A Novel Nonsense INS Mutation Causes Inefficient Preproinsulin Translocation Into the Endoplasmic Reticulum

Preproinsulin (PPI) translocation across the membrane of the endoplasmic reticulum (ER) is the first and critical step of insulin biosynthesis. Inefficient PPI translocation caused by signal peptide (SP) mutations can lead to β-cell failure and diabetes. However, the effect of proinsulin domain on the efficiency of PPI translocation remains unknown. With whole exome sequencing, we identified a novel INS nonsense mutation resulting in an early termination at the 46th residue of PPI (PPI-R46X) in two unrelated patients with early-onset diabetes. We examined biological behaviors of the mutant and compared them to that of an established neonatal diabetes causing mutant PPI-C96Y. Although both mutants were retained in the cells, unlike C96Y, R46X did not induce ER stress or form abnormal disulfide-linked proinsulin complexes. More importantly, R46X did not interact with co-expressed wild-type (WT) proinsulin in the ER, and did not impair proinsulin-WT folding, trafficking, and insulin production. Metabolic labeling experiments established that, despite with an intact SP, R46X failed to be efficiently translocated into the ER, suggesting that proinsulin domain downstream of SP plays an important unrecognized role in PPI translocation across the ER membrane. The study not only expends the list of INS mutations associated with diabetes, but also provides genetic and biological evidence underlying the regulation mechanism of PPI translocation.

Types of infractions of trademark property rights. Аnalysis of judicial practice

Keywords: Property rights to the trademark, infractions of property rights, judicialpractice, protection of trademark rights, invalidation of the trademark certificate,early termination of the certificate The relevance of this article is that the largest number of legaldisputes in the sphere of intellectual property is disputes concerning violation of propertyrights for trademarks. The article examined the theoretical provisions of propertyrights for trademarks, as well as practical issues of violations of these rights. Specialattention is paid to the analysis of judicial practice concerning protection of rightsto trademarks. The categories of the mentioned cases have been highlighted and discussedin detail, statistical data and decisions have been made. It has been found thatthe overwhelming number of cases investigated concerns recognition of the Ukrainiantrademark certificate as invalid.The court cases on protection of rights to trademarks can be divided into severalcategories according to the claim requirements:1) On the recognition of the Ukrainian trademark certificate as invalid in whole orin part (for all or part of goods and/or services);2) On termination of infringement of intellectual property rights on the trademarkand obligation to take certain actions;3) On early termination of the Ukrainian trademark certificate in whole or in part(for all or part of goods and/or services);4) Other court cases. For example, the recognition of the non-legal patent ofUkraine for industrial design due to violation of rights for the registered trademark.The article contains detailed consideration of the mentioned categories of casesand statistical data about them.The analysis of judicial practice made it possible to establish the following statisticaldata: cases of invalidation of a trademark certificate are 47 %; cases on termination of infringementof rights to the trademark are 25 %; cases on early termination of the trademarkcertificate are 25 %; other cases on protection of rights to trademarks make 3 %.In addition, the analysis of court practice allowed to establish that 75 % of courtcases concerning protection of rights to trademarks are decided to satisfy the claim infull or in part.

Legality of Applying Coercive Medical Measures in Criminal Law

The objective of the study was to determine the legality of the application of coercive medical measures and to develop recommendations to improve the legislative regulation of their use. The study included data on the number of offenders with mental disorders; the empirical background was the decision of the European Court of Human Rights on the application of coercive medical measures; provisions of the legislation of 31 countries. Methods of system approach, comparison, descriptive analysis, pragmatic approach, prognosis were used. The national criminal law of most states regulates the application of coercive medical measures to persons who have committed a crime in a state of limited sanity or insanity or have acquired it before sentencing or during the execution of the sentence, but its practical application causes several complications. It is concluded that the legislative definition of coercive medical measures corresponds to human rights legislation. But there are problems with its practical application. Proposals were made to amend national and international legislation: to broaden the range of grounds for the application of coercive medical measures; regulate the possibility of early termination of a coercive medical measure; oblige the courts to determine the appropriate terms.

