Regulator Function Research Articles

Analysis and Formal and Substantive Evaluation of the Proposal of the European Regulation Authorizing the Marketing of Construction Products in the Harmonized Area

Aim: The aim of the article is to discuss issues related to the functioning of the current Regulation of the European Parliament and of the Council (EU) No. 305/2011 establishing harmonized conditions for the marketing of construction products and the problems identified in this regard, as well as to discuss the assumptions of the proposal of the European regulation for construction products in the harmonized area. This article analyses and indicates the links of the proposal in question to the “European Green Deal” manifested in its inclusion of the assessment and communication of information on the environmental performance of construction products and the promotion of the circulation of construction products. Introduction: The area of conformity assessment of construction products in the EU is currently regulated by the Regulation 305/2011. Its main objective was to improve the functioning of the single market and improve the free movement of construction products in the EU by establishing harmonized conditions for their marketing. In practice, this meant allowing construction products to be legally marketed in one member state. However, the European Commission, after its analysis, identified some shortcomings in its implementation, which required further analysis and discussion. As a consequence, a draft of a new regulation establishing harmonized conditions for the marketing of construction products, amending Regulation (EU) 2019/1020 and repealing Regulation (EU) 305/2011 was developed to address a significant number of issues related to standardization, simplification for micro-enterprises, market surveillance and the enforcement of regulations. Methodology: The article uses theoretical research methods, including an analysis of the EC’s report on the ongoing analyses of Regulation 305/2011 and reports from entities directly involved in the opinion of the proposed regulation. The publication also includes the authors’ own formal and substantive interpretation of selected passages of the proposed regulation, which establishes harmonized conditions for the marketing of construction products. Conclusions: The proposal of the new regulation has both strengths and opportunities from the revision, as well as weaknesses and threats, or poses new challenges. Identifying the problems hindering the functioning of the single market for construction products, the EC pointed to two general goals of the CPR revision, i.e. to create a smoothly functioning single market for construction products and to contribute to the goals of green and digital transformation. The implementation of measures resulting from the entry into force of the new regulation will only show in practice whether the changes introduced have had the intended effect. Keywords: construction products, standardization, harmonized area, European Green Deal, sustainable environment, CPR

A Navigation Algorithm to Enable Sustainable Control of Insect-Computer Hybrid Robot with Stimulus Signal Regulator and Habituation-Breaking Function.

The insect-computer hybrid soft robots are receiving increasing attention due to their excellent motor capabilities, small size, and low power consumption. However, the effective control of insects is limited to minutes since the response from insects is reduced as the number of stimulus signal increase. This phenomenon is known as habituation, which causes the loss of control of robots and hinders their application in practical tasks such as search and rescue missions that require several hours. It has been shown that constantly switching the pattern of stimulus signals can slow down the onset of habituation. Moreover, when habituation occurs, applying a different stimulus signal can break the habituation. Based on this, we have designed a navigation algorithm that can extend the control time of insects to several hours. The algorithm is composed of a stimulation decision-making core responsible for deciding on the type of stimulus signal (left, right, acceleration), a stimulation parameters adjustment (SPA) core responsible for adjusting the stimulus signal voltage constantly to delay the occurrence of habituation, and a reactivation function (RF), as a different stimulus signal from the normal stimulus signal, is used to break insects' habituation to the normal stimulus signal. Experiments have shown that our SPA regulator and RF can significantly extend the control time of insects. Navigation experiments demonstrating effective control of the insects for up to 3 h verified the effectiveness of the navigation algorithm, which strikes a balance between control accuracy and control time.

Determination of Attitude Towards Oneself by Personal and Situational Factors

Purpose. The article presents a descriptive characteristic of the functioning of a person’s attitude to oneself, the formation of self-awareness through a combination of one’s emotional and creative features with the components of attitude toward oneself, which allows one to study in depth the process of formation and development of a mature, adapted personality. Theoretical basis. The existing variety of scientific approaches makes it difficult to systematize the aspect under study and prevents the formation of a clear structure of a person’s attitude toward oneself. The study of self-consciousness of the personality remains relevant in connection with a wide range of issues related to the development of knowledge of the mechanisms that act as internal determinants of the individual originality of the personality’s life realization. The theoretical and methodological basis of the study is as follows: the principles of determinism of mental phenomena, the activity concept of self-consciousness, the provision on the regulative function of emotions in activity, the concept of creative activity and ideas about the personality’s creative characteristics. Originality. The author supplemented and expanded knowledge about the phenomenon of self-attitude, the mechanisms of its formation and features of determination based on the systematization of thematic issues; the idea of the determination of attitude toward oneself, in particular, by personal and situational factors, in the context of its functioning in the conditions of activity with creative elements has been further developed. Conclusions. Attitude toward oneself, emotional and creative features of the personality have a common problematic aspect with regard to their nature of interaction and the necessity for the expediency of their unification as a subject of interaction with the world.

