Regulation Of Contraction Research Articles

Testosterone Modulation of Muscle Transcriptomic Profile During Lifestyle Therapy in Older Men with Obesity and Hypogonadism

ABSTRACTBackgroundTestosterone replacement therapy (TRT) added to lifestyle therapy can mitigate weight‐loss–induced reduction of muscle mass and bone mineral density (BMD) in older men with obesity and hypogonadism.ObjectiveTo investigate the molecular mechanisms underlying the attenuation of muscle and BMD loss in response to TRT during intensive lifestyle intervention in this high‐risk older population.MethodsAmong 83 older (≥ 65 years) men with obesity (BMI ≥ 30 kg/m2) and hypogonadism (early AM testosterone persistently < 300 ng/dL) associated with frailty (Modified Physical Performance Test score ≤ 31) randomized into 26‐week lifestyle therapy plus testosterone (LT+TRT) or placebo (LT+Pbo) in the LITROS trial, 38 underwent serial muscle biopsies for the muscle transcriptomics substudy.ResultsDespite similar ~10% weight loss, lean body mass and thigh muscle volume decreased less in LT+TRT than LT+Pbo (−2% vs. −4%, respectively; p = 0.04). Hip BMD was preserved in LT+TRT compared with LT+Pbo (0.4% vs. −1.3%; p = 0.03). Muscle strength increased similarly in LT+TRT and LT+Pbo (23% vs. 24%; p = 0.95). Total testosterone increased more in LT+TRT than LT+Pbo (133% vs. 32%; p = 0.005). Based on Next Generation Sequencing, of the 39 160 and 39 115 genes detected in LT+TRT and LT+Pbo, respectively, 195 were differentially expressed in LT+TRT and 158 in LT+Pbo. Gene Ontology enrichment analyses revealed that in LT+TRT, just four muscle‐related pathways (muscle organ development, muscle organ morphogenesis, regulation of skeletal muscle contraction, muscle atrophy) were downregulated and one pathway (muscle system process) was upregulated. In contrast, in LT+Pbo, nine muscle‐related pathways (muscle system process, muscle tissue development, muscle organ development, skeletal muscle tissue development, skeletal muscle organ development, skeletal muscle cell differentiation, muscle organ morphogenesis, response to stimuli involved in regulation of muscle adaptation, muscle atrophy) and one pathway related to bone (bone mineralization involved in bone maturation) were downregulated. Muscle system process was upregulated in LT+TRT but downregulated in LT+Pbo. RT‐PCR analyses showed that LT+TRT resulted in a higher expression of MYOD1 (p = 0.02) and WNT4 (p = 0.02), key genes involved in muscle and bone metabolism, respectively, compared with LT+Pbo. We also observed significantly higher mRNA expression of MYBPH (p = 0.006), SCN3B (p = 0.02) and DSC2 (p = 0.01), genes involved in the muscle system process, in response to LT+TRT compared with LT+Pbo.ConclusionThe addition of TRT to lifestyle therapy mitigates the weight‐loss–induced reduction of muscle mass and BMD via countering the weight‐loss–induced downregulation of genes involved in muscle and bone anabolism.

Integration of Law and Business: The Collaborative Construction of Legal Regulation of Commercial Contracts and the Contract Management System in Enterprise Business

Against the backdrop of globalization and the rapid development of the market economy, the intersection of commercial contract legal issues and the construction of corporate business management systems has become increasingly important. The organic integration of law and business management can effectively promote the improvement of corporate compliance and management efficiency. This article explores the integration and synergy of law and business management by analyzing the legal risks in commercial contracts and the legal protection needs in the construction of corporate management systems, and proposes a comprehensive interdisciplinary management model. Research shows that the optimization of a company's legal compliance system, risk control mechanism, and contract management system is the key to promoting the long-term and stable development of the company.

