VCP/p97 inhibitor CB-5083 modulates muscle pathology in a mouse model of VCP inclusion body myopathy

Background Pathogenic gain of function variants in Valosin-containing protein (VCP) cause a unique disease characterized by inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia (also known as Multisystem proteinopathy (MSP)). Previous studies in drosophila models of VCP disease indicate treatment with VCP inhibitors mitigates disease pathology. Earlier-generation VCP inhibitors display off-target effects and relatively low therapeutic potency. New generation of VCP inhibitors needs to be evaluated in a mouse model of VCP disease. In this study, we tested the safety and efficacy of a novel and potent VCP inhibitor, CB-5083 using VCP patient-derived myoblast cells and an animal model of VCP disease. Methods First, we analyzed the effect of CB-5083 in patient-derived myoblasts on the typical disease autophagy and TDP-43 profile by Western blot. Next, we determined the maximum tolerated dosage of CB-5083 in mice and treated the 2-month-old VCPR155H/R155H mice for 5 months with 15 mg/kg CB-5083. We analyzed motor function monthly by Rotarod; and we assessed the end-point blood toxicology, and the muscle and brain pathology, including autophagy and TDP-43 profile, using Western blot and immunohistochemistry. We also treated 12-month-old VCPR155H/+ mice for 6 months and performed similar analysis. Finally, we assessed the potential side effects of CB-5083 on retinal function, using electroretinography in chronically treated VCPR155H/155H mice. Results In vitro analyses using patient-derived myoblasts confirmed that CB-5083 can modulate expression of the proteins in the autophagy pathways. We found that chronic CB-5083 treatment is well tolerated in the homozygous mice harboring patient-specific VCP variant, R155H, and can ameliorate the muscle pathology characteristic of the disease. VCP-associated pathology biomarkers, such as elevated TDP-43 and p62 levels, were significantly reduced. Finally, to address the potential adverse effect of CB-5083 on visual function observed in a previous oncology clinical trial, we analyzed retinal function in mice treated with moderate doses of CB-5083 for 5 months and documented the absence of permanent ocular toxicity. Conclusions Altogether, these findings suggest that long-term use of CB-5083 by moderate doses is safe and can improve VCP disease-associated muscle pathology. Our results provide translationally relevant evidence that VCP inhibitors could be beneficial in the treatment of VCP disease.

Key concepts for searching evidence: an introduction for healthcare professionals

The currently abundant bibliography on healthcare can make the search process an exhausting and frustrating experience. For this reason, it is essential to learn the basic concepts of research question formulation, information sources, and search strategies to make this process more efficient and user-friendly. The search strategy is an iterative process that allows the incorporation of tools and terms in the strategy design to optimize evidence retrieval. Each strategy varies according to the questions, the language used, the source of information accessed, and the available tools. This article is part of a methodological series of narrative reviews on biostatistics and clinical epidemiology. This narrative review describes the essential elements for developing a literature search strategy and identifying the relevant evidence concerning a clinical question through familiar and accessible sources (such as Google and Google Scholar), as well as search interfaces and technical-scientific databases focused on biomedical knowledge (PubMed and The Cochrane Library).

Zwycięzcy i przegrani pandemii Covid-19: perspektywa globalna z uwzględnieniem gospodarki rolno-żywnościowej

The worldwide literature on the socio-economic impacts of the Covid-19 is extensive, covering individual enterprises and markets, economic sectors or branches, or the national and global economy. The current study is unique as it is a comprehensive compilation of the relevant evidence regarding economic entities and sectors of global or international significance and the societal groups from an angle of so-called "pandemic game" with some implications for the agri-food economy. Its main aim is to identify the actual and potential winners and losers of the pandemic. The winners’ notion covers actors, e.g. economic sectors or people groups those extraordinarily benefited or will benefit from a pandemic, extremely upgrading their financial or other performance. In turn, the losers include individuals or entities that incurred unusual costs or losses, worsened their results, or probably will face such pandemic consequences in the future. Some economic ideas also are considered. The article is based on the scientific, popular and grey literature as well as publicly available data to support research. The research uses deductive explanation methods. Results show that the biopharmaceutical industry, leading digital companies, shareholders in international retail chains, global financial holdings, food delivery companies, and the World’s richest people are among those who thrived exceptionally well in the new living and doing business conditions and can therefore be admitted as the current crisis’ winners. Adversely, the coronavirus victims, energy and air transport sectors, and food processing labour, all of them being harmfully affected by the pandemic, are examples of losers. Albeit the presented winners and losers represent various spheres of economic life, they are more or less related to the agriculture and food processing industry. The study confirms that the functioning and condition of the latter depend on the situation of other economic sectors, agents, and markets, and international disturbances spreading within an open economy. The paper can be of interest both to the research community, and decision-makers in different economic and social policy areas.