Dual species sphingosine-1-phosphate lyase inhibitors to combine antifungal and anti-inflammatory activities in cystic fibrosis: a feasibility study

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by respiratory failure due to a vicious cycle of defective Cystic Fibrosis Transmembrane conductance Regulator (CFTR) function, chronic inflammation and recurrent bacterial and fungal infections. Although the recent introduction of CFTR correctors/potentiators has revolutionized the clinical management of CF patients, resurgence of inflammation and persistence of pathogens still posit a major concern and should be targeted contextually. On the background of a network-based selectivity that allows to target the same enzyme in the host and microbes with different outcomes, we focused on sphingosine-1-phosphate (S1P) lyase (SPL) of the sphingolipid metabolism as a potential candidate to uniquely induce anti-inflammatory and antifungal activities in CF. As a feasibility study, herein we show that interfering with S1P metabolism improved the immune response in a murine model of CF with aspergillosis while preventing germination of Aspergillus fumigatus conidia. In addition, in an early drug discovery process, we purified human and A. fumigatus SPL, characterized their biochemical and structural properties, and performed an in silico screening to identify potential dual species SPL inhibitors. We identified two hits behaving as competitive inhibitors of pathogen and host SPL, thus paving the way for hit-to-lead and translational studies for the development of drug candidates capable of restraining fungal growth and increasing antifungal resistance.

Sociocultural Power of Biblical Translation in Early Modern Europe: The Cases of the Ostroh Bible (1581) and the King James Bible (1611)

This paper presents sociocultural profiles of the Ostroh Bible (1581) and the King James Version of the Bible (1611) in terms of their agency, authoritative status and regulative functions. Despite scholarly and popular attention given to both texts, no attempts have been made so far to compare them. This paper intends to break the mold and focuses on the causes and results of the collective agency of the two versions at the textual, paratextual and extratextual levels as well as on the gatekeeping role of these translations and the ways they affected the development of their respective cultures. It is also demonstrated that the OB and the KJV performed the function of “the second originals.” Also subject to analysis are the prefaces to the two editions, which disclose information about important translation figures and deal with issues of universal and sacred history.

Why Is Biological Teleology Non-constitutive (Merely Regulative) for Kant?

There is no doubt that Kant assigns a merely regulative function to biological teleology. But the reasons for Kant’s doing so are less clear. For some Kant scholars, Kant does so because, for him, the concept of natural purpose amounts at best to a subjective maxim of certain heuristic values. Appealing as it is, this view runs into difficulties when other Kant scholars note that Kant takes biological teleology to be indispensable and uses the natural purpose concept to identify biological organisms (or, more precisely speaking, formative powers). I argue that Kant treats biological teleology as non-constitutive (i.e., merely regulative), because the concept of natural purpose is not associated with any supporting laws (biological organisms as instances or particulars of the concept of natural purpose are given, but the concept itself as a universal is only assumed).

Characterization of Common Minke Whale (Balaenoptera Acutorostrata) Cell Lines Immortalized with the Expression of Cell Cycle Regulators.

Primary cultured cells cannot proliferate infinite. The overcoming of this limit can be classified as immortalization. Bypass of p16 senescence protein induces efficient immortalization various types of mammalians is previously reported. However, the Cetacea species is not known. Here, that common minke whale-derived cells can be immortalized with a combination of human genes, mutant cyclin-dependent kinase 4 (CDK4R24C ), cyclin D1, and Telomerase Reverse Transcriptase (TERT)is reported. These results indicate that the function of cell cycle regulators in premature senescence is evolutionarily conserved. This study describes the conserved roles of cell cycle regulators in the immortalization of cells from humans to Cetacea species. Furthermore, using RNA-seq based on next-generation sequencing, the gene expression profiles of immortalized cells are compared with parental cells as well as those immortalized with SV40 large T antigen, which is once a popular method for cellular immortalization. The profiling results show that newly established common minke-whale-derived immortaliozed cells have completely different profiles from SV40 cells. This result indicates that the expression of mutant CDK4, cyclin D1, and TERT enables to establish immortalized cell lines with different biological nature from SV40 expressing cells.