ANALYSIS OF JUDGMENT No. 40/PDT.G/2023/PN.BNA ON DEFAULT OF DAYAH BUILDING PROJECT ACCORDING TO THEORY OF IJARAH 'ALA AL-'AMAL

The default case in the Dayah Safinatussalamah construction project in Aceh Singkil is an example of the complexity of implementing construction contracts based on ijârah 'ala al-'mâl contracts in Islamic law. CV Afdi Pratama as the contractor sued the Aceh Dyah Education Office for changes and additional costs that were not in accordance with the contract. This study aims to analyse the judge's consideration in rejecting the lawsuit over the construction contract dispute in Decision Number 40/Pdt.G/Pn.Bna and also the review of this decision according to the ijârah 'ala al-'amâl contract. The research method used is a normative juridical approach with a case study method. The main data is in the form of judge's decision documents, supported by literature review related to fiqh muamalah and contract regulations. Analysis was carried out qualitatively with content analysis to analyse trial facts, lawsuit materials, and legal considerations. The results showed that judges tended to use a formalistic approach by prioritising written evidence, ignoring technical realities and oral directions in project implementation. This decision does not reflect substantive justice, especially in recognising the plaintiff's right to additional costs due to work changes. In the perspective of ijârah 'la al-'amâl, this decision does not fully comply with the principles of justice (al-'is) and mutual consent (at-taradhin), which are the core of the contract in Islamic law so that the contract becomes fasid.

The sole essential low molecular weight tropomyosin isoform of Caenorhabditis elegans is essential for pharyngeal muscle function.

Tropomyosin is an actin-binding protein that plays roles ranging from regulating muscle contraction to controlling cytokinesis and cell migration. The simple nematode Caenorhabditis elegans provides a useful model for studying the core functions of tropomyosin in an animal, having a relatively simple anatomy, and a single tropomyosin gene, lev-11 , that produces seven isoforms. Three higher molecular weight isoforms (LEV-11A, D, O) regulate contraction of body wall and other muscles, but comparatively less is known of the functions of four lower molecular weight isoforms (LEV-11C, E, T, U). We demonstrate here C. elegans can survive with a single low molecular weight isoform, LEV-11E. Mutants disrupted for LEV-11E die as young larvae, whereas mutants disrupted for all other short isoforms are viable with no overt phenotype. Vertebrate low molecular weight tropomyosins are often considered "nonmuscle" isoforms, but we find LEV-11E localizes to sarcomeric thin filaments in pharyngeal muscle, and co-precipitates from worm extracts with the formin FHOD-1, which is also associated with thin filaments in pharyngeal muscle. Pharyngeal sarcomere organization is grossly normal in larvae lacking LEV-11E, indicating the tropomyosin is not required to stabilize thin filaments, but pharyngeal pumping is absent, suggesting LEV-11E regulates actomyosin activity similar to higher molecular weight sarcomeric tropomyosin isoforms.

Legal regulation of IT employees

This article is aimed at studying the labour regulation of IT workers in the context of labour law. Particular attention is paid to issues related to remote work, flexible working and conditions that are typical in this area. Many aspects are devoted to the analysis of the employment contract, especially in the context of the growing demand for IT specialists and new forms of employment. The issue of flexible working hours for IT employees is one of the most important, as this area of work requires more adapted conditions aimed at ensuring a balance between professional duties and personal life. The availability of opportunities for remote work or flexible working requires certain changes in labour legislation. It is important to define not only the rights and obligations of the parties to labour relations, but also the conditions for the proper protection of such rights, in particular in terms of occupational health and safety, confidentiality of information, social guarantees, and liability for breach of employment duties. Most IT employees prefer civil law contracts, as they offer more benefits and flexibility than labour law in some aspects. However, it is necessary to analyse both contracts in detail and understand that this form of cooperation can lead to social insecurity for employees, as they do not have the rights provided for by labour law. Many employees choose gig contracts, which offer new opportunities but also have their limitations, especially social guarantees and the lack of guaranteed salary. The IT sector involves intellectual property, trade secrets and other confidential information, which requires appropriate legal regulation. To ensure the protection of confidentiality, it is important to define the rights and obligations of employees in the employment contract and internal labour regulations. Failure to comply with confidentiality terms can lead to legal consequences and a negative reputation for the employee and the employer. Another important aspect is occupational health and safety, especially when working remotely. The issue of labour protection in the context of remote work is not sufficiently regulated in labour legislation, so employers need to conduct appropriate briefings, especially in the context of martial law. In Ukraine, the IT sector continues to be important for the economy, contributing about 5% of GDP, but exports of IT services have declined during the war. The process of European integration will contribute to the development of the IT sector, as well as change the legal and economic situation, which will directly affect the working conditions, rights and obligations of IT professionals in Ukraine. Ukraine’s accession to the EU creates new opportunities for IT workers, such as career growth, improving their skills and access to European labour markets. However, this process also requires significant changes in national legislation to adapt to European standards.