Early Termination of Acute Stroke Randomized Controlled Trials Published Between 2013 and 2020: A Systematic Review

Background: Termination of a clinical trial before the maximum planned sample size is accrued can occur for multiple valid reasons but has implications for the interpretation of results. We undertook a systematic review of contemporary acute stroke trials to document the prevalence of and reasons for early termination. Methods: We searched MEDLINE for randomized controlled trials of acute stroke therapies published between 2013 and 2020 in 9 major clinical journals. Manuscripts describing the primary results of phase 2 and phase 3 trials of acute stroke care were included. Data on study characteristics and adherence to CONSORT reporting guidelines were abstracted and summarized using descriptive statistics. Where feasible, we compared treatment effect sizes between trials terminated early and those not terminated early. Results: Of 96 randomized controlled trials, 39 (41%) were terminated early, 84 (88%) had a data and safety monitoring board, and 57 (59%) reported a prespecified statistical stopping rule. Among the 39 trials terminated early, 10 were discontinued for benefit, 10 due to logistical issues, 8 for futility, 6 because of newly available evidence, 1 for harm, and 4 for other or a combination of reasons. The median percentage of the maximum planned sample size accrued among trials terminated early was 63% (range, 8%–89%). Only 55% of trials (53 of 96) reported whether interim efficacy analyses were conducted, as recommended by the CONSORT guidelines. When 10 endovascular therapy trials were compared according to early termination status, the effect sizes of trials terminated early for benefit were only modestly larger than those not terminated early. Conclusions: The high prevalence of early termination in combination with the wide variety of reasons underscores the necessity of meticulous trial planning and adherence to methodological and reporting guidelines for early termination. Registration: URL: https://www.crd.york.ac.uk/prospero/ ; Unique identifier: CRD42019128727.

A haszonkölcsön-szerződés és ennek felbontási lehetőségei az új román Polgári törvénykönyv és az új Polgári eljárási törvénykönyv alapján, abban az esetben, ha a kölcsönadónak sürgős és előre nem látott módon lakhatási igénye lett az ingatlant tekintve

The legal institution of loan agreement is undoubtedly an important part of commercial and social life. Extensive use of the legal institution generates facts whose regulation is not always satisfactory. This is also the case with regard to the possibility of early termination of the loan agreement. Although the Civil Code and the Code of Civil Procedure contain provisions for this possibility, they are not enforceable in all cases. The analysis of the relevant regulation and its substantiation with a legal case can be read below.

Uses of equipoise in discussions of the ethics of randomized controlled trials of COVID-19 therapies

Background Early in the COVID-19 pandemic, the urgent need to discover effective therapies for COVID-19 prompted questions about the ethical problem of randomization along with its widely accepted solution: equipoise. In this scoping review, uses of equipoise in discussions of randomized controlled trials (RCT) of COVID-19 therapies are evaluated to answer three questions. First, how has equipoise been applied to COVID-19 research? Second, has equipoise been employed accurately? And third, do concerns about equipoise pose a barrier to the ethical conduct of COVID-19 RCTs? Methods Google Scholar and Pubmed were searched for articles containing substantial discussion about equipoise and COVID-19 RCTs. 347 article titles were screened, 91 full text articles were assessed, and 48 articles were included. Uses of equipoise were analyzed and abstracted into seven categories. Results and discussion Approximately two-thirds of articles (33/48 articles) used equipoise in a way that is consistent with the concept. They invoked equipoise to support (1) RCTs of specific therapies, (2) RCTs in general, and (3) the early termination of RCTs after achieving the primary outcome. Approximately one-third of articles (15/48 articles) used equipoise in a manner that is inconsistent with the concept. These articles argued that physician preference, widespread use of unproven therapies, patient preference, or expectation of therapeutic benefit may undermine equipoise and render RCTs unethical. In each case, the purported ethical problem can be resolved by correcting the use of equipoise. Conclusions Our findings highlight the continued relevance of equipoise as it supports the conduct of well-conceived RCTs and provides moral guidance to physicians and researchers as they search for effective therapies for COVID-19.