Key m6A regulators mediated methylation modification pattern and immune infiltration characterization in hepatic ischemia-reperfusion injury

BackgroundN6-methyladenosine (m6A) mRNA modification plays a critical role in various human biological processes. However, there has been no study reported to elucidate its role in hepatic ischemia-reperfusion injury (IRI). This study was aimed to explore the expression pattern together with the potential functions of m6A regulators in hepatic IRI.MethodsThe gene expression data (GSE23649) of m6A regulators in human liver tissue samples before cold perfusion and within 2 h after portal vein perfusion from Gene Expression Omnibus database was analyzed. The candidate m6A regulators were screened using random forest (RF) model to predict the risk of hepatic IRI. The evaluation of infiltrating abundance of 23 immune cells was performed using single sample gene set enrichment analysis. Besides, quantitative real time polymerase chain reaction (qRT-PCR) assay was carried out to validate the expression of key m6A regulators in mouse hepatic IRI model.ResultsThe expressions of WTAP, CBLL1, RBM15, and YTHDC1 were found to be increased in liver tissues 2 h after portal vein perfusion; in contrast, the expressions of LRPPRC, FTO, METTL3, and ALKBH5 were decreased. Based on RF model, we identified eight m6A methylation regulators for the prediction of the risk of hepatic IRI. Besides, a nomogram was built to predict the probability of hepatic IRI. In addition, the levels of WTAP, ALKBH5, CBLL1, FTO, RBM15B, LRPPRC and YTHDC1 were correlated with the immune infiltration of activated CD4 T cell, activated dendritic cell (DC), immature DC, mast cell, neutrophil, plasmacytoid DC, T helper (Th) cell (type 1, 2, and 17), gamma delta T cell, T follicular helper (Tfh) cell, myeloid-derived suppressor cell (MDSC), macrophage, natural killer cell, and regulatory Th cell. Among mouse hepatic IRI model, the mRNA level of CBLL1 and YTHDC1 was increased with statistical significance; however, the mRNA level of FTO and METTL3 was decreased among post-reperfusion liver samples compared with those in pre-reperfusion samples with statistical significance.ConclusionsThe m6A regulators exerted a pivotal impact on hepatic IRI. The m6A patterns that found in this study might provide novel targets and strategies for the alleviation/treatment of hepatic IRI in the future.

Targeting the ‘DNA methylation mark’: Analysis of early epigenetic-alterations in children chronically exposed to arsenic

Chronic exposure to arsenic causes adverse health effects in children. Aberrant epigenetic modifications including altered DNA methylation pattern are one of the major steps towards malignant transformation of cells. Our group has previously identified significant alteration in DNA methylation mark in arsenic exposed adults, affecting major biological pathways. Till date, no information is available exploring the altered DNA methylation mark in telomere regulation and altered mitochondrial functionality in association with DNA damage in arsenic-exposed children. Our study aims in identifying signature epigenetic pattern associated with telomere lengthening, mitochondrial functionality and DNA damage repair in children with special emphasis on DNA methylation. Biological samples (blood and urine) and drinking water were collected from the children aged between 5 and 16 years of arsenic exposed areas (N = 52) of Murshidabad district and unexposed areas (N = 50) of East Midnapur districts, West Bengal, India. Methylation-specific PCR was performed to analyse subtelomeric methylation status and promoter methylation status of target genes. Results revealed altered DNA methylation profile in the exposed children compared to unexposed. Promoter hypermethylation was observed in MLH1 and MSH2 (p < 0.05 and p < 0.001) indicating inefficiency in DNA damage repair. Hypomethylation in mitochondrial D-loop (p < 0.05) and TFAM promoter region (p < 0.05) along with increased mitochondrial DNA copy number among exposed children was also observed. Significant increase in telomere length and region specific subtelomeric hypermethylation (XpYp, p < 0.05) was found. Analysis of S-Adenosyl Methionine (SAM) and 8-oxoDG level revealed significant depletion of SAM (p < 0.001) and elevated oxidative DNA damage (p < 0.001) respectively in arsenic toxicity. Our study identified key methylation patterns in arsenic-exposed children which may act as an early predictive biomarker in the near future. Further in-depth studies involving large sample size and transcriptomic analysis are required for understanding the mechanistic details.