The N-Terminal Mutations of cMyBP-C Affect Calcium Regulation, Kinetics, and Force of Muscle Contraction.

The cardiac myosin binding protein-C (cMyBP-C) regulates cross-bridge formation and controls the duration of systole and diastole at the whole heart level. As known, mutations in cMyBP-C increase the cross-bridge number and rate of their cycling, hypercontractility, and myocardial hypertrophy. We investigated the effects of the mutations D75N and P161S of cMyBP-C related to hypertrophic cardiomyopathy on the mechanism of force generation in isolated slow skeletal muscle fibers. The mutation D75N slowed the kinetics of force development but did not affect the relaxation rate. The mutation P161S slowed both the relaxation and force development. The mutation D75N increased the calcium sensitivity of force, and the mutation P161S decreased it. The mutation D75N decreased the maximal isometric tension and increased the tension and stiffness at low calcium. Both mutations studied disrupt the calcium regulation of contractile force and affect the kinetics of its development and thus may impair cardiac diastolic function and cause myocardial hypertrophy.

Legal Protection for Fixed-Term Employment Contract Patterns based on Law No. 6 of 2023 on The Stipulation of Government Regulation in Lieu of Law No. 2 of 2022 on Job Creation

Legal Protection for Fixed-Term Employment Contract Patterns based on the Law of the Republic of Indonesia Number 6 of 2023 concerning the Stipulation of Government Regulation in Lieu of Law No. 2 of 2022 on Job Creation into Law is an interesting topic to study to provide the public with information regarding Fixed-Term Employment Contracts. This is because the sector of Fixed-Term Employment Contracts plays a very important role for workers in determining their welfare. The research method used is qualitative, with secondary legal sources utilizing normative and empirical legal research. The data obtained from the research show that both the government and society play a crucial role in shaping and supervising labor law policies. Legal protection for workers in Fixed-Term Employment Contracts must be fair and balanced between Fixed-Term and Permanent Employment Contract Workers. However, in the government's efforts to protect the workforce, there are still obstacles. It can be concluded that the regulation of Fixed-Term Employment Contracts in various laws and regulations reflects the government's ability to protect its people. These regulations must continuously be improved in accordance with the changing times, and oversight from the public is necessary as a control function to ensure that the latest regulations aim for the welfare of the people.

ZFP36 Regulates Vascular Smooth Muscle Contraction and Maintains Blood Pressure.

Hypertension remains a major risk factor for cardiovascular diseases, but the underlying mechanisms are not well understood. Zinc finger protein 36 (ZFP36) is an RNA-binding protein that regulates mRNA stability by binding to adenylate-uridylate-rich elements in the mRNA 3'-untranslated region. This study reveals that ZFP36 expression is highly elevated in the arteries of hypertensive patients and rodents. In cultured vascular smooth muscle cell (VSMC), angiotensin II (AngII) activates poly (ADP-ribose) polymerases1 (PARP1) to stimulate Zfp36 expression at the transcriptional level. VSMC-specific ZFP36 deletion reduces vessel contractility and blood pressure levels in mice. Mechanistically, ZFP36 regulates G protein-coupled receptors (GPCRs)-mediated increases in intracellular calcium levels through impairing the mRNA stability of regulator of G protein signaling 2 (RGS2). Moreover, the VSMC-specific ZFP36 deficiency attenuates AngII-induced hypertension and vascular remodeling in mice. AAV-mediated ZFP36 knockdown ameliorates spontaneous hypertension in rats. These findings elucidate that ZFP36 plays an important role in the regulation of smooth muscle contraction and blood pressure through modulating RGS2 expression. ZFP36 inhibition may represent a new therapeutic strategy for the treatment of hypertension.