Generating Political Commitment for Regulatory Interventions Targeting Dietary Harms and Poor Nutrition: A Case Study on Sugar-Sweetened Beverage Taxation in Australia

Background: Sugar-sweetened beverage (SSB) taxes are an effective public health policy intervention for improving nutrition and public health. Although implemented in over 50 jurisdictions worldwide, this intervention remains vastly underutilised, and in Australia political commitment for such a tax is low. The aim of this study is to understand the politics of SSB taxation in Australia, what factors have constrained political commitment for a tax, and what might enable such commitment in future. Methods: We adopted a case study design, guided by a theoretical framework developed from the political economy of nutrition literature. Data were collected from 16 interviews with informants from multiple sectors, supported by media articles, journal articles, and grey literature. Data were coded and organized by thematic analysis, and synthesised into the final results. Results: Nutrition actors have made significant progress in generating commitment for a SSB tax by producing relevant evidence, raising awareness, advocating for action, employing resonating frames, collaborating with civil society organisations, and forming coalitions increasing their overall cohesion. Nevertheless, political commitment for a SSB tax is low and was found to be impeded by the powerful influence of the food, beverage, and sugar industries, opposition from both major Australian political parties, ideological resistance to regulation, a low quality monitoring and surveillance system for food and nutrition, and limited public advocacy. The influence of nutrition actors was also impeded by weak connections to key policymakers and missed collaborative opportunities with pro-SSB tax organisations. Conclusion: The identification of several impediments provides an explanation for why political commitment for a SSB tax is low in Australia and reveals several opportunities for how it might be generated in the future. Political commitment may come about through, for example, actions to limit the influence of industry in policy decision-making, and by strengthening the existing pro-SSB tax coalition.

REASONABLENESS OF NOTARIAL ACTS AS A COMPONENT OF ENSURING STANDARDS OF LATIN NOTARIES: THE EXPERIENCE OF UKRAINE

Background: This article is devoted to the study of the rules of notarial acts, the observance of which ensures the reasonableness of notarial acts as exemplified by Ukraine as a state belonging to the countries with Latin notaries. At the same time, the standardisation of Latin notary standards in Ukrainian legislation is associated with certain problems that do not fully reveal the potential of the notary and its functions as a body of undisputed civil jurisdiction. In this regard, the purpose of the work is to determine the components of the procedural mechanism to ensure the reasonableness of notarial acts, identify those shortcomings in their standardisation that lead to litigation, and formulate proposals for further improvement of notarial law on this basis. Methods: In the present research, we used the following methods: logical, systemic, specific sociological, hermeneutic, and modelling. It is established that the reasonableness of notarial acts is ensured by compliance with the rules on submission of evidence documents, requests for evidence documents by a notary, the signing of notarial documents, sending documents for examination, the compliance of documents submitted for notarial acts with statutory requests, and clarifying the will of the persons concerned. Results and Conclusions: It is proved that a notarial act issued based on the actual circumstances established within the notarial case, confirmed by the relevant evidence provided by the notarial legislation, should be considered reasonable. The grounds for exercising the powers of a notary to demand documents are determined, and the need to differentiate the order of recovery depending on the subjects in which such information is requested is emphasised. The content of the notary’s powers to request documents is clarified, and the conditions under which the exercise of such powers should be considered the notary’s duty are determined. The necessity of extending the duties of a notary to establish the will and real intentions of the persons concerned to all notarial acts and, in this regard, the standardisation of such a duty as a general rule of notarial acts is substantiated. It is concluded that the distinction between documents for which the originals are subject to preservation in the notarial file and those that are photocopied then returned to interested persons should be made, taking into account the loss or preservation of their validity and legal significance after said notarial action. The author determines the grounds and conditions for sending a document for examination, which is a procedural action of a notary that can be made only at the initiative or consent of the person who submitted the document. The proposals on the tendencies of standardisation of the content of the requirements of the validity of notarial acts and the consequences of their violation are formulated.

Obstetrical Ultrasound During Pregnancy

No relevant evidence was identified comparing the safety of frequent obstetrical ultrasounds compared to the routine use of obstetrical ultrasound during pregnancy. This review identified 10 evidence-based guidelines that provided recommendations regarding various indications for obstetrical ultrasound, as well as the frequency of obstetrical ultrasound; however, the methodological rigour of these guidelines is limited and recommendations should be interpreted with caution. One guideline recommended against obstetrical ultrasound for non-medical purposes and recommended that ultrasound exposure be as low as reasonably possible during pregnancy. These recommendations were based on moderate-quality evidence and expert opinion, and should be interpreted with caution. The guidelines made recommendations for specific patient populations for whom more frequent obstetrical ultrasound examinations may be required. These populations included pregnancies affected by certain congenital infections, people pregnant with twins, pregnant adolescents, and pregnant people at high risk for fetal anomalies or for whom mid-trimester transabdominal ultrasound would be challenging.