Histone Modifications and Their Contributions to Hypertension.

Essential hypertension, a multifaceted disorder, is a worldwide health problem. A complex network of genetic, epigenetic, physiological, and environmental components regulates blood pressure (BP), and any dysregulation of this network may result in hypertension. Growing evidence suggests a role for epigenetic factors in BP regulation. Any alterations in the expression or functions of these epigenetic regulators may dysregulate various determinants of BP, thereby promoting the development of hypertension. Histone posttranslational modifications are critical epigenetic regulators that have been implicated in hypertension. Several studies have demonstrated a clear association between the increased expression of some histone-modifying enzymes, especially HDACs (histone deacetylases), and hypertension. In addition, treatment with HDAC inhibitors lowers BP in hypertensive animal models, providing an excellent opportunity to design new drugs to treat hypertension. In this review, we discuss the potential contribution of different histone modifications to the regulation of BP.

Use of elexacaftor/tezacaftor/ivacaftor leads to changes in detection frequencies of Staphylococcus aureus and Pseudomonas aeruginosa dependent on age and lung function in people with cystic fibrosis

ObjectivesThe impressive improvements of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) function by elexacaftor/tezacaftor/ivacaftor (ETI) result in changes in the detection frequencies of Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA). We assessed determinants of the response to ETI with regards to SA and PA detection frequencies as documented in the German CF registry for people with CF (pwCF) ≥12 years. MethodsWe evaluated changes in the detection frequencies of SA and PA for 21 months before and after initiation of ETI and used different statistical tests to identify determinants of detection changes. ResultsWe included data from 1092 pwCF with results from culture-dependent diagnostics for SA and PA detection from 7944 microbiological samples before and 6.845 microbiological samples after initiation of ETI. Detections of SA decreased from 54.3% to 44.3% and 40.2% and those of PA from 39.9% to 31.9% and 22.6% 3 and 21 months after initiation of therapy, respectively (all P <0.001). Reduction of SA and PA were observed in throat swabs and sputa, associated significantly with age, previous lung function, and were dependent on pre-ETI colonization status. ConclusionsThe different patterns of reductions of SA and PA suggest that pathogen-specific biological processes govern the responsiveness of microbiological colonization towards ETI in pwCF.

SlMYB7, an AtMYB4-Like R2R3-MYB Transcription Factor, Inhibits Anthocyanin Accumulation in Solanum lycopersicum Fruits.

Tomato is a horticultural crop with an incomplete flavonoid metabolic pathway that does not typically accumulate anthocyanins in the fruit. In recent years, intensive studies of the loci Anthocyanin fruit (Aft) and atroviolacium (atv) have clarified the functions of positive regulators (R2R3-MYBs) and a negative regulator (CPC-MYB) in anthocyanin biosynthesis in the fruits. However, little is known about the R2R3-MYB repressors. Here, we used transient overexpression analysis to show that SlMYB7, a subgroup 4 AtMYB4-like R2R3-MYB, inhibited anthocyanin accumulation and reduced expression of anthocyanin synthase genes in the 'black pearl' tomato fruits, which usually accumulate high concentrations of anthocyanins. These findings revealed that SlMYB7 served as a repressor of anthocyanin production. Furthermore, SlMYB7 actively repressed SlANS expression by binding its promoter and passively inhibited anthocyanin synthesis by interacting with the basic helix-loop-helix (bHLH) proteins SlJAF13 and SlAN1, which are involved in the formation of MBW complexes. Thus, SlMYB7 and the MBW complex may coregulate the anthocyanin content of 'black pearl' tomato fruits via a negative feedback loop. These findings provide a theoretical basis for the future enhancement of tomato anthocyanin contents through genetic manipulation of the biosynthetic regulatory network.