Regulation of Vascular Smooth Muscle Cell Contraction during Early Postnatal Ontogenesis

Regulation of Vascular Smooth Muscle Cell Contraction during Early Postnatal Ontogenesis

The impact of digitalization on the development of e-commerce and its legal regulation

This scientific article is devoted to the analysis of key aspects that arise in connection with the digitalization of the economy and the growth of electronic commerce. The impact of technology on business models, legal regulation of electronic transactions, protection of consumer rights and cyber security issues are investigated. The article emphasizes that digitization opens new opportunities for business, in particular through the implementation of digital platforms, omnichannel strategies and process automation. Digital platforms such as Amazon and Alibaba are becoming important tools for business globalization as they facilitate access to international markets, reduce the need for physical infrastructure, and enable the integration of business processes. The legal regulation of electronic transactions and contracts has been studied. It is noted that the development of e-commerce requires legal certainty, regarding electronic signatures, electronic documents and digital identifiers. There are differences in approaches to these issues in different countries, which creates challenges for cross-border trade. In Ukraine, this issue is regulated by the Law «On electronic identification and electronic trust services», which meets EU standards, particularly the eIDAS Regulation. Challenges related to the protection of consumer rights in the digital economy are analyzed. Consumers face new risks such as privacy breaches and fraud in the online environment. International standards, such as GDPR, ensure a high level of personal data protection, while Ukrainian legislation needs further harmonization with international norms to increase the level of consumer rights protection. The policy of cyber security in the field of implementation of legal relations in electronic commerce was studied. Data protection, cybercrime prevention and information security are becoming key challenges for national governments and international organizations. It is important to implement international standards, such as PCI DSS, which guarantee the security of payment card data during their processing and storage. The fact that digitalization, on the one hand, requires adaptation of legal regulation to new conditions, but on the other hand, creates new opportunities for improving legal mechanisms, is summarized. Studying these aspects allows for a deeper understanding of how to adapt legal systems to further the development of e-commerce and ensure a balance between innovation and the protection of the rights of participants in the digital economy.

Abstract 4117594: Fetal Synthetic Glucocorticoid (sGC) Exposure Results in Later Life Cardiac Dysfunction and Ventricular Remodeling in Male Baboon Offspring

The “theory of developmental origins of health and disease” posits that stress in critical developmental periods will program life-course health and may affect cardiovascular (CV) health. Mothers at risk for premature delivery receive synthetic glucocorticoids (sGC) to enhance fetal lung maturation and manage fetal respiratory distress, but sGC exposure is linked to long-term CV dysfunction in offspring. Four groups of male baboons were studied: sGC exposed in utero at middle age (sGC-MA, 13.8±0.2Y), older sGC exposed in utero (sGC-O, 17.1±0.4Y), middle age unexposed (CTR-MA, 13.5±0.6Y), and older, unexposed baboons (CTR-O, 17.4±0.4Y). Gated, breath-hold, cine cardiac magnetic resonance imaging was performed at 3 Tesla (Siemens TIM Trio) to assess left ventricular (LV) function and myocardial strain, analyzed using cvi42® software. Mitochondrial electron transport chain (ETC) complex activity was analyzed using LV tissue from sGC-O and CTR-O euthanized baboons. Protein quantification was used to measure mitochondrial function and RNA-seq assessed differential gene expression and gene ontology (GO) enrichment. Unpaired t-tests were used. Data are reported as mean ± SD. Stroke volume and ejection fraction were similar in the elderly groups (4 sGC-O, 8 CTR-O). However, higher end-systolic and end-diastolic sphericity indexes (SI) and shorter LV axis lengths indicated remodeling. Also, global longitudinal and radial strains were reduced (both p<0.04) in sGC-O vs. CTR-O. Reduced LV cardiac output (p=0.005) was found in 5 sGC-MA animals vs 4 sGC-O animals, but not in 5 CTR-MA vs 8 CTR-O. In sGC-MA vs sGC-O, but not CTR-MA vs CTR-O, significant increases in SI (p=0.001), radial strain (p=0.02), and longitudinal (p=0.03) strain were found, but LV axis length (p=0.03) was reduced. LV mitochondrial analysis in 4 sGC-O vs 4 CTR-O myocardial samples revealed 33.5% less ETC activity (p=0.002) and 19.8% less complex I expression (p=0.048) in sGC. LV RNA-seq identified 63 upregulated and 20 downregulated genes in the sGC-O samples. GO pathway enrichment included changes in heart contraction, wounding responses, and leukocyte regulation pathways. These findings indicate that fetal sGC exposure developmentally programs offspring with LV remodeling and long-term cardiac and gene expression changes in male baboons, the closest available experimental nonhuman primate species to man. Future studies on females will probe sexual dimorphism in developmental programming.

