanconi anemia (FA) is a genetically and clinically heterogenous inherited disorder. Clinically, Fanca subtype patients exhibited milder phenotypes compared to Fancd2 subtypes. Increasing evidence suggests that Fancd2 perform independent functions, but the detailed mechanisms are not well characterized. In this study, we developed a Fanca KO mice model in C57BL/6 background with ATG region deletion, then performed a detailed FA phenotypes characterization and analysis with Fanca KO mice and Fancd2 KO mice in the same congenic background. We found that both the Fanca KO and Fancd2 KO cause severe FA phenotypes in mice. However, Fanca KO mice exhibited milder FA phenotypes comparing to Fancd2 KO mice. Fanca KO mice showed higher embryonic and postnatal survival rate, less congenital eye defects in early development. At adult stage, Fanca KO mice showed increased HSC number and reconstitution function. Furthermore, we did RNA-seq study and identified differential expression of Dlk1 and Dlk1 pathway genes in Fanca KO and Fancd2 KO embryonic cells and adult HSCs. Finally, we revealed that Fancd2 was expressed and physically interact with Dlk1 in Fanca KO cells. Collectively, our findings suggested that Fancd2 has distinct functions in the absence of Fanca.

A general continuum modelling approach for variable shear stress as a separable function in stored bulk solids

Granular materials stored in a bin exert pressure on its walls. The Janssen equation describes how this pressure changes with depth in a deep column of granular material. However, it does not address any change in lateral stress throughout stored bulk materials. In this work, we present a general approach for vertical and arbitrary lateral stress in the horizontal (radial) direction. The vertical and lateral stress are described by independent one-dimensional functions whose product describes the stress state throughout the entire bin. Our approach is general, and able to accommodate numerically defined functions such as splines. We are planning future experiments to determine the form of the radial stress. We report on the mathematical analysis here. This research will potentially impact the designing of bulk storage structures, inform grain drying processes and aid in inventory management of stored grain.

An encoder–decoder deep neural network for binary segmentation of seismic facies

To explore hydrocarbons, it is necessary to interpret seismic data to identify facies and geological features. Traditionally, this work is performed by visually choosing points representing the limits of seismic features and using a tool to infer the other limit points. This process requires much manual work and may leave some features aside, making the work less accurate. Recently, deep learning has shown promising results in image segmentation. Deep learning methods can help reduce the analysis time and dependence on geometry in facies segmentation to study geological areas. This work investigates the application of neural networks to identify lines that separate seismic facies geometry. In particular, we present a Deep Neural Network for Facies Segmentation (DNFS), which builds upon StNet and U-Net with different hyper-parameters and loss functions to obtain state-of-the-art results concerning facies segmentation. We combine two independent loss functions, namely cross-entropy and Jaccard loss, for training DNFS; together, these functions lead to better results for seismic facies segmentation. The input data comprises small segments of seismic images in the Project Netherlands Offshore F3 Block dataset. Our results demonstrate that it is possible to train an encoder–decoder architecture using a dataset for binary segmentation and a composite loss function and to offer accurate predictions with a neural network designed to be trained within only a few minutes.

Toxoplasma gondii mitochondrial association factor 1b interactome reveals novel binding partners including Ral GTPase accelerating protein α1

The intracellular parasite, Toxoplasma gondii, has developed sophisticated molecular strategies to subvert host processes and promote growth and survival. During infection, T.gondii replicates in a parasitophorous vacuole (PV) and modulates host functions through a network of secreted proteins. Of these, Mitochondrial Association Factor 1b (MAF1b) recruits host mitochondria to the PV, a process that confers an invivo growth advantage, though the precise mechanisms remain enigmatic. To address this knowledge gap, we mapped the MAF1b interactome in human fibroblasts using a commercial Yeast-2-hybrid (Y2H) screen, which revealed several previously unidentified binding partners including the GAP domain of Ral GTPase Accelerating Protein α1 (RalGAPα1(GAP)). Recombinantly produced MAF1b and RalGAPα1(GAP) formed as a stable binary complex as shown by size exclusion chromatography with a Kd of 334nM as measured by isothermal titration calorimetry (ITC). Notably, no binding was detected between RalGAPα1(GAP) and the structurally conserved MAF1b homolog, MAF1a, which does not recruit host mitochondria. Next, we used hydrogen deuterium exchange mass spectrometry (HDX-MS) to map the RalGAPα1(GAP)-MAF1b interface, which led to identification of the "GAP-binding loop" on MAF1b that was confirmed by mutagenesis and ITC to be necessary for complex formation. A high-confidence Alphafold model predicts the GAP-binding loop to lie at the RalGAPα1(GAP)-MAF1b interface further supporting the HDX-MS data. Mechanistic implications of a RalGAPα1(GAP)-MAF1b complex are discussed in the context of T.gondii infection and indicates that MAF1b may have evolved multiple independent functions to increase T.gondii fitness.