Orphan response regulator CovR plays positive regulative functions in the survivability and pathogenicity of Streptococcus suis serotype 2 isolated from a pig

BackgroundStreptococcus suis serotype 2 (S. suis 2) is an important zoonotic pathogen. Orphan response regulator CovR plays crucial regulative functions in the survivability and pathogenicity of S. suis 2. However, research on the CovR in S. suis 2 is limited.ResultsIn this study, the regulative functions of CovR in the survivability and pathogenicity were investigated in S. suis 2 isolated from a diseased pig. The deletion of CovR significantly weakened the survivability and pathogenicity of S. suis 2. Compared with the wild-type strain, ΔcovR showed slower growth rates and thinner capsular polysaccharides. Moreover, ΔcovR showed reduced adhesion and invasion to Hep-2 cells as well as anti-phagocytosis and anti-killing ability to 3D4 cells and anti-serum killing ability. In addition, the deletion of CovR significantly reduced the colonisation ability of S. suis 2 in mice. The survival rate of mice infected with ΔcovR was increased by 16.7% compared with that of mice infected with S. suis 2. Further, the deletion of CovR led to dramatic changes in metabolism-related pathways in S. suis 2, five of those, including fructose and mannose metabolism, glycerolipid metabolism, ABC transporters, amino sugar and nucleotide sugar metabolism and phosphotransferase system, were significantly down-regulated.ConclusionsBased on the results, CovR plays positive regulative functions in the survivability and pathogenicity of S. suis 2 SC19 strain isolated from a pig.

Methylation of the epigenetic JMJD2D protein by SET7/9 promotes prostate tumorigenesis.

How the function of the JMJD2D epigenetic regulator is regulated or whether it plays a role in prostate cancer has remained elusive. We found that JMJD2D was overexpressed in prostate tumors, stimulated prostate cancer cell growth and became methylated by SET7/9 on K427. Mutation of this lysine residue in JMJD2D reduced the ability of DU145 prostate cancer cells to grow, invade and form tumors and elicited extensive transcriptomic changes. This included downregulation of CBLC, a ubiquitin ligase gene with hitherto unknown functions in prostate cancer, and upregulation of PLAGL1, a transcription factor with reported tumor suppressive characteristics in the prostate. Bioinformatic analyses indicated that CBLC expression was elevated in prostate tumors. Further, downregulation of CBLC largely phenocopied the effects of the K427 mutation on DU145 cells. In sum, these data have unveiled a novel mode of regulation of JMJD2D through lysine methylation, illustrated how this can affect oncogenic properties by influencing expression of the CBLC gene, and established a pro-tumorigenic role for CBLC in the prostate. A corollary is that JMJD2D and CBLC inhibitors could have therapeutic benefits in the treatment of prostate and possibly other cancers.

A Machine Learning-Based Classification of Immunogenic Cell Death Regulators and Characterisation of Immune Microenvironment in Acute Ischemic Stroke.

Immunogenic cell death (ICD) regulators exert a crucial part in quite a few in numerous biological processes. This study aimed to determine the function and diagnostic value of ICD regulators in acute ischemic stroke (AIS). 31 significant ICD regulators were identified from the gene expression omnibus (GEO) database in this work (the combination of the GSE16561 dataset and the GSE37587 dataset in the comparison of non-AIS and AIS patients). The random forest model was applied and 15 potential ICD regulators were screened to forecast the probability of AIS. A nomogram, on the basis of 11 latent ICD regulators, was performed. The resolution curve analysis indicated that patients can gain benefits from the nomogram. The consensus clustering approach was applied, and AIS patients were divided into 2 ICD clusters (cluster A and cluster B) based on the identified key ICD regulatory factors. To quantify the ICD pattern, 181 ICD-related dissimilarly expressed genes (DEGs) were selected for further investigation. The expression levels of NFKB1, NFKB2, and PARP1 were greater in gene cluster A than in gene cluster B. In conclusion, ICD regulators exerted a crucial part in the progress of AIS. The investigation made by us on ICD patterns perhaps informs prospective immunotherapeutic methods for AIS.