The Prenuptial Agreement of Business Spouses: Guarantees of Respect for Mutual Interests and Protection of the Rights of the Parties

Introduction: in the light of modern socio-economic realities, an urgent problem is the effective protection of the property interests and rights of spouses who own a family business. The conclusion of a prenuptial agreement provides spouses who have a family business and are parties to the prenuptial agreement with the opportunity to reduce financial risks and provide themselves with additional legal protection in the event of termination of the marital relationship. The inclusion of legally verified contractual structures in a prenuptial agreement is very effective in preventing future conflicts between spouses who own a joint business. Purpose: to reveal the legal content of the prenuptial agreement concluded between spouses who own a joint business in the system of contractual structures and to develop recommendations for improving the contractual regulation. Objectives: to identify conflicts related to the legal guarantees of respect for mutual interests of spouses who have a family business and are parties to a prenuptial agreement; to identify contractual structures used to minimize conflicts between the subjects of a prenuptial agreement; and to develop a conceptual model for concluding a prenuptial agreement between spouses who own a joint business remotely via the Internet. Methods: the methodological framework for the research is based on the general scientific methods: systematic analysis, abstraction, and the dialectical method, as well as a set of specific scientific methods: structural and functional, formal legal, comparative law, forecasting, and modeling. Results: it is proposed to amend Art. 11 of Federal Law No. 193-FZ dated July 27, 2010, “On an Alternative Dispute Settlement Procedure with the Participation of an Intermediary (Mediation Procedure),” supplementing its paragraph 8; in the context of the effective implementation of the concept of “Electronic State,” the Federal Notary Chamber it is proposed to develop, test, and implement a virtual assistant based on artificial intelligence technologies, which will function not only on the Federal Notary Chamber website but also on the online resources of the notary chambers of the constituent entities of the Russian Federation. Conclusions: it is recommended to normalize the mediation procedure for spouses who have a family business and are parties to a prenuptial agreement through information and communication technologies; as part of the implementation of the concept of “Electronic State,” the Federal Notary Chamber should develop, test, and implement a virtual assistant (“chatbot”) based on artificial intelligence, which will be available not only on the Federal Notary Chamber website but also on the websites of notary chambers of the constituent entities of the Russian Federation, and at the request of users, including spouses who have a joint family business, it will perform an advisory function when drafting a prenuptial agreement.