THE JURIDICAL REVIEW OF LEGAL POWER OF GROSSE DEED AS THE BASIS FOR EXECUTING MORTGAGE EXECUTION AUCTIONS

One of the executions of the mortgage object is the sale of the mortgage object through a public auction based on the executorial title contained in the Mortgage Certificate. Before the implementation is carried out by the creditor, a permit (fiat) is required by the local district court. The application for an auction for the execution of mortgage rights through a district court is closely related to obstacles, for example, a lawsuit from a third party (derden verzet) who feels he has the right to the object of execution even though it has nothing to do with creditors and debtors. This opposition made the Chief Justice of the District Court unable to grant the request for execution even though the creditor had a mortgage certificate that was encumbered but was forced to examine the relevant evidence in the trial forum to determine whether the resistance was sufficient reason or just a conspiracy with the debtor to delay the execution. Based on this explanation, the author wants to examine the legal force of the Grosse deed as the basis for the implementation of the mortgage execution auction. The type of research in writing scientific papers is a normative legal research type, with a statutory approach and a legal concept analysis approach (Analytical and Conceptual Approach). The sources of legal materials used in writing this scientific paper came from primary legal materials, secondary legal materials, and tertiary legal materials. The legal materials were collected using library research techniques. Then analyzed using description, systematization, evaluation and finally concluded with argumentation technique. The results of this study are expected to provide scientific knowledge for academics, law enforcers, and the public.

Network Structure Impacts the Synchronization of Collective Beliefs

People’s beliefs are influenced by interactions within their communities. The propagation of this influence through conversational social networks should impact the degree to which community members synchronize their beliefs. To investigate, we recruited a sample of 140 participants and constructed fourteen 10-member communities. Participants first rated the accuracy of a set of statements (pre-test) and were then provided with relevant evidence about them. Then, participants discussed the statements in a series of conversational interactions, following pre-determined network structures (clustered/non-clustered). Finally, they rated the accuracy of the statements again (post-test). The results show that belief synchronization, measuring the increase in belief similarity among individuals within a community from pre-test to post-test, is influenced by the community’s conversational network structure. This synchronization is circumscribed by a degree of separation effect and is equivalent in the clustered and non-clustered networks. We also find that conversational content predicts belief change from pre-test to post-test.

Drivers of Mobility in the Global South

Empirical studies in developing countries tend to find higher levels of socioeconomic persistence across generations compared with those of high-income economies. However, there have been relatively few advances in the identification of the drivers of such higher levels of intergenerational persistence. By focusing on relevant evidence from developing countries and emerging economies, this chapter points to some of the potential drivers of social mobility that are either outside those typically considered in high-income countries or likely to be of greater relevance in the developing world. The chapter builds on the standard model of intergenerational mobility to discuss the appropriateness of some of its assumptions in a developing-country context. It will then advance some suggestions for future theoretical and empirical investigations of social mobility in the Global South.

A Worldwide Bibliometric Analysis of Publications on Coronavirus in the Past 3 Decades: A Bibliometric Article

Background: Coronaviruses caused three pandemics and impact public health globally in the 21st century. However, limited data were for the evaluation of the trend of coronavirus researches. We aimed to analyze quantitatively, qualitatively, and visually evaluate global scientific publications on coronavirus by using bibliometric analysis. Methods: Coronavirus-related research from 1990-2019 was retrieved from the Web of Science Core Collection database (WoS). Microsoft Excel and VOS viewer software were used to assess the characteristics of publications. Results: Overall, 9,553 publications on coronavirus were retrieved on 12 Mar 2020. The United States took a leading position in coronavirus-related research and accounted for more than one-thirds (36.7%) of all publications. The most productive journal in this field was Journal of Virology (1,056, 11.1%), and the most productive institution was University of Hong Kong (394, 4.1%). The main hot topics in coronavirus field were virus infection and protein. Active collaborations between countries were observed. Conclusion: Over the past three decades, coronavirus research has gradually increased due to two global outbreaks. Through this global bibliometric evaluation, some relevant evidence could be provided. Corresponding to the impact of novel coronavirus (COVID-19), a large number of articles can be expected to appear in the next few years, and international cooperation should be strengthened to solve the problem.