Acquired Venetoclax Resistance in an In Vivo Model of B-Cell Precursor Acute Lymphoblastic Leukemia Is Characterized By Altered Functions of Apoptosis Regulators

Deregulation of cell death pathways such as apoptosis is a hallmark of cancer and contributes to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Apoptosis is controlled by different pro- and anti-apoptotic molecules either inducing or counteracting cell death signaling. Inhibition of anti-apoptotic molecules of BCL-2 family cell death inhibitors has been developed as therapeutic strategy. Venetoclax (VEN) binds selectively to BCL-2 resulting in apoptosis induction and has shown clinical activity in hematologic malignancies, but primary and secondary resistance have also been described. In this study, we aimed to identify resistance mechanisms acquired during VEN treatment leading to therapy failure of BCL-2 inhibition. In order to mimic a clinical situation with consecutive treatment cycles, we employed a patient-derived human BCP-ALL xenograft mouse model with subsequent courses of VEN administration to ALL bearing recipients in vivo. First, we estimated VEN-sensitivities in a series of BCP-ALL PDX samples (N=30) by ex vivo titration of individual VEN-EC 50 values and identified a range of heterogeneous VEN-activities. A VEN-sensitive (low VEN-EC50) PDX-ALL sample with a pro-B ALL phenotype carrying a KMT2A:: MLL1 gene fusion was selected and transplanted onto immunodeficient NOD/SCID recipient mice. Upon leukemia manifestation (presence of 5% human ALL cells in peripheral blood), mice were either treated with VEN (100 mg/kg, two times five days) or vehicle control. Recipients were sacrificed upon onset of leukemia-related morbidity and ALL cells isolated from spleens were transplanted onto secondary recipients, which were again treated with VEN or vehicle. ALL cells isolated from secondary recipients were retransferred onto tertiary mice and again exposed to in vivo VEN-treatment providing a total of three subsequent transplantation and in vivo VEN-therapy cycles. Assessing VEN sensitivities of the ALL cells initially transplanted and isolated after VEN-treatment cycles by using an ex vivo cytochrome c release assay showed increasing VEN-resistance. Accordingly, comparison of VEN to control in vivo treated cells showed significantly decreased sensitivities over treatment cycles. Importantly, also the time periods between treatment and leukemia re-occurrence in mice indicating decreasing VEN-sensitivity became shorter with every additional in vivo therapy course. Paired RNA- seq analysis revealed that transcript levels of the pro-apoptotic molecules BAX and BIM were significantly downregulated in VEN-exposed/resistant ALL as compared to vehicle control treated cells. Basal BH3 profiling analysis showed impaired apoptotic priming (significantly lower cytochrome c release after BIM and PUMA peptide exposure) and decreased dependence on anti-apoptotic BCL-2 and MCL-1 indicating a shift from a pro-apoptotic to a pro-survival state. This shift was also reflected in an e x vivo drug treatment assay showing decreased sensitivity to the MCL-1 inhibitor S63845 and the BCL-XL inhibitor A-1331852 in ALL cells from VEN- treated mice compared to control- treated mice (S63845 EC 50 1.5 vs. 2.2 µM, A-1331852 EC 50 9.3 vs. 15.3 µM). In line with the low BAX levels in ALL cells with acquired VEN-resistance, PDX BCP-ALL samples with intrinsic VEN resistance also showed lower BAX protein expression. Taken together, acquired VEN-resistance was recapitulated in a co-clinical trial model of BCP-ALL with repeated in vivo treatment cycles showing lower drug sensitivities along with increasingly reduced in vivo anti-ALL activity of VEN. Characterization of acquired VEN-resistance revealed decreased functional dependency on anti-apoptotic proteins and downregulation of pro-apoptotic BIM and BAX, thus pointing to an imbalance of pro- and anti-apoptotic molecules, which can be potentially targeted by directed compounds bypassing resistance to specific BCL-2 inhibition.

The regulation of antiviral innate immunity through non-m6A RNA modifications.

The post-transcriptional RNA modifications impact the dynamic regulation of gene expression in diverse biological and physiological processes. Host RNA modifications play an indispensable role in regulating innate immune responses against virus infection in mammals. Meanwhile, the viral RNAs can be deposited with RNA modifications to interfere with the host immune responses. The N6-methyladenosine (m6A) has boosted the recent emergence of RNA epigenetics, due to its high abundance and a transcriptome-wide widespread distribution in mammalian cells, proven to impact antiviral innate immunity. However, the other types of RNA modifications are also involved in regulating antiviral responses, and the functional roles of these non-m6A RNA modifications have not been comprehensively summarized. In this Review, we conclude the regulatory roles of 2'-O-methylation (Nm), 5-methylcytidine (m5C), adenosine-inosine editing (A-to-I editing), pseudouridine (Ψ), N1-methyladenosine (m1A), N7-methylguanosine (m7G), N6,2'-O-dimethyladenosine (m6Am), and N4-acetylcytidine (ac4C) in antiviral innate immunity. We provide a systematic introduction to the biogenesis and functions of these non-m6A RNA modifications in viral RNA, host RNA, and during virus-host interactions, emphasizing the biological functions of RNA modification regulators in antiviral responses. Furthermore, we discussed the recent research progress in the development of antiviral drugs through non-m6A RNA modifications. Collectively, this Review conveys knowledge and inspiration to researchers in multiple disciplines, highlighting the challenges and future directions in RNA epitranscriptome, immunology, and virology.