Social dialogue as a contractual tool for regulating the right to work

The essence of social dialogue as a legal phenomenon has been analysed, with one of its main objectives being the implementation of contractual legal regulation of labour and social rights through reconciliation and compromises. Attention is drawn to international interest in the application of social dialogue procedures within the legal mechanism for ensuring the labour and social rights of workers. Focus is given to the form of social dialogue involving collective bargaining for the conclusion of collective agreements and contracts. The study provides a detailed analysis of certain conclusions made by the European Committee of Social Rights regarding reports from the member states of the European Social Charter (revised) on the compliance of their national legislation with the provisions of this Charter. Certain aspects of the implementation of the right to collective bargaining, enshrined in Article 6 §2 of this international treaty, are highlighted. Attention is drawn to the fact that if an industry agreement includes provisions allowing for the non-application of some of its clauses - thereby initiating a mechanism that restricts the right to work for individuals covered by this agreement or complicates the procedures for exercising the right to work - clear contractual legal conditions for applying these norms must be established. The parties to the industry agreement must define the conditions and procedures under which such a non-application clause may be invoked. The article examines the limitations of this right within the context of wage regulation. It is noted that if a collective agreement or contract has been duly concluded by the subjects of contractual regulation, any unilateral interference with its provisions can only be justified by the need to protect the rights of other workers or safeguard public interests, national security, public health, etc. The importance of improving collective contractual regulation of labour relations through mechanisms of social dialogue is emphasized, as the anticipated reform of labour legislation foresees an expansion of labour and social rights, which will need to be defined in collective agreements and contracts. The issue of the representativeness of the parties involved in social dialogue is addressed through an analysis of innovations in Ukrainian labour legislation.

Sportsman’s employment contract: problematic issues and prospects for their solution

Individual contractual regulation, which reflects the real needs of the development of relations between an employee-athlete and an employer-sports organization, plays an important role in regulating the labor activities of athletes. Thus, the employment contract concluded with an athlete contains a number of conditions that objectively and significantly individualize his work, i.e. conditions inherent only to this category of employees. Moreover, it enshrines differential conditions for each specifically defined employee­athlete. The purpose of the article is to consider the specifics of the labor contract concluded between an employee-athlete and an employer­sports organization. It was concluded that the labor relations of a professional athlete should be regulated precisely by the norms of labor law and a special law on professional sports, which regulates the entire complex of relations between the state and participants in professional sports, although today there are opinions that the work of professional athletes should be provided with the help of civil - legal regulation. It is noted that, as of today, the main national law in the field of sports - the Law «On physical culture and sports» dated 12.24.1993 concerns only the general foundations of activities in the field of physical culture and sports, at the same time, it does not even contain an acceptable definition of such a concept as «labor contract with a professional athlete». Therefore, it is proposed to supplement the specified Law with a norm to provide for the definition of an employment contract with a professional athlete. In particular, as an employment agreement between an employee­athlete and an employer-sports organization with all appendices, changes and additions, concluded in accordance with the legislation of Ukraine, on the basis of which labor relations arise regarding the preparation and participation of the athlete in competitions for a monetary reward paid by the club. At the same time, in addition to defining and enshrining at the legislative level the concept of an athlete’s employment contract, the proposal to develop a standard form of contract with athletes of various sports was supported, the development of which should be based on the main directions of the joint sports activities of the athlete and the sports organization, which directly consists in the preparation athlete to a successful performance at competitions.

Regulation of vascular smooth muscle cell contraction during early postnatal ontogenesis

Growth of the body in early postnatal ontogenesis is associated with changes in the functioning of many organ systems, including the cardiovascular system. The circulatory system of newborns is characterized by numerous structural and functional features, which at the systemic level is manifested in a significantly lower level of blood pressure. This review describes the differences in the mechanisms of regulation of vascular smooth muscle cell contraction in early postnatal ontogenesis and in adulthood, including age-related changes in the functioning of ion channels, which activity affects membrane potential level and intracellular concentration of calcium ions, as well as changes in calcium sensitivity of the contractile apparatus. The final section of the review discusses the connection between the mechanisms regulating contraction and differentiation of vascular smooth muscle cells during maturation.

The role of NAADP in maintaining spontaneous heart contractions: comparative physiological studies

The goal of the work was to study the role of the second messenger NAADP (Nicotinic Acid Adenine Dinucleotide Phosphate), which causes the release of Ca2+ ions from lysosomes and endosomes, in the regulation of heart contractions. Isolated hearts of the grape snail Helix pomatia and a chicken embryo were used as models. Using the membrane-permeable acetooxymethyl ester NAADP-AM, we showed that NAADP at nanomolar concentrations increases the frequency and amplitude of spontaneous cardiac contractions in H. pomatia. The NAADP antagonist NED19, without affecting the amplitude of contractions, dose-dependently reduces their frequency, completely blocking spontaneous contractions of the mollusk heart at a concentration of 5 μM. The V-type H+-ATPase inhibitor bafilomycin A1 suppresses the accumulation of calcium ions in lysosomes and acidic endosomes. We have shown that bafilomycin A1 causes attenuation of spontaneous contractions and cardiac arrest in H. pomatia. Serotonin increases the amplitude of contractions of the H. pomatia heart without affecting heart rate. NED19 at saturating concentrations (10 μM) reduces the frequency of contractions when the snail heart is activated by serotonin, but only partially reduces their amplitude. In experiments with the isolated chick embryo heart, we showed that NED19 reduces the frequency of spontaneous contractions without affecting the amplitude of contractions. Based on the data obtained, a hypothesis was put forward that the release of calcium ions from lysosomes and endosomes under the influence of endogenous NAADP ensures the maintenance of spontaneous contractions of the heart.

7138 Testosterone Modulation of Muscle Transcriptome Profile During Intensive Lifestyle Intervention in Older Men With Obesity and Hypogonadism

Abstract Disclosure: V. Viola: None. T. Samanta: None. M. Duremdes Nava: None. A. Celli: None. R.C. Villareal: None. N.H. Nguyen: None. G. Colleluori: None. Y. Barnouin: None. N. Napoli: None. C. Qualls: None. B.A. Kaipparettu: None. D.T. Villareal: None. Background: We reported that testosterone replacement added to lifestyle therapy can mitigate weight loss-induced reduction of muscle mass and bone mineral density (BMD) in older men with obesity and hypogonadism (Barnouin et al., J Clin Endocrinol Metab, 2021). Objective: To investigate the molecular mechanisms underlying the mitigation of muscle and BMD loss in response to testosterone replacement therapy during intensive lifestyle intervention in this at-risk population. Materials and Methods: Among the 83 older (≥ 65 y) men with obesity (BMI ≥ 30 kg/m2) and hypogonadism (early AM testosterone persistently <300 ng/dl) associated with frailty (PPT score ≤ 31) who were randomized into 26-week lifestyle therapy plus testosterone (LT+Test) or placebo (LT+Pbo), 38 underwent serial muscle biopsies for the muscle transcriptomics substudy. Results: Despite a similar 9% weight loss, lean body mass and thigh muscle volume decreased less in LT+Test than LT+Pbo (both -2% vs -4%, respectively; p=0.04). Hip BMD was preserved in LT+Test compared with LT+Pbo (0.4% vs -1.1%; p=0.03). Muscle strength increased similarly in LT+Test and LT+Pbo (23% vs 24%; p=0.95). Total testosterone increased more in LT+Test than LT+Pbo (133% vs 32%; p=0.01). Based on Next Generation Sequencing, of the 39,160 and 39,115 genes detected in LT+Test and LT+Pbo, respectively, 151 genes were differentially expressed (DEGs) in LT+Test and 114 in LT+Pbo group. Gene Ontology enrichment analyses revealed that in the LT+Test group, just four muscle-related terms (muscle organ development, muscle organ morphogenesis, regulation of skeletal muscle contraction, muscle atrophy) were downregulated, and one term (muscle system process) was upregulated while in the LT+Pbo, nine terms related to muscle (muscle system process, muscle tissue development, muscle organ development, skeletal muscle tissue development, skeletal muscle organ development, skeletal muscle cell differentiation, muscle organ morphogenesis, response to stimuli involved in regulation of muscle adaptation, muscle atrophy), and one term related to bone (bone mineralization involved in bone maturation) were downregulated. Notably, muscle system process was upregulated in the LT+Test but downregulated in the LT+Pbo. The RT-PCR analyses showed that LT+Test resulted in a higher expression of MYOD1 (p=0.02) and WNT4 (p= 0.08), key genes involved in muscle and bone metabolism, respectively, compared to LT+Pbo. Furthermore, we observed significantly higher mRNA expression of MYBPH (p=0.01), SCN3B (p=0.02), and DSC2 (p=0.01), genes involved in the muscle system process, in response to LT+Test compared to LT+Pbo. Conclusion: The addition of testosterone replacement to lifestyle therapy mitigates the weight loss-induced reduction of muscle mass and BMD via countering the weight loss-induced downregulation of genes involved in muscle and bone anabolism. Presentation: 6/2/2024

The T-Type Calcium Channel CACNA1H is Required for Smooth Muscle Cytoskeletal Organization During Tracheal Tubulogenesis.