Language representations and language attitudes in the Mishar dialect continuum

To forecast the sociolinguistic dynamics of the language, to determine the level of its vitality and to provide adequate measures of language policy and planning, it seems important to analyze the structures of the symbolic components of the language situation, which include language representations and language attitudes, that is, social attitudes towards language. The article presents the results of the analysis of the main types of Tatar language representations and linguistic attitudes among speakers of the Mishar idiom of the Tatar language. The data were collected in the regions where the Mishary Tatars live, namely in the Middle Volga region and in Prisurie. The main research method was a semi-structured interview with subsequent analysis of the obtained data, its classification and interpretation. The paper proposes five clusters of language representations in the minority situation: representations related to the instrumental, symbolic and regulative functions of language, on the one hand, and representations related to the actualized identity structures and to the deontic attitudes of the individual, on the other. In connection with these classes of representations and taking into account language forms, language competences and language practices, a typology of language loyalty is proposed, which includes instrumental loyalty, symbolic loyalty, loyalty according to the forms of language used, loyalty according to language competences and prescriptive loyalty. The material analysis showed the prevalence of positive representations of the Mishar idiom among its speakers, the presence of active positive loyalty in oral spheres of communication at the local level, a high level of idiom preservation, and the integrative nature of sociolinguistic dynamics. At the same time, the situation should be regarded as diglossic both in relation to the Russian language and to the literary Tatar language, which is considered to be prestigious.

A Systematic Review of the Effect of Cystic Fibrosis Treatments on the Nasal Potential Difference Test in Animals and Humans.

To address unmet treatment needs in cystic fibrosis (CF), preclinical and clinical studies are warranted. Because it directly reflects the function of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR), the nasal potential difference test (nPD) can not only be used as a reliable diagnostic test for CF but also to assess efficacy of experimental treatments. We performed a full comprehensive systematic review of the effect of CF treatments on the nPD compared to control conditions tested in separate groups of animal and human subjects. Our review followed a preregistered protocol. We included 34 references: 20 describing mouse studies, 12 describing human studies, and 2 describing both. We provide a comprehensive list of these studies, which assessed the effects of antibiotics, bone marrow transplant, CFTR protein, CFTR RNA, directly and indirectly CFTR-targeting drugs, non-viral and viral gene transfer, and other treatments. Our results support the nPD representing a reliable method for testing treatment effects in both animal models and human patients, as well as for diagnosing CF. However, we also observed the need for improved reporting to ensure reproducibility of the experiments and quantitative comparability of the results within and between species (e.g., with meta-analyses). Currently, data gaps warrant further primary studies.

Abuse of Dominant Position in the Realm of the Professional Sports Industry

The abuse of dominant position by sports regulators is a concerning issue that can significantly impact the integrity and fairness of sports competitions. Sports regulators, who are entrusted with maintaining the balance and promoting fair play within the industry, may sometimes exploit their authority to gain an unfair advantage or control over certain aspects of the sports landscape. When sports regulators abuse their dominant position, several detrimental consequences may arise.Competition law plays a crucial role in ensuring a fair and open market, free from anti-competitive practices. In recent years, there has been increasing attention towards applying competition law principles to oversee the actions of sports regulating bodies. This article aims to explore the potential of competition law in preventing sports governing organizations from abusing their monopoly power. It is imperative that the sports industry and the sports regulator function in an anti-competitive manner and avoid abuse of the powers instilled in them. It delves into suitable legal frameworks, examines relevant cases, and discusses the impact of enforcing competition law within the sports industry. The results highlight the significance of competition laws in fostering equitable competition, safeguarding athletes’ rights, and sustaining a dynamic and competitive sports landscape.