Abnormalities of tracheal smooth muscle (SM) formation are associated with several clinical disorders including tracheal stenosis and tracheomalacia. However, the cellular and molecular mechanisms underlying tracheal SM formation remain poorly understood. Here, it is shown that the T-type calcium channel CACNA1H is a novel regulator of tracheal SM formation and contraction. Cacna1h in an ethylnitrosourea forward genetic screen for regulators of respiratory disease using the mouse as a model is identified. Cacna1h mutants exhibit tracheal stenosis, disorganized SM and compromised tracheal contraction. CACNA1H is essential to maintain actin polymerization, which is required for tracheal SM organization and tube formation. This process appears to be partially mediated through activation of the actin regulator RhoA, as pharmacological increase of RhoA activity ameliorates the Cacna1h-mutant trachea phenotypes. Analysis of human tracheal tissues indicates that a decrease in CACNA1H protein levels is associated with congenital tracheostenosis. These results provide insight into the role for the T-type calcium channel in cytoskeletal organization and SM formation during tracheal tube formation and suggest novel targets for congenital tracheostenosis intervention.

The concept of a smart contract: advantages and current situation of legal regulation in the Republic of Kazakhstan

This scientific article outlines the current provisions of the legal regulation of smart contracts, the relevance of which will grow as such contracts spread in various spheres and areas of life. Thus, the main problem of regulating relations on the use of a smart contract is the ambiguity of its legal essence, the lack of regulation in legislation, including in the Civil Code of the Republic of Kazakhstan. At the same time, some advantages of a smart contract are clearly shown by examples, which will help facilitate the process of concluding, changing, terminating and executing contracts. The main advantages of a smart contract are also discussed in detail, such as automation, transparency, security, efficiency, low intermediary costs, decentralization, flexibility and programmability. In the research, the authors touched upon the problems of fulfilling obligations in debt relations, the potential advantages and assistance of a smart contract in enforcement proceedings. The result of the exploration is a formulated definition of a smart contract and the identification of specific potential advantages of this type of non-traditional contracts. The authors summarize the results, noting the absence of a legal definition of a smart contract in the legislation of the Republic of Kazakhstan, the exclusively declarative nature of its legal regulation; the ambiguity of the range of public relations where contracts in this form are applicable, which does not allow the widespread dissemination and use of a smart contract.

THE ISSUES OF LEGAL LIABILITY IN TRANSFER RELATIONS

A transfer contract is a specific type of legal contract, which can be regulated not only by civil law but also by the corporate rules of sports federations. The regulation of transfer contracts in football is particularly relevant, as the Russian Football Union (RFU) regulates each stage of transfer relations in detail. Specifically, the RFU Regulations establish sanctions for violating the procedure of athlete transfer. These sanctions can be applied to both sports clubs and athletes. At the same time, the legal nature of these sanctions remains ambiguous, as the RFU is not a governmental body authorized to hold individuals legally liable. Nevertheless, the doctrine often highlights the concept of sports liability as a unique type of liability because the RFU has the authority to hold individuals liable under this type of liability. In addition to sports liability, the possibility of holding participants in transfer relations liable under civil law remains debatable. On the one hand, a transfer contract is a civil law agreement and, accordingly, the general provisions of the Civil Code of the Russian Federation on obligations should apply to it. On the other hand, questions arise about the possibility of combining civil sanctions with sports sanctions and about the possibility of considering civil liability prior to sports liability. In this article, the authors answered the above questions and structured the liability systems in transfer relations. Conclusions were made about situations in which sports or civil liability is applied, as well as about the possibility of applying both types of liability for a single violation by a sports club or